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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)., Methods: 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)., Results: 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., Conclusion: Higher education is not related with greater tolerance against dopamine loss in PD, but may nonetheless assert protective effects at more advanced age., Competing Interests: Declaration of competing interest VD, MB and AA report no conflicts of interest. MH reports having received research funding from the German Research Foundation (DFG). AD reports research support from Siemens Healthineers, Life Molecular Imaging, GE Healthcare, AVID Radiopharmaceuticals, Sofie, Eisai, Novartis/AAA; Speaker Honorary/Advisory Boards: Siemens Healthineers, Sanofi, GE Healthcare, Biogen, Novo Nordisk, Invicro, Novartis/AAA, Bayer Vital; Stock: Siemens Healthineers, Lantheus Holding; Patents: Patent for 18F-PSMA7 (PSMA PET imaging tracer). 2-Alkoxy-6-[18F]Fluoronicotinoyl substituted Lys-C(O)-Glu derivatives as efficient probes for imaging of PSMA expressing tissues (Patent No.: EP3765097A1; Date of patent: Jan. 20, 2021). TvE reports having received consulting and lecture fees from Lundbeck A/S, Lilly Germany, Shire Germany and research funding from the German Research Foundation (DFG), the Leibniz Association and the EU-joint program for neurodegenerative disease research (JPND)., (Copyright © 2023. Published by Elsevier Ltd.)

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., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: There are promising novel genetic-based therapies under development intended to modify the disease trajectory in Huntington disease (HD). Valid biomarkers that can facilitate the development of such disease-modifying therapies are urgently needed. There are currently no studies that appraise the quality of research for validation of biomarkers in HD., Objective: To review studies for disease progression biomarkers in HD and evaluate their methodological quality., Methods: A systematic review of all HD biomarker studies up to June 2020 was conducted. Each study was assessed for methodological quality using a 24-item standardized checklist. We completed a subgroup analyses based on year of publication and biomarker type., Results: We included 218 HD biomarker studies, 76 (34.9%) were longitudinal and 161 (74%) included premanifest HD. On average, 10 ± 3 items (out of 24) were rated as good quality. The items more commonly rated as poor quality were: reporting of validity and reliability of assessments, sampling method, report of adverse events associated with the biomarker test, power calculation and appropriateness of study enrolment. Publications from 2016 to 2020 (mean score = 11.2 ± 2.3) had a better methodological quality than publications prior to 2016 (mean score = 9.8 ± 3.1; p = 0.018)., Conclusion: Overall, the reported methodological quality of the existing research on biomarkers for disease progression is low, which undermines the confidence of biomarkers use in drug development studies. It will be important to invest in better designed studies to support the use of biomarkers as valid drug development tools., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: To determine the feasibility and evaluate effects of a computerized working memory (WM) training (WMT) in patients with Parkinson's Disease (PD) on cognitive and clinical outcomes., Methods: 76 patients with PD without cognitive impairment were randomized to either the WMT group (n = 37), who participated in a 5-week adaptive WMT, or a passive waiting-list control group (CG, n = 39). Patients underwent clinical and neuropsychological examination at baseline, after training, and at 3-months follow-up, with verbal WM and non-verbal WM as primary outcomes. Outcome assessors were blinded for group allocation., Results: All WMT participants completed the training successfully and reported high levels of motivation for and satisfaction with the training. Repeated-measures, linear mixed-effects models revealed positive training effects for the WMT group compared to the CG in verbal working memory with a small relative effect size 0.39 [95%CI 0.05; 0.76] for the 3-months follow-up only. No other reliable training effects in cognitive and clinical variables were found for either point of time., Conclusions: In this randomized controlled trial, WMT was feasible and yielded some evidence for 3-months follow-up training gains in patients with PD. WMT might be an effective intervention to prevent cognitive decline in this patient group, however, more longitudinal studies with longer follow-up periods and more sensitive assessment tools will have to proof this concept., Trial Registration: German Clinical Trials Register (DRKS00009379)., Competing Interests: Declaration of competing interest AO, KG, and SR report no disclosures. CE has received grants from the German Research Foundation (KFO219, TP 10), the Medical Faculty of the Philipps University Marburg, Germany, the German Ministry of Education and Research; honoraria from Abbvie, Wiesbaden, Germany; UCB, Monheim, Germany; Daiichi Sankyo, Munich; Medtronic, Meerbusch, Germany; Bayer Vital, Leverkusen, Germany; Bial, Mörfelden-Walldorf, Germany. PR received a travel grant from AbbVie. TvE reports having received consulting and speaker honoraria as well as research support from Siemens Healthcare, AVID Radiopharmaceuticals, Lilly, Shire Germany, Piramal (now Life Molecular Imaging) and GE Healthcare. EK has received grants from the German Ministry of Education and Research, Parkinson Fonds Deutschland gGmbH, the German Parkinson Society; honoraria from: Oticon GmbH, Hamburg, Germany; Lilly Pharma GmbH, Bad Homburg, Germany; Bernafon AG, Bern, Switzerland; Desitin GmbH, Hamburg, Germany., (Copyright © 2020. Published by Elsevier Ltd.)

Introduction: Patients with Parkinson's disease (PD) are known to have decision-making impairments in tasks involving probabilistic information. How PD patients utilize task-relevant probabilistic advance information to plan and initiate common motor tasks like grasping has not yet been studied., Methods: PD patients (n = 15, OFF medication) and control participants repeatedly grasped and lifted an object, the weight of which could be light, medium, or heavy. Visual cues provided explicit probabilistic information about the upcoming weight at the start of each grip-lift trial. This information allows the force of the grasping fingers to be scaled predictively so that it matches the likely weight, with a suitable rate of initial force increase. Deterministic cues announced the upcoming weight with certainty in other grip-lift trials. In a weight adjustment experiment, participants associated each probabilistic cue with a specific heaviness., Results: The weight adjustment experiments showed that the probabilistic cues were understood correctly. However, PD patients utilized the probabilistic information significantly less than controls during the grip-lift task. Specifically, patients did not initiate their grasp more forcefully when probabilistic cues announced a high likelihood (66.7% probability) of a heavy weight, in contrast to controls. Thus, probabilistic cues that encouraged a more vigorous action had no effect in PD. Nevertheless, patients and controls scaled their forces appropriately when deterministic cues announced the forthcoming weights unambiguously., Conclusions: PD patients do not invest a high movement effort to initiate a grip-lift unless the necessity of such a vigorous action initiation is decidedly clear., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Executive dysfunction is a common and early cognitive symptom in Parkinson's disease (PD) with a detrimental effect on quality of life of patients and their care givers. Thus, a number of neuroimaging studies investigated the underlying neural correlates of such an impairment. Results of individual studies, however, are not univocal in terms of location and directionality of associated functional brain changes., Objective: To assess convergence of abnormal brain activation in patients with PD during the performance of tasks probing executive functions (EF)., Methods: We screened the functional imaging literature on EF in PD using the PubMed database, extracted reported stereotactic data and tested for convergence of deviant neural activation in patients with PD when compared to healthy controls (HC) using a coordinate-based activation likelihood estimation approach., Results: We identified 22 eligible papers from which the main proportion was targeted at the investigation of working memory encompassing 354 patients and 306 HC. Surprisingly, no significant converging aberrant activation between HC and patients (ON, OFF or ON + OFF medication, respectively) could be observed when controlling for multiple comparisons using family-wise error correction on cluster-level., Conclusion: We conclude that there is currently not enough available evidence to pinpoint a specific neural correlate associated with executive dysfunction in PD. This might be due to the small number of studies performed and their methodical inconsistency. Therefore, it is important to conduct more research regarding functional brain changes associated with EF in these patients using more consistent frameworks and bigger samples., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Treatment-related motor complications such as dyskinesias are a major problem in the long-term management of Parkinson's disease (PD). In sporadic PD, a relatively early onset of the disease is known to be associated with an early development of dyskinesias. Although linked with early onset, patients with Parkin-associated PD often show a stable long-term response to dopaminergic therapy without developing treatment-induced motor complications. Therefore, we reasoned that this difference in vulnerability to develop dyskinesias under long-term dopaminergic therapy may be associated with differences in movement-related activation patterns in Parkin-associated compared to sporadic PD. To test this hypothesis, medicated non-dyskinetic patients with either Parkin-associated or sporadic PD underwent functional magnetic resonance imaging (fMRI) while performing externally specified or internally selected movements. Patients with Parkin-associated and sporadic PD showed no difference in movement-related activation patterns. Moreover, the covariates 'age' and 'disease duration' similarly influenced brain activation in both patient groups. The present finding suggests that a stable long-term motor response in some patients with Parkin-associated PD may not be related to differences in cortical recruitment. In conclusion, our findings corroborate a substantial pathophysiologic overlap between Parkin-associated and sporadic PD and lend further support to the notion that Parkin-associated PD is a suitable genetic model for sporadic PD., (Copyright 2010 Elsevier Ltd. All rights reserved.)