Publications by authors named "Daniela Berg"

439 Publications

Long-Term Cognitive Decline Related to the Motor Phenotype in Parkinson's Disease.

J Parkinsons Dis 2022 Jan 21. Epub 2022 Jan 21.

Department of Neurology, RWTH Aachen University Hospital, Aachen, Germany.

Background: Parkinson's disease (PD) is associated with various non-motor symptoms, including cognitive deterioration.

Objective: Here, we used data from the DEMPARK/LANDSCAPE cohort to describe the association between progression of cognitive profiles and the PD motor phenotypes: postural instability and gait disorder (PIGD), tremor-dominant (TR-D), and not-determined (ND).

Methods: Demographic, clinical, and neuropsychological six-year longitudinal data of 711 PD-patients were included (age: M = 67.57; 67.4% males). We computed z-transformed composite scores for a priori defined cognitive domains. Analyses were controlled for age, gender, education, and disease duration. To minimize missing data and drop-outs, three-year follow-up data of 442 PD-patients was assessed with regard to the specific role of motor phenotype on cognitive decline using linear mixed modelling (age: M = 66.10; 68.6% males).

Results: Our study showed that in the course of the disease motor symptoms increased while MMSE and PANDA remained stable in all subgroups. After three-year follow-up, significant decline of overall cognitive performance for PIGD-patients were present and we found differences for motor phenotypes in attention (β= -0.08, SE = 0.003, p <  0.006) and memory functions showing that PIGD-patients deteriorate per months by -0.006 compared to the ND-group (SE = 0.003, p = 0.046). Furthermore, PIGD-patients experienced more often difficulties in daily living.

Conclusion: Over a period of three years, we identified distinct neuropsychological progression patterns with respect to different PD motor phenotypes, with early executive deficits yielding to a more amnestic profile in the later course. Here, in particular PIGD-patients worsened over time compared to TR-D and ND-patients, highlighting the greater risk of dementia for this motor phenotype.
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http://dx.doi.org/10.3233/JPD-212787DOI Listing
January 2022

Association of Essential Tremor With Novel Risk Loci: A Genome-Wide Association Study and Meta-analysis.

JAMA Neurol 2022 Jan 4. Epub 2022 Jan 4.

Parkinson's and Movement Disorders Center, Department of Neurology, Virginia Commonwealth University, Richmond.

Importance: Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified.

Objective: To identify common genetic factors associated with risk of ET.

Design, Setting, And Participants: Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485 250 individuals, data for 483 054 passed data quality control and were used.

Main Outcomes And Measures: Genotypes of common variants associated with risk of ET.

Results: Of the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10-8) and depression (r, 0.12; P = 9.78 × 10-4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum.

Conclusions And Relevance: The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.
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http://dx.doi.org/10.1001/jamaneurol.2021.4781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728658PMC
January 2022

Effect of Fear of Falling on Mobility Measured During Lab and Daily Activity Assessments in Parkinson's Disease.

Front Aging Neurosci 2021 30;13:722830. Epub 2021 Nov 30.

Laboratory of Movement Analysis and Measurement, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

In chronic disorders such as Parkinson's disease (PD), fear of falling (FOF) is associated with falls and reduced quality of life. With inertial measurement units (IMUs) and dedicated algorithms, different aspects of mobility can be obtained during supervised tests in the lab and also during daily activities. To our best knowledge, the effect of FOF on mobility has not been investigated in both of these settings simultaneously. Our goal was to evaluate the effect of FOF on the mobility of 26 patients with PD during clinical assessments and 14 days of daily activity monitoring. Parameters related to gait, sit-to-stand transitions, and turns were extracted from IMU signals on the lower back. Fear of falling was assessed using the Falls Efficacy Scale-International (FES-I) and the patients were grouped as with (PD-FOF+) and without FOF (PD-FOF-). Mobility parameters between groups were compared using logistic regression as well as the effect size values obtained using the Wilcoxon rank-sum test. The peak angular velocity of the turn-to-sit transition of the timed-up-and-go (TUG) test had the highest discriminative power between PD-FOF+ and PD-FOF- (-value of effect size = 0.61). Moreover, PD-FOF+ had a tendency toward lower gait speed at home and a lower amount of walking bouts, especially for shorter walking bouts. The combination of lab and daily activity parameters reached a higher discriminative power [area under the curve (AUC) = 0.75] than each setting alone (AUC = 0.68 in the lab, AUC = 0.54 at home). Comparing the gait speed between the two assessments, the PD-FOF+ showed higher gait speeds in the capacity area compared with their TUG test in the lab. The mobility parameters extracted from both lab and home-based assessments contribute to the detection of FOF in PD. This study adds further evidence to the usefulness of mobility assessments that include different environments and assessment strategies. Although this study was limited in the sample size, it still provides a helpful method to consider the daily activity measurement of the patients with PD into clinical evaluation. The obtained results can help the clinicians with a more accurate prevention and treatment strategy.
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http://dx.doi.org/10.3389/fnagi.2021.722830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669821PMC
November 2021

Autonomic Symptoms in Older Adults Are Common and Associated With Health-Related Quality of Life.

Front Neurol 2021 23;12:757748. Epub 2021 Nov 23.

Center for Neurology, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Autonomic symptoms are common in older adults, and a large body of literature focusing on age-related diseases shows that autonomic symptoms in these diseases constrain Health-Related Quality of Life (HRQoL). To our best knowledge, the association between autonomic symptoms in older adults, independent of specific diseases, and HRQoL has not yet been assessed. To assess the frequency and the effect of autonomic symptoms in general, as well as orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor symptoms, on HRQoL in older adults. Cross-sectional data of the fourth visit of the Tübinger evaluation of Risk factors for Early detection of Neurodegeneration (TREND) study were included. Autonomic symptoms, as assessed with the Composite Autonomic Symptom Score 31 (COMPASS 31), were quantified and compared with HRQoL, as assessed with the EuroQol five-level version (EQ-5D-5L). Statistical analyses included Spearman's rank correlation and multiple linear regression analysis. The analysis included 928 participants with a median of 68 years; 47% were women. Of those, 85% reported at least one autonomic symptom. Gastrointestinal and secretomotor symptoms were most common. The COMPASS 31 total score and all subdomains were significantly associated with reduced HRQoL. Among the subdomains, the strongest correlations with HRQoL were found for gastrointestinal and bladder symptoms. Overall, autonomic symptoms alone explained 20% of the variance of HRQoL; when depressive mood was added, the model explained 32%. Autonomic symptoms are associated with HRQoL and depressive symptoms in older adults.
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http://dx.doi.org/10.3389/fneur.2021.757748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649956PMC
November 2021

Increased Intake of Fast-Acting Carbohydrates in Patients with Parkinson's Disease.

Neurodegener Dis 2021 Nov 9. Epub 2021 Nov 9.

Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany.

Background: Patients with Parkinson's disease (PD) regularly report an increased desire for food or beverages with high sugar content.

Objective: The aim of this study was to verify the hypothesis of an increased intake of fast-acting carbohydrates in PD patients.

Methods: This study investigated the consumption of high-sugar content food products in 221 PD patients compared with 184 healthy controls using a self-administered questionnaire.

Results: Male PD patients reported a significantly more often high consumption of chocolate (p = 0.005) and other sweets (p < 0.001) than healthy controls. Moreover, PD patients with a high intake of these products showed a significantly longer disease duration (p = 0.002).

Conclusion: Our study confirmed changes in intake of fast-acting carbohydrates derived from sweets in PD. Future studies should address the observed association with disease progression to understand underlying pathophysiological mechanisms leading to this behavioral change.
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http://dx.doi.org/10.1159/000520594DOI Listing
November 2021

Effects of exergaming on hippocampal volume and brain-derived neurotrophic factor levels in Parkinson's disease.

Eur J Neurol 2022 Feb 14;29(2):441-449. Epub 2021 Nov 14.

Department of Neurology, Christian-Albrecht-University Kiel, Kiel, Germany.

Background And Objective: Cognitive impairment is among the most burdensome non-motor symptoms in Parkinson's disease (PD) and has been associated with hippocampal atrophy. Exercise has been reported to enhance neuroplasticity in the hippocampus in correlation with an improvement of cognitive function. We present data from the Training-PD study, which was designed to evaluate effects of an "" training protocol on neuronal plasticity in PD.

Methods: We initiated a 6-week exergaming training program, combining visually stimulating computer games with physical exercise in 17 PD patients and 18 matched healthy controls. Volumetric segmentation of hippocampal subfields on T1- and T2-weighted magnetic resonance imaging and brain-derived neurotrophic factor (BDNF) serum levels were analyzed before and after the training protocol.

Results: The PD group showed a group-dependent significant volume increase of the left hippocampal subfields CA1, CA4/dentate gyrus (DG) and subiculum after the 6-week training protocol. The effect was most pronounced in the left DG of PD patients, who showed a significantly smaller percentage volume compared to healthy controls at baseline, but not at follow-up. Both groups had a significant increase in serum BDNF levels after training.

Conclusions: The results of the present study indicate that exergaming might be a suitable approach to induce hippocampal volume changes in PD patients. Further and larger studies are needed to verify our findings.
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http://dx.doi.org/10.1111/ene.15165DOI Listing
February 2022

Increased functional connectivity in a population at risk of developing Parkinson's disease.

Parkinsonism Relat Disord 2021 11 6;92:1-6. Epub 2021 Oct 6.

Center for Neurology and Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, Tübingen, Germany; Department of Neurology, Christian-Albrechts-University, Kiel, Germany.

Background: While the concept of prodromal Parkinson's disease (PD) is well established, reliable markers for the diagnosis of this disease stage are still lacking. We investigated the functional connectivity of the putamina in a resting-state functional MRI analysis in persons with at least two prodromal factors for PD, which is considered a high risk for PD (HRPD) group, in comparison to PD patients and controls.

Methods: We included 16 PD patients, 20 healthy controls and 20 HRPD subjects. Resting state echo planar images and anatomical T1-weighted images were acquired with a Siemens Prisma 3 T scanner. The computation of correlation maps of the left and the right putamen to the rest of the brain was done in a voxel-wise approach using the REST toolbox. Finally, group differences in the correlation maps were compared on voxel-level and summarized in cluster z-statistics.

Results: Compared to both PD patients and healthy controls, the HRPD group showed higher functional connectivity of both putamina to brain regions involved in execution of motion and coordination (cerebellum, vermis, pre- and postcentral gyrus, supplementary motor area) as well as the planning of movement (precuneus, cuneus, superior medial frontal lobe).

Conclusions: Higher functional connectivity of the putamina of HRPD subjects to other brain regions involved in motor execution and planning may indicate a compensatory mechanism. Follow-up evaluation and independent longitudinal studies should test whether our results reflect a dynamic process associated with a prodromal PD state.
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http://dx.doi.org/10.1016/j.parkreldis.2021.09.026DOI Listing
November 2021

Brain age and Alzheimer's-like atrophy are domain-specific predictors of cognitive impairment in Parkinson's disease.

Neurobiol Aging 2022 01 6;109:31-42. Epub 2021 Sep 6.

Department of Neurology, Goethe University, Frankfurt am Main, Germany; Brain Imaging Center, Goethe University, Frankfurt am Main, Germany. Electronic address:

Recently, it was shown that patients with Parkinson's disease (PD) who exhibit an "Alzheimer's disease (AD)-like" pattern of brain atrophy are at greater risk for future cognitive decline. This study aimed to investigate whether this association is domain-specific and whether atrophy associated with brain aging also relates to cognitive impairment in PD. SPARE-AD, an MRI index capturing AD-like atrophy, and atrophy-based estimates of brain age were computed from longitudinal structural imaging data of 178 PD patients and 84 healthy subjects from the LANDSCAPE cohort. All patients underwent an extensive neuropsychological test battery. Patients diagnosed with mild cognitive impairment or dementia were found to have higher SPARE-AD scores as compared to patients with normal cognition and healthy controls. All patient groups showed increased brain age. SPARE-AD predicted impairment in memory, language and executive functions, whereas advanced brain age was associated with deficits in attention and working memory. Data suggest that SPARE-AD and brain age are differentially related to domain-specific cognitive decline in PD. The underlying pathomechanisms remain to be determined.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.08.020DOI Listing
January 2022

Arm swing responsiveness to dopaminergic medication in Parkinson's disease depends on task complexity.

NPJ Parkinsons Dis 2021 Oct 5;7(1):89. Epub 2021 Oct 5.

Department of Neurology, Kiel University, Kiel, Germany.

The evidence of the responsiveness of dopaminergic medication on gait in patients with Parkinson's disease is contradicting. This could be due to differences in complexity of the context gait was in performed. This study analysed the effect of dopaminergic medication on arm swing, an important movement during walking, in different contexts. Forty-five patients with Parkinson's disease were measured when walking at preferred speed, fast speed, and dual-tasking conditions in both OFF and ON medication states. At preferred, and even more at fast speed, arm swing improved with medication. However, during dual-tasking, there were only small or even negative effects of medication on arm swing. Assuming that dual-task walking most closely reflects real-life situations, the results suggest that the effect of dopaminergic medication on mobility-relevant movements, such as arm swing, might be small in everyday conditions. This should motivate further studies to look at medication effects on mobility in Parkinson's disease, as it could have highly relevant implications for Parkinson's disease treatment and counselling.
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http://dx.doi.org/10.1038/s41531-021-00235-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492858PMC
October 2021

Cognitive profiles of patients with mild cognitive impairment due to Alzheimer's versus Parkinson's disease defined using a base rate approach: Implications for neuropsychological assessments.

Alzheimers Dement (Amst) 2021 14;13(1):e12223. Epub 2021 Sep 14.

Department of Neurodegenerative Diseases and Gerontopsychiatry University Hospital of Bonn University of Bonn Bonn Germany.

Introduction: Large studies on cognitive profiles of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD-MCI) compared to Parkinson's disease (PD-MCI) are rare.

Methods: Data from two multicenter cohort studies in AD and PD were merged using a unified base rate approach for the MCI diagnosis. Cognitive profiles were compared using scores derived from the Consortium to Establish a Registry for Alzheimer's Disease battery.

Results: Patients with AD-MCI showed lower standardized scores on all memory test scores and a language test. Patients with PD-MCI showed lower standardized scores in a set-shifting measure as an executive task. A cross-validated logistic regression with test scores as predictors was able to classify 72% of patients correctly to AD-MCI versus PD-MCI.

Discussion: The applied test battery successfully discriminated between AD-MCI and PD-MCI. Neuropsychological test batteries in clinical practice should always include a broad spectrum of cognitive domains to capture any cognitive changes.
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http://dx.doi.org/10.1002/dad2.12223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438680PMC
September 2021

LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort.

Front Neurol 2021 9;12:710572. Epub 2021 Aug 9.

Department of Neurology, University Hospital Würzburg, Würzburg, Germany.

Pathogenic variants in the Leucine-rich repeat kinase 2 ( gene are the most common known monogenic cause of Parkinson's disease (PD). -linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions. To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of pathogenic variants using genetic and environmental data. Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with -linked PD, 200 with pathogenic variants but without PD, 100 PD patients with pathogenic variants in the or genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants. The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn &Yahr, and Schwab & England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021). LIPAD is a large-scale international scientific effort focusing on deep phenotyping of -linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivity ClinicalTrials.gov, NCT04214509.
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http://dx.doi.org/10.3389/fneur.2021.710572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406937PMC
August 2021

A new CERAD total score with equally weighted z-scores and additional executive and non-amnestic "CERAD-Plus" tests enhances cognitive diagnosis in patients with Parkinson's disease: Evidence from the LANDSCAPE study.

Parkinsonism Relat Disord 2021 09 4;90:90-97. Epub 2021 Aug 4.

University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Medical Psychology | Neuropsychology & Gender Studies, Center for Neuropsychological Diagnostic and Intervention (CeNDI), 50937, Cologne, Germany. Electronic address:

Introduction: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) is a renowned cognitive test battery, which has been extended in its German version to the CERAD-Plus including tests of executive functions and processing speed. The most commonly used total score (TS) is based on the restricted CERAD version and reflects the sum of selected raw-values (Chandler et al., 2005). The CERAD-Plus extensions might be of particular diagnostic utility for cognitive assessments in Parkinson's Disease (PD), as executive functions and processing speed belong to the most vulnerable domains in PD.

Objective: The aim was to develop a CERAD-TS based on the extended CERAD-Plus' age-, gender-, and education-corrected z-scores and to evaluate its diagnostic accuracy compared to the established CERAD-Chandler-TS.

Methods: Baseline data of n = 679 patients with PD (69% male, n = 277 PD without cognitive impairment, n = 307 PD-MCI, n = 95 PD-D) from the multicenter, prospective DEMPARK/LANDSCAPE study were analyzed. ROC-analyses were conducted for four different TS that were either based on the original CERAD or CERAD-Plus, on raw-values or z-scores, and equally-weighted or based on factor scores. AUC-comparisons were conducted to determine the best yet most parsimonious TS.

Results: The newly designed CERAD-Plus-TS based on equally-weighted z-scores outperformed both the CERAD-Chandler-TS and cognitive screening instruments when differentiating between individuals with PD of varying cognitive impairment (0.78 ≤ AUC ≤ 0.98).

Conclusion: Results suggest a high relevance of non-amnestic subscales for the cognitive assessment in PD populations. The proposed CERAD-Plus-TS needs further validation. The extensions might offer diagnostic potential for non-PD populations as well.
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http://dx.doi.org/10.1016/j.parkreldis.2021.07.034DOI Listing
September 2021

Risk Disclosure in Prodromal Parkinson's Disease.

Mov Disord 2021 Dec 5;36(12):2833-2839. Epub 2021 Aug 5.

Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany.

Background: Impressive progress in the understanding of the prodromal phase of Parkinson's disease (PD) in recent years has enabled the generation of disease prediction models. However, a remaining diagnostic uncertainty and lack of therapeutic options for affected individuals has resulted in a variety of ethical issues that have not to date been addressed sufficiently. Moreover, differences in the specificity of prodromal symptoms and possible subtypes of PD, especially the presence of rapid eye movement (REM) sleep behavior disorder (RBD), may have an important impact on prognostic counseling.

Objectives: To derive a guideline for risk disclosure in prodromal PD based on the current literature and expert opinion.

Methods: We performed (1) a literature review on prognostic counseling in PD and (2) consulted with international experts on prodromal PD using a semi-structured questionnaire based on a Delphi approach to evaluate recommendations for risk disclosure in PD.

Results: The literature research revealed only 11 publications addressing prognostic counseling, with only two studies directly addressing affected individuals and most studies focusing on risk disclosure in RBD. The expert survey revealed the importance of distinguishing between individuals with and without RBD in prognostic counseling.

Conclusions: Based on the current literature and expert recommendations, a guideline for risk disclosure in prodromal PD for clinical care and research could be elaborated. Prognostic counseling should include differentiation between individuals with and without RBD, taking into account the high uncertainty of risk calculation in RBD-negative prodromal PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28723DOI Listing
December 2021

Asymmetric Dopaminergic Dysfunction in Brain-First versus Body-First Parkinson's Disease Subtypes.

J Parkinsons Dis 2021 ;11(4):1677-1687

Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark.

Background: We have hypothesized that Parkinson's disease (PD) comprises two subtypes. Brain-first, where pathogenic α-synuclein initially forms unilaterally in one hemisphere leading to asymmetric nigrostriatal degeneration, and body-first with initial enteric pathology, which spreads through overlapping vagal innervation leading to more symmetric brainstem involvement and hence more symmetric nigrostriatal degeneration. Isolated REM sleep behaviour disorder has been identified as a strong marker of the body-first type.

Objective: To analyse striatal asymmetry in [18F]FDOPA PET and [123I]FP-CIT DaT SPECT data from iRBD patients, de novo PD patients with RBD (PD+RBD) and de novo PD patients without RBD (PD-RBD). These groups were defined as prodromal body-first, de novo body-first, and de novo brain-first, respectively.

Methods: We included [18F]FDOPA PET scans from 21 iRBD patients, 11 de novo PD+RBD, 22 de novo PD-RBD, and 18 controls subjects. Also, [123I]FP-CIT DaT SPECT data from iRBD and de novo PD patients with unknown RBD status from the PPPMI dataset was analysed. Lowest putamen specific binding ratio and putamen asymmetry index (AI) was defined.

Results: Nigrostriatal degeneration was significantly more symmetric in patients with RBD versus patients without RBD or with unknown RBD status in both FDOPA (p = 0.001) and DaT SPECT (p = 0.001) datasets.

Conclusion: iRBD subjects and de novo PD+RBD patients present with significantly more symmetric nigrostriatal dopaminergic degeneration compared to de novo PD-RBD patients. The results support the hypothesis that body-first PD is characterized by more symmetric distribution most likely due to more symmetric propagation of pathogenic α-synuclein compared to brain-first PD.
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http://dx.doi.org/10.3233/JPD-212761DOI Listing
December 2021

White Matter Hyperintensities Are Associated With Severity of Essential Tremor in the Elderly.

Front Neurol 2021 28;12:694286. Epub 2021 Jun 28.

Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.

Essential tremor (ET) occurs with steeply increasing prevalence in the elderly, and apart from disease duration, age is independently associated with an increase of tremor amplitude and a decrease of frequency. White matter hyperintensities (WMHs) are a common finding in the elderly, and their role in the pathophysiology of ET is unknown. The aims of this study were to examine whether ET patients differ in their total or region-specific WMH volumes from healthy controls and to determine the impact of WMH on tremor characteristics. A total of 47 elderly ET patients with a mean age of 72 years and 39 age-matched healthy controls underwent a thorough clinical assessment and 3T MRI. Total WMH volumes were derived from T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Additionally, region of interest-based WMH volumes for the Johns Hopkins University (JHU) white matter tracts and labels were calculated, and WMHs were assessed semiquantitatively using the Fazekas scale. Essential tremor patients and healthy controls did not differ in their total or tract-specific WMH volumes or Fazekas scores. However, WMH volume was significantly positively correlated with tremor severity on the TETRAS scale, and there was a significant negative correlation with the mean accelerometric tremor frequency. In a multiple linear regression model including disease duration, age, and age-adjusted total WMH volume, only the WMH volume significantly predicted tremor severity, while age and disease duration were not significant. We found evidence for a direct association between WMH volume and tremor severity. If confirmed by larger studies, our findings could explain the well-known relation between age and tremor severity.
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http://dx.doi.org/10.3389/fneur.2021.694286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273287PMC
June 2021

Abnormally reduced frontal cortex activity during Trail-Making-Test in prodromal parkinson's disease-a fNIRS study.

Neurobiol Aging 2021 09 28;105:148-158. Epub 2021 Apr 28.

Department of Psychiatry and Psychotherapy, University Hospital of Tübingen, Tübingen, Germany; Geriatric Center, University Hospital of Tübingen, Tübingen, Germany; Vitos Hospital for Psychiatry and Psychotherapy Haina, Haina, Germany.

Parkinson's Disease (PD) is a neurodegenerative disorder leading to typical motor as well as a range of non-motor symptoms, including cognitive decline mainly characterized by executive deficits. The latter are known to appear years before the typical motor signs, thus representing the prodromal phase of PD. However, appropriate methods for measuring executive dysfunction in this context are not well established yet. Traditionally, executive performance is associated with frontal structures. Here, we investigated prodromal, early PD patients and healthy controls regarding their executive functioning on the behavioral and neural level, measured by the Trail-Making-Test (TMT) combined with functional near-infrared spectroscopy. We observed significantly reduced neural activity in the right dorsolateral prefrontal cortex within PD patients compared to controls completing the TMT-A and -B in contrast to the TMT-C, but no differences on a behavioral level. These promising results need to be confirmed and checked for reliability in future studies to extend the spectrum of markers applied in prodromal PD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.014DOI Listing
September 2021

Gut Microbiome Signatures of Risk and Prodromal Markers of Parkinson Disease.

Ann Neurol 2021 09 16;90(3):E1-E12. Epub 2021 Jul 16.

Department of Neurology, Helsinki University Hospital and Department of Clinical Neurosciences (Neurology), University of Helsinki, Helsinki, Finland.

Objective: Alterations of the gut microbiome in Parkinson disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they relate to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition.

Methods: Established risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function, and medication were studied in relation to bacterial α-/β-diversity, enterotypes, and differential abundance in stool samples of 666 elderly TREND (Tübingen Evaluation of Risk Factors for Early Detection of Neurodegeneration) study participants.

Results: Among risk and prodromal markers, physical inactivity, occupational solvent exposure, and constipation showed associations with α-diversity. Physical inactivity, sex, constipation, possible rapid eye movement sleep behavior disorder (RBD), and smoking were associated with β-diversity. Subthreshold parkinsonism and physical inactivity showed an interaction effect. Among other factors, age and urate-lowering medication were associated with α- and β-diversity. Constipation was highest in individuals with the Firmicutes-enriched enterotype, and physical inactivity was most frequent in the Bacteroides-enriched enterotype. Constipation was lowest and subthreshold parkinsonism least frequent in individuals with the Prevotella-enriched enterotype. Differentially abundant taxa were linked to constipation, physical inactivity, possible RBD, smoking, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history, and the prodromal PD probability showed no significant microbiome associations.

Interpretation: Several risk and prodromal markers of PD are associated with gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome-dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases. ANN NEUROL 2021;90:E1-E12.
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http://dx.doi.org/10.1002/ana.26128DOI Listing
September 2021

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

Ann Neurol 2021 07 17;90(1):76-88. Epub 2021 May 17.

23andMe, Inc., Sunnyvale, CA.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.

Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.

Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.

Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.
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http://dx.doi.org/10.1002/ana.26094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252519PMC
July 2021

Comparing the Two Prodromal Parkinson's Disease Research Criteria-Lessons for Future Studies.

Mov Disord 2021 07 30;36(7):1731-1732. Epub 2021 Apr 30.

Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.

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http://dx.doi.org/10.1002/mds.28637DOI Listing
July 2021

Memory enhancement by multidomain group cognitive training in patients with Parkinson's disease and mild cognitive impairment: long-term effects of a multicenter randomized controlled trial.

J Neurol 2021 Dec 27;268(12):4655-4666. Epub 2021 Apr 27.

Department of Neurology, University Oldenburg, Steinweg 13-17, 26122, Oldenburg, Germany.

Background: Meta-analyses indicate positive effects of cognitive training (CT) in patients with Parkinson's disease (PD), however, most previous studies had small sample sizes and did not evaluate long-term follow-up. Therefore, a multicenter randomized controlled, single-blinded trial (Train-ParC study) was conducted to examine CT effects in PD patients with mild cognitive impairment (PD-MCI). Immediately after CT, an enhancement of executive functions was demonstrated. Here, we present the long-term results 6 and 12 months after CT.

Methods: At baseline, 64 PD-MCI patients were randomized to a multidomain CT group (n = 33) or to a low-intensity physical activity training control group (PT) (n = 31). Both interventions included 90 min training sessions twice a week for 6 weeks. 54 patients completed the 6 months (CT: n = 28, PT: n = 26) and 49 patients the 12 months follow-up assessment (CT: n = 25, PT: n = 24). Primary study outcomes were memory and executive functioning composite scores. Mixed repeated measures ANOVAs, post-hoc t tests and multiple regression analyses were conducted.

Results: We found a significant time x group interaction effect for the memory composite score (p = 0.006, η = 0.214), but not for the executive composite score (p = 0.967, η = 0.002). Post-hoc t tests revealed significant verbal and nonverbal memory improvements from pre-intervention to 6 months, but not to 12 months follow-up assessment in the CT group. No significant predictors were found for predicting memory improvement after CT.

Conclusions: This study provides Class 1 evidence that multidomain CT enhances memory functioning in PD-MCI after 6 months but not after 12 months, whereas executive functioning did not change in the long-term.

Clinical Trial Registration: German Clinical Trials Register (ID: DRKS00010186), 21.3.2016 (The study registration is outlined as retrospective due to an administrative delay. The first patient was enrolled three months after the registration process was started. A formal confirmation of this process from the German Clinical Trials Register can be obtained from the authors.).
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http://dx.doi.org/10.1007/s00415-021-10568-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563628PMC
December 2021

Prodromal Parkinson disease subtypes - key to understanding heterogeneity.

Nat Rev Neurol 2021 06 20;17(6):349-361. Epub 2021 Apr 20.

Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.

In Parkinson disease (PD), pathological processes and neurodegeneration begin long before the cardinal motor symptoms develop and enable clinical diagnosis. In this prodromal phase, risk and prodromal markers can be used to identify individuals who are likely to develop PD, as in the recently updated International Parkinson and Movement Disorders Society research criteria for prodromal PD. However, increasing evidence suggests that clinical and prodromal PD are heterogeneous, and can be classified into subtypes with different clinical manifestations, pathomechanisms and patterns of spatial and temporal progression in the CNS and PNS. Genetic, pathological and imaging markers, as well as motor and non-motor symptoms, might define prodromal subtypes of PD. Moreover, concomitant pathology or other factors, including amyloid-β and tau pathology, age and environmental factors, can cause variability in prodromal PD. Patients with REM sleep behaviour disorder (RBD) exhibit distinct patterns of α-synuclein pathology propagation and might indicate a body-first subtype rather than a brain-first subtype. Identification of prodromal PD subtypes and a full understanding of variability at this stage of the disease is crucial for early and accurate diagnosis and for targeting of neuroprotective interventions to ensure efficacy.
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http://dx.doi.org/10.1038/s41582-021-00486-9DOI Listing
June 2021

Validation of α-Synuclein in L1CAM-Immunocaptured Exosomes as a Biomarker for the Stratification of Parkinsonian Syndromes.

Mov Disord 2021 Nov 7;36(11):2663-2669. Epub 2021 Apr 7.

Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.

Background: Parkinson's disease is characterized by intraneuronal α-synuclein aggregation. Currently there is no α-synuclein-based blood test in clinical practice.

Objectives: Our aim was to assess by means of further testing and analysis whether α-synuclein measurements in serum L1CAM-immunocaptured exosomes can differentiate Parkinson's disease from related movement disorders.

Methods: We used poly(carboxybetaine-methacrylate)-coated magnetic beads to isolate L1CAM-positive exosomes and triplexed electrochemiluminescence to measure exosomal α-synuclein, clusterin, and syntenin-1 from 267 serum samples. Combined analysis of our current and previously published data from the Oxford, Kiel, Brescia, and PROSPECT cohorts consisting of individuals (total n = 735) with Parkinson's disease (n = 290), multiple system atrophy (MSA, n = 50), progressive supranuclear palsy (n = 116), corticobasal syndrome (n = 88), and healthy controls (n = 191) was done using 2-stage (training vs validation) receiver operating characteristic analysis.

Results: We established that α-synuclein level in L1CAM-immunocaptured exosomes above 14 pg/mL is a robust biomarker across cohorts that distinguishes Parkinson's disease from MSA (AUC, 0.90 vs 0.98) or 4-repeat tauopathies (AUC, 0.93 vs 0.94). We confirmed that exosomal clusterin is elevated in subjects with 4-repeat tauopathy, and when combined with α-synuclein, it improved the performance of the assay in differentiating Parkinson's disease from 4-repeat tauopathies to AUC, 0.98 versus 0.99. Correction for the generic exosomal protein syntenin-1 did not consistently improve the performance of the assay.

Conclusions: α-Synuclein and clusterin in L1CAM-immunocaptured serum exosomes is a validated blood test for the molecular stratification of neuronal α-synucleinopathy (ie, Lewy body pathology) versus phenotypically related neurodegenerative movement disorders. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663480PMC
November 2021

Step Length Is a Promising Progression Marker in Parkinson's Disease.

Sensors (Basel) 2021 Mar 25;21(7). Epub 2021 Mar 25.

Department of Neurology, Kiel University, Arnold-Heller-Straße 3, 24105 Kiel, Germany.

Current research on Parkinson's disease (PD) is increasingly concerned with the identification of objective and specific markers to make reliable statements about the effect of therapy and disease progression. Parameters from inertial measurement units (IMUs) are objective and accurate, and thus an interesting option to be included in the regular assessment of these patients. In this study, 68 patients with PD (PwP) in Hoehn and Yahr (H&Y) stages 1-4 were assessed with two gait tasks-20 m straight walk and circular walk-using IMUs. In an ANCOVA model, we found a significant and large effect of the H&Y scores on step length in both tasks, and only a minor effect on step time. This study provides evidence that from the two potentially most important gait parameters currently accessible with wearable technology under supervised assessment strategies, step length changes substantially over the course of PD, while step time shows surprisingly little change in the progression of PD. These results show the importance of carefully evaluating quantitative gait parameters to make assumptions about disease progression, and the potential of the granular evaluation of symptoms such as gait deficits when monitoring chronic progressive diseases such as PD.
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http://dx.doi.org/10.3390/s21072292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037757PMC
March 2021

Complications following REM sleep behavior disorder.

Brain Behav 2021 05 30;11(5):e02129. Epub 2021 Mar 30.

Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany.

REM sleep behavior disorder (RBD) is gaining increasing attention as important prodromal marker for the development of neurodegenerative disorders such as Parkinson's Disease. However, the clinical relevance of this disorder and its association with other prodromal markers is often underestimated in clinical routine. We here report a case of severe clinical complications following extensive nocturnal movements due to RBD, aggravated by occurrence of additional prodromal non-motor symptoms. This case stresses the importance of recognizing RBD as a multisystem disease by all clinical disciplines.
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http://dx.doi.org/10.1002/brb3.2129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119867PMC
May 2021

Parkinson's Disease Subtypes: Critical Appraisal and Recommendations.

J Parkinsons Dis 2021 ;11(2):395-404

Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, Canada.

Background: In Parkinson's disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential contribution for the knowledge of disease pathophysiology, natural history and therapeutic development. There have been many studies of PD subtypes but their impact remains unclear with limited application in research or clinical practice.

Objective: To critically evaluate PD subtyping systems.

Methods: We conducted a systematic review of PD subtypes, assessing the characteristics of the studies reporting a subtyping system for the first time. We completed a critical appraisal of their methodologic quality and clinical applicability using standardized checklists.

Results: We included 38 studies. The majority were cross-sectional (n = 26, 68.4%), used a data-driven approach (n = 25, 65.8%), and non-clinical biomarkers were rarely used (n = 5, 13.1%). Motor characteristics were the domain most commonly reported to differentiate PD subtypes. Most of the studies did not achieve the top rating across items of a Methodologic Quality checklist. In a Clinical Applicability Checklist, the clinical importance of differences between subtypes, potential treatment implications and applicability to the general population were rated poorly, and subtype stability over time and prognostic value were largely unknown.

Conclusion: Subtyping studies undertaken to date have significant methodologic shortcomings and most have questionable clinical applicability and unknown biological relevance. The clinical and biological signature of PD may be unique to the individual, rendering PD resistant to meaningful cluster solutions. New approaches that acknowledge the individual-level heterogeneity and that are more aligned with personalized medicine are needed.
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http://dx.doi.org/10.3233/JPD-202472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150501PMC
December 2021

Measurement of the adult human midbrain with transcranial ultrasound.

PLoS One 2021 1;16(3):e0247920. Epub 2021 Mar 1.

UniSA Clinical and Health Sciences and Alliance for Research in Exercise, Nutrition and Activity (ARENA), University of South Australia, Adelaide, SA, Australia.

Background: Transcranial sonography is increasingly used to aid clinical diagnoses of movement disorders, for example, to identify an enlarged area of substantia nigra echogenicity in patients with Parkinson's disease.

Objective: The current study investigated characteristics of the midbrain at the anatomical plane for quantification of substantia nigra echogenicity. METHODS: Area of substantia nigra echogenicity, cross-sectional area of the midbrain, and interpeduncular angle were quantified in two groups of adults aged 18-50 years: 47 healthy non-drug-using controls (control group) and 22 individuals with a history of methamphetamine use (methamphetamine group), a cohort with a high prevalence of enlarged substantia nigra echogenicity and thus risk of Parkinson's disease.

Results: In the control group, cross-sectional area of the midbrain (4.47±0.44 cm2) and interpeduncular angle were unaffected by age, sex, or image acquisition side. In the methamphetamine group, cross-sectional midbrain area (4.72±0.60 cm2) and area of substantia nigra echogenicity were enlarged compared to the control group, and the enlargement was sex-dependent (larger in males than females). Whole midbrain area and interpeduncular angle were found to be weak predictors of area of substantia nigra echogenicity after accounting for group and sex.

Conclusions: History of methamphetamine use is associated with an enlarged midbrain and area of substantia nigra echogenicity, and the abnormality is more pronounced in males than females. Thus, males may be more susceptible to methamphetamine-induced changes to the brainstem, and risk of Parkinson's disease, than females.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247920PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920378PMC
October 2021

Motor cortical excitability and paired-associative stimulation-induced plasticity in amnestic mild cognitive impairment and Alzheimer's disease.

Clin Neurophysiol 2021 09 3;132(9):2264-2273. Epub 2021 Feb 3.

Department of Neurology & Stroke, University of Tübingen, Tübingen, Germany; Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. Electronic address:

Objective: Synaptopathy including alterations of synaptic plasticity (long-term potentiation, LTP) may precede neurodegeneration in Alzheimer's disease (AD). We studied LTP-like corticospinal plasticity induced by paired-associative stimulation (PAS) in AD and its prodromal stage, amnestic mild cognitive impairment (aMCI).

Methods: 15 AD and 15 aMCI patients, and 23 demographically matched healthy controls (HC) were included. Resting motor threshold (RMT) and stimulus intensity needed to evoke motor evoked potentials (MEP) of 1 mV (SI1mV) were obtained as single-pulse transcranial magnetic stimulation (TMS) measures of corticospinal excitability in a hand muscle at baseline, followed by PAS using standard methodology. MEP amplitude change after PAS normalized to baseline was defined as plasticity effect. All measures were repeated in two visits for examining test-retest reliability.

Results: SI1mV were lower in aMCI compared to HC, while there was no difference between AD and HC. RMT and SI1mV showed excellent test-retest reliability in all groups. PAS indiscriminately did not induce LTP-like plasticity in any of the groups, and expressed poor test-retest reliability.

Conclusions: aMCI shows corticospinal hyperexcitability, consistent with glutamatergic excitotoxicity in early-stage AD. Possible abnormalities of LTP-like plasticity could not be reliably tested with the standard PAS protocol due to massive inter-subject variability even in HC, and poor test-retest reliability.

Significance: Findings indicate corticospinal hyperexcitability in prodromal AD, and reliability of single-pulse TMS measures for identifying such abnormality. In contrast, the standard PAS protocol may not be suitable for assessing LTP-like motor cortical plasticity, given its overall nil effect and poor test-retest reliability.
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http://dx.doi.org/10.1016/j.clinph.2021.01.011DOI Listing
September 2021

The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PD.

Mov Disord 2021 05 6;36(5):1216-1228. Epub 2021 Feb 6.

Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Background: With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PD ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement.

Objective: To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI).

Methods: We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PD patients compared to PD patients.

Results: Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PD compared to PD . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PD compared to PD . (3) CSF levels of total α-synuclein were lower in PD compared to PD . All of these findings were most pronounced in PD with severe mutations (PD ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PD . Cross-sectionally in TUEPAC-MIGAP by-products sphinganine and sphingosine-1-phosphate and longitudinally in PPMI species of by-products lactosylceramides and sphingomyelin were higher in PD .

Interpretation: These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PD with severe variants. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28472DOI Listing
May 2021

Effects of Levodopa on quality of sleep and nocturnal movements in Parkinson's Disease.

J Neurol 2021 Jul 5;268(7):2506-2514. Epub 2021 Feb 5.

Department of Neurology, Christian-Albrecht-University Kiel, Arnold-Heller-Straße 3, Kiel, Germany.

Background: Sleep disturbances are common in Parkinson's Disease (PD), with nocturnal akinesia being one of the most burdensome. Levodopa is frequently used in clinical routine to improve nocturnal akinesia, although evidence is not well proven.

Methods: We assessed associations of Levodopa intake with quality of sleep and perception of nocturnal akinesia in three PD cohorts, using the Parkinson's Disease Sleep Scale (PDSS-2) in two cohorts and a question on nocturnal immobility in one cohort. In one cohort also objective assessment of mobility during sleep was performed, using mobile health technology.

Results: In an independent analysis of all three cohorts (in total n = 1124 PD patients), patients taking Levodopa CR reported a significantly higher burden by nocturnal akinesia than patients without Levodopa. Higher Levodopa intake and MDS-UPDRS part IV scores (indicating motor fluctuations) predicted worse PDSS-2 and higher subjective nocturnal immobility scores, while disease duration and severity were not predictive. Levodopa intake was not associated with objectively changed mobility during sleep.

Conclusion: Our results showed an association of higher Levodopa intake with perception of worse quality of sleep and nocturnal immobility in PD, indicating that Levodopa alone might not be suitable to improve subjective feeling of nocturnal akinesia in PD. In contrast, Levodopa intake was not relevantly associated with objectively measured mobility during sleep. PD patients with motor fluctuations may be particularly affected by subjective perception of nocturnal mobility. This study should motivate further pathophysiological and clinical investigations on the cause of perception of immobility during sleep in PD.
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http://dx.doi.org/10.1007/s00415-021-10419-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216994PMC
July 2021
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