2025
Smith, Elke; Theis, Hendrik; van Eimeren, Thilo; Knauth, Kilian; Tuzsus, Deniz; Zhang, Lei; Mathar, David; Peters, Jan
Dopamine and Temporal Discounting: Revisiting Pharmacology and Individual Differences Journal Article
In: J Neurosci, vol. 45, no. 49, 2025, ISSN: 1529-2401.
@article{pmid41136339,
title = {Dopamine and Temporal Discounting: Revisiting Pharmacology and Individual Differences},
author = {Elke Smith and Hendrik Theis and Thilo van Eimeren and Kilian Knauth and Deniz Tuzsus and Lei Zhang and David Mathar and Jan Peters},
doi = {10.1523/JNEUROSCI.0786-25.2025},
issn = {1529-2401},
year = {2025},
date = {2025-12-01},
journal = {J Neurosci},
volume = {45},
number = {49},
abstract = {Disorders characterized by changes in dopamine (DA) neurotransmission are often linked to changes in the temporal discounting of future rewards. Likewise, pharmacological manipulations of DA neurotransmission in healthy individuals modulate temporal discounting, but there is considerable variability in the directionality of reported pharmacological effects, as enhancements and reductions of DA signaling have been linked to both increases and reductions of temporal discounting. This may be due to meaningful individual differences in drug effects and/or false-positive findings in small samples. To resolve these inconsistencies, we (1) revisited pharmacological effects of the DA precursor l-DOPA on temporal discounting in a large sample of = 76 healthy participants ( = 44 male) and (2) examined several putative proxy measures for DA to revisit the role of individual differences in a randomized, double-blind placebo-controlled preregistered study (https://osf.io/a4k9j/). Replicating previous findings, higher rewards were discounted less (magnitude effect). Computational modeling using hierarchical Bayesian parameter estimation confirmed that the data in both drug conditions were best accounted for by a nonlinear temporal discounting drift diffusion model. In line with recent animal and human work, l-DOPA reliably reduced the discount rate with a small effect size, challenging earlier findings in substantially smaller samples. We found no credible evidence for effects of putative DA proxy measures on model parameters, calling into question the role of these measures in accounting for individual differences in DA drug effects.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Disorders characterized by changes in dopamine (DA) neurotransmission are often linked to changes in the temporal discounting of future rewards. Likewise, pharmacological manipulations of DA neurotransmission in healthy individuals modulate temporal discounting, but there is considerable variability in the directionality of reported pharmacological effects, as enhancements and reductions of DA signaling have been linked to both increases and reductions of temporal discounting. This may be due to meaningful individual differences in drug effects and/or false-positive findings in small samples. To resolve these inconsistencies, we (1) revisited pharmacological effects of the DA precursor l-DOPA on temporal discounting in a large sample of = 76 healthy participants ( = 44 male) and (2) examined several putative proxy measures for DA to revisit the role of individual differences in a randomized, double-blind placebo-controlled preregistered study (https://osf.io/a4k9j/). Replicating previous findings, higher rewards were discounted less (magnitude effect). Computational modeling using hierarchical Bayesian parameter estimation confirmed that the data in both drug conditions were best accounted for by a nonlinear temporal discounting drift diffusion model. In line with recent animal and human work, l-DOPA reliably reduced the discount rate with a small effect size, challenging earlier findings in substantially smaller samples. We found no credible evidence for effects of putative DA proxy measures on model parameters, calling into question the role of these measures in accounting for individual differences in DA drug effects.
de Bruin, Hannah; Groot, Colin; Barthel, Henryk; Bischof, Gérard N; Blazhenets, Ganna; Boellaard, Ronald; Boon, Baayla D C; Brendel, Matthias; Cash, David M; Coath, William; Day, Gregory S; Dickerson, Bradford C; Doering, Elena; Drzezga, Alexander; van Dyck, Christopher H; van Eimeren, Thilo; van der Flier, Wiesje M; Fredericks, Carolyn A; Fryer, Tim D; van de Giessen, Elsmarieke; Gordon, Brian A; Graff-Radford, Jonathan; Grinberg, Lea T; Hansson, Oskar; Hobbs, Diana A; Hoenig, Merle C; Höglinger, Günter; Irwin, David J; Jones, P Simon; Josephs, Keith A; Katsumi, Yuta; Joie, Renaud La; Lee, Edward B; Levin, Johannes; Malpetti, Maura; McGinnis, Scott M; Mecca, Adam P; Mohanty, Rosaleena; Nasrallah, Ilya M; O'Brien, John T; O'Dell, Ryan S; Palleis, Carla; Perneczky, Robert; Phillips, Jeffrey S; Putcha, Deepti; Rabinovici, Gil D; Rahmouni, Nesrine; Rosa-Neto, Pedro; Rowe, James B; Rullmann, Michael; Sabri, Osama; Saur, Dorothee; Schildan, Andreas; Schott, Jonathan M; Schroeter, Matthias L; Seeley, William W; Servaes, Stijn; Sintini, Irene; Smith, Ruben; Spina, Salvatore; Stevenson, Jenna; Stomrud, Erik; Strandberg, Olof; Therriault, Joseph; Tideman, Pontus; Touroutoglou, Alexandra; Trainer, Anne E; Visser, Denise; Wekselman, Fattin; Weston, Philip S J; Whitwell, Jennifer L; Wolk, David A; Yong, Keir; Pijnenburg, Yolande A L; Franzmeier, Nicolai; Ossenkoppele, Rik
Connectivity as a universal predictor of tau progression in atypical Alzheimer's disease Journal Article
In: Brain, vol. 148, no. 11, pp. 3893–3912, 2025, ISSN: 1460-2156.
@article{pmid40810361,
title = {Connectivity as a universal predictor of tau progression in atypical Alzheimer's disease},
author = {Hannah de Bruin and Colin Groot and Henryk Barthel and Gérard N Bischof and Ganna Blazhenets and Ronald Boellaard and Baayla D C Boon and Matthias Brendel and David M Cash and William Coath and Gregory S Day and Bradford C Dickerson and Elena Doering and Alexander Drzezga and Christopher H van Dyck and Thilo van Eimeren and Wiesje M van der Flier and Carolyn A Fredericks and Tim D Fryer and Elsmarieke van de Giessen and Brian A Gordon and Jonathan Graff-Radford and Lea T Grinberg and Oskar Hansson and Diana A Hobbs and Merle C Hoenig and Günter Höglinger and David J Irwin and P Simon Jones and Keith A Josephs and Yuta Katsumi and Renaud La Joie and Edward B Lee and Johannes Levin and Maura Malpetti and Scott M McGinnis and Adam P Mecca and Rosaleena Mohanty and Ilya M Nasrallah and John T O'Brien and Ryan S O'Dell and Carla Palleis and Robert Perneczky and Jeffrey S Phillips and Deepti Putcha and Gil D Rabinovici and Nesrine Rahmouni and Pedro Rosa-Neto and James B Rowe and Michael Rullmann and Osama Sabri and Dorothee Saur and Andreas Schildan and Jonathan M Schott and Matthias L Schroeter and William W Seeley and Stijn Servaes and Irene Sintini and Ruben Smith and Salvatore Spina and Jenna Stevenson and Erik Stomrud and Olof Strandberg and Joseph Therriault and Pontus Tideman and Alexandra Touroutoglou and Anne E Trainer and Denise Visser and Fattin Wekselman and Philip S J Weston and Jennifer L Whitwell and David A Wolk and Keir Yong and Yolande A L Pijnenburg and Nicolai Franzmeier and Rik Ossenkoppele},
doi = {10.1093/brain/awaf279},
issn = {1460-2156},
year = {2025},
date = {2025-11-01},
journal = {Brain},
volume = {148},
number = {11},
pages = {3893--3912},
abstract = {The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD ('visual AD') and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD ('language AD'). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD ('visual AD') and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD ('language AD'). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.
Hoenig, Merle C; Dzialas, Verena; Doering, Elena; Bischof, Gérard N; van Eimeren, Thilo; and, Alexander Drzezga
Modifiable Factors Associated with the Longitudinal Increase and Spatial Extent of Tau Pathology in Alzheimer Disease Journal Article
In: J Nucl Med, 2025, ISSN: 1535-5667.
@article{pmid41266256,
title = {Modifiable Factors Associated with the Longitudinal Increase and Spatial Extent of Tau Pathology in Alzheimer Disease},
author = {Merle C Hoenig and Verena Dzialas and Elena Doering and Gérard N Bischof and Thilo van Eimeren and Alexander Drzezga and },
doi = {10.2967/jnumed.125.270593},
issn = {1535-5667},
year = {2025},
date = {2025-11-01},
journal = {J Nucl Med},
abstract = {There are 14 modifiable factors that are associated with a significantly lower risk of dementia. We tested the interactive effect of modifiable factors, genetic determinants, and initial pathologic burden on the spatial progression and local amplification of tau pathology. In total, 162 amyloid-positive individuals were included, for whom longitudinal [F]AV-1451 PET scans, baseline information on global amyloid burden, ApoE4 status, body mass index (BMI), hypertension, education, neuropsychiatric symptom severity, and demographic information were available in the Alzheimer Disease Neuroimaging Initiative. All [F]AV-1451 scans were intensity-standardized (reference: inferior cerebellum), -transformed (control sample: 147 amyloid-negative subjects), thresholded ( score, >1.96), and converted to volume maps. Longitudinal tau changes were then assessed in terms of tau spatial extent (i.e., newly affected volume at follow-up) and tau level rise (i.e., tau increase in previously affected volume). These 2 measures were entered as dependent variables in linear mixed-effects models, including baseline modifiable risk factors (BMI, education, hypertension, neuropsychiatric symptom severity), global amyloid, tau volume or tau burden, ApoE4 status, clinical stage, sex, and age as predictors. Next, we tested the interactive effects between baseline amyloid or tau burden with the 4 modifiable factors on tau extent or tau level rise, respectively. Greater tau extent was linked to higher BMI (β = 0.002; 95% CI, 0.0003-0.003), ApoE4 status (β = 0.024; 95% CI, 0.001-0.046), and baseline tau volume (β = 0.207; 95% CI, 0.107-0.308) across groups. In terms of tau level rise, we observed that absence of hypertension (β = 0.295; 95% CI, -0.477 to -0.114), dementia group (β = 0.305; 95% CI, 0.088-0.522), and BMI (β = 0.011; 95% CI, 0.00004-0.022) were linked to increased tau burden. A load-dependent effect of baseline amyloid and tau volume/burden was found for both tau extent (β = -0.005; 95% CI, -0.008 to -0.002) and tau level rise (β = -0.003; 95% CI, -0.005 to -0.001). Higher amyloid and BMI (β = 0.001; 95% CI, 0.0004-0.001) and lower education and higher tau burden (β = -0.035; 95% CI, -0.064 to -0.006) were linked to greater tau level rise. Education, BMI, and hypertension differentially influence tau's spatial extent and increase by its interaction with initial pathologic burden. Timely modification of these factors may overall slow tau progression.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
There are 14 modifiable factors that are associated with a significantly lower risk of dementia. We tested the interactive effect of modifiable factors, genetic determinants, and initial pathologic burden on the spatial progression and local amplification of tau pathology. In total, 162 amyloid-positive individuals were included, for whom longitudinal [F]AV-1451 PET scans, baseline information on global amyloid burden, ApoE4 status, body mass index (BMI), hypertension, education, neuropsychiatric symptom severity, and demographic information were available in the Alzheimer Disease Neuroimaging Initiative. All [F]AV-1451 scans were intensity-standardized (reference: inferior cerebellum), -transformed (control sample: 147 amyloid-negative subjects), thresholded ( score, >1.96), and converted to volume maps. Longitudinal tau changes were then assessed in terms of tau spatial extent (i.e., newly affected volume at follow-up) and tau level rise (i.e., tau increase in previously affected volume). These 2 measures were entered as dependent variables in linear mixed-effects models, including baseline modifiable risk factors (BMI, education, hypertension, neuropsychiatric symptom severity), global amyloid, tau volume or tau burden, ApoE4 status, clinical stage, sex, and age as predictors. Next, we tested the interactive effects between baseline amyloid or tau burden with the 4 modifiable factors on tau extent or tau level rise, respectively. Greater tau extent was linked to higher BMI (β = 0.002; 95% CI, 0.0003-0.003), ApoE4 status (β = 0.024; 95% CI, 0.001-0.046), and baseline tau volume (β = 0.207; 95% CI, 0.107-0.308) across groups. In terms of tau level rise, we observed that absence of hypertension (β = 0.295; 95% CI, -0.477 to -0.114), dementia group (β = 0.305; 95% CI, 0.088-0.522), and BMI (β = 0.011; 95% CI, 0.00004-0.022) were linked to increased tau burden. A load-dependent effect of baseline amyloid and tau volume/burden was found for both tau extent (β = -0.005; 95% CI, -0.008 to -0.002) and tau level rise (β = -0.003; 95% CI, -0.005 to -0.001). Higher amyloid and BMI (β = 0.001; 95% CI, 0.0004-0.001) and lower education and higher tau burden (β = -0.035; 95% CI, -0.064 to -0.006) were linked to greater tau level rise. Education, BMI, and hypertension differentially influence tau's spatial extent and increase by its interaction with initial pathologic burden. Timely modification of these factors may overall slow tau progression.
Kling, Agnes; Kusche-Palenga, Julia; Palleis, Carla; Jäck, Alexander; Bernhardt, Alexander M; Frontzkowski, Lukas; Roemer, Sebastian N; Slemann, Luna; Zaganjori, Mirlind; Scheifele, Maximilian; Paeger, Lars; Bischof, Gérard N; van Eimeren, Thilo; Drzezga, Alexander; Sabri, Osama; Rullmann, Michael; Barthel, Henryk; Levin, Johannes; Herms, Jochen; Franzmeier, Nicolai; Höglinger, Günter; Roeber, Sigrun; Brendel, Matthias; Gnörich, Johannes
Exploring the origins of frequent tau-PET signal in vermal and adjacent regions Journal Article
In: Eur J Nucl Med Mol Imaging, vol. 52, no. 10, pp. 3519–3533, 2025, ISSN: 1619-7089.
@article{pmid40100387,
title = {Exploring the origins of frequent tau-PET signal in vermal and adjacent regions},
author = {Agnes Kling and Julia Kusche-Palenga and Carla Palleis and Alexander Jäck and Alexander M Bernhardt and Lukas Frontzkowski and Sebastian N Roemer and Luna Slemann and Mirlind Zaganjori and Maximilian Scheifele and Lars Paeger and Gérard N Bischof and Thilo van Eimeren and Alexander Drzezga and Osama Sabri and Michael Rullmann and Henryk Barthel and Johannes Levin and Jochen Herms and Nicolai Franzmeier and Günter Höglinger and Sigrun Roeber and Matthias Brendel and Johannes Gnörich},
doi = {10.1007/s00259-025-07199-x},
issn = {1619-7089},
year = {2025},
date = {2025-08-01},
journal = {Eur J Nucl Med Mol Imaging},
volume = {52},
number = {10},
pages = {3519--3533},
abstract = {PURPOSE: Off-target binding remains a significant challenge in tau-PET neuroimaging. While off-targets including monoamine oxidase enzymes and neuromelanin-containing cells have been identified, recent studies indicated a relevant binding of novel tau tracers to melanin-containing structures. To date, little is known about the effect of melanocytes in the meninges on tracer signals in brain PET data. Thus, we aimed to identify the target structure causal for the frequently observed [F]PI-2620 PET signal in the vermis and adjacent cerebellar regions.nnMETHODS: 274 participants underwent dynamic [F]PI-2620 tau-PET: 3/4R-tauopathies (n = 85), 4R-tauopathies (n = 147), tau-negative disease controls (n = 24), and healthy controls (n = 18). Standardized uptake value ratio (SUVR) and kinetic parameters including the distribution volume ratio (DVR), tracer clearance (k2) and relative perfusion (R1), were compared among the cohorts and sexes using the Automated Anatomical Labelling (AAL) atlas. Age and p-Tau levels in cerebrospinal fluid (CSF) were assessed for their relationship with vermal tau-PET signal. Furthermore, we combined autoradiographic and histochemical experiments on post-mortem brain tissue of deceased patients (n = 9).nnRESULTS: Male participants revealed higher mean vermal [F]PI-2620 DVR (0.95 ± 0.13; vs. females 0.88 ± 0.10, p < 0.0001). Sex-related differences were most pronounced in the 3/4R-tauopathy cohort (p < 0.0001). Mean SUVR, k2 and correlation analyses of kinetic parameters did not differ among groups. Histological assessments revealed co-localization of leptomeningeal pigmented cells with strong autoradiography signal spots within the vermal fissures. Tau-related autoradiography signals, age or p-Tau levels did not correlate significantly with tau-PET signals. Iron deposits did not cause relevant autoradiography signals in the vermis.nnCONCLUSION: Leptomeningeal melanocytes are the primary target structure for [F]PI-2620 PET binding in anterior vermis, whereas iron and tau deposits do not contribute significantly.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
PURPOSE: Off-target binding remains a significant challenge in tau-PET neuroimaging. While off-targets including monoamine oxidase enzymes and neuromelanin-containing cells have been identified, recent studies indicated a relevant binding of novel tau tracers to melanin-containing structures. To date, little is known about the effect of melanocytes in the meninges on tracer signals in brain PET data. Thus, we aimed to identify the target structure causal for the frequently observed [F]PI-2620 PET signal in the vermis and adjacent cerebellar regions.nnMETHODS: 274 participants underwent dynamic [F]PI-2620 tau-PET: 3/4R-tauopathies (n = 85), 4R-tauopathies (n = 147), tau-negative disease controls (n = 24), and healthy controls (n = 18). Standardized uptake value ratio (SUVR) and kinetic parameters including the distribution volume ratio (DVR), tracer clearance (k2) and relative perfusion (R1), were compared among the cohorts and sexes using the Automated Anatomical Labelling (AAL) atlas. Age and p-Tau levels in cerebrospinal fluid (CSF) were assessed for their relationship with vermal tau-PET signal. Furthermore, we combined autoradiographic and histochemical experiments on post-mortem brain tissue of deceased patients (n = 9).nnRESULTS: Male participants revealed higher mean vermal [F]PI-2620 DVR (0.95 ± 0.13; vs. females 0.88 ± 0.10, p < 0.0001). Sex-related differences were most pronounced in the 3/4R-tauopathy cohort (p < 0.0001). Mean SUVR, k2 and correlation analyses of kinetic parameters did not differ among groups. Histological assessments revealed co-localization of leptomeningeal pigmented cells with strong autoradiography signal spots within the vermal fissures. Tau-related autoradiography signals, age or p-Tau levels did not correlate significantly with tau-PET signals. Iron deposits did not cause relevant autoradiography signals in the vermis.nnCONCLUSION: Leptomeningeal melanocytes are the primary target structure for [F]PI-2620 PET binding in anterior vermis, whereas iron and tau deposits do not contribute significantly.
Dzialas, Verena; Bischof, Gérard N; Möllenhoff, Kathrin; Drzezga, Alexander; van Eimeren, Thilo
Dopamine Transporter Imaging as Objective Monitoring Biomarker in Parkinson's Disease Journal Article
In: Ann Neurol, vol. 98, no. 1, pp. 120–135, 2025, ISSN: 1531-8249.
@article{pmid40145540,
title = {Dopamine Transporter Imaging as Objective Monitoring Biomarker in Parkinson's Disease},
author = {Verena Dzialas and Gérard N Bischof and Kathrin Möllenhoff and Alexander Drzezga and Thilo van Eimeren},
doi = {10.1002/ana.27223},
issn = {1531-8249},
year = {2025},
date = {2025-07-01},
journal = {Ann Neurol},
volume = {98},
number = {1},
pages = {120--135},
abstract = {OBJECTIVE: Although dopamine transporter (DaT) imaging is a valuable diagnostic biomarker, few studies have investigated its utility in objectively monitoring disease progression in patients with Parkinson's disease (PD). To date, no study has established a longitudinal relationship between the DaT signal decline and the motor symptom increase, potentially due to neglected factors such as brain regions, disease laterality, and symptom subtypes, which this study addresses.nnMETHODS: This cohort study included participants who met the Movement Disorder Society (MDS) criteria for PD, with longitudinal imaging and clinical data from the Parkinson's Progression Markers Initiative Database. Linear mixed model analyses were used to investigate the relationship between the DaT signal decline and the motor symptom severity increase over time. We hypothesized that a decline in putaminal DaT availability in the less affected hemisphere would be associated with increasing contralateral motor symptoms, measured by the Unified Parkinson's Disease Rating Scale (UPDRS). Additional models explored the effects of different brain regions (caudate and putamen), symptom categories (MDS UPDRSIII score with and without tremor items), and disease onset laterality (left or right hemisphere).nnRESULTS: We included 719 participants (443 male patients and 276 female patients; mean age = 62.2 ± 9.5 years) with 1,981 available data points. As hypothesized, we observed a significant association between the decrease in the less affected putaminal DaT signal and motor symptom increase in the contralateral body side, independent of including or excluding tremor scores.nnINTERPRETATION: Our findings support the use of repetitive DaT imaging for objectively monitoring PD progression. This could facilitate personalized disease tracking, subtyping, and intervention testing in the future. ANN NEUROL 2025;98:120-135.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVE: Although dopamine transporter (DaT) imaging is a valuable diagnostic biomarker, few studies have investigated its utility in objectively monitoring disease progression in patients with Parkinson's disease (PD). To date, no study has established a longitudinal relationship between the DaT signal decline and the motor symptom increase, potentially due to neglected factors such as brain regions, disease laterality, and symptom subtypes, which this study addresses.nnMETHODS: This cohort study included participants who met the Movement Disorder Society (MDS) criteria for PD, with longitudinal imaging and clinical data from the Parkinson's Progression Markers Initiative Database. Linear mixed model analyses were used to investigate the relationship between the DaT signal decline and the motor symptom severity increase over time. We hypothesized that a decline in putaminal DaT availability in the less affected hemisphere would be associated with increasing contralateral motor symptoms, measured by the Unified Parkinson's Disease Rating Scale (UPDRS). Additional models explored the effects of different brain regions (caudate and putamen), symptom categories (MDS UPDRSIII score with and without tremor items), and disease onset laterality (left or right hemisphere).nnRESULTS: We included 719 participants (443 male patients and 276 female patients; mean age = 62.2 ± 9.5 years) with 1,981 available data points. As hypothesized, we observed a significant association between the decrease in the less affected putaminal DaT signal and motor symptom increase in the contralateral body side, independent of including or excluding tremor scores.nnINTERPRETATION: Our findings support the use of repetitive DaT imaging for objectively monitoring PD progression. This could facilitate personalized disease tracking, subtyping, and intervention testing in the future. ANN NEUROL 2025;98:120-135.
Asendorf, Adrian L; Guerra, Elena; Dzialas, Verena; Banwinkler, Magdalena; Theis, Hendrik; Hagemann, Niklas; Möllenhoff, Kathrin; van Eimeren, Thilo; Hoenig, Merle C
Physical activity and network attack tolerance preserve motor function in Parkinson's disease: A pilot study Journal Article
In: NPJ Parkinsons Dis, vol. 11, no. 1, pp. 183, 2025, ISSN: 2373-8057.
@article{pmid40581669,
title = {Physical activity and network attack tolerance preserve motor function in Parkinson's disease: A pilot study},
author = {Adrian L Asendorf and Elena Guerra and Verena Dzialas and Magdalena Banwinkler and Hendrik Theis and Niklas Hagemann and Kathrin Möllenhoff and Thilo van Eimeren and Merle C Hoenig},
doi = {10.1038/s41531-025-01033-9},
issn = {2373-8057},
year = {2025},
date = {2025-06-01},
journal = {NPJ Parkinsons Dis},
volume = {11},
number = {1},
pages = {183},
abstract = {We tested whether network resilience, quantified by network attack tolerance (NAT), is associated with dopamine terminal (DaT) integrity, motor function and lifestyle factors in Parkinson's disease (PD). Data from 22 individuals with PD and 39 healthy controls included information on lifetime physical activity (PA), cognitive/motor performance, putaminal DaT integrity, and resting-state fMRI. NAT was assessed at global and subnetwork level by calculating global efficiency upon iterative node removal. Linear-mixed-effects models were used to test the effects of PA, education, and dopamine integrity on NAT. Next, the moderating effect of lifestyle factors on the association between NAT and motor function were assessed, controlling for DaT integrity. Greater putaminal DaT integrity was linked to higher somatomotor NAT. Higher global and somatomotor NAT supported motor function, especially in patients with moderate lifetime PA. These preliminary results indicate that lifestyle factors serve network-specific attack tolerance, thereby aiding maintenance of motor function in early-stage PD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We tested whether network resilience, quantified by network attack tolerance (NAT), is associated with dopamine terminal (DaT) integrity, motor function and lifestyle factors in Parkinson's disease (PD). Data from 22 individuals with PD and 39 healthy controls included information on lifetime physical activity (PA), cognitive/motor performance, putaminal DaT integrity, and resting-state fMRI. NAT was assessed at global and subnetwork level by calculating global efficiency upon iterative node removal. Linear-mixed-effects models were used to test the effects of PA, education, and dopamine integrity on NAT. Next, the moderating effect of lifestyle factors on the association between NAT and motor function were assessed, controlling for DaT integrity. Greater putaminal DaT integrity was linked to higher somatomotor NAT. Higher global and somatomotor NAT supported motor function, especially in patients with moderate lifetime PA. These preliminary results indicate that lifestyle factors serve network-specific attack tolerance, thereby aiding maintenance of motor function in early-stage PD.
Dzialas, Verena; Bischof, Gérard N.; Möllenhoff, Kathrin; Drzezga, Alexander; van Eimeren, Thilo
Dopamine Transporter Imaging as Objective Monitoring Biomarker in Parkinson's Disease Journal Article
In: Annals of Neurology, 2025, ISSN: 1531-8249.
@article{Dzialas2025,
title = {Dopamine Transporter Imaging as Objective Monitoring Biomarker in Parkinson's Disease},
author = {Verena Dzialas and Gérard N. Bischof and Kathrin Möllenhoff and Alexander Drzezga and Thilo van Eimeren},
doi = {10.1002/ana.27223},
issn = {1531-8249},
year = {2025},
date = {2025-03-27},
urldate = {2025-03-27},
journal = {Annals of Neurology},
publisher = {Wiley},
abstract = {<jats:sec><jats:title>Objective</jats:title><jats:p>Although dopamine transporter (DaT) imaging is a valuable diagnostic biomarker, few studies have investigated its utility in objectively monitoring disease progression in patients with Parkinson's disease (PD). To date, no study has established a longitudinal relationship between the DaT signal decline and the motor symptom increase, potentially due to neglected factors such as brain regions, disease laterality, and symptom subtypes, which this study addresses.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>This cohort study included participants who met the Movement Disorder Society (MDS) criteria for PD, with longitudinal imaging and clinical data from the Parkinson's Progression Markers Initiative Database. Linear mixed model analyses were used to investigate the relationship between the DaT signal decline and the motor symptom severity increase over time. We hypothesized that a decline in putaminal DaT availability in the less affected hemisphere would be associated with increasing contralateral motor symptoms, measured by the Unified Parkinson's Disease Rating Scale (UPDRS). Additional models explored the effects of different brain regions (caudate and putamen), symptom categories (MDS UPDRSIII score with and without tremor items), and disease onset laterality (left or right hemisphere).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We included 719 participants (443 male patients and 276 female patients; mean age = 62.2 ± 9.5 years) with 1,981 available data points. As hypothesized, we observed a significant association between the decrease in the less affected putaminal DaT signal and motor symptom increase in the contralateral body side, independent of including or excluding tremor scores.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Our findings support the use of repetitive DaT imaging for objectively monitoring PD progression. This could facilitate personalized disease tracking, subtyping, and intervention testing in the future. ANN NEUROL 2025</jats:p></jats:sec>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:sec><jats:title>Objective</jats:title><jats:p>Although dopamine transporter (DaT) imaging is a valuable diagnostic biomarker, few studies have investigated its utility in objectively monitoring disease progression in patients with Parkinson's disease (PD). To date, no study has established a longitudinal relationship between the DaT signal decline and the motor symptom increase, potentially due to neglected factors such as brain regions, disease laterality, and symptom subtypes, which this study addresses.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>This cohort study included participants who met the Movement Disorder Society (MDS) criteria for PD, with longitudinal imaging and clinical data from the Parkinson's Progression Markers Initiative Database. Linear mixed model analyses were used to investigate the relationship between the DaT signal decline and the motor symptom severity increase over time. We hypothesized that a decline in putaminal DaT availability in the less affected hemisphere would be associated with increasing contralateral motor symptoms, measured by the Unified Parkinson's Disease Rating Scale (UPDRS). Additional models explored the effects of different brain regions (caudate and putamen), symptom categories (MDS UPDRSIII score with and without tremor items), and disease onset laterality (left or right hemisphere).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We included 719 participants (443 male patients and 276 female patients; mean age = 62.2 ± 9.5 years) with 1,981 available data points. As hypothesized, we observed a significant association between the decrease in the less affected putaminal DaT signal and motor symptom increase in the contralateral body side, independent of including or excluding tremor scores.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Our findings support the use of repetitive DaT imaging for objectively monitoring PD progression. This could facilitate personalized disease tracking, subtyping, and intervention testing in the future. ANN NEUROL 2025</jats:p></jats:sec>
Kling, Agnes; Kusche-Palenga, Julia; Palleis, Carla; Jäck, Alexander; Bernhardt, Alexander M.; Frontzkowski, Lukas; Roemer, Sebastian N.; Slemann, Luna; Zaganjori, Mirlind; Scheifele, Maximilian; Paeger, Lars; Bischof, Gérard N.; van Eimeren, Thilo; Drzezga, Alexander; Sabri, Osama; Rullmann, Michael; Barthel, Henryk; Levin, Johannes; Herms, Jochen; Franzmeier, Nicolai; Höglinger, Günter; Roeber, Sigrun; Brendel, Matthias; Gnörich, Johannes
Exploring the origins of frequent tau-PET signal in vermal and adjacent regions Journal Article
In: Eur J Nucl Med Mol Imaging, 2025, ISSN: 1619-7089.
@article{Kling2025,
title = {Exploring the origins of frequent tau-PET signal in vermal and adjacent regions},
author = {Agnes Kling and Julia Kusche-Palenga and Carla Palleis and Alexander Jäck and Alexander M. Bernhardt and Lukas Frontzkowski and Sebastian N. Roemer and Luna Slemann and Mirlind Zaganjori and Maximilian Scheifele and Lars Paeger and Gérard N. Bischof and Thilo van Eimeren and Alexander Drzezga and Osama Sabri and Michael Rullmann and Henryk Barthel and Johannes Levin and Jochen Herms and Nicolai Franzmeier and Günter Höglinger and Sigrun Roeber and Matthias Brendel and Johannes Gnörich},
doi = {10.1007/s00259-025-07199-x},
issn = {1619-7089},
year = {2025},
date = {2025-03-18},
urldate = {2025-03-18},
journal = {Eur J Nucl Med Mol Imaging},
publisher = {Springer Science and Business Media LLC},
abstract = {<jats:title>Abstract</jats:title>
<jats:sec>
<jats:title>Purpose</jats:title>
<jats:p>Off-target binding remains a significant challenge in tau-PET neuroimaging. While off-targets including monoamine oxidase enzymes and neuromelanin-containing cells have been identified, recent studies indicated a relevant binding of novel tau tracers to melanin-containing structures. To date, little is known about the effect of melanocytes in the meninges on tracer signals in brain PET data. Thus, we aimed to identify the target structure causal for the frequently observed [<jats:sup>18</jats:sup>F]PI-2620 PET signal in the vermis and adjacent cerebellar regions.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods</jats:title>
<jats:p>274 participants underwent dynamic [<jats:sup>18</jats:sup>F]PI-2620 tau-PET: 3/4R-tauopathies (n = 85), 4R-tauopathies (n = 147), tau-negative disease controls (n = 24), and healthy controls (n = 18). Standardized uptake value ratio (SUVR) and kinetic parameters including the distribution volume ratio (DVR), tracer clearance (k2) and relative perfusion (R1), were compared among the cohorts and sexes using the Automated Anatomical Labelling (AAL) atlas. Age and p-Tau levels in cerebrospinal fluid (CSF) were assessed for their relationship with vermal tau-PET signal. Furthermore, we combined autoradiographic and histochemical experiments on post-mortem brain tissue of deceased patients (n = 9).</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<jats:p>Male participants revealed higher mean vermal [<jats:sup>18</jats:sup>F]PI-2620 DVR (0.95 ± 0.13; vs. females 0.88 ± 0.10, p < 0.0001). Sex-related differences were most pronounced in the 3/4R-tauopathy cohort (p < 0.0001). Mean SUVR<jats:sub>Ver/Cbl</jats:sub>, k2 and correlation analyses of kinetic parameters did not differ among groups. Histological assessments revealed co-localization of leptomeningeal pigmented cells with strong autoradiography signal spots within the vermal fissures. Tau-related autoradiography signals, age or p-Tau levels did not correlate significantly with tau-PET signals. Iron deposits did not cause relevant autoradiography signals in the vermis.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>Leptomeningeal melanocytes are the primary target structure for [<jats:sup>18</jats:sup>F]PI-2620 PET binding in anterior vermis, whereas iron and tau deposits do not contribute significantly.
</jats:p>
</jats:sec>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:title>Abstract</jats:title>
<jats:sec>
<jats:title>Purpose</jats:title>
<jats:p>Off-target binding remains a significant challenge in tau-PET neuroimaging. While off-targets including monoamine oxidase enzymes and neuromelanin-containing cells have been identified, recent studies indicated a relevant binding of novel tau tracers to melanin-containing structures. To date, little is known about the effect of melanocytes in the meninges on tracer signals in brain PET data. Thus, we aimed to identify the target structure causal for the frequently observed [<jats:sup>18</jats:sup>F]PI-2620 PET signal in the vermis and adjacent cerebellar regions.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods</jats:title>
<jats:p>274 participants underwent dynamic [<jats:sup>18</jats:sup>F]PI-2620 tau-PET: 3/4R-tauopathies (n = 85), 4R-tauopathies (n = 147), tau-negative disease controls (n = 24), and healthy controls (n = 18). Standardized uptake value ratio (SUVR) and kinetic parameters including the distribution volume ratio (DVR), tracer clearance (k2) and relative perfusion (R1), were compared among the cohorts and sexes using the Automated Anatomical Labelling (AAL) atlas. Age and p-Tau levels in cerebrospinal fluid (CSF) were assessed for their relationship with vermal tau-PET signal. Furthermore, we combined autoradiographic and histochemical experiments on post-mortem brain tissue of deceased patients (n = 9).</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<jats:p>Male participants revealed higher mean vermal [<jats:sup>18</jats:sup>F]PI-2620 DVR (0.95 ± 0.13; vs. females 0.88 ± 0.10, p < 0.0001). Sex-related differences were most pronounced in the 3/4R-tauopathy cohort (p < 0.0001). Mean SUVR<jats:sub>Ver/Cbl</jats:sub>, k2 and correlation analyses of kinetic parameters did not differ among groups. Histological assessments revealed co-localization of leptomeningeal pigmented cells with strong autoradiography signal spots within the vermal fissures. Tau-related autoradiography signals, age or p-Tau levels did not correlate significantly with tau-PET signals. Iron deposits did not cause relevant autoradiography signals in the vermis.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>Leptomeningeal melanocytes are the primary target structure for [<jats:sup>18</jats:sup>F]PI-2620 PET binding in anterior vermis, whereas iron and tau deposits do not contribute significantly.
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Purpose</jats:title>
<jats:p>Off-target binding remains a significant challenge in tau-PET neuroimaging. While off-targets including monoamine oxidase enzymes and neuromelanin-containing cells have been identified, recent studies indicated a relevant binding of novel tau tracers to melanin-containing structures. To date, little is known about the effect of melanocytes in the meninges on tracer signals in brain PET data. Thus, we aimed to identify the target structure causal for the frequently observed [<jats:sup>18</jats:sup>F]PI-2620 PET signal in the vermis and adjacent cerebellar regions.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods</jats:title>
<jats:p>274 participants underwent dynamic [<jats:sup>18</jats:sup>F]PI-2620 tau-PET: 3/4R-tauopathies (n = 85), 4R-tauopathies (n = 147), tau-negative disease controls (n = 24), and healthy controls (n = 18). Standardized uptake value ratio (SUVR) and kinetic parameters including the distribution volume ratio (DVR), tracer clearance (k2) and relative perfusion (R1), were compared among the cohorts and sexes using the Automated Anatomical Labelling (AAL) atlas. Age and p-Tau levels in cerebrospinal fluid (CSF) were assessed for their relationship with vermal tau-PET signal. Furthermore, we combined autoradiographic and histochemical experiments on post-mortem brain tissue of deceased patients (n = 9).</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<jats:p>Male participants revealed higher mean vermal [<jats:sup>18</jats:sup>F]PI-2620 DVR (0.95 ± 0.13; vs. females 0.88 ± 0.10, p < 0.0001). Sex-related differences were most pronounced in the 3/4R-tauopathy cohort (p < 0.0001). Mean SUVR<jats:sub>Ver/Cbl</jats:sub>, k2 and correlation analyses of kinetic parameters did not differ among groups. Histological assessments revealed co-localization of leptomeningeal pigmented cells with strong autoradiography signal spots within the vermal fissures. Tau-related autoradiography signals, age or p-Tau levels did not correlate significantly with tau-PET signals. Iron deposits did not cause relevant autoradiography signals in the vermis.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>Leptomeningeal melanocytes are the primary target structure for [<jats:sup>18</jats:sup>F]PI-2620 PET binding in anterior vermis, whereas iron and tau deposits do not contribute significantly.
</jats:p>
</jats:sec>
Doering, Elena; Hoenig, Merle C; Giehl, Kathrin; Dzialas, Verena; Andrassy, Grégory; Bader, Abdelmajid; Bauer, Andreas; Elmenhorst, David; Ermert, Johannes; Frensch, Silke; Jäger, Elena; Jessen, Frank; Krapf, Philipp; Kroll, Tina; Lerche, Christoph; Lothmann, Julia; Matusch, Andreas; Neumaier, Bernd; Onur, Oezguer A; Ramirez, Alfredo; Richter, Nils; Sand, Frederik; Tellmann, Lutz; Theis, Hendrik; Zeyen, Philip; van Eimeren, Thilo; Drzezga, Alexander; and, Gérard N Bischof
"Fill States": PET-derived Markers of the Spatial Extent of Alzheimer Disease Pathology Journal Article
In: Radiology, vol. 314, no. 3, pp. e241482, 2025, ISSN: 1527-1315.
@article{pmid40131110,
title = {"Fill States": PET-derived Markers of the Spatial Extent of Alzheimer Disease Pathology},
author = {Elena Doering and Merle C Hoenig and Kathrin Giehl and Verena Dzialas and Grégory Andrassy and Abdelmajid Bader and Andreas Bauer and David Elmenhorst and Johannes Ermert and Silke Frensch and Elena Jäger and Frank Jessen and Philipp Krapf and Tina Kroll and Christoph Lerche and Julia Lothmann and Andreas Matusch and Bernd Neumaier and Oezguer A Onur and Alfredo Ramirez and Nils Richter and Frederik Sand and Lutz Tellmann and Hendrik Theis and Philip Zeyen and Thilo van Eimeren and Alexander Drzezga and Gérard N Bischof and },
doi = {10.1148/radiol.241482},
issn = {1527-1315},
year = {2025},
date = {2025-03-01},
journal = {Radiology},
volume = {314},
number = {3},
pages = {e241482},
abstract = {Background Alzheimer disease (AD) progression can be monitored by tracking intensity changes in PET standardized uptake value (SUV) ratios of amyloid, tau, and neurodegeneration. The spatial extent ("fill state") of these three hallmark pathologic abnormalities may serve as critical pathophysiologic information, pending further investigation. Purpose To examine the clinical utility and increase the accessibility of PET-derived fill states. Materials and Methods This secondary analysis of two prospective studies used data from two independent cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Tau Propagation over Time study (T-POT). Each cohort comprised amyloid-negative cognitively normal individuals (controls) and patients with subjective cognitive decline, mild cognitive impairment, or probable-AD dementia. Fill states of amyloid, tau, and neurodegeneration were computed as the percentages of significantly abnormal voxels relative to controls across PET scans. Fill states and SUV ratios were compared across stages (Kruskal-Wallis test, area under the receiver operating characteristic curve analysis) and tested for association with the severity of cognitive impairment (Spearman correlation, multivariate regression analysis). Additionally, a convolutional neural network (CNN) was developed to estimate fill states from patients' PET scans without requiring controls. Results The ADNI cohort included 324 individuals (mean age, 72 years ± 6.8 [SD]; 173 [53%] female), and the T-POT cohort comprised 99 individuals (mean age, 66 years ± 8.7; 63 [64%] female). Higher fill states were associated with higher stages of cognitive impairment ( < .001), and tau and neurodegeneration fill states showed higher diagnostic performance for cognitive impairment compared with SUV ratio ( < .05) across cohorts. Similarly, all fill states were negatively correlated with cognitive performance ( < .001) and uniquely characterized the degree of cognitive impairment even after adjustment for SUV ratio ( < .05). The CNN estimated amyloid and tau accurately, but not neurodegeneration fill states. Conclusion Fill states provided reliable markers of AD progression, potentially improving early detection, staging, and monitoring of AD in clinical practice and trials beyond SUV ratio. Clinical trial registration no. NCT00106899 © RSNA, 2025 See also the editorial by Yun and Kim in this issue.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background Alzheimer disease (AD) progression can be monitored by tracking intensity changes in PET standardized uptake value (SUV) ratios of amyloid, tau, and neurodegeneration. The spatial extent ("fill state") of these three hallmark pathologic abnormalities may serve as critical pathophysiologic information, pending further investigation. Purpose To examine the clinical utility and increase the accessibility of PET-derived fill states. Materials and Methods This secondary analysis of two prospective studies used data from two independent cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Tau Propagation over Time study (T-POT). Each cohort comprised amyloid-negative cognitively normal individuals (controls) and patients with subjective cognitive decline, mild cognitive impairment, or probable-AD dementia. Fill states of amyloid, tau, and neurodegeneration were computed as the percentages of significantly abnormal voxels relative to controls across PET scans. Fill states and SUV ratios were compared across stages (Kruskal-Wallis test, area under the receiver operating characteristic curve analysis) and tested for association with the severity of cognitive impairment (Spearman correlation, multivariate regression analysis). Additionally, a convolutional neural network (CNN) was developed to estimate fill states from patients' PET scans without requiring controls. Results The ADNI cohort included 324 individuals (mean age, 72 years ± 6.8 [SD]; 173 [53%] female), and the T-POT cohort comprised 99 individuals (mean age, 66 years ± 8.7; 63 [64%] female). Higher fill states were associated with higher stages of cognitive impairment ( < .001), and tau and neurodegeneration fill states showed higher diagnostic performance for cognitive impairment compared with SUV ratio ( < .05) across cohorts. Similarly, all fill states were negatively correlated with cognitive performance ( < .001) and uniquely characterized the degree of cognitive impairment even after adjustment for SUV ratio ( < .05). The CNN estimated amyloid and tau accurately, but not neurodegeneration fill states. Conclusion Fill states provided reliable markers of AD progression, potentially improving early detection, staging, and monitoring of AD in clinical practice and trials beyond SUV ratio. Clinical trial registration no. NCT00106899 © RSNA, 2025 See also the editorial by Yun and Kim in this issue.
Doering, Elena; Hoenig, Merle C.; Giehl, Kathrin; Dzialas, Verena; Andrassy, Grégory; Bader, Abdelmajid; Bauer, Andreas; Elmenhorst, David; Ermert, Johannes; Frensch, Silke; Jäger, Elena; Jessen, Frank; Krapf, Philipp; Kroll, Tina; Lerche, Christoph; Lothmann, Julia; Matusch, Andreas; Neumaier, Bernd; Onur, Oezguer A.; Ramirez, Alfredo; Richter, Nils; Sand, Frederik; Tellmann, Lutz; Theis, Hendrik; Zeyen, Philip; van Eimeren, Thilo; Drzezga, Alexander; Bischof, Gérard N.
“Fill States”: PET-derived Markers of the Spatial Extent of Alzheimer Disease Pathology Journal Article
In: Radiology, vol. 314, no. 3, 2025, ISSN: 1527-1315.
@article{Doering2025,
title = {“Fill States”: PET-derived Markers of the Spatial Extent of Alzheimer Disease Pathology},
author = {Elena Doering and Merle C. Hoenig and Kathrin Giehl and Verena Dzialas and Grégory Andrassy and Abdelmajid Bader and Andreas Bauer and David Elmenhorst and Johannes Ermert and Silke Frensch and Elena Jäger and Frank Jessen and Philipp Krapf and Tina Kroll and Christoph Lerche and Julia Lothmann and Andreas Matusch and Bernd Neumaier and Oezguer A. Onur and Alfredo Ramirez and Nils Richter and Frederik Sand and Lutz Tellmann and Hendrik Theis and Philip Zeyen and Thilo van Eimeren and Alexander Drzezga and Gérard N. Bischof},
doi = {10.1148/radiol.241482},
issn = {1527-1315},
year = {2025},
date = {2025-03-01},
urldate = {2025-03-01},
journal = {Radiology},
volume = {314},
number = {3},
publisher = {Radiological Society of North America (RSNA)},
abstract = {<jats:p> The spatial extent of amyloid, tau, and neurodegeneration, derived from PET imaging, has higher diagnostic performance for cognitive impairment severity compared with standardized uptake value ratios. </jats:p>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:p> The spatial extent of amyloid, tau, and neurodegeneration, derived from PET imaging, has higher diagnostic performance for cognitive impairment severity compared with standardized uptake value ratios. </jats:p>
Bauer, Theresa; Brendel, Matthias; Zaganjori, Mirlind; Bernhardt, Alexander M.; Jäck, Alexander; Stöcklein, Sophia; Scheifele, Maximilian; Levin, Johannes; van Eimeren, Thilo; Drzezga, Alexander; Sabri, Osama; Barthel, Henryk; Perneczky, Robert; Höglinger, Günter; Franzmeier, Nicolai; Gnörich, Johannes
Pragmatic algorithm for visual assessment of 4-Repeat tauopathies in [18F]PI-2620 PET Scans Journal Article
In: NeuroImage, vol. 306, 2025, ISSN: 1053-8119.
@article{Bauer2025,
title = {Pragmatic algorithm for visual assessment of 4-Repeat tauopathies in [18F]PI-2620 PET Scans},
author = {Theresa Bauer and Matthias Brendel and Mirlind Zaganjori and Alexander M. Bernhardt and Alexander Jäck and Sophia Stöcklein and Maximilian Scheifele and Johannes Levin and Thilo van Eimeren and Alexander Drzezga and Osama Sabri and Henryk Barthel and Robert Perneczky and Günter Höglinger and Nicolai Franzmeier and Johannes Gnörich},
doi = {10.1016/j.neuroimage.2025.121001},
issn = {1053-8119},
year = {2025},
date = {2025-02-00},
urldate = {2025-02-00},
journal = {NeuroImage},
volume = {306},
publisher = {Elsevier BV},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2024
Dzialas, Verena; Doering, Elena; Eich, Helena; Strafella, Antonio P; Vaillancourt, David E; Simonyan, Kristina; van Eimeren and, Thilo
Houston, We Have AI Problem! Quality Issues with Neuroimaging-Based Artificial Intelligence in Parkinson's Disease: A Systematic Review Journal Article
In: Mov Disord, vol. 39, no. 12, pp. 2130–2143, 2024, ISSN: 1531-8257.
@article{pmid39235364,
title = {Houston, We Have AI Problem! Quality Issues with Neuroimaging-Based Artificial Intelligence in Parkinson's Disease: A Systematic Review},
author = {Verena Dzialas and Elena Doering and Helena Eich and Antonio P Strafella and David E Vaillancourt and Kristina Simonyan and Thilo van Eimeren and },
doi = {10.1002/mds.30002},
issn = {1531-8257},
year = {2024},
date = {2024-12-01},
journal = {Mov Disord},
volume = {39},
number = {12},
pages = {2130--2143},
abstract = {In recent years, many neuroimaging studies have applied artificial intelligence (AI) to facilitate existing challenges in Parkinson's disease (PD) diagnosis, prognosis, and intervention. The aim of this systematic review was to provide an overview of neuroimaging-based AI studies and to assess their methodological quality. A PubMed search yielded 810 studies, of which 244 that investigated the utility of neuroimaging-based AI for PD diagnosis, prognosis, or intervention were included. We systematically categorized studies by outcomes and rated them with respect to five minimal quality criteria (MQC) pertaining to data splitting, data leakage, model complexity, performance reporting, and indication of biological plausibility. We found that the majority of studies aimed to distinguish PD patients from healthy controls (54%) or atypical parkinsonian syndromes (25%), whereas prognostic or interventional studies were sparse. Only 20% of evaluated studies passed all five MQC, with data leakage, non-minimal model complexity, and reporting of biological plausibility as the primary factors for quality loss. Data leakage was associated with a significant inflation of accuracies. Very few studies employed external test sets (8%), where accuracy was significantly lower, and 19% of studies did not account for data imbalance. Adherence to MQC was low across all observed years and journal impact factors. This review outlines that AI has been applied to a wide variety of research questions pertaining to PD; however, the number of studies failing to pass the MQC is alarming. Therefore, we provide recommendations to enhance the interpretability, generalizability, and clinical utility of future AI applications using neuroimaging in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In recent years, many neuroimaging studies have applied artificial intelligence (AI) to facilitate existing challenges in Parkinson's disease (PD) diagnosis, prognosis, and intervention. The aim of this systematic review was to provide an overview of neuroimaging-based AI studies and to assess their methodological quality. A PubMed search yielded 810 studies, of which 244 that investigated the utility of neuroimaging-based AI for PD diagnosis, prognosis, or intervention were included. We systematically categorized studies by outcomes and rated them with respect to five minimal quality criteria (MQC) pertaining to data splitting, data leakage, model complexity, performance reporting, and indication of biological plausibility. We found that the majority of studies aimed to distinguish PD patients from healthy controls (54%) or atypical parkinsonian syndromes (25%), whereas prognostic or interventional studies were sparse. Only 20% of evaluated studies passed all five MQC, with data leakage, non-minimal model complexity, and reporting of biological plausibility as the primary factors for quality loss. Data leakage was associated with a significant inflation of accuracies. Very few studies employed external test sets (8%), where accuracy was significantly lower, and 19% of studies did not account for data imbalance. Adherence to MQC was low across all observed years and journal impact factors. This review outlines that AI has been applied to a wide variety of research questions pertaining to PD; however, the number of studies failing to pass the MQC is alarming. Therefore, we provide recommendations to enhance the interpretability, generalizability, and clinical utility of future AI applications using neuroimaging in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Slemann, Luna; Gnörich, Johannes; Hummel, Selina; Bartos, Laura M.; Klaus, Carolin; Kling, Agnes; Kusche-Palenga, Julia; Kunte, Sebastian T.; Kunze, Lea H.; Englert, Amelie L.; Li, Yunlei; Vogler, Letizia; Katzdobler, Sabrina; Palleis, Carla; Bernhardt, Alexander; Jäck, Alexander; Zwergal, Andreas; Hopfner, Franziska; Roemer-Cassiano, Sebastian N.; Biechele, Gloria; Stöcklein, Sophia; Bischof, Gerard; van Eimeren, Thilo; Drzezga, Alexander; Sabri, Osama; Barthel, Henryk; Respondek, Gesine; Grimmer, Timo; Levin, Johannes; Herms, Jochen; Paeger, Lars; Willroider, Marie; Beyer, Leonie; Höglinger, Günter U.; Roeber, Sigrun; Franzmeier, Nicolai; Brendel, Matthias
Neuronal and oligodendroglial, but not astroglial, tau translates to in vivo tau PET signals in individuals with primary tauopathies Journal Article
In: Acta Neuropathol, vol. 148, no. 1, 2024, ISSN: 1432-0533.
@article{Slemann2024,
title = {Neuronal and oligodendroglial, but not astroglial, tau translates to in vivo tau PET signals in individuals with primary tauopathies},
author = {Luna Slemann and Johannes Gnörich and Selina Hummel and Laura M. Bartos and Carolin Klaus and Agnes Kling and Julia Kusche-Palenga and Sebastian T. Kunte and Lea H. Kunze and Amelie L. Englert and Yunlei Li and Letizia Vogler and Sabrina Katzdobler and Carla Palleis and Alexander Bernhardt and Alexander Jäck and Andreas Zwergal and Franziska Hopfner and Sebastian N. Roemer-Cassiano and Gloria Biechele and Sophia Stöcklein and Gerard Bischof and Thilo van Eimeren and Alexander Drzezga and Osama Sabri and Henryk Barthel and Gesine Respondek and Timo Grimmer and Johannes Levin and Jochen Herms and Lars Paeger and Marie Willroider and Leonie Beyer and Günter U. Höglinger and Sigrun Roeber and Nicolai Franzmeier and Matthias Brendel},
doi = {10.1007/s00401-024-02834-7},
issn = {1432-0533},
year = {2024},
date = {2024-12-00},
urldate = {2024-12-00},
journal = {Acta Neuropathol},
volume = {148},
number = {1},
publisher = {Springer Science and Business Media LLC},
abstract = {<jats:title>Abstract</jats:title><jats:p>Tau PET has attracted increasing interest as an imaging biomarker for 4-repeat (4R)-tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau PET signals is still unclear. Therefore, we performed a translational study using a broad spectrum of advanced methodologies to investigate the sources of [<jats:sup>18</jats:sup>F]PI-2620 tau PET signals in individuals with 4R-tauopathies, including a pilot PET autopsy study in patients. First, we conducted a longitudinal [<jats:sup>18</jats:sup>F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and detected elevated [<jats:sup>18</jats:sup>F]PI-2620 PET signals in the presence of high levels of neuronal tau. An innovative approach involving cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons than in the astrocytes of PS19 mice. Regional [<jats:sup>18</jats:sup>F]PI-2620 tau PET signals during the lifetime correlated with the abundance of fibrillary tau and with autoradiography signal intensity in PSP patients and disease controls who underwent autopsy 2–63 months after tau PET. In autoradiography, tau-positive neurons and oligodendrocytes with a high AT8 density, but not tau-positive astrocytes, were the drivers of [<jats:sup>18</jats:sup>F]PI-2620 autoradiography signals in individuals with PSP. The high tau abundance in oligodendrocytes at the boundary of gray and white matter facilitated the identification of an optimized frontal lobe target region to detect the tau burden in patients with PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau PET radiotracer binding in 4-repeat-tauopathies, translating to an in vivo signal.</jats:p>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:title>Abstract</jats:title><jats:p>Tau PET has attracted increasing interest as an imaging biomarker for 4-repeat (4R)-tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau PET signals is still unclear. Therefore, we performed a translational study using a broad spectrum of advanced methodologies to investigate the sources of [<jats:sup>18</jats:sup>F]PI-2620 tau PET signals in individuals with 4R-tauopathies, including a pilot PET autopsy study in patients. First, we conducted a longitudinal [<jats:sup>18</jats:sup>F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and detected elevated [<jats:sup>18</jats:sup>F]PI-2620 PET signals in the presence of high levels of neuronal tau. An innovative approach involving cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons than in the astrocytes of PS19 mice. Regional [<jats:sup>18</jats:sup>F]PI-2620 tau PET signals during the lifetime correlated with the abundance of fibrillary tau and with autoradiography signal intensity in PSP patients and disease controls who underwent autopsy 2–63 months after tau PET. In autoradiography, tau-positive neurons and oligodendrocytes with a high AT8 density, but not tau-positive astrocytes, were the drivers of [<jats:sup>18</jats:sup>F]PI-2620 autoradiography signals in individuals with PSP. The high tau abundance in oligodendrocytes at the boundary of gray and white matter facilitated the identification of an optimized frontal lobe target region to detect the tau burden in patients with PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau PET radiotracer binding in 4-repeat-tauopathies, translating to an in vivo signal.</jats:p>
Witt, Karsten; Levin, Johannes; van Eimeren, Thilo; Hasan, Alkomiet; Ebersbach, Georg; and Mathias Bähr,; Becktepe, Jos; Berg, Daniela; Brockmann, Kathrin; Buhmann, Carsten; Ceballos-Baumann, Andrés; Claßen, Joseph; Deuschl, Cornelius; Deuschl, Günther; Dodel, Richard; Ebersbach, Georg; Eggers, Carsten; van Eimeren, Thilo; Fanciulli, Alessandra; Fimm, Bruno; Folkerts, Ann-Kristin; Gausepohl, Madeleine; Hasan, Alkomiet; Hermann, Wiebke; Hilker-Roggendorf, Rüdiger; Höglinger, Günter; Höllerhage, Matthias; Hopfner, Franziska; Jost, Wolfgang; Kalbe, Elke; Kassubek, Jan; Klebe, Stephan; Klein, Christine; Klietz, Martin; Köglsperger, Thomas; Kühn, Andrea; Krack, Paul; Krismer, Florian; Kuhlenbäumer, Gregor; Levin, Johannes; Liepelt-Scarfone, Inga; Lingor, Paul; Loewenbrück, Kai; Löhle, Matthias; Lorenzl, Stefan; Maaß, Sylvia; Maetzler, Walter; Menzel, Regina; Meyer, Philipp T.; Mollenhauer, Brit; Neumann, Manuela; Odin, Per; Outeiro, Tiago; Pötter-Nerger, Monika; Reese, René; Reetz, Kathrin; Rieß, Olaf; Ruf, Viktoria; Schneider, Anja; Schrader, Christoph; Schnitzler, Alfons; Seppi, Klaus; Sixel-Döring, Friederike; Storch, Alexander; Tönges, Lars; Trenkwalder, Claudia; van Eimeren, Thilo; Walter, Uwe; Wächter, Tobias; Warnecke, Tobias; Wegner, Florian; Winkler, Christian; Witt, Karsten; Woitalla, Dirk; Zeuner, Kirsten; Bantel, Martina; Witt, Jonas L.
In: J Neurol, vol. 271, no. 12, pp. 7402–7421, 2024, ISSN: 1432-1459.
@article{Witt2024,
title = {Diagnostics and treatment of impulse control disorders, psychosis and delirium: systemic review-based recommendations - guideline “Parkinson’s disease” of the German Society of Neurology},
author = {Karsten Witt and Johannes Levin and Thilo van Eimeren and Alkomiet Hasan and Georg Ebersbach and and Mathias Bähr and Jos Becktepe and Daniela Berg and Kathrin Brockmann and Carsten Buhmann and Andrés Ceballos-Baumann and Joseph Claßen and Cornelius Deuschl and Günther Deuschl and Richard Dodel and Georg Ebersbach and Carsten Eggers and Thilo van Eimeren and Alessandra Fanciulli and Bruno Fimm and Ann-Kristin Folkerts and Madeleine Gausepohl and Alkomiet Hasan and Wiebke Hermann and Rüdiger Hilker-Roggendorf and Günter Höglinger and Matthias Höllerhage and Franziska Hopfner and Wolfgang Jost and Elke Kalbe and Jan Kassubek and Stephan Klebe and Christine Klein and Martin Klietz and Thomas Köglsperger and Andrea Kühn and Paul Krack and Florian Krismer and Gregor Kuhlenbäumer and Johannes Levin and Inga Liepelt-Scarfone and Paul Lingor and Kai Loewenbrück and Matthias Löhle and Stefan Lorenzl and Sylvia Maaß and Walter Maetzler and Regina Menzel and Philipp T. Meyer and Brit Mollenhauer and Manuela Neumann and Per Odin and Tiago Outeiro and Monika Pötter-Nerger and René Reese and Kathrin Reetz and Olaf Rieß and Viktoria Ruf and Anja Schneider and Christoph Schrader and Alfons Schnitzler and Klaus Seppi and Friederike Sixel-Döring and Alexander Storch and Lars Tönges and Claudia Trenkwalder and Thilo van Eimeren and Uwe Walter and Tobias Wächter and Tobias Warnecke and Florian Wegner and Christian Winkler and Karsten Witt and Dirk Woitalla and Kirsten Zeuner and Martina Bantel and Jonas L. Witt},
doi = {10.1007/s00415-024-12576-x},
issn = {1432-1459},
year = {2024},
date = {2024-12-00},
urldate = {2024-12-00},
journal = {J Neurol},
volume = {271},
number = {12},
pages = {7402--7421},
publisher = {Springer Science and Business Media LLC},
abstract = {<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background and objective</jats:title>
<jats:p>Impulse control disorders (ICD), psychosis and delirium are part of the spectrum of behavioural changes associated with Parkinson’s disease (PD). The diagnostic and therapeutic management of these rather complex neuropsychiatric conditions has been updated in the clinical guideline by the German Society of Neurology (DGN).</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>Recommendations are based on a systematic literature reviews, other relevant guidelines and expert opinion.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>Patients receiving dopamine agonists (DA) therapy should be informed about the symptoms and risks of an ICD and should be routinely screened for ICD symptoms. In the presence of an ICD, DA should be reduced or discontinued and psychotherapeutic treatment may be considered. Non-oral therapies (levodopa/carbidopa intestinal gel infusion or deep brain stimulation) may also be an option for appropriate candidates. Psychosis in PD often has a gradual onset. Cognitive and affective disorders, psychiatric and medical comorbidities as well as polypharmacy are risk factors for a psychosis. Non-pharmacological treatments should be implemented as soon as possible and anti-parkinsonian medications should be adjusted/reduced if feasible. For psychosis associated with PD, quetiapine or clozapine should be used on an as-needed basis and for as short a time as is necessary, with safety monitoring. Delirium in PD may be underdiagnosed due to an overlap with chronic neuropsychiatric features of PD. Although transient by definition, delirium in PD can lead to permanent cognitive decline, motor impairment and increased mortality. Management of delirium includes pharmacological and non-pharmacological interventions.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>The updated guideline encompasses the evidence-based diagnostic, non-pharmacological and pharmacological management of ICD, psychosis and delirium in PD.</jats:p>
</jats:sec>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background and objective</jats:title>
<jats:p>Impulse control disorders (ICD), psychosis and delirium are part of the spectrum of behavioural changes associated with Parkinson’s disease (PD). The diagnostic and therapeutic management of these rather complex neuropsychiatric conditions has been updated in the clinical guideline by the German Society of Neurology (DGN).</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>Recommendations are based on a systematic literature reviews, other relevant guidelines and expert opinion.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>Patients receiving dopamine agonists (DA) therapy should be informed about the symptoms and risks of an ICD and should be routinely screened for ICD symptoms. In the presence of an ICD, DA should be reduced or discontinued and psychotherapeutic treatment may be considered. Non-oral therapies (levodopa/carbidopa intestinal gel infusion or deep brain stimulation) may also be an option for appropriate candidates. Psychosis in PD often has a gradual onset. Cognitive and affective disorders, psychiatric and medical comorbidities as well as polypharmacy are risk factors for a psychosis. Non-pharmacological treatments should be implemented as soon as possible and anti-parkinsonian medications should be adjusted/reduced if feasible. For psychosis associated with PD, quetiapine or clozapine should be used on an as-needed basis and for as short a time as is necessary, with safety monitoring. Delirium in PD may be underdiagnosed due to an overlap with chronic neuropsychiatric features of PD. Although transient by definition, delirium in PD can lead to permanent cognitive decline, motor impairment and increased mortality. Management of delirium includes pharmacological and non-pharmacological interventions.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>The updated guideline encompasses the evidence-based diagnostic, non-pharmacological and pharmacological management of ICD, psychosis and delirium in PD.</jats:p>
</jats:sec>
<jats:title>Background and objective</jats:title>
<jats:p>Impulse control disorders (ICD), psychosis and delirium are part of the spectrum of behavioural changes associated with Parkinson’s disease (PD). The diagnostic and therapeutic management of these rather complex neuropsychiatric conditions has been updated in the clinical guideline by the German Society of Neurology (DGN).</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>Recommendations are based on a systematic literature reviews, other relevant guidelines and expert opinion.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>Patients receiving dopamine agonists (DA) therapy should be informed about the symptoms and risks of an ICD and should be routinely screened for ICD symptoms. In the presence of an ICD, DA should be reduced or discontinued and psychotherapeutic treatment may be considered. Non-oral therapies (levodopa/carbidopa intestinal gel infusion or deep brain stimulation) may also be an option for appropriate candidates. Psychosis in PD often has a gradual onset. Cognitive and affective disorders, psychiatric and medical comorbidities as well as polypharmacy are risk factors for a psychosis. Non-pharmacological treatments should be implemented as soon as possible and anti-parkinsonian medications should be adjusted/reduced if feasible. For psychosis associated with PD, quetiapine or clozapine should be used on an as-needed basis and for as short a time as is necessary, with safety monitoring. Delirium in PD may be underdiagnosed due to an overlap with chronic neuropsychiatric features of PD. Although transient by definition, delirium in PD can lead to permanent cognitive decline, motor impairment and increased mortality. Management of delirium includes pharmacological and non-pharmacological interventions.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>The updated guideline encompasses the evidence-based diagnostic, non-pharmacological and pharmacological management of ICD, psychosis and delirium in PD.</jats:p>
</jats:sec>
Dzialas, Verena; Hoenig, Merle C.; Prange, Stéphane; Bischof, Gérard N.; and Alexander Drzezga,; van Eimeren, Thilo
Structural underpinnings and long-term effects of resilience in Parkinson’s disease Journal Article
In: npj Parkinsons Dis., vol. 10, no. 1, 2024, ISSN: 2373-8057.
@article{Dzialas2024b,
title = {Structural underpinnings and long-term effects of resilience in Parkinson’s disease},
author = {Verena Dzialas and Merle C. Hoenig and Stéphane Prange and Gérard N. Bischof and and Alexander Drzezga and Thilo van Eimeren},
doi = {10.1038/s41531-024-00699-x},
issn = {2373-8057},
year = {2024},
date = {2024-12-00},
urldate = {2024-12-00},
journal = {npj Parkinsons Dis.},
volume = {10},
number = {1},
publisher = {Springer Science and Business Media LLC},
abstract = {<jats:title>Abstract</jats:title><jats:p>Resilience in neuroscience generally refers to an individual’s capacity to counteract the adverse effects of a neuropathological condition. While resilience mechanisms in Alzheimer’s disease are well-investigated, knowledge regarding its quantification, neurobiological underpinnings, network adaptations, and long-term effects in Parkinson’s disease is limited. Our study involved 151 Parkinson’s patients from the Parkinson’s Progression Marker Initiative Database with available Magnetic Resonance Imaging, Dopamine Transporter Single-Photon Emission Computed Tomography scans, and clinical information. We used an improved prediction model linking neuropathology to symptom severity to estimate individual resilience levels. Higher resilience levels were associated with a more active lifestyle, increased grey matter volume in motor-associated regions, a distinct structural connectivity network and maintenance of relative motor functioning for up to a decade. Overall, the results indicate that relative maintenance of motor function in Parkinson’s patients may be associated with greater neuronal substrate, allowing higher tolerance against neurodegenerative processes through dynamic network restructuring.</jats:p>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:title>Abstract</jats:title><jats:p>Resilience in neuroscience generally refers to an individual’s capacity to counteract the adverse effects of a neuropathological condition. While resilience mechanisms in Alzheimer’s disease are well-investigated, knowledge regarding its quantification, neurobiological underpinnings, network adaptations, and long-term effects in Parkinson’s disease is limited. Our study involved 151 Parkinson’s patients from the Parkinson’s Progression Marker Initiative Database with available Magnetic Resonance Imaging, Dopamine Transporter Single-Photon Emission Computed Tomography scans, and clinical information. We used an improved prediction model linking neuropathology to symptom severity to estimate individual resilience levels. Higher resilience levels were associated with a more active lifestyle, increased grey matter volume in motor-associated regions, a distinct structural connectivity network and maintenance of relative motor functioning for up to a decade. Overall, the results indicate that relative maintenance of motor function in Parkinson’s patients may be associated with greater neuronal substrate, allowing higher tolerance against neurodegenerative processes through dynamic network restructuring.</jats:p>
Oltra, Javier; Segura, Barbara; Strafella, Antonio P.; van Eimeren, Thilo; Ibarretxe-Bilbao, Naroa; Diez-Cirarda, Maria; Eggers, Carsten; Lucas-Jiménez, Olaia; Monté-Rubio, Gemma C.; Ojeda, Natalia; Peña, Javier; Ruppert, Marina C.; Sala-Llonch, Roser; Theis, Hendrik; Uribe, Carme; Junque, Carme
A multi-site study on sex differences in cortical thickness in non-demented Parkinson’s disease Journal Article
In: npj Parkinsons Dis., vol. 10, no. 1, 2024, ISSN: 2373-8057.
@article{Oltra2024,
title = {A multi-site study on sex differences in cortical thickness in non-demented Parkinson’s disease},
author = {Javier Oltra and Barbara Segura and Antonio P. Strafella and Thilo van Eimeren and Naroa Ibarretxe-Bilbao and Maria Diez-Cirarda and Carsten Eggers and Olaia Lucas-Jiménez and Gemma C. Monté-Rubio and Natalia Ojeda and Javier Peña and Marina C. Ruppert and Roser Sala-Llonch and Hendrik Theis and Carme Uribe and Carme Junque},
doi = {10.1038/s41531-024-00686-2},
issn = {2373-8057},
year = {2024},
date = {2024-12-00},
urldate = {2024-12-00},
journal = {npj Parkinsons Dis.},
volume = {10},
number = {1},
publisher = {Springer Science and Business Media LLC},
abstract = {<jats:title>Abstract</jats:title><jats:p>Clinical, cognitive, and atrophy characteristics depending on sex have been previously reported in Parkinson’s disease (PD). However, though sex differences in cortical gray matter measures in early drug naïve patients have been described, little is known about differences in cortical thickness (CTh) as the disease advances. Our multi-site sample comprised 211 non-demented PD patients (64.45% males; mean age 65.58 ± 8.44 years old; mean disease duration 6.42 ± 5.11 years) and 86 healthy controls (50% males; mean age 65.49 ± 9.33 years old) with available T1-weighted 3 T MRI data from four international research centers. Sex differences in regional mean CTh estimations were analyzed using generalized linear models. The relation of CTh in regions showing sex differences with age, disease duration, and age of onset was examined through multiple linear regression. PD males showed thinner cortex than PD females in six frontal (bilateral caudal middle frontal, bilateral superior frontal, left precentral and right pars orbitalis), three parietal (bilateral inferior parietal and left supramarginal), and one limbic region (right posterior cingulate). In PD males, lower CTh values in nine out of ten regions were associated with longer disease duration and older age, whereas in PD females, lower CTh was associated with older age but with longer disease duration only in one region. Overall, male patients show a more widespread pattern of reduced CTh compared with female patients. Disease duration seems more relevant to explain reduced CTh in male patients, suggesting worse prognostic over time. Further studies should explore sex-specific cortical atrophy trajectories using large longitudinal multi-site data.</jats:p>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:title>Abstract</jats:title><jats:p>Clinical, cognitive, and atrophy characteristics depending on sex have been previously reported in Parkinson’s disease (PD). However, though sex differences in cortical gray matter measures in early drug naïve patients have been described, little is known about differences in cortical thickness (CTh) as the disease advances. Our multi-site sample comprised 211 non-demented PD patients (64.45% males; mean age 65.58 ± 8.44 years old; mean disease duration 6.42 ± 5.11 years) and 86 healthy controls (50% males; mean age 65.49 ± 9.33 years old) with available T1-weighted 3 T MRI data from four international research centers. Sex differences in regional mean CTh estimations were analyzed using generalized linear models. The relation of CTh in regions showing sex differences with age, disease duration, and age of onset was examined through multiple linear regression. PD males showed thinner cortex than PD females in six frontal (bilateral caudal middle frontal, bilateral superior frontal, left precentral and right pars orbitalis), three parietal (bilateral inferior parietal and left supramarginal), and one limbic region (right posterior cingulate). In PD males, lower CTh values in nine out of ten regions were associated with longer disease duration and older age, whereas in PD females, lower CTh was associated with older age but with longer disease duration only in one region. Overall, male patients show a more widespread pattern of reduced CTh compared with female patients. Disease duration seems more relevant to explain reduced CTh in male patients, suggesting worse prognostic over time. Further studies should explore sex-specific cortical atrophy trajectories using large longitudinal multi-site data.</jats:p>
Passaretti, Massimiliano; Cilia, Roberto; Rinaldo, Sara; Sebastiano, Davide Rossi; Orunesu, Eva; Devigili, Grazia; Braccia, Arianna; Paparella, Giulia; Riggi, Martina De; van Eimeren, Thilo; Strafella, Antonio Paolo; Lanteri, Paola; Berardelli, Alfredo; Bologna, Matteo; Eleopra, Roberto
Neurophysiological markers of motor compensatory mechanisms in early Parkinson’s disease Journal Article
In: vol. 147, no. 11, pp. 3714–3726, 2024, ISSN: 1460-2156.
@article{Passaretti2024,
title = {Neurophysiological markers of motor compensatory mechanisms in early Parkinson’s disease},
author = {Massimiliano Passaretti and Roberto Cilia and Sara Rinaldo and Davide Rossi Sebastiano and Eva Orunesu and Grazia Devigili and Arianna Braccia and Giulia Paparella and Martina De Riggi and Thilo van Eimeren and Antonio Paolo Strafella and Paola Lanteri and Alfredo Berardelli and Matteo Bologna and Roberto Eleopra},
doi = {10.1093/brain/awae210},
issn = {1460-2156},
year = {2024},
date = {2024-11-04},
volume = {147},
number = {11},
pages = {3714--3726},
publisher = {Oxford University Press (OUP)},
abstract = {Abstract
Compensatory mechanisms in Parkinson’s disease are defined as the changes that the brain uses to adapt to neurodegeneration and progressive dopamine reduction. Motor compensation in early Parkinson’s disease could, in part, be responsible for a unilateral onset of clinical motor signs despite the presence of bilateral nigrostriatal degeneration. Although several mechanisms have been proposed for compensatory adaptations in Parkinson’s disease, the underlying pathophysiology is unclear.
Here, we investigate motor compensation in Parkinson’s disease by investigating the relationship between clinical signs, dopamine transporter imaging data and neurophysiological measures of the primary motor cortex (M1), using transcranial magnetic stimulation in presymptomatic and symptomatic hemispheres of patients. In this cross-sectional, multicentre study, we screened 82 individuals with Parkinson’s disease. Patients were evaluated clinically in their medication OFF state using standardized scales. Sixteen Parkinson’s disease patients with bilateral dopamine transporter deficit in the putamina but unilateral symptoms were included. Twenty-eight sex- and age-matched healthy controls were also investigated. In all participants, we tested cortical excitability using single- and paired-pulse techniques, interhemispheric inhibition and cortical plasticity with paired associative stimulation. Data were analysed with ANOVAs, multiple linear regression and logistic regression models. Individual coefficients of motor compensation were defined in patients based on clinical and imaging data, i.e. the motor compensation coefficient. The motor compensation coefficient includes an asymmetry score to balance motor and dopamine transporter data between the two hemispheres, in addition to a hemispheric ratio accounting for the relative mismatch between the magnitude of motor signs and dopaminergic deficit.
In patients, corticospinal excitability and plasticity were higher in the presymptomatic compared with the symptomatic M1. Also, interhemispheric inhibition from the presymptomatic to the symptomatic M1 was reduced. Lower putamen binding was associated with higher plasticity and reduced interhemispheric inhibition in the presymptomatic hemisphere. The motor compensation coefficient distinguished the presymptomatic from the symptomatic hemisphere. Finally, in the presymptomatic hemisphere, a higher motor compensation coefficient was associated with lower corticospinal excitability and interhemispheric inhibition and with higher plasticity.
In conclusion, the present study suggests that motor compensation involves M1–striatal networks and intercortical connections becoming more effective with progressive loss of dopaminergic terminals in the putamen. The balance between these motor networks seems to be driven by cortical plasticity. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Banwinkler, Magdalena; Dzialas, Verena; Rigoux, Lionel; Asendorf, Adrian L; Theis, Hendrik; Giehl, Kathrin; Tittgemeyer, Marc; Hoenig, Merle C; van Eimeren, Thilo
Putaminal dopamine modulates movement motivation in Parkinson’s disease Journal Article
In: Brain, vol. 147, no. 10, pp. 3352–3357, 2024, ISSN: 1460-2156.
@article{Banwinkler2024,
title = {Putaminal dopamine modulates movement motivation in Parkinson’s disease},
author = {Magdalena Banwinkler and Verena Dzialas and Lionel Rigoux and Adrian L Asendorf and Hendrik Theis and Kathrin Giehl and Marc Tittgemeyer and Merle C Hoenig and Thilo van Eimeren},
doi = {10.1093/brain/awae214},
issn = {1460-2156},
year = {2024},
date = {2024-10-03},
urldate = {2024-10-03},
journal = {Brain},
volume = {147},
number = {10},
pages = {3352--3357},
publisher = {Oxford University Press (OUP)},
abstract = {<jats:title>Abstract</jats:title>
<jats:p>The relative inability to produce effortful movements is the most specific motor sign of Parkinson’s disease, which is primarily characterized by loss of dopaminergic terminals in the putamen. The motor motivation hypothesis suggests that this motor deficit may not reflect a deficiency in motor control per se, but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinson’s disease.</jats:p>
<jats:p>A total of 21 early-stage, unmedicated patients with Parkinson’s disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed.</jats:p>
<jats:p>Our results demonstrate that patients with Parkinson’s disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor.</jats:p>
<jats:p>Taken together, we provide direct evidence that the reduction of effortful movements in Parkinson’s disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration.</jats:p>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:title>Abstract</jats:title>
<jats:p>The relative inability to produce effortful movements is the most specific motor sign of Parkinson’s disease, which is primarily characterized by loss of dopaminergic terminals in the putamen. The motor motivation hypothesis suggests that this motor deficit may not reflect a deficiency in motor control per se, but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinson’s disease.</jats:p>
<jats:p>A total of 21 early-stage, unmedicated patients with Parkinson’s disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed.</jats:p>
<jats:p>Our results demonstrate that patients with Parkinson’s disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor.</jats:p>
<jats:p>Taken together, we provide direct evidence that the reduction of effortful movements in Parkinson’s disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration.</jats:p>
<jats:p>The relative inability to produce effortful movements is the most specific motor sign of Parkinson’s disease, which is primarily characterized by loss of dopaminergic terminals in the putamen. The motor motivation hypothesis suggests that this motor deficit may not reflect a deficiency in motor control per se, but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinson’s disease.</jats:p>
<jats:p>A total of 21 early-stage, unmedicated patients with Parkinson’s disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed.</jats:p>
<jats:p>Our results demonstrate that patients with Parkinson’s disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor.</jats:p>
<jats:p>Taken together, we provide direct evidence that the reduction of effortful movements in Parkinson’s disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration.</jats:p>
Banwinkler, Magdalena; Dzialas, Verena; Rigoux, Lionel; Asendorf, Adrian L; Theis, Hendrik; Giehl, Kathrin; Tittgemeyer, Marc; Hoenig, Merle C; van Eimeren, Thilo
Putaminal dopamine modulates movement motivation in Parkinson's disease Journal Article
In: Brain, vol. 147, no. 10, pp. 3352–3357, 2024, ISSN: 1460-2156.
@article{pmid38941444,
title = {Putaminal dopamine modulates movement motivation in Parkinson's disease},
author = {Magdalena Banwinkler and Verena Dzialas and Lionel Rigoux and Adrian L Asendorf and Hendrik Theis and Kathrin Giehl and Marc Tittgemeyer and Merle C Hoenig and Thilo van Eimeren},
doi = {10.1093/brain/awae214},
issn = {1460-2156},
year = {2024},
date = {2024-10-01},
journal = {Brain},
volume = {147},
number = {10},
pages = {3352--3357},
abstract = {The relative inability to produce effortful movements is the most specific motor sign of Parkinson's disease, which is primarily characterized by loss of dopaminergic terminals in the putamen. The motor motivation hypothesis suggests that this motor deficit may not reflect a deficiency in motor control per se, but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinson's disease. A total of 21 early-stage, unmedicated patients with Parkinson's disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed. Our results demonstrate that patients with Parkinson's disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor. Taken together, we provide direct evidence that the reduction of effortful movements in Parkinson's disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The relative inability to produce effortful movements is the most specific motor sign of Parkinson's disease, which is primarily characterized by loss of dopaminergic terminals in the putamen. The motor motivation hypothesis suggests that this motor deficit may not reflect a deficiency in motor control per se, but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinson's disease. A total of 21 early-stage, unmedicated patients with Parkinson's disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed. Our results demonstrate that patients with Parkinson's disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor. Taken together, we provide direct evidence that the reduction of effortful movements in Parkinson's disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration.
Theis, Hendrik; Pavese, Nicola; Rektorová, Irena; van Eimeren, Thilo
Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson’s Disease Journal Article
In: Journal of Parkinson’s Disease, vol. 14, no. s2, pp. S353–S365, 2024, ISSN: 1877-718X.
@article{Theis2024b,
title = {Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson’s Disease},
author = {Hendrik Theis and Nicola Pavese and Irena Rektorová and Thilo van Eimeren},
doi = {10.3233/jpd-230385},
issn = {1877-718X},
year = {2024},
date = {2024-10-01},
urldate = {2024-10-01},
journal = {Journal of Parkinson’s Disease},
volume = {14},
number = {s2},
pages = {S353--S365},
publisher = {SAGE Publications},
abstract = {<jats:p> Assessing imaging biomarker in the prodromal and early phases of Parkinson’s disease (PD) is of great importance to ensure an early and safe diagnosis. In the last decades, imaging modalities advanced and are now able to assess many different aspects of neurodegeneration in PD. MRI sequences can measure iron content or neuromelanin. Apart from SPECT imaging with Ioflupane, more specific PET tracers to assess degeneration of the dopaminergic system are available. Furthermore, metabolic PET patterns can be used to anticipate a phenoconversion from prodromal PD to manifest PD. In this regard, it is worth mentioning that PET imaging of inflammation will gain significance. Molecular imaging of neurotransmitters like serotonin, noradrenaline and acetylcholine shed more light on non-motor symptoms. Outside of the brain, molecular imaging of the heart and gut is used to measure PD-related degeneration of the autonomous nervous system. Moreover, optical coherence tomography can noninvasively detect degeneration of retinal fibers as a potential biomarker in PD. In this review, we describe these state-of-the-art imaging modalities in early and prodromal PD and point out in how far these techniques can and will be used in the future to pave the way towards a biomarker-based staging of PD. </jats:p>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:p> Assessing imaging biomarker in the prodromal and early phases of Parkinson’s disease (PD) is of great importance to ensure an early and safe diagnosis. In the last decades, imaging modalities advanced and are now able to assess many different aspects of neurodegeneration in PD. MRI sequences can measure iron content or neuromelanin. Apart from SPECT imaging with Ioflupane, more specific PET tracers to assess degeneration of the dopaminergic system are available. Furthermore, metabolic PET patterns can be used to anticipate a phenoconversion from prodromal PD to manifest PD. In this regard, it is worth mentioning that PET imaging of inflammation will gain significance. Molecular imaging of neurotransmitters like serotonin, noradrenaline and acetylcholine shed more light on non-motor symptoms. Outside of the brain, molecular imaging of the heart and gut is used to measure PD-related degeneration of the autonomous nervous system. Moreover, optical coherence tomography can noninvasively detect degeneration of retinal fibers as a potential biomarker in PD. In this review, we describe these state-of-the-art imaging modalities in early and prodromal PD and point out in how far these techniques can and will be used in the future to pave the way towards a biomarker-based staging of PD. </jats:p>
Theis, Hendrik; Barbe, Michael T.; Drzezga, Alexander; Fink, Gereon R.; Neumaier, Bernd; Bischof, Gérard N.; van Eimeren, Thilo
Progressive Supranuclear Palsy: Subcortical Tau Depositions Are Associated with Cortical Perfusion in Frontal and Limbic Regions Journal Article
In: Journal of Parkinson’s Disease, vol. 14, no. 6, pp. 1271–1276, 2024, ISSN: 1877-718X.
@article{Theis2024,
title = {Progressive Supranuclear Palsy: Subcortical Tau Depositions Are Associated with Cortical Perfusion in Frontal and Limbic Regions},
author = {Hendrik Theis and Michael T. Barbe and Alexander Drzezga and Gereon R. Fink and Bernd Neumaier and Gérard N. Bischof and Thilo van Eimeren},
doi = {10.3233/jpd-240210},
issn = {1877-718X},
year = {2024},
date = {2024-09-03},
urldate = {2024-09-03},
journal = {Journal of Parkinson’s Disease},
volume = {14},
number = {6},
pages = {1271--1276},
publisher = {SAGE Publications},
abstract = { In progressive supranuclear palsy (PSP), subcortical tau and cortical perfusion can be assessed using the tracer ^{18</jsup>F]PI-2620. We investigated if subcortical tau (globus pallidus internus, dentate nucleus) and frontal/limbic perfusion correlate in a cohort of 32 PSP patients. Tau in subcortical regions showed significant negative correlation with perfusion in limbic cortex. Perfusion in frontal regions was negatively associated with tau in both subcortical regions, but the significance threshold was only passed for the dentate nucleus. A reason could be a diaschisis-like phenomenon; that is, subcortical tau could lead to reduced connectivity to frontal regions and, thereby, to decreased perfusion. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In progressive supranuclear palsy (PSP), subcortical tau and cortical perfusion can be assessed using the tracer 18</jsup>F]PI-2620. We investigated if subcortical tau (globus pallidus internus, dentate nucleus) and frontal/limbic perfusion correlate in a cohort of 32 PSP patients. Tau in subcortical regions showed significant negative correlation with perfusion in limbic cortex. Perfusion in frontal regions was negatively associated with tau in both subcortical regions, but the significance threshold was only passed for the dentate nucleus. A reason could be a diaschisis-like phenomenon; that is, subcortical tau could lead to reduced connectivity to frontal regions and, thereby, to decreased perfusion.
Asendorf, Adrian L.; Theis, Hendrik; Tittgemeyer, Marc; Timmermann, Lars; Fink, Gereon R.; Drzezga, Alexander; Eggers, Carsten; Ruppert‐Junck, Marina C.; Pedrosa, David J.; Hoenig, Merle C.; van Eimeren, Thilo
Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease Journal Article
In: Human Brain Mapping, vol. 45, no. 10, 2024, ISSN: 1097-0193.
@article{Asendorf2024,
title = {Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease},
author = {Adrian L. Asendorf and Hendrik Theis and Marc Tittgemeyer and Lars Timmermann and Gereon R. Fink and Alexander Drzezga and Carsten Eggers and Marina C. Ruppert‐Junck and David J. Pedrosa and Merle C. Hoenig and Thilo van Eimeren},
doi = {10.1002/hbm.26776},
issn = {1097-0193},
year = {2024},
date = {2024-07-15},
urldate = {2024-07-15},
journal = {Human Brain Mapping},
volume = {45},
number = {10},
publisher = {Wiley},
abstract = {<jats:title>Abstract</jats:title><jats:sec><jats:label/><jats:p>Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine‐related changes in large‐scale brain network dynamics and its implications in clinical features. We pooled data from two disease‐control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting‐state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single‐photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age‐ and sex‐matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age‐ and sex‐matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent <jats:sup>18</jats:sup>F‐DOPA‐positron emission tomography (PET) imaging. The striatal synthesis capacity of <jats:sup>18</jats:sup>F‐DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre‐processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k‐means clustering were conducted separately for each cohort to derive dFC states (reemerging intra‐ and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L‐dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large‐scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD.</jats:p></jats:sec><jats:sec><jats:title>Practitioner Points</jats:title><jats:p><jats:list list-type="bullet">
<jats:list-item><jats:p>Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD‐specific changes in dynamic functional connectivity.</jats:p></jats:list-item>
<jats:list-item><jats:p>Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state.</jats:p></jats:list-item>
<jats:list-item><jats:p>Results only in the PPMI cohort suggest striatal dopamine availability influences large‐scale network dynamics that are relevant in motor control.</jats:p></jats:list-item>
</jats:list></jats:p></jats:sec>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:title>Abstract</jats:title><jats:sec><jats:label/><jats:p>Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine‐related changes in large‐scale brain network dynamics and its implications in clinical features. We pooled data from two disease‐control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting‐state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single‐photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age‐ and sex‐matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age‐ and sex‐matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent <jats:sup>18</jats:sup>F‐DOPA‐positron emission tomography (PET) imaging. The striatal synthesis capacity of <jats:sup>18</jats:sup>F‐DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre‐processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k‐means clustering were conducted separately for each cohort to derive dFC states (reemerging intra‐ and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L‐dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large‐scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD.</jats:p></jats:sec><jats:sec><jats:title>Practitioner Points</jats:title><jats:p><jats:list list-type="bullet">
<jats:list-item><jats:p>Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD‐specific changes in dynamic functional connectivity.</jats:p></jats:list-item>
<jats:list-item><jats:p>Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state.</jats:p></jats:list-item>
<jats:list-item><jats:p>Results only in the PPMI cohort suggest striatal dopamine availability influences large‐scale network dynamics that are relevant in motor control.</jats:p></jats:list-item>
</jats:list></jats:p></jats:sec>
<jats:list-item><jats:p>Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD‐specific changes in dynamic functional connectivity.</jats:p></jats:list-item>
<jats:list-item><jats:p>Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state.</jats:p></jats:list-item>
<jats:list-item><jats:p>Results only in the PPMI cohort suggest striatal dopamine availability influences large‐scale network dynamics that are relevant in motor control.</jats:p></jats:list-item>
</jats:list></jats:p></jats:sec>
Asendorf, Adrian L; Theis, Hendrik; Tittgemeyer, Marc; Timmermann, Lars; Fink, Gereon R; Drzezga, Alexander; Eggers, Carsten; Ruppert-Junck, Marina C; Pedrosa, David J; Hoenig, Merle C; van Eimeren, Thilo
Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease Journal Article
In: Hum Brain Mapp, vol. 45, no. 10, pp. e26776, 2024, ISSN: 1097-0193.
@article{pmid38958131,
title = {Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease},
author = {Adrian L Asendorf and Hendrik Theis and Marc Tittgemeyer and Lars Timmermann and Gereon R Fink and Alexander Drzezga and Carsten Eggers and Marina C Ruppert-Junck and David J Pedrosa and Merle C Hoenig and Thilo van Eimeren},
doi = {10.1002/hbm.26776},
issn = {1097-0193},
year = {2024},
date = {2024-07-01},
journal = {Hum Brain Mapp},
volume = {45},
number = {10},
pages = {e26776},
abstract = {Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.
Giehl, Kathrin; Mutsaerts, Henk-Jan; Aarts, Kristien; Barkhof, Frederik; Caspers, Svenja; Chetelat, Gaël; Colin, Marie-Elisabeth; Düzel, Emrah; Frisoni, Giovanni B; Ikram, M Arfan; Jovicich, Jorge; Morbelli, Silvia; Oertel, Wolfgang; Paret, Christian; Perani, Daniela; Ritter, Petra; Segura, Bàrbara; Wisse, Laura E M; Witte, Elke De; Cappa, Stefano F; van Eimeren, Thilo
Sharing brain imaging data in the Open Science era: how and why? Journal Article
In: Lancet Digit Health, vol. 6, no. 7, pp. e526–e535, 2024, ISSN: 2589-7500.
@article{pmid38906618,
title = {Sharing brain imaging data in the Open Science era: how and why?},
author = {Kathrin Giehl and Henk-Jan Mutsaerts and Kristien Aarts and Frederik Barkhof and Svenja Caspers and Gaël Chetelat and Marie-Elisabeth Colin and Emrah Düzel and Giovanni B Frisoni and M Arfan Ikram and Jorge Jovicich and Silvia Morbelli and Wolfgang Oertel and Christian Paret and Daniela Perani and Petra Ritter and Bàrbara Segura and Laura E M Wisse and Elke De Witte and Stefano F Cappa and Thilo van Eimeren},
doi = {10.1016/S2589-7500(24)00069-4},
issn = {2589-7500},
year = {2024},
date = {2024-07-01},
journal = {Lancet Digit Health},
volume = {6},
number = {7},
pages = {e526--e535},
abstract = {The sharing of human neuroimaging data has great potential to accelerate the development of imaging biomarkers in neurological and psychiatric disorders; however, major obstacles remain in terms of how and why to share data in the Open Science context. In this Health Policy by the European Cluster for Imaging Biomarkers, we outline the current main opportunities and challenges based on the results of an online survey disseminated among senior scientists in the field. Although the scientific community fully recognises the importance of data sharing, technical, legal, and motivational aspects often prevent active adoption. Therefore, we provide practical advice on how to overcome the technical barriers. We also call for a harmonised application of the General Data Protection Regulation across EU countries. Finally, we suggest the development of a system that makes data count by recognising the generation and sharing of data as a highly valuable contribution to the community.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The sharing of human neuroimaging data has great potential to accelerate the development of imaging biomarkers in neurological and psychiatric disorders; however, major obstacles remain in terms of how and why to share data in the Open Science context. In this Health Policy by the European Cluster for Imaging Biomarkers, we outline the current main opportunities and challenges based on the results of an online survey disseminated among senior scientists in the field. Although the scientific community fully recognises the importance of data sharing, technical, legal, and motivational aspects often prevent active adoption. Therefore, we provide practical advice on how to overcome the technical barriers. We also call for a harmonised application of the General Data Protection Regulation across EU countries. Finally, we suggest the development of a system that makes data count by recognising the generation and sharing of data as a highly valuable contribution to the community.
Smith, Elke; Michalski, Simon; Knauth, Kilian; Tuzsus, Deniz; Theis, Hendrik; van Eimeren, Thilo; Peters, Jan
Pharmacological Enhancement of Dopamine Neurotransmission Does Not Affect Illusory Pattern Perception Journal Article
In: eNeuro, vol. 11, no. 7, 2024, ISSN: 2373-2822.
@article{pmid38997143,
title = {Pharmacological Enhancement of Dopamine Neurotransmission Does Not Affect Illusory Pattern Perception},
author = {Elke Smith and Simon Michalski and Kilian Knauth and Deniz Tuzsus and Hendrik Theis and Thilo van Eimeren and Jan Peters},
doi = {10.1523/ENEURO.0465-23.2024},
issn = {2373-2822},
year = {2024},
date = {2024-07-01},
journal = {eNeuro},
volume = {11},
number = {7},
abstract = {Psychotic symptoms and delusional beliefs have been linked to dopamine transmission in both healthy and clinical samples and are assumed to result at least in part from perceiving illusory patterns in noise. However, the existing literature on the role of dopamine in detecting patterns in noise is inconclusive. To address this issue, we assessed the effect of manipulating dopaminergic neurotransmission on illusory pattern perception in healthy individuals (= 48, = 19 female) in a double-blind placebo-controlled within-subjects design (see preregistration at https://osf.io/a4k9j/). We predicted individuals on versus off ʟ-DOPA to be more likely to perceive illusory patterns, specifically objects in images containing only noise. Using a signal detection model, however, we found no credible evidence that ʟ-DOPA compared with placebo increased false alarm rates. Further, ʟ-DOPA did not reliably modulate measures of accuracy, discrimination sensitivity, and response bias. In all cases, Bayesian statistics revealed strong evidence in favor of the null hypothesis. The task design followed previous work on illusory pattern perception and comprised a limited number of items per condition. The results therefore need to be interpreted with caution, as power was limited. Future studies should address illusory pattern perception using more items and take into account potential dose-dependent effects and differential effects in healthy versus clinical samples.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Psychotic symptoms and delusional beliefs have been linked to dopamine transmission in both healthy and clinical samples and are assumed to result at least in part from perceiving illusory patterns in noise. However, the existing literature on the role of dopamine in detecting patterns in noise is inconclusive. To address this issue, we assessed the effect of manipulating dopaminergic neurotransmission on illusory pattern perception in healthy individuals (= 48, = 19 female) in a double-blind placebo-controlled within-subjects design (see preregistration at https://osf.io/a4k9j/). We predicted individuals on versus off ʟ-DOPA to be more likely to perceive illusory patterns, specifically objects in images containing only noise. Using a signal detection model, however, we found no credible evidence that ʟ-DOPA compared with placebo increased false alarm rates. Further, ʟ-DOPA did not reliably modulate measures of accuracy, discrimination sensitivity, and response bias. In all cases, Bayesian statistics revealed strong evidence in favor of the null hypothesis. The task design followed previous work on illusory pattern perception and comprised a limited number of items per condition. The results therefore need to be interpreted with caution, as power was limited. Future studies should address illusory pattern perception using more items and take into account potential dose-dependent effects and differential effects in healthy versus clinical samples.
Smith, Elke; Michalski, Simon; Knauth, Kilian; Tuzsus, Deniz; Theis, Hendrik; van Eimeren, Thilo; Peters, Jan
Pharmacological Enhancement of Dopamine Neurotransmission Does Not Affect Illusory Pattern Perception Journal Article
In: eNeuro, vol. 11, no. 7, pp. ENEURO.0465–23.2024, 2024, ISSN: 2373-2822.
@article{Smith2024,
title = {Pharmacological Enhancement of Dopamine Neurotransmission Does Not Affect Illusory Pattern Perception},
author = {Elke Smith and Simon Michalski and Kilian Knauth and Deniz Tuzsus and Hendrik Theis and Thilo van Eimeren and Jan Peters},
doi = {10.1523/eneuro.0465-23.2024},
issn = {2373-2822},
year = {2024},
date = {2024-07-00},
urldate = {2024-07-00},
journal = {eNeuro},
volume = {11},
number = {7},
pages = {ENEURO.0465--23.2024},
publisher = {Society for Neuroscience},
abstract = {<jats:p>Psychotic symptoms and delusional beliefs have been linked to dopamine transmission in both healthy and clinical samples and are assumed to result at least in part from perceiving illusory patterns in noise. However, the existing literature on the role of dopamine in detecting patterns in noise is inconclusive. To address this issue, we assessed the effect of manipulating dopaminergic neurotransmission on illusory pattern perception in healthy individuals (<italic>n </italic>= 48,<italic>n </italic>= 19 female) in a double-blind placebo-controlled within-subjects design. We predicted individuals on versus off ʟ-DOPA to be more likely to perceive illusory patterns, specifically objects in images containing only noise. Using a signal detection model, however, we found no credible evidence that ʟ-DOPA compared with placebo increased false alarm rates. Further, ʟ-DOPA did not reliably modulate measures of accuracy, discrimination sensitivity, and response bias. In all cases, Bayesian statistics revealed strong evidence in favor of the null hypothesis. The task design followed previous work on illusory pattern perception and comprised a limited number of items per condition. The results therefore need to be interpreted with caution, as power was limited. Future studies should address illusory pattern perception using more items and take into account potential dose-dependent effects and differential effects in healthy versus clinical samples.</jats:p>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:p>Psychotic symptoms and delusional beliefs have been linked to dopamine transmission in both healthy and clinical samples and are assumed to result at least in part from perceiving illusory patterns in noise. However, the existing literature on the role of dopamine in detecting patterns in noise is inconclusive. To address this issue, we assessed the effect of manipulating dopaminergic neurotransmission on illusory pattern perception in healthy individuals (<italic>n </italic>= 48,<italic>n </italic>= 19 female) in a double-blind placebo-controlled within-subjects design. We predicted individuals on versus off ʟ-DOPA to be more likely to perceive illusory patterns, specifically objects in images containing only noise. Using a signal detection model, however, we found no credible evidence that ʟ-DOPA compared with placebo increased false alarm rates. Further, ʟ-DOPA did not reliably modulate measures of accuracy, discrimination sensitivity, and response bias. In all cases, Bayesian statistics revealed strong evidence in favor of the null hypothesis. The task design followed previous work on illusory pattern perception and comprised a limited number of items per condition. The results therefore need to be interpreted with caution, as power was limited. Future studies should address illusory pattern perception using more items and take into account potential dose-dependent effects and differential effects in healthy versus clinical samples.</jats:p>
Giehl, Kathrin; Mutsaerts, Henk-Jan; Aarts, Kristien; Barkhof, Frederik; Caspers, Svenja; Chetelat, Gaël; Colin, Marie-Elisabeth; Düzel, Emrah; Frisoni, Giovanni B; Ikram, M Arfan; Jovicich, Jorge; Morbelli, Silvia; Oertel, Wolfgang; Paret, Christian; Perani, Daniela; Ritter, Petra; Segura, Bàrbara; Wisse, Laura E M; Witte, Elke De; Cappa, Stefano F; van Eimeren, Thilo
Sharing brain imaging data in the Open Science era: how and why? Journal Article
In: The Lancet Digital Health, vol. 6, no. 7, pp. e526–e535, 2024, ISSN: 2589-7500.
@article{Giehl2024,
title = {Sharing brain imaging data in the Open Science era: how and why?},
author = {Kathrin Giehl and Henk-Jan Mutsaerts and Kristien Aarts and Frederik Barkhof and Svenja Caspers and Gaël Chetelat and Marie-Elisabeth Colin and Emrah Düzel and Giovanni B Frisoni and M Arfan Ikram and Jorge Jovicich and Silvia Morbelli and Wolfgang Oertel and Christian Paret and Daniela Perani and Petra Ritter and Bàrbara Segura and Laura E M Wisse and Elke De Witte and Stefano F Cappa and Thilo van Eimeren},
doi = {10.1016/s2589-7500(24)00069-4},
issn = {2589-7500},
year = {2024},
date = {2024-07-00},
urldate = {2024-07-00},
journal = {The Lancet Digital Health},
volume = {6},
number = {7},
pages = {e526--e535},
publisher = {Elsevier BV},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Bischof, Gérard N; Brendel, Matthias; Barthel, Henryk; Theis, Hendrik; Barbe, Michael; Bartenstein, Peter; Claasen, Joseph; Danek, Adrian; Höglinger, Günter; Levin, Johannes; Marek, Ken; Neumaier, Bernd; Palleis, Carla; Patt, Marianne; Rullmann, Michael; Saur, Dorothee; Schroeter, Matthias L; Seibyl, John; Song, Mengmeng; Stephens, Andrew; Sabri, Osama; Drzezga, Alexander; van Eimeren and, Thilo
Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [F]PI-2620 Journal Article
In: J Nucl Med, vol. 65, no. 6, pp. 952–955, 2024, ISSN: 1535-5667.
@article{pmid38575191,
title = {Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [F]PI-2620},
author = {Gérard N Bischof and Matthias Brendel and Henryk Barthel and Hendrik Theis and Michael Barbe and Peter Bartenstein and Joseph Claasen and Adrian Danek and Günter Höglinger and Johannes Levin and Ken Marek and Bernd Neumaier and Carla Palleis and Marianne Patt and Michael Rullmann and Dorothee Saur and Matthias L Schroeter and John Seibyl and Mengmeng Song and Andrew Stephens and Osama Sabri and Alexander Drzezga and Thilo van Eimeren and },
doi = {10.2967/jnumed.123.265930},
issn = {1535-5667},
year = {2024},
date = {2024-06-01},
journal = {J Nucl Med},
volume = {65},
number = {6},
pages = {952--955},
abstract = {We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers.
Bischof, Gérard N.; Brendel, Matthias; Barthel, Henryk; Theis, Hendrik; Barbe, Michael; Bartenstein, Peter; Claasen, Joseph; Danek, Adrian; Höglinger, Günter; Levin, Johannes; Marek, Ken; Neumaier, Bernd; Palleis, Carla; Patt, Marianne; Rullmann, Michael; Saur, Dorothee; Schroeter, Matthias L.; Seibyl, John; Song, Mengmeng; Stephens, Andrew; Sabri, Osama; Drzezga, Alexander; van Eimeren, Thilo
Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [18F]PI-2620 Journal Article
In: J Nucl Med, vol. 65, no. 6, pp. 952–955, 2024, ISSN: 2159-662X.
@article{Bischof2024,
title = {Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [^{18}F]PI-2620},
author = {Gérard N. Bischof and Matthias Brendel and Henryk Barthel and Hendrik Theis and Michael Barbe and Peter Bartenstein and Joseph Claasen and Adrian Danek and Günter Höglinger and Johannes Levin and Ken Marek and Bernd Neumaier and Carla Palleis and Marianne Patt and Michael Rullmann and Dorothee Saur and Matthias L. Schroeter and John Seibyl and Mengmeng Song and Andrew Stephens and Osama Sabri and Alexander Drzezga and Thilo van Eimeren},
doi = {10.2967/jnumed.123.265930},
issn = {2159-662X},
year = {2024},
date = {2024-06-00},
urldate = {2024-06-00},
journal = {J Nucl Med},
volume = {65},
number = {6},
pages = {952--955},
publisher = {Society of Nuclear Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Langerscheidt, Felix; Wied, Tamara; Kabbani, Mohamed Aghyad Al; van Eimeren, Thilo; Wunderlich, Gilbert; Zempel, Hans
Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies Journal Article
In: J Neurol, vol. 271, no. 6, pp. 2992–3018, 2024, ISSN: 1432-1459.
@article{Langerscheidt2024,
title = {Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies},
author = {Felix Langerscheidt and Tamara Wied and Mohamed Aghyad Al Kabbani and Thilo van Eimeren and Gilbert Wunderlich and Hans Zempel},
doi = {10.1007/s00415-024-12314-3},
issn = {1432-1459},
year = {2024},
date = {2024-06-00},
urldate = {2024-06-00},
journal = {J Neurol},
volume = {271},
number = {6},
pages = {2992--3018},
publisher = {Springer Science and Business Media LLC},
abstract = {<jats:title>Abstract</jats:title><jats:p>Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation of the microtubule-associated protein TAU, encoded by the gene <jats:italic>MAPT</jats:italic>. Neuronal dysfunction, dementia, and neurodegeneration are common features of these often detrimental diseases. A neurodegenerative disease is considered a primary tauopathy when <jats:italic>MAPT</jats:italic> mutations/haplotypes are its primary cause and/or TAU is the main pathological feature. In case TAU pathology is observed but superimposed by another pathological hallmark, the condition is classified as a secondary tauopathy. In some tauopathies (e.g. <jats:italic>MAPT</jats:italic>-associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease (AD)) TAU is recognized as a significant pathogenic driver of the disease. In many secondary tauopathies, including Parkinson's disease (PD) and Huntington's disease (HD), TAU is suggested to contribute to the development of dementia, but in others (e.g. Niemann-Pick disease (NPC)) TAU may only be a bystander. The genetic and pathological mechanisms underlying TAU pathology are often not fully understood. In this review, the genetic predispositions and variants associated with both primary and secondary tauopathies are examined in detail, assessing evidence for the role of TAU in these conditions. We highlight less common genetic forms of tauopathies to increase awareness for these disorders and the involvement of TAU in their pathology. This approach not only contributes to a deeper understanding of these conditions but may also lay the groundwork for potential TAU-based therapeutic interventions for various tauopathies.</jats:p>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:title>Abstract</jats:title><jats:p>Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation of the microtubule-associated protein TAU, encoded by the gene <jats:italic>MAPT</jats:italic>. Neuronal dysfunction, dementia, and neurodegeneration are common features of these often detrimental diseases. A neurodegenerative disease is considered a primary tauopathy when <jats:italic>MAPT</jats:italic> mutations/haplotypes are its primary cause and/or TAU is the main pathological feature. In case TAU pathology is observed but superimposed by another pathological hallmark, the condition is classified as a secondary tauopathy. In some tauopathies (e.g. <jats:italic>MAPT</jats:italic>-associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease (AD)) TAU is recognized as a significant pathogenic driver of the disease. In many secondary tauopathies, including Parkinson's disease (PD) and Huntington's disease (HD), TAU is suggested to contribute to the development of dementia, but in others (e.g. Niemann-Pick disease (NPC)) TAU may only be a bystander. The genetic and pathological mechanisms underlying TAU pathology are often not fully understood. In this review, the genetic predispositions and variants associated with both primary and secondary tauopathies are examined in detail, assessing evidence for the role of TAU in these conditions. We highlight less common genetic forms of tauopathies to increase awareness for these disorders and the involvement of TAU in their pathology. This approach not only contributes to a deeper understanding of these conditions but may also lay the groundwork for potential TAU-based therapeutic interventions for various tauopathies.</jats:p>
Dzialas, Verena; Hoenig, Merle C; Prange, Stéphane; Bischof, Gérard N; ; Drzezga, Alexander; van Eimeren, Thilo
Structural underpinnings and long-term effects of resilience in Parkinson's disease Journal Article
In: NPJ Parkinsons Dis, vol. 10, no. 1, pp. 94, 2024, ISSN: 2373-8057.
@article{pmid38697984,
title = {Structural underpinnings and long-term effects of resilience in Parkinson's disease},
author = {Verena Dzialas and Merle C Hoenig and Stéphane Prange and Gérard N Bischof and and Alexander Drzezga and Thilo van Eimeren},
doi = {10.1038/s41531-024-00699-x},
issn = {2373-8057},
year = {2024},
date = {2024-05-01},
journal = {NPJ Parkinsons Dis},
volume = {10},
number = {1},
pages = {94},
abstract = {Resilience in neuroscience generally refers to an individual's capacity to counteract the adverse effects of a neuropathological condition. While resilience mechanisms in Alzheimer's disease are well-investigated, knowledge regarding its quantification, neurobiological underpinnings, network adaptations, and long-term effects in Parkinson's disease is limited. Our study involved 151 Parkinson's patients from the Parkinson's Progression Marker Initiative Database with available Magnetic Resonance Imaging, Dopamine Transporter Single-Photon Emission Computed Tomography scans, and clinical information. We used an improved prediction model linking neuropathology to symptom severity to estimate individual resilience levels. Higher resilience levels were associated with a more active lifestyle, increased grey matter volume in motor-associated regions, a distinct structural connectivity network and maintenance of relative motor functioning for up to a decade. Overall, the results indicate that relative maintenance of motor function in Parkinson's patients may be associated with greater neuronal substrate, allowing higher tolerance against neurodegenerative processes through dynamic network restructuring.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Resilience in neuroscience generally refers to an individual's capacity to counteract the adverse effects of a neuropathological condition. While resilience mechanisms in Alzheimer's disease are well-investigated, knowledge regarding its quantification, neurobiological underpinnings, network adaptations, and long-term effects in Parkinson's disease is limited. Our study involved 151 Parkinson's patients from the Parkinson's Progression Marker Initiative Database with available Magnetic Resonance Imaging, Dopamine Transporter Single-Photon Emission Computed Tomography scans, and clinical information. We used an improved prediction model linking neuropathology to symptom severity to estimate individual resilience levels. Higher resilience levels were associated with a more active lifestyle, increased grey matter volume in motor-associated regions, a distinct structural connectivity network and maintenance of relative motor functioning for up to a decade. Overall, the results indicate that relative maintenance of motor function in Parkinson's patients may be associated with greater neuronal substrate, allowing higher tolerance against neurodegenerative processes through dynamic network restructuring.
Oltra, Javier; Segura, Barbara; Strafella, Antonio P; van Eimeren, Thilo; Ibarretxe-Bilbao, Naroa; Diez-Cirarda, Maria; Eggers, Carsten; Lucas-Jiménez, Olaia; Monté-Rubio, Gemma C; Ojeda, Natalia; Peña, Javier; Ruppert, Marina C; Sala-Llonch, Roser; Theis, Hendrik; Uribe, Carme; Junque, Carme
A multi-site study on sex differences in cortical thickness in non-demented Parkinson's disease Journal Article
In: NPJ Parkinsons Dis, vol. 10, no. 1, pp. 69, 2024, ISSN: 2373-8057.
@article{pmid38521776,
title = {A multi-site study on sex differences in cortical thickness in non-demented Parkinson's disease},
author = {Javier Oltra and Barbara Segura and Antonio P Strafella and Thilo van Eimeren and Naroa Ibarretxe-Bilbao and Maria Diez-Cirarda and Carsten Eggers and Olaia Lucas-Jiménez and Gemma C Monté-Rubio and Natalia Ojeda and Javier Peña and Marina C Ruppert and Roser Sala-Llonch and Hendrik Theis and Carme Uribe and Carme Junque},
doi = {10.1038/s41531-024-00686-2},
issn = {2373-8057},
year = {2024},
date = {2024-03-01},
journal = {NPJ Parkinsons Dis},
volume = {10},
number = {1},
pages = {69},
abstract = {Clinical, cognitive, and atrophy characteristics depending on sex have been previously reported in Parkinson's disease (PD). However, though sex differences in cortical gray matter measures in early drug naïve patients have been described, little is known about differences in cortical thickness (CTh) as the disease advances. Our multi-site sample comprised 211 non-demented PD patients (64.45% males; mean age 65.58 ± 8.44 years old; mean disease duration 6.42 ± 5.11 years) and 86 healthy controls (50% males; mean age 65.49 ± 9.33 years old) with available T1-weighted 3 T MRI data from four international research centers. Sex differences in regional mean CTh estimations were analyzed using generalized linear models. The relation of CTh in regions showing sex differences with age, disease duration, and age of onset was examined through multiple linear regression. PD males showed thinner cortex than PD females in six frontal (bilateral caudal middle frontal, bilateral superior frontal, left precentral and right pars orbitalis), three parietal (bilateral inferior parietal and left supramarginal), and one limbic region (right posterior cingulate). In PD males, lower CTh values in nine out of ten regions were associated with longer disease duration and older age, whereas in PD females, lower CTh was associated with older age but with longer disease duration only in one region. Overall, male patients show a more widespread pattern of reduced CTh compared with female patients. Disease duration seems more relevant to explain reduced CTh in male patients, suggesting worse prognostic over time. Further studies should explore sex-specific cortical atrophy trajectories using large longitudinal multi-site data.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Clinical, cognitive, and atrophy characteristics depending on sex have been previously reported in Parkinson's disease (PD). However, though sex differences in cortical gray matter measures in early drug naïve patients have been described, little is known about differences in cortical thickness (CTh) as the disease advances. Our multi-site sample comprised 211 non-demented PD patients (64.45% males; mean age 65.58 ± 8.44 years old; mean disease duration 6.42 ± 5.11 years) and 86 healthy controls (50% males; mean age 65.49 ± 9.33 years old) with available T1-weighted 3 T MRI data from four international research centers. Sex differences in regional mean CTh estimations were analyzed using generalized linear models. The relation of CTh in regions showing sex differences with age, disease duration, and age of onset was examined through multiple linear regression. PD males showed thinner cortex than PD females in six frontal (bilateral caudal middle frontal, bilateral superior frontal, left precentral and right pars orbitalis), three parietal (bilateral inferior parietal and left supramarginal), and one limbic region (right posterior cingulate). In PD males, lower CTh values in nine out of ten regions were associated with longer disease duration and older age, whereas in PD females, lower CTh was associated with older age but with longer disease duration only in one region. Overall, male patients show a more widespread pattern of reduced CTh compared with female patients. Disease duration seems more relevant to explain reduced CTh in male patients, suggesting worse prognostic over time. Further studies should explore sex-specific cortical atrophy trajectories using large longitudinal multi-site data.
Giehl, Kathrin; Theis, Hendrik; Ophey, Anja; Hammes, Jochen; Reker, Paul; Eggers, Carsten; Fink, Gereon R.; Kalbe, Elke; van Eimeren, Thilo
Working Memory Training Responsiveness in Parkinson’s Disease Is Not Determined by Cortical Thickness or White Matter Lesions Journal Article
In: Journal of Parkinson’s Disease, vol. 14, no. 2, pp. 347–351, 2024, ISSN: 1877-718X.
@article{Giehl2024b,
title = {Working Memory Training Responsiveness in Parkinson’s Disease Is Not Determined by Cortical Thickness or White Matter Lesions},
author = {Kathrin Giehl and Hendrik Theis and Anja Ophey and Jochen Hammes and Paul Reker and Carsten Eggers and Gereon R. Fink and Elke Kalbe and Thilo van Eimeren},
doi = {10.3233/jpd-230367},
issn = {1877-718X},
year = {2024},
date = {2024-02-03},
urldate = {2024-02-03},
journal = {Journal of Parkinson’s Disease},
volume = {14},
number = {2},
pages = {347--351},
publisher = {SAGE Publications},
abstract = {<jats:p> Patients with Parkinson’s disease are highly vulnerable for cognitive decline. Thus, early intervention by means of working memory training (WMT) may be effective for the preservation of cognition. However, the influence of structural brain properties, i.e., cortical thickness and volume of white matter lesions on training responsiveness have not been studied. Here, behavioral and neuroimaging data of 46 patients with Parkinson’s disease, 21 of whom engaged in home-based, computerized adaptive WMT, was analyzed. While cortical thickness and white matter lesions volume were associated with cognitive performance at baseline, these structural brain properties do not seem to determine WMT responsiveness. </jats:p>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:p> Patients with Parkinson’s disease are highly vulnerable for cognitive decline. Thus, early intervention by means of working memory training (WMT) may be effective for the preservation of cognition. However, the influence of structural brain properties, i.e., cortical thickness and volume of white matter lesions on training responsiveness have not been studied. Here, behavioral and neuroimaging data of 46 patients with Parkinson’s disease, 21 of whom engaged in home-based, computerized adaptive WMT, was analyzed. While cortical thickness and white matter lesions volume were associated with cognitive performance at baseline, these structural brain properties do not seem to determine WMT responsiveness. </jats:p>
Theis, Hendrik; Pavese, Nicola; Rektorová, Irena; van Eimeren, Thilo
Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson's Disease Journal Article
In: J Parkinsons Dis, vol. 14, no. s2, pp. S353–S365, 2024, ISSN: 1877-718X.
@article{pmid38339941,
title = {Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson's Disease},
author = {Hendrik Theis and Nicola Pavese and Irena Rektorová and Thilo van Eimeren},
doi = {10.3233/JPD-230385},
issn = {1877-718X},
year = {2024},
date = {2024-01-01},
journal = {J Parkinsons Dis},
volume = {14},
number = {s2},
pages = {S353--S365},
abstract = {Assessing imaging biomarker in the prodromal and early phases of Parkinson's disease (PD) is of great importance to ensure an early and safe diagnosis. In the last decades, imaging modalities advanced and are now able to assess many different aspects of neurodegeneration in PD. MRI sequences can measure iron content or neuromelanin. Apart from SPECT imaging with Ioflupane, more specific PET tracers to assess degeneration of the dopaminergic system are available. Furthermore, metabolic PET patterns can be used to anticipate a phenoconversion from prodromal PD to manifest PD. In this regard, it is worth mentioning that PET imaging of inflammation will gain significance. Molecular imaging of neurotransmitters like serotonin, noradrenaline and acetylcholine shed more light on non-motor symptoms. Outside of the brain, molecular imaging of the heart and gut is used to measure PD-related degeneration of the autonomous nervous system. Moreover, optical coherence tomography can noninvasively detect degeneration of retinal fibers as a potential biomarker in PD. In this review, we describe these state-of-the-art imaging modalities in early and prodromal PD and point out in how far these techniques can and will be used in the future to pave the way towards a biomarker-based staging of PD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Assessing imaging biomarker in the prodromal and early phases of Parkinson's disease (PD) is of great importance to ensure an early and safe diagnosis. In the last decades, imaging modalities advanced and are now able to assess many different aspects of neurodegeneration in PD. MRI sequences can measure iron content or neuromelanin. Apart from SPECT imaging with Ioflupane, more specific PET tracers to assess degeneration of the dopaminergic system are available. Furthermore, metabolic PET patterns can be used to anticipate a phenoconversion from prodromal PD to manifest PD. In this regard, it is worth mentioning that PET imaging of inflammation will gain significance. Molecular imaging of neurotransmitters like serotonin, noradrenaline and acetylcholine shed more light on non-motor symptoms. Outside of the brain, molecular imaging of the heart and gut is used to measure PD-related degeneration of the autonomous nervous system. Moreover, optical coherence tomography can noninvasively detect degeneration of retinal fibers as a potential biomarker in PD. In this review, we describe these state-of-the-art imaging modalities in early and prodromal PD and point out in how far these techniques can and will be used in the future to pave the way towards a biomarker-based staging of PD.
Doering, Elena; Antonopoulos, Georgios; Hoenig, Merle; van Eimeren, Thilo; Daamen, Marcel; Boecker, Henning; Jessen, Frank; Düzel, Emrah; Eickhoff, Simon; Patil, Kaustubh; and, Alexander Drzezga
MRI or F-FDG PET for Brain Age Gap Estimation: Links to Cognition, Pathology, and Alzheimer Disease Progression Journal Article
In: J Nucl Med, vol. 65, no. 1, pp. 147–155, 2024, ISSN: 1535-5667.
@article{pmid38050112,
title = {MRI or F-FDG PET for Brain Age Gap Estimation: Links to Cognition, Pathology, and Alzheimer Disease Progression},
author = {Elena Doering and Georgios Antonopoulos and Merle Hoenig and Thilo van Eimeren and Marcel Daamen and Henning Boecker and Frank Jessen and Emrah Düzel and Simon Eickhoff and Kaustubh Patil and Alexander Drzezga and },
doi = {10.2967/jnumed.123.265931},
issn = {1535-5667},
year = {2024},
date = {2024-01-01},
journal = {J Nucl Med},
volume = {65},
number = {1},
pages = {147--155},
abstract = {Deviations of brain age from chronologic age, known as the brain age gap (BAG), have been linked to neurodegenerative diseases such as Alzheimer disease (AD). Here, we compare the associations of MRI-derived (atrophy) or F-FDG PET-derived (brain metabolism) BAG with cognitive performance, neuropathologic burden, and disease progression in cognitively normal individuals (CNs) and individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Machine learning pipelines were trained to estimate brain age from 185 matched T1-weighted MRI or F-FDG PET scans of CN from the Alzheimer's Disease Neuroimaging Initiative and validated in external test sets from the Open Access of Imaging and German Center for Neurodegenerative Diseases-Longitudinal Cognitive Impairment and Dementia studies. BAG was correlated with measures of cognitive performance and AD neuropathology in CNs, SCD subjects, and MCI subjects. Finally, BAG was compared between cognitively stable and declining individuals and subsequently used to predict disease progression. MRI (mean absolute error, 2.49 y) and F-FDG PET (mean absolute error, 2.60 y) both estimated chronologic age well. At the SCD stage, MRI-based BAG correlated significantly with beta-amyloid (Aβ) in cerebrospinal fluid, whereas F-FDG PET BAG correlated with memory performance. At the MCI stage, both BAGs were associated with memory and executive function performance and cerebrospinal fluid Aβ, but only MRI-derived BAG correlated with phosphorylated-tau/Aβ Lastly, MRI-estimated BAG predicted MCI-to-AD progression better than F-FDG PET-estimated BAG (areas under the curve, 0.73 and 0.60, respectively). Age was reliably estimated from MRI or F-FDG PET. MRI BAG reflected cognitive and pathologic markers of AD in SCD and MCI, whereas F-FDG PET BAG was sensitive mainly to early cognitive impairment, possibly constituting an independent biomarker of brain age-related changes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Deviations of brain age from chronologic age, known as the brain age gap (BAG), have been linked to neurodegenerative diseases such as Alzheimer disease (AD). Here, we compare the associations of MRI-derived (atrophy) or F-FDG PET-derived (brain metabolism) BAG with cognitive performance, neuropathologic burden, and disease progression in cognitively normal individuals (CNs) and individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Machine learning pipelines were trained to estimate brain age from 185 matched T1-weighted MRI or F-FDG PET scans of CN from the Alzheimer's Disease Neuroimaging Initiative and validated in external test sets from the Open Access of Imaging and German Center for Neurodegenerative Diseases-Longitudinal Cognitive Impairment and Dementia studies. BAG was correlated with measures of cognitive performance and AD neuropathology in CNs, SCD subjects, and MCI subjects. Finally, BAG was compared between cognitively stable and declining individuals and subsequently used to predict disease progression. MRI (mean absolute error, 2.49 y) and F-FDG PET (mean absolute error, 2.60 y) both estimated chronologic age well. At the SCD stage, MRI-based BAG correlated significantly with beta-amyloid (Aβ) in cerebrospinal fluid, whereas F-FDG PET BAG correlated with memory performance. At the MCI stage, both BAGs were associated with memory and executive function performance and cerebrospinal fluid Aβ, but only MRI-derived BAG correlated with phosphorylated-tau/Aβ Lastly, MRI-estimated BAG predicted MCI-to-AD progression better than F-FDG PET-estimated BAG (areas under the curve, 0.73 and 0.60, respectively). Age was reliably estimated from MRI or F-FDG PET. MRI BAG reflected cognitive and pathologic markers of AD in SCD and MCI, whereas F-FDG PET BAG was sensitive mainly to early cognitive impairment, possibly constituting an independent biomarker of brain age-related changes.
Theis, Hendrik; Barbe, Michael T; Drzezga, Alexander; Fink, Gereon R; Neumaier, Bernd; Bischof, Gérard N; van Eimeren, Thilo
Progressive Supranuclear Palsy: Subcortical Tau Depositions Are Associated with Cortical Perfusion in Frontal and Limbic Regions Journal Article
In: J Parkinsons Dis, vol. 14, no. 6, pp. 1271–1276, 2024, ISSN: 1877-718X.
@article{pmid38995804,
title = {Progressive Supranuclear Palsy: Subcortical Tau Depositions Are Associated with Cortical Perfusion in Frontal and Limbic Regions},
author = {Hendrik Theis and Michael T Barbe and Alexander Drzezga and Gereon R Fink and Bernd Neumaier and Gérard N Bischof and Thilo van Eimeren},
doi = {10.3233/JPD-240210},
issn = {1877-718X},
year = {2024},
date = {2024-01-01},
journal = {J Parkinsons Dis},
volume = {14},
number = {6},
pages = {1271--1276},
abstract = {In progressive supranuclear palsy (PSP), subcortical tau and cortical perfusion can be assessed using the tracer [18F]PI-2620. We investigated if subcortical tau (globus pallidus internus, dentate nucleus) and frontal/limbic perfusion correlate in a cohort of 32 PSP patients. Tau in subcortical regions showed significant negative correlation with perfusion in limbic cortex. Perfusion in frontal regions was negatively associated with tau in both subcortical regions, but the significance threshold was only passed for the dentate nucleus. A reason could be a diaschisis-like phenomenon; that is, subcortical tau could lead to reduced connectivity to frontal regions and, thereby, to decreased perfusion.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In progressive supranuclear palsy (PSP), subcortical tau and cortical perfusion can be assessed using the tracer [18F]PI-2620. We investigated if subcortical tau (globus pallidus internus, dentate nucleus) and frontal/limbic perfusion correlate in a cohort of 32 PSP patients. Tau in subcortical regions showed significant negative correlation with perfusion in limbic cortex. Perfusion in frontal regions was negatively associated with tau in both subcortical regions, but the significance threshold was only passed for the dentate nucleus. A reason could be a diaschisis-like phenomenon; that is, subcortical tau could lead to reduced connectivity to frontal regions and, thereby, to decreased perfusion.
Giehl, Kathrin; Theis, Hendrik; Ophey, Anja; Hammes, Jochen; Reker, Paul; Eggers, Carsten; Fink, Gereon R; Kalbe, Elke; van Eimeren, Thilo
Working Memory Training Responsiveness in Parkinson's Disease Is Not Determined by Cortical Thickness or White Matter Lesions Journal Article
In: J Parkinsons Dis, vol. 14, no. 2, pp. 347–351, 2024, ISSN: 1877-718X.
@article{pmid38277302,
title = {Working Memory Training Responsiveness in Parkinson's Disease Is Not Determined by Cortical Thickness or White Matter Lesions},
author = {Kathrin Giehl and Hendrik Theis and Anja Ophey and Jochen Hammes and Paul Reker and Carsten Eggers and Gereon R Fink and Elke Kalbe and Thilo van Eimeren},
doi = {10.3233/JPD-230367},
issn = {1877-718X},
year = {2024},
date = {2024-01-01},
journal = {J Parkinsons Dis},
volume = {14},
number = {2},
pages = {347--351},
abstract = {Patients with Parkinson's disease are highly vulnerable for cognitive decline. Thus, early intervention by means of working memory training (WMT) may be effective for the preservation of cognition. However, the influence of structural brain properties, i.e., cortical thickness and volume of white matter lesions on training responsiveness have not been studied. Here, behavioral and neuroimaging data of 46 patients with Parkinson's disease, 21 of whom engaged in home-based, computerized adaptive WMT, was analyzed. While cortical thickness and white matter lesions volume were associated with cognitive performance at baseline, these structural brain properties do not seem to determine WMT responsiveness.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Patients with Parkinson's disease are highly vulnerable for cognitive decline. Thus, early intervention by means of working memory training (WMT) may be effective for the preservation of cognition. However, the influence of structural brain properties, i.e., cortical thickness and volume of white matter lesions on training responsiveness have not been studied. Here, behavioral and neuroimaging data of 46 patients with Parkinson's disease, 21 of whom engaged in home-based, computerized adaptive WMT, was analyzed. While cortical thickness and white matter lesions volume were associated with cognitive performance at baseline, these structural brain properties do not seem to determine WMT responsiveness.
Doering, Elena; Antonopoulos, Georgios; Hoenig, Merle; van Eimeren, Thilo; Daamen, Marcel; Boecker, Henning; Jessen, Frank; Düzel, Emrah; Eickhoff, Simon; Patil, Kaustubh; Drzezga, Alexander
MRI or18F-FDG PET for Brain Age Gap Estimation: Links to Cognition, Pathology, and Alzheimer Disease Progression Journal Article
In: J Nucl Med, vol. 65, no. 1, pp. 147–155, 2024, ISSN: 2159-662X.
@article{Doering2023,
title = {MRI or^{18}F-FDG PET for Brain Age Gap Estimation: Links to Cognition, Pathology, and Alzheimer Disease Progression},
author = {Elena Doering and Georgios Antonopoulos and Merle Hoenig and Thilo van Eimeren and Marcel Daamen and Henning Boecker and Frank Jessen and Emrah Düzel and Simon Eickhoff and Kaustubh Patil and Alexander Drzezga},
doi = {10.2967/jnumed.123.265931},
issn = {2159-662X},
year = {2024},
date = {2024-01-00},
urldate = {2024-01-00},
journal = {J Nucl Med},
volume = {65},
number = {1},
pages = {147--155},
publisher = {Society of Nuclear Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2023
Theis, Hendrik; Prange, Stéphane; Bischof, Gérard N.; Hoenig, Merle C.; Tittgemeyer, Marc; Timmermann, Lars; Fink, Gereon R.; Drzezga, Alexander; Eggers, Carsten; van Eimeren, Thilo
Impulsive-compulsive behaviour in early Parkinson’s disease is determined by apathy and dopamine receptor D3 polymorphism Journal Article
In: npj Parkinsons Dis., vol. 9, no. 1, 2023, ISSN: 2373-8057.
@article{Theis2023,
title = {Impulsive-compulsive behaviour in early Parkinson’s disease is determined by apathy and dopamine receptor D3 polymorphism},
author = {Hendrik Theis and Stéphane Prange and Gérard N. Bischof and Merle C. Hoenig and Marc Tittgemeyer and Lars Timmermann and Gereon R. Fink and Alexander Drzezga and Carsten Eggers and Thilo van Eimeren},
doi = {10.1038/s41531-023-00596-9},
issn = {2373-8057},
year = {2023},
date = {2023-12-00},
urldate = {2023-12-00},
journal = {npj Parkinsons Dis.},
volume = {9},
number = {1},
publisher = {Springer Science and Business Media LLC},
abstract = {<jats:title>Abstract</jats:title><jats:p>Impulsive-compulsive behaviour (ICB) is a frequently observed non-motor symptom in early Parkinson’s disease after initiating dopamine replacement therapy. At the opposite end of the motivated behaviour spectrum, apathy occurs in early Parkinson’s disease even before dopamine replacement is started. The co-occurrence of these behavioural conditions in Parkinson’s disease raises questions about their relationship and underlying pathophysiological determinants. In previous imaging or genetic studies, both conditions have been associated with the limbic dopaminergic system. The risk variant of the Ser9Gly polymorphism of the dopamine receptor D3 (DRD3) is linked to increased dopamine affinity in the limbic striatum. With this in mind, we investigated how ICB expression is explained by apathy and DRD3 polymorphisms and their effects on grey matter volume and dopamine synthesis capacity. Fifty-four patients with early Parkinson’s disease took part in anatomical T1-weighted MRI. Forty of them also underwent dynamic PET imaging using [18F]DOPA to measure striatal dopamine synthesis capacity. Further, Ser9Gly (rs6280) gene polymorphism influencing the DRD3 dopamine-binding affinity was determined in all patients. The severity of impulsive-compulsive behaviour and apathy was assessed using the Questionnaire for Impulsive-Compulsive Disorders Rating Scale and the Apathy Evaluation Scale. ICB and the severity of apathy were indeed positively correlated. Apathy and the DRD3 polymorphism were interactive risk factors for ICB severity. Apathy was significantly linked to atrophy of the bilateral putamen. Patients with the DRD3 risk type had reduced dopamine synthesis capacity in the putamen and limbic striatum, apathy was associated with reduced dopamine synthesis capacity in the limbic striatum. The results of [18F]DOPA reached only trend significance. Apathy in drug-naïve PD patients might be a consequence of impaired striatal dopaminergic tone. This may represent a predisposing factor for the development of ICB after the initiation of dopamine replacement therapy. The risk type of DRD3 could further amplify this predisposition due to its higher affinity to dopamine.</jats:p>},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
<jats:title>Abstract</jats:title><jats:p>Impulsive-compulsive behaviour (ICB) is a frequently observed non-motor symptom in early Parkinson’s disease after initiating dopamine replacement therapy. At the opposite end of the motivated behaviour spectrum, apathy occurs in early Parkinson’s disease even before dopamine replacement is started. The co-occurrence of these behavioural conditions in Parkinson’s disease raises questions about their relationship and underlying pathophysiological determinants. In previous imaging or genetic studies, both conditions have been associated with the limbic dopaminergic system. The risk variant of the Ser9Gly polymorphism of the dopamine receptor D3 (DRD3) is linked to increased dopamine affinity in the limbic striatum. With this in mind, we investigated how ICB expression is explained by apathy and DRD3 polymorphisms and their effects on grey matter volume and dopamine synthesis capacity. Fifty-four patients with early Parkinson’s disease took part in anatomical T1-weighted MRI. Forty of them also underwent dynamic PET imaging using [18F]DOPA to measure striatal dopamine synthesis capacity. Further, Ser9Gly (rs6280) gene polymorphism influencing the DRD3 dopamine-binding affinity was determined in all patients. The severity of impulsive-compulsive behaviour and apathy was assessed using the Questionnaire for Impulsive-Compulsive Disorders Rating Scale and the Apathy Evaluation Scale. ICB and the severity of apathy were indeed positively correlated. Apathy and the DRD3 polymorphism were interactive risk factors for ICB severity. Apathy was significantly linked to atrophy of the bilateral putamen. Patients with the DRD3 risk type had reduced dopamine synthesis capacity in the putamen and limbic striatum, apathy was associated with reduced dopamine synthesis capacity in the limbic striatum. The results of [18F]DOPA reached only trend significance. Apathy in drug-naïve PD patients might be a consequence of impaired striatal dopaminergic tone. This may represent a predisposing factor for the development of ICB after the initiation of dopamine replacement therapy. The risk type of DRD3 could further amplify this predisposition due to its higher affinity to dopamine.</jats:p>
Chakroun, Karima; Wiehler, Antonius; Wagner, Ben; Mathar, David; Ganzer, Florian; van Eimeren, Thilo; Sommer, Tobias; Peters, Jan
Dopamine regulates decision thresholds in human reinforcement learning in males Journal Article
In: Nat Commun, vol. 14, no. 1, 2023, ISSN: 2041-1723.
@article{Chakroun2023,
title = {Dopamine regulates decision thresholds in human reinforcement learning in males},
author = {Karima Chakroun and Antonius Wiehler and Ben Wagner and David Mathar and Florian Ganzer and Thilo van Eimeren and Tobias Sommer and Jan Peters},
doi = {10.1038/s41467-023-41130-y},
issn = {2041-1723},
year = {2023},
date = {2023-12-00},
journal = {Nat Commun},
volume = {14},
number = {1},
publisher = {Springer Science and Business Media LLC},
abstract = {Abstract Dopamine fundamentally contributes to reinforcement learning, but recent accounts also suggest a contribution to specific action selection mechanisms and the regulation of response vigour. Here, we examine dopaminergic mechanisms underlying human reinforcement learning and action selection via a combined pharmacological neuroimaging approach in male human volunteers (n = 31, within-subjects; Placebo, 150 mg of the dopamine precursor L-dopa, 2 mg of the D2 receptor antagonist Haloperidol). We found little credible evidence for previously reported beneficial effects of L-dopa vs. Haloperidol on learning from gains and altered neural prediction error signals, which may be partly due to differences experimental design and/or drug dosages. Reinforcement learning drift diffusion models account for learning-related changes in accuracy and response times, and reveal consistent decision threshold reductions under both drugs, in line with the idea that lower dosages of D2 receptor antagonists increase striatal DA release via an autoreceptor-mediated feedback mechanism. These results are in line with the idea that dopamine regulates decision thresholds during reinforcement learning, and may help to bridge action selection and response vigor accounts of dopamine. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Theis, Hendrik; Bischof, Gérard N.; Brüggemann, Norbert; Dargvainiene, Justina; Drzezga, Alexander; Grüter, Thomas; Lewerenz, Jan; Leypoldt, Frank; Neumaier, Bernd; Wandinger, Klaus-Peter; Ayzenberg, Ilya; van Eimeren, Thilo
In Vivo Measurement of Tau Depositions in Anti-IgLON5 Disease Using [18F]PI-2620 PET Journal Article
In: Neurology, vol. 101, no. 22, 2023, ISSN: 1526-632X.
@article{Theis2023b,
title = {In Vivo Measurement of Tau Depositions in Anti-IgLON5 Disease Using [18F]PI-2620 PET},
author = {Hendrik Theis and Gérard N. Bischof and Norbert Brüggemann and Justina Dargvainiene and Alexander Drzezga and Thomas Grüter and Jan Lewerenz and Frank Leypoldt and Bernd Neumaier and Klaus-Peter Wandinger and Ilya Ayzenberg and Thilo van Eimeren},
doi = {10.1212/wnl.0000000000207870},
issn = {1526-632X},
year = {2023},
date = {2023-11-28},
journal = {Neurology},
volume = {101},
number = {22},
publisher = {Ovid Technologies (Wolters Kluwer Health)},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Theis, Hendrik; Bischof, Gérard N; Brüggemann, Norbert; Dargvainiene, Justina; Drzezga, Alexander; Grüter, Thomas; Lewerenz, Jan; Leypoldt, Frank; Neumaier, Bernd; Wandinger, Klaus-Peter; Ayzenberg, Ilya; van Eimeren, Thilo
In Vivo Measurement of Tau Depositions in Anti-IgLON5 Disease Using [18F]PI-2620 PET Journal Article
In: Neurology, vol. 101, no. 22, pp. e2325–e2330, 2023, ISSN: 1526-632X.
@article{pmid37879939,
title = {In Vivo Measurement of Tau Depositions in Anti-IgLON5 Disease Using [18F]PI-2620 PET},
author = {Hendrik Theis and Gérard N Bischof and Norbert Brüggemann and Justina Dargvainiene and Alexander Drzezga and Thomas Grüter and Jan Lewerenz and Frank Leypoldt and Bernd Neumaier and Klaus-Peter Wandinger and Ilya Ayzenberg and Thilo van Eimeren},
doi = {10.1212/WNL.0000000000207870},
issn = {1526-632X},
year = {2023},
date = {2023-11-01},
journal = {Neurology},
volume = {101},
number = {22},
pages = {e2325--e2330},
abstract = {OBJECTIVES: Anti-IgLON5 disease is a recently discovered neurologic disorder combining autoimmunity and neurodegeneration. Core manifestations include sleep disorders, bulbar symptoms, gait abnormalities, and cognitive dysfunction, but other presentations have been reported. Hallmarks are autoantibodies targeting the neuronal surface protein IgLON5, a strong human leukocyte antigen system Class II association, and brainstem and hypothalamus-dominant tau deposits. The purpose of this cohort study was to visualize tau deposition in vivo with the second-generation tau-PET tracer.nnMETHODS: A cohort of 4 patients with anti-IgLON5 disease underwent a dynamic PET scan with [18F]PI-2620. One patient received a follow-up scan. Z-deviation maps and a 2-sample test in comparison with healthy controls (n = 10) were performed. Antibody titers, neurofilament light chain, and disease duration were correlated with brainstem binding potentials.nnRESULTS: Patients demonstrated increased [18F]PI2620 tau binding potentials in the pons, dorsal medulla, and cerebellum. The longitudinal scan after 28 months showed an increase of tracer uptake in the medulla despite immunotherapy. Higher antibody titers and neurofilament light chain correlated with higher tracer retention.nnDISCUSSION: The results indicate that tau depositions in anti-IgLON5 disease can be visualized with [18F]PI-2620 and might correlate with the extent of disease. For validation, a larger longitudinal study is necessary.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVES: Anti-IgLON5 disease is a recently discovered neurologic disorder combining autoimmunity and neurodegeneration. Core manifestations include sleep disorders, bulbar symptoms, gait abnormalities, and cognitive dysfunction, but other presentations have been reported. Hallmarks are autoantibodies targeting the neuronal surface protein IgLON5, a strong human leukocyte antigen system Class II association, and brainstem and hypothalamus-dominant tau deposits. The purpose of this cohort study was to visualize tau deposition in vivo with the second-generation tau-PET tracer.nnMETHODS: A cohort of 4 patients with anti-IgLON5 disease underwent a dynamic PET scan with [18F]PI-2620. One patient received a follow-up scan. Z-deviation maps and a 2-sample test in comparison with healthy controls (n = 10) were performed. Antibody titers, neurofilament light chain, and disease duration were correlated with brainstem binding potentials.nnRESULTS: Patients demonstrated increased [18F]PI2620 tau binding potentials in the pons, dorsal medulla, and cerebellum. The longitudinal scan after 28 months showed an increase of tracer uptake in the medulla despite immunotherapy. Higher antibody titers and neurofilament light chain correlated with higher tracer retention.nnDISCUSSION: The results indicate that tau depositions in anti-IgLON5 disease can be visualized with [18F]PI-2620 and might correlate with the extent of disease. For validation, a larger longitudinal study is necessary.
Theis, Hendrik; Prange, Stéphane; Bischof, Gérard N; Hoenig, Merle C; Tittgemeyer, Marc; Timmermann, Lars; Fink, Gereon R; Drzezga, Alexander; Eggers, Carsten; van Eimeren, Thilo
Impulsive-compulsive behaviour in early Parkinson's disease is determined by apathy and dopamine receptor D3 polymorphism Journal Article
In: NPJ Parkinsons Dis, vol. 9, no. 1, pp. 154, 2023, ISSN: 2373-8057.
@article{pmid37968562,
title = {Impulsive-compulsive behaviour in early Parkinson's disease is determined by apathy and dopamine receptor D3 polymorphism},
author = {Hendrik Theis and Stéphane Prange and Gérard N Bischof and Merle C Hoenig and Marc Tittgemeyer and Lars Timmermann and Gereon R Fink and Alexander Drzezga and Carsten Eggers and Thilo van Eimeren},
doi = {10.1038/s41531-023-00596-9},
issn = {2373-8057},
year = {2023},
date = {2023-11-01},
journal = {NPJ Parkinsons Dis},
volume = {9},
number = {1},
pages = {154},
abstract = {Impulsive-compulsive behaviour (ICB) is a frequently observed non-motor symptom in early Parkinson's disease after initiating dopamine replacement therapy. At the opposite end of the motivated behaviour spectrum, apathy occurs in early Parkinson's disease even before dopamine replacement is started. The co-occurrence of these behavioural conditions in Parkinson's disease raises questions about their relationship and underlying pathophysiological determinants. In previous imaging or genetic studies, both conditions have been associated with the limbic dopaminergic system. The risk variant of the Ser9Gly polymorphism of the dopamine receptor D3 (DRD3) is linked to increased dopamine affinity in the limbic striatum. With this in mind, we investigated how ICB expression is explained by apathy and DRD3 polymorphisms and their effects on grey matter volume and dopamine synthesis capacity. Fifty-four patients with early Parkinson's disease took part in anatomical T1-weighted MRI. Forty of them also underwent dynamic PET imaging using [18F]DOPA to measure striatal dopamine synthesis capacity. Further, Ser9Gly (rs6280) gene polymorphism influencing the DRD3 dopamine-binding affinity was determined in all patients. The severity of impulsive-compulsive behaviour and apathy was assessed using the Questionnaire for Impulsive-Compulsive Disorders Rating Scale and the Apathy Evaluation Scale. ICB and the severity of apathy were indeed positively correlated. Apathy and the DRD3 polymorphism were interactive risk factors for ICB severity. Apathy was significantly linked to atrophy of the bilateral putamen. Patients with the DRD3 risk type had reduced dopamine synthesis capacity in the putamen and limbic striatum, apathy was associated with reduced dopamine synthesis capacity in the limbic striatum. The results of [18F]DOPA reached only trend significance. Apathy in drug-naïve PD patients might be a consequence of impaired striatal dopaminergic tone. This may represent a predisposing factor for the development of ICB after the initiation of dopamine replacement therapy. The risk type of DRD3 could further amplify this predisposition due to its higher affinity to dopamine.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Impulsive-compulsive behaviour (ICB) is a frequently observed non-motor symptom in early Parkinson's disease after initiating dopamine replacement therapy. At the opposite end of the motivated behaviour spectrum, apathy occurs in early Parkinson's disease even before dopamine replacement is started. The co-occurrence of these behavioural conditions in Parkinson's disease raises questions about their relationship and underlying pathophysiological determinants. In previous imaging or genetic studies, both conditions have been associated with the limbic dopaminergic system. The risk variant of the Ser9Gly polymorphism of the dopamine receptor D3 (DRD3) is linked to increased dopamine affinity in the limbic striatum. With this in mind, we investigated how ICB expression is explained by apathy and DRD3 polymorphisms and their effects on grey matter volume and dopamine synthesis capacity. Fifty-four patients with early Parkinson's disease took part in anatomical T1-weighted MRI. Forty of them also underwent dynamic PET imaging using [18F]DOPA to measure striatal dopamine synthesis capacity. Further, Ser9Gly (rs6280) gene polymorphism influencing the DRD3 dopamine-binding affinity was determined in all patients. The severity of impulsive-compulsive behaviour and apathy was assessed using the Questionnaire for Impulsive-Compulsive Disorders Rating Scale and the Apathy Evaluation Scale. ICB and the severity of apathy were indeed positively correlated. Apathy and the DRD3 polymorphism were interactive risk factors for ICB severity. Apathy was significantly linked to atrophy of the bilateral putamen. Patients with the DRD3 risk type had reduced dopamine synthesis capacity in the putamen and limbic striatum, apathy was associated with reduced dopamine synthesis capacity in the limbic striatum. The results of [18F]DOPA reached only trend significance. Apathy in drug-naïve PD patients might be a consequence of impaired striatal dopaminergic tone. This may represent a predisposing factor for the development of ICB after the initiation of dopamine replacement therapy. The risk type of DRD3 could further amplify this predisposition due to its higher affinity to dopamine.
Hoenig, Merle C; Dzialas, Verena; Banwinkler, Magdalena; Asendorf, Adrian; Drzezga, Alexander; van Eimeren, Thilo
Educational level and its association with dopamine transporter loss in patients with Parkinson's disease Journal Article
In: Parkinsonism Relat Disord, vol. 115, pp. 105844, 2023, ISSN: 1873-5126.
@article{pmid37690218,
title = {Educational level and its association with dopamine transporter loss in patients with Parkinson's disease},
author = {Merle C Hoenig and Verena Dzialas and Magdalena Banwinkler and Adrian Asendorf and Alexander Drzezga and Thilo van Eimeren},
doi = {10.1016/j.parkreldis.2023.105844},
issn = {1873-5126},
year = {2023},
date = {2023-10-01},
journal = {Parkinsonism Relat Disord},
volume = {115},
pages = {105844},
abstract = {BACKGROUND: According to the cognitive-reserve concept, higher educated dementia patients tolerate more brain pathology than lower educated patients with similar impairment. Here, we examined whether higher education is associated with more severe dopamine terminal loss at the diagnosis of Parkinson's disease (PD).nnMETHODS: Dopamine transporter (DaT) SPECT information of 352 de novo PD patients and 172 healthy controls (HC) were retrieved from PPMI. Correlation analyses were performed between education years and regional DaT signal (i.e., putamen, caudate, striatum), correcting for UPDRS-III, age, sex and MoCA. Second, using a median split on education (Md = 16 yrs), high and low education groups were determined, which were matched for demographic and/or clinical scores and compared based on regional DaT signals. Finally, moderation analyses were conducted in the PD cohort, assessing the effect of education on the relation between putaminal DaT capacity and UPDRS-III. All analyses were performed across the entire cohorts and separately for three age ranges (sixth, seventh and eighth life decade).nnRESULTS: Only PD patients in their eighth life decade presented a positive association between education and regional dopamine signalling. A significant moderation effect of education on the association between putaminal DaT signal loss and motor symptom severity was observed in this group (B=3.377, t=3.075, p = .003). The remaining analyses did not yield any significant results, neither in the PD nor HC cohort.nnCONCLUSION: Higher education is not related with greater tolerance against dopamine loss in PD, but may nonetheless assert protective effects at more advanced age.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: According to the cognitive-reserve concept, higher educated dementia patients tolerate more brain pathology than lower educated patients with similar impairment. Here, we examined whether higher education is associated with more severe dopamine terminal loss at the diagnosis of Parkinson's disease (PD).nnMETHODS: Dopamine transporter (DaT) SPECT information of 352 de novo PD patients and 172 healthy controls (HC) were retrieved from PPMI. Correlation analyses were performed between education years and regional DaT signal (i.e., putamen, caudate, striatum), correcting for UPDRS-III, age, sex and MoCA. Second, using a median split on education (Md = 16 yrs), high and low education groups were determined, which were matched for demographic and/or clinical scores and compared based on regional DaT signals. Finally, moderation analyses were conducted in the PD cohort, assessing the effect of education on the relation between putaminal DaT capacity and UPDRS-III. All analyses were performed across the entire cohorts and separately for three age ranges (sixth, seventh and eighth life decade).nnRESULTS: Only PD patients in their eighth life decade presented a positive association between education and regional dopamine signalling. A significant moderation effect of education on the association between putaminal DaT signal loss and motor symptom severity was observed in this group (B=3.377, t=3.075, p = .003). The remaining analyses did not yield any significant results, neither in the PD nor HC cohort.nnCONCLUSION: Higher education is not related with greater tolerance against dopamine loss in PD, but may nonetheless assert protective effects at more advanced age.
Hoenig, Merle C.; Dzialas, Verena; Banwinkler, Magdalena; Asendorf, Adrian L.; Drzezga, Alexander; van Eimeren, Thilo
Educational level and its association with dopamine transporter loss in patients with Parkinson's disease Journal Article
In: Parkinsonism & Related Disorders, vol. 115, 2023, ISSN: 1353-8020.
@article{Hoenig2023,
title = {Educational level and its association with dopamine transporter loss in patients with Parkinson's disease},
author = {Merle C. Hoenig and Verena Dzialas and Magdalena Banwinkler and Adrian L. Asendorf and Alexander Drzezga and Thilo van Eimeren},
doi = {10.1016/j.parkreldis.2023.105844},
issn = {1353-8020},
year = {2023},
date = {2023-10-00},
urldate = {2023-10-00},
journal = {Parkinsonism & Related Disorders},
volume = {115},
publisher = {Elsevier BV},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
van Eimeren, Thilo; Giehl, Kathrin; Reetz, Kathrin; Sampaio, Cristina; Mestre, Tiago A
Neuroimaging biomarkers in Huntington's disease: Preparing for a new era of therapeutic development Journal Article
In: Parkinsonism Relat Disord, vol. 114, pp. 105488, 2023, ISSN: 1873-5126.
@article{pmid37407343,
title = {Neuroimaging biomarkers in Huntington's disease: Preparing for a new era of therapeutic development},
author = {Thilo van Eimeren and Kathrin Giehl and Kathrin Reetz and Cristina Sampaio and Tiago A Mestre},
doi = {10.1016/j.parkreldis.2023.105488},
issn = {1873-5126},
year = {2023},
date = {2023-09-01},
journal = {Parkinsonism Relat Disord},
volume = {114},
pages = {105488},
abstract = {BACKGROUND: A critical challenge for Huntington's disease (HD) clinical trials in disease modification is the definition of endpoints that can capture change when clinical signs are subtle/non-existent. Reliable biomarkers are therefore urgently needed to facilitate drug development by allowing the enrichment of clinical trial populations and providing measures of benefit that can support the establishment of efficacy.nnMETHODS: By systematically examining the published literature on HD neuroimaging biomarker studies, we sought to advance knowledge to guide the validation of neuroimaging biomarkers. We started by reviewing both cross-sectional and longitudinal studies and then conducted an in-depth review to make quantitative comparisons between biomarkers using data only from longitudinal studies with samples sizes larger than ten participants in PET studies or 30 participants in MRI studies.nnRESULTS: From a total of 2202 publications initially identified, we included 32 studies, 19 of which underwent in-depth comparative review. The majority of included studies used various MRI-based methods (manual to automatic) to longitudinally assess either the volume of the putamen or the caudate, which have been shown to undergo significant structural change during HD natural history.nnCONCLUSION: Despite the impressively large number of neuroimaging biomarker studies, only a small number of adequately designed studies met our criteria. Among these various biomarkers, MRI-based volumetric analyses of the caudate and putamen are currently the best validated for use in the disease phase before clinical motor diagnosis. A biomarker that can be used to demonstrate a disease-modifying effect is still missing.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: A critical challenge for Huntington's disease (HD) clinical trials in disease modification is the definition of endpoints that can capture change when clinical signs are subtle/non-existent. Reliable biomarkers are therefore urgently needed to facilitate drug development by allowing the enrichment of clinical trial populations and providing measures of benefit that can support the establishment of efficacy.nnMETHODS: By systematically examining the published literature on HD neuroimaging biomarker studies, we sought to advance knowledge to guide the validation of neuroimaging biomarkers. We started by reviewing both cross-sectional and longitudinal studies and then conducted an in-depth review to make quantitative comparisons between biomarkers using data only from longitudinal studies with samples sizes larger than ten participants in PET studies or 30 participants in MRI studies.nnRESULTS: From a total of 2202 publications initially identified, we included 32 studies, 19 of which underwent in-depth comparative review. The majority of included studies used various MRI-based methods (manual to automatic) to longitudinally assess either the volume of the putamen or the caudate, which have been shown to undergo significant structural change during HD natural history.nnCONCLUSION: Despite the impressively large number of neuroimaging biomarker studies, only a small number of adequately designed studies met our criteria. Among these various biomarkers, MRI-based volumetric analyses of the caudate and putamen are currently the best validated for use in the disease phase before clinical motor diagnosis. A biomarker that can be used to demonstrate a disease-modifying effect is still missing.
van Eimeren, Thilo; Giehl, Kathrin; Reetz, Kathrin; Sampaio, Cristina; Mestre, Tiago A.
Neuroimaging biomarkers in Huntington's disease: Preparing for a new era of therapeutic development Journal Article
In: Parkinsonism & Related Disorders, vol. 114, 2023, ISSN: 1353-8020.
@article{vanEimeren2023,
title = {Neuroimaging biomarkers in Huntington's disease: Preparing for a new era of therapeutic development},
author = {Thilo van Eimeren and Kathrin Giehl and Kathrin Reetz and Cristina Sampaio and Tiago A. Mestre},
doi = {10.1016/j.parkreldis.2023.105488},
issn = {1353-8020},
year = {2023},
date = {2023-09-00},
journal = {Parkinsonism & Related Disorders},
volume = {114},
publisher = {Elsevier BV},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Schröter, Nils; van Eimeren, Thilo; Classen, Joseph; Levin, Johannes; Redecker, Christoph; Wolz, Martin; Tönges, Lars
Significance of clinical symptoms and red flags in early differential diagnosis of Parkinson’s disease and atypical Parkinsonian syndromes Journal Article
In: J Neural Transm, vol. 130, no. 6, pp. 839–846, 2023, ISSN: 1435-1463.
@article{Schröter2023,
title = {Significance of clinical symptoms and red flags in early differential diagnosis of Parkinson’s disease and atypical Parkinsonian syndromes},
author = {Nils Schröter and Thilo van Eimeren and Joseph Classen and Johannes Levin and Christoph Redecker and Martin Wolz and Lars Tönges},
doi = {10.1007/s00702-023-02634-5},
issn = {1435-1463},
year = {2023},
date = {2023-06-00},
journal = {J Neural Transm},
volume = {130},
number = {6},
pages = {839--846},
publisher = {Springer Science and Business Media LLC},
abstract = {Abstract The clinical presentation of Parkinson’s disease and atypical Parkinsonian syndromes is often heterogeneous. Additional diagnostic procedures including brain imaging and biomarker analyses can help to appreciate the various syndromes, but a precise clinical evaluation and differentiation is always necessary. To better assess the relevance of distinct clinical symptoms that arose within 1 year of disease manifestation and evaluate their indicative potential for an atypical Parkinsonian syndrome, we conducted a modified Delphi panel with seven movement disorder specialists. Five different topics with several clinical symptom items were discussed and consensus criteria were tested. This resulted in distinct symptom patterns for each atypical Parkinsonian syndrome showing the multitude of clinical involvement in each neurodegenerative disease. Strongly discriminating clinical signs were few and levels of indication were variable. A prospective validation of the assessments made is needed. This demonstrates that both clinical evaluation and elaborate additional diagnostic procedures are needed to achieve a high diagnostic standard. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Madlener, Marie; Breuninger, Marianne; Meißner, Arne; Stetefeld, Henning; Telentschak, Sergej; Wille, Thorsten; van Eimeren, Thilo; Jung, Norma
Brain abscess with Ureaplasma parvum in a patient with granulomatosis with polyangiitis Journal Article
In: Infection, vol. 51, no. 3, pp. 779–782, 2023, ISSN: 1439-0973.
@article{Madlener2022,
title = {Brain abscess with Ureaplasma parvum in a patient with granulomatosis with polyangiitis},
author = {Marie Madlener and Marianne Breuninger and Arne Meißner and Henning Stetefeld and Sergej Telentschak and Thorsten Wille and Thilo van Eimeren and Norma Jung},
doi = {10.1007/s15010-022-01966-w},
issn = {1439-0973},
year = {2023},
date = {2023-06-00},
journal = {Infection},
volume = {51},
number = {3},
pages = {779--782},
publisher = {Springer Science and Business Media LLC},
abstract = {Abstract
Purpose
Ureaplasma species are associated with urogenital infections, infertility and adverse pregnancy outcomes as well as neonatal infections. Involvement of the central nervous system in adults is extremely rare. We report an unusual case of a brain abscess secondary to otitis media with Ureaplasma parvum in a patient with granulomatosis with polyangiitis (GPA).
Methods
Imaging and laboratory findings, treatment decisions, and outcome of this case are explicated.
Results
A young adult with GPA presented with progredient earache after ambulant diagnosis of otitis media. Despite different courses of broad-spectrum antibiotic therapy, she developed meningoencephalitis due to mastoiditis following temporal abscess formation. Mastoidectomy and neurosurgical abscess removal were performed. Standard cultures of cerebrospinal fluid, blood and intracranial abscess material, as well as polymerase chain reaction (PCR) for common bacterial and viral meningitis pathogens remained negative. Only eubacterial PCR of intracranial abscess material returned positive for Ureaplasma parvum. The patient finally improved under antibiotic therapy with moxifloxacin and doxycycline.
Conclusion
Ureaplasma species are rare causative pathogens in immunocompromised patients. They should be considered in patients with humoral immunodeficiencies with culture-negative infections failing standard therapy. Eubacterial PCR should be performed in early states of infection in these patients for immediate diagnosis and initiation of appropriate treatment to prevent adverse outcomes.
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Maier, Franziska; Greuel, Andrea; Hoock, Marius; Kaur, Rajbir; Tahmasian, Masoud; Schwartz, Frank; Csoti, Ilona; Jessen, Frank; Drzezga, Alexander; van Eimeren, Thilo; Timmermann, Lars; Eggers, Carsten
Impaired self-awareness of cognitive deficits in Parkinson's disease relates to cingulate cortex dysfunction Journal Article
In: Psychol. Med., vol. 53, no. 4, pp. 1244–1253, 2023, ISSN: 1469-8978.
@article{Maier2021,
title = {Impaired self-awareness of cognitive deficits in Parkinson's disease relates to cingulate cortex dysfunction},
author = {Franziska Maier and Andrea Greuel and Marius Hoock and Rajbir Kaur and Masoud Tahmasian and Frank Schwartz and Ilona Csoti and Frank Jessen and Alexander Drzezga and Thilo van Eimeren and Lars Timmermann and Carsten Eggers},
doi = {10.1017/s0033291721002725},
issn = {1469-8978},
year = {2023},
date = {2023-03-00},
journal = {Psychol. Med.},
volume = {53},
number = {4},
pages = {1244--1253},
publisher = {Cambridge University Press (CUP)},
abstract = {Abstract Background Impaired self-awareness of cognitive deficits (ISAcog) has rarely been investigated in Parkinson's disease (PD). ISAcog is associated with poorer long-term outcome in other diseases. This study examines ISAcog in PD with and without mild cognitive impairment (PD-MCI), compared to healthy controls, and its clinical-behavioral and neuroimaging correlates. Methods We examined 63 PD patients and 30 age- and education-matched healthy controls. Cognitive state was examined following the Movement Disorder Society Level II criteria. ISAcog was determined by subtracting z -scores (based on controls' scores) of objective tests and subjective questionnaires. Neural correlates were assessed by structural magnetic resonance imaging (MRI) and 2-[fluorine-18]fluoro-2-deoxy-d -glucose-positron emission tomography (FDG-PET) in 47 patients (43 with MRI) and 11 controls. We analyzed whole-brain glucose metabolism and cortical thickness in regions where FDG-uptake correlated with ISAcog. Results PD-MCI patients (N = 23) showed significantly more ISAcog than controls and patients without MCI (N = 40). When all patients who underwent FDG-PET were examined, metabolism in the bilateral superior medial frontal gyrus, anterior and midcingulate cortex negatively correlated with ISAcog (FWE-corrected p < 0.001). In PD-MCI, ISAcog was related to decreased metabolism in the right superior temporal lobe and insula (N = 13; FWE-corrected p = 0.023) as well as the midcingulate cortex (FWE-corrected p = 0.002). Cortical thickness was not associated with ISAcog in these regions. No significant correlations were found between ISAcog and glucose metabolism in controls and patients without MCI. Conclusions Similar to Alzheimer's disease, the cingulate cortex seems to be relevant in ISAcog in PD. In PD-MCI patients, ISAcog might result from a disrupted network that regulates awareness of cognition and error processes.
keywords = {},
pubstate = {published},
tppubtype = {article}
}