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Background and purpose: Orthostatic hypotension is frequent with aging with a prevalence of 20%–30% in people aged 65 or older and is considered to increase the risk for coronary events, strokes and dementia. Our objective was to characterize the association of orthostatic hypotension and cognitive function longitudinally over 6 years in a large cohort of the elderly aged over 50 years. Methods: In all, 495 participants were assessed longitudinally with the Schellong test and comprehensive cognitive testing using the extended CERAD neuropsychological test battery at baseline and after 6 years. In a subgroup of 92 participants, cerebral magnetic resonance imaging was evaluated for white matter changes using a modified version of the Fazekas score. Results: The prevalence of orthostatic hypotension increases with aging reaching up to 30% in participants aged >70 years. Participants with orthostatic hypotension presented with a higher vascular burden index (1.03 vs. 0.69, P ≤ 0.001), tended to have a higher prevalence of cerebral white matter hyperintensities (91.7% vs. 68.8%, P = 0.091) and showed a faster deterioration in executive and memory function (Trail Making Test B 95 vs. 87 s, P ≤ 0.001; word list learning sum −0.53 vs. 0.38, P = 0.002) compared to participants without orthostatic hypotension. Conclusion: Orthostatic hypotension seems to be associated with cognitive decline longitudinally. [ABSTRACT FROM AUTHOR]

Introduction: With age, sensory, cognitive, and motor abilities decline, and the risk for neurodegenerative disorders increases. These impairments influence the quality of life and increase the need for care, thus putting a high burden on society, the economy, and the healthcare system. Therefore, it is important to identify factors that influence healthy aging, particularly ones that are potentially modifiable through lifestyle choices. However, large-scale studies investigating the influence of multi-modal factors on a global description of healthy aging measured by multiple clinical assessments are sparse., Methods: We propose a machine learning model that simultaneously predicts multiple cognitive and motor outcome measurements on a personalized level recorded from one learned composite score. This personalized composite score is derived from a large set of multi-modal components from the TREND cohort, including genetic, biofluid, clinical, demographic, and lifestyle factors., Results: We found that a model based on a single composite score was able to predict cognitive and motor abilities almost as well as a classical flexible regression model specifically trained for each single clinical score. In contrast to the flexible regression model, our composite score model is able to identify factors that globally influence cognitive and motoric abilities as measured by multiple clinical scores. The model identified several risk and protective factors for healthy aging and recovered physical exercise as a major, modifiable, protective factor., Discussion: We conclude that our low parametric modeling approach successfully recovered known risk and protective factors of healthy aging on a personalized level while providing an interpretable composite score. We suggest validating this modeling approach in other cohorts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Schalkamp, Lerche, Wurster, Roeben, Zimmermann, Fries, von Thaler, Eschweiler, Maetzler, Berg, Sinz and Brockmann.)

The CSF1R gene, located on chromosome 5, encodes a 108 kDa protein and plays a critical role in regulating myeloid cell function. Mutations in CSF1R have been identified as a cause of a rare white matter disease called adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP, also known as CSF1R-related leukoencephalopathy), characterized by progressive neurological dysfunction. This study aimed to broaden the genetic basis of ALSP by identifying novel CSF1R variants in patients with characteristic clinical and imaging features of ALSP. Genetic analysis was performed through whole-exome sequencing or panel analysis for leukodystrophy genes. Variant annotation and classification were conducted using computational tools, and the identified variants were categorized following the recommendations of the American College of Medical Genetics and Genomics (ACMG). To assess the evolutionary conservation of the novel variants within the CSF1R protein, amino acid sequences were compared across different species. The study identified six previously unreported CSF1R variants (c.2384G>T, c.2133_2919del, c.1837G>A, c.2304C>A, c.2517G>T, c.2642C>T) in seven patients with ALSP, contributing to the expanding knowledge of the genetic diversity underlying this rare disease. The analysis revealed considerable genetic and clinical heterogeneity among these patients. The findings emphasize the need for a comprehensive understanding of the genetic basis of rare diseases like ALSP and underscored the importance of genetic testing, even in cases with no family history of the disease. The study's contribution to the growing spectrum of ALSP genetics and phenotypes enhances our knowledge of this condition, which can be crucial for both diagnosis and potential future treatments., (© 2024. The Author(s).)

Background: Identifying individuals with Parkinson's disease (PD) already in the prodromal phase of the disease has become a priority objective for opening a window for early disease-modifying therapies., Objective: The aim was to evaluate a blood-based α-synuclein seed amplification assay (α-syn SAA) as a novel biomarker for diagnosing PD in the prodromal phase., Methods: In the TREND study (University of Tuebingen) biennial blood samples of n = 1201 individuals with/without increased risk for PD were taken prospectively over 4 to 10 years. We retrospectively analyzed blood samples of 12 participants later diagnosed with PD during the study to detect and amplify pathological α-syn conformers derived from neuronal extracellular vesicles using (1) immunoblot analyses with an antibody against these conformers and (2) an α-syn-SAA. Additionally, blood samples of n = 13 healthy individuals from the TREND cohort and n = 20 individuals with isolated rapid eye movement sleep behavior disorder (iRBD) from the University Hospital Cologne were analyzed., Results: All individuals with PD showed positive immunoblots and a positive α-syn SAA at the time of diagnosis. Moreover, all PD patients showed a positive α-syn SAA 1 to 10 years before clinical diagnosis. In the iRBD cohort, 30% showed a positive α-syn SAA. All healthy controls had a negative SAA., Conclusions: We here demonstrate the possibility to detect and amplify pathological α-syn conformers in peripheral blood up to 10 years before the clinical diagnosis of PD in individuals with and without iRBD. The findings of this study indicate that this blood-based α-syn SAA assay has the potential to serve as a diagnostic biomarker for prodromal PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

With disease-modifying treatment for Parkinson's disease (PD) associated with variants in the glucocerebrosidase gene (GBA1) under way, the challenge to design clinical trials with non-PD-manifest GBA mutation carriers (GBA1 NMC ) comes within close reach. To delineate trajectories of motor and non-motor markers as well as serum neurofilament light (sNfL) levels and to evaluate clinical endpoints as outcomes for clinical trials in GBA1 NMC , longitudinal data of 56 GBA1 NMC carriers and 112 age- and sex-matched GBA1 wildtype participants (GBA1 wildtype ) with up to 9 years of follow-up was analyzed using linear mixed-effects models (LMEM) and Kaplan-Meier survival analysis of clinical endpoints for motor and cognitive function. GBA1 NMC showed worse performance in Pegboard, 20 m fast walking, global cognition as well as in executive and memory function at baseline. Longitudinally, LMEM revealed a higher annual increase of the MDS-UPDRS III bradykinesia subscore in GBA1 NMC compared to GBA1 wildtype , but comparable trajectories of all other motor and non-motor markers as well as sNfL. Kaplan-Meier survival analysis showed a significantly earlier progression to clinical endpoints of cognitive decline in GBA1 NMC . Incidence of PD was significantly higher in GBA1 NMC . In conclusion, our study extends data on GBA1 NMC indicating early cognitive decline as a potentially characteristic feature. Comprehensive longitudinal assessments of cognitive function are crucial to delineate the evolution of early changes in GBA1 NMC enabling a more accurate stratification and allow for a more precise definition of trial design and sample size., (© 2024. The Author(s).)

Seed amplification assays have been implemented in Parkinson's disease to reveal disease-specific misfolded alpha-synuclein aggregates in biospecimens. While the assays' qualitative dichotomous seeding response is valuable to stratify and enrich cohorts for alpha-synuclein pathology in general, more quantitative parameters that are associated with clinical dynamics of disease progression and that might potentially serve as exploratory outcome measures in clinical trials targeting alpha-synuclein would add important information. To evaluate whether the seeding kinetic parameters time required to reach the seeding threshold (LAG phase), the peak of fluorescence response (Imax), and the area under the curve (AUC) are associated with clinical trajectories, we analyzed LAG, Imax, and AUC in relation to the development of cognitive decline in a longitudinal cohort of 199 people with Parkinson's disease with positive CSF alpha-synuclein seeding status. Patients were stratified into tertiles based on their individual CSF alpha-synuclein seeding kinetic properties. The effect of the kinetic parameters on longitudinal development of cognitive impairment defined by MoCA ≤25 was analyzed by Cox-Regression. Patients with a higher number of positive seeding replicates and tertile groups of shorter LAG, higher Imax, and higher AUC showed a higher prevalence of and a shorter duration until cognitive impairment longitudinally (3, 6, and 3 years earlier with p ≤ 0.001, respectively). Results remained similar in separate subgroup analyses of patients with and without GBA mutation. We conclude that a more prominent alpha-synuclein seeding kinetic profile translates into a more rapid development of cognitive decline., (© 2024. The Author(s).)

Objective: Cerebral amyloid angiopathy (CAA) is a common cause of lobar and subarachnoid hemorrhages in the elderly. A diagnosis of CAA requires multiple lobar hemorrhagic lesions (intracerebral hemorrhage and/or cerebral microbleeds) and/or cortical superficial siderosis (cSS). In contrast, hemorrhagic lesions located in the deep structures are the hallmark of hypertensive arteriopathy (HTN-A). They are an exclusion criterion for CAA, and when present with lobar hemorrhagic lesions considered a separate entity: mixed location hemorrhages/microbleeds (MLHs). We compared clinical, radiological, and cerebrospinal fluid (CSF) marker data in patients with CAA, MLH, and Alzheimer's disease (AD), and healthy controls (HCs) and used it to position MLH in the disease spectrum., Patients and Methods: Retrospective cohort study of consecutive patients with CAA (n = 31), MLH (n = 31), AD (n = 28), and HC (n = 30). Analysis of clinical, radiological, CSF biomarker (Aß42, Aß40, t-tau, and p-tau), and histopathological data in patients each group., Results: cSS was significantly more common in CAA than MLH (45% vs 13%, p = 0.011), and cSS in MLH was associated with intracerebral hemorrhage (ICH) (p = 0.037). Aß42 levels and the Aß42/Aß40 ratio, diagnostic groups followed the order HC > MLH > CAA > AD and the opposite order for t -tau and p-tau. No clear order was apparent forAß40. Aß40 and Aß42 levels as well as the Aß42/Aß40 ratio were lower in both CAA and MLH patients with cSS than in patients without cSS. Aß40 and Aß42 levels were higher in CAA and MLH patients with lacunar infarcts than in those without., Conclusion: Our data suggest that MLH and CAA are mutually not exclusive diagnoses, and are part of a spectrum with variable contributions of both CAA and HTN-A.

Inflammation modifies the incidence and progression of Parkinson's disease (PD). By using 30 inflammatory markers in CSF in 498 people with PD and 67 people with dementia with Lewy bodies (DLB) we show that: (1) levels of ICAM-1, Interleukin-8, MCP-1, MIP-1 beta, SCF and VEGF were associated with clinical scores and neurodegenerative CSF biomarkers (Aβ1-42, t-Tau, p181-Tau, NFL and α-synuclein). (2) PD patients with GBA mutations show similar levels of inflammatory markers compared to PD patients without GBA mutations, even when stratified by mutation severity. (3) PD patients who longitudinally developed cognitive impairment during the study had higher levels of TNF-alpha at baseline compared to patients without the development of cognitive impairment. (4) Higher levels of VEGF and MIP-1 beta were associated with a longer duration until the development of cognitive impairment. We conclude that the majority of inflammatory markers is limited in robustly predicting longitudinal trajectories of developing cognitive impairment., (© 2023. The Author(s).)

Background: An involvement of the central-nervous and peripheral, innate and adaptive immune system in the pathogenesis of Parkinson's disease (PD) is nowadays well established., Objectives: We face several open questions in preparation of clinical trials aiming at disease-modification by targeting the immune system: Do peripheral (blood) inflammatory profiles reflect central (CSF) inflammatory processes? Are blood/CSF inflammatory markers associated with CSF levels of neurodegenerative/PD-specific biomarkers?, Methods: Using a multiplex assay we assessed 41 inflammatory markers in CSF/serum pairs in 453 sporadic PD patients. We analyzed CSF/serum correlation as well as associations of inflammatory markers with clinical outcome measures (UPDRS-III, H&Y, MoCA) and with CSF levels of α-synuclein, Aβ 1-42 , t- Tau, p181-Tau and NFL. All analyses were stratified by sex as the immune system shows relevant sex-specific differences., Results: Correlations between CSF and serum were sparse and detected in only 25% (9 out of 36) of the analysable inflammatory markers in male PD patients and in only 38% (12 out of 32) of female PD patients. The most important pro-inflammatory mediators associated with motor and cognitive decline as well as with neurodegenerative/PD-specific biomarkers were FABP, ICAM-1, IL-8, MCP-1, MIP-1-beta, and SCF. Results were more robust for CSF than for serum., Interpretation: Levels of central-nervous and peripheral inflammatory markers might be regulated independently of each other with CSF inflammatory markers reflecting CNS pathology more accurately than peripheral markers. These findings along with sex-specific characteristics have to be considered when designing clinical trials aiming at disease-modification by targeting the immune system., Competing Interests: KW and IL are employed by Roboscreen GmbH which manufactures the ELISA kit for measurements of total human α-synuclein used in the present study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lerche, Zimmermann, Wurster, Roeben, Fries, Deuschle, Waniek, Lachmann, Gasser, Jakobi, Joos, Schneiderhan-Marra and Brockmann.)

Background: To evaluate the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers in patients with probable cerebral amyloid angiopathy (CAA) according to the modified Boston criteria in a retrospective multicentric cohort., Methods: Beta-amyloid 1-40 (Aβ40), beta-amyloid 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau 181 (p-tau 181 ) were measured in 31 patients with probable CAA, 28 patients with Alzheimer's disease (AD), and 30 controls. Receiver-operating characteristics (ROC) analyses were performed for the measured parameters as well as the Aβ42/40 ratio to estimate diagnostic parameters. A meta-analysis of all amenable published studies was conducted., Results: In our data Aβ42/40 (AUC 0.88) discriminated best between CAA and controls while Aβ40 did not perform well (AUC 0.63). Differentiating between CAA and AD, p-tau 181 (AUC 0.75) discriminated best in this study while Aβ40 (AUC 0.58) and Aβ42 (AUC 0.54) provided no discrimination. In the meta-analysis, Aβ42/40 (AUC 0.90) showed the best discrimination between CAA and controls followed by t-tau (AUC 0.79), Aβ40 (AUC 0.76), and p-tau 181 (AUC 0.71). P-tau 181 (AUC 0.76), Aβ40 (AUC 0.73), and t-tau (AUC 0.71) differentiated comparably between AD and CAA while Aβ42 (AUC 0.54) did not. In agreement with studies examining AD biomarkers, Aβ42/40 discriminated excellently between AD and controls (AUC 0.92-0.96) in this study as well as the meta-analysis., Conclusion: The analyzed parameters differentiate between controls and CAA with clinically useful accuracy (AUC > ∼0.85) but not between CAA and AD. Since there is a neuropathological, clinical and diagnostic continuum between CAA and AD, other diagnostic markers, e.g., novel CSF biomarkers or other parameters might be more successful., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Margraf, Jensen-Kondering, Weiler, Leypoldt, Maetzler, Philippen, Bartsch, Flüh, Röcken, Möller, Royl, Neumann, Brüggemann, Roeben, Schulte, Bender, Berg and Kuhlenbäumer.)

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., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Molecular pathways associated with α-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids., Objective: The objective of this study was to evaluate CSF protein profiles of pathways related to α-synuclein proteostasis., Methods: We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α-synuclein pathology with pronounced clinical trajectories., Results: (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α-synuclein, with lower levels of proteostasis proteins related to lower levels of total α-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α-synuclein longitudinally compared with PD patients with a normal proteostasis profile., Conclusion: CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α-synuclein proteostasis in PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF.These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn., (© 2021. The Author(s).)

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.

Background: With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PD GBA ) 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 GBA patients compared to PD GBA_wildtype patients., Results: Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PD GBA compared to PD GBA_wildtype . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PD GBA compared to PD GBA_wildtype . (3) CSF levels of total α-synuclein were lower in PD GBA compared to PD GBA_wildtype . All of these findings were most pronounced in PD GBA with severe mutations (PD GBA_severe ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PD GBA_severe . 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 GBA_severe ., 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 GBA with severe variants. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Objective: To examine whether hippocampal volume loss is primarily associated with cognitive status or pathologic β-amyloid 1-42 (Aβ42) levels, this study compared hippocampal subfield volumes between patients with Parkinson disease (PD) with mild cognitive impairment (PD-MCI) and without cognitive impairment (PD-CN) and between patients with low and high Aβ42 levels, in addition exploring the relationship among hippocampal subfield volumes, CSF biomarkers (Aβ42, phosphorylated and total tau), neuropsychological tests, and activities of daily living., Methods: Forty-five patients with PD without dementia underwent CSF analyses and MRI as well as comprehensive motor and neuropsychological examinations. Hippocampal segmentation was conducted using FreeSurfer image analysis suite 6.0. Regression models were used to compare hippocampal subfield volumes between groups, and partial correlations defined the association between variables while controlling for intracranial volume (ICV)., Results: Linear regressions revealed cognitive group as a statistically significant predictor of both the hippocampal-amygdaloid transition area (HATA; β = -0.23, 95% CI -0.44 to -0.02) and the cornu ammonis 1 region (CA1; β = -0.28, 95% confidence interval [CI] -0.56 to -0.02), independent of disease duration and ICV, with patients with PD-MCI showing significantly smaller volumes than PD-CN. In contrast, no subfields were predicted by Aβ42 levels. Smaller hippocampal volumes were associated with worse performance on memory, language, spatial working memory, and executive functioning tests. The subiculum was negatively correlated with total tau levels ( r = -0.37, 95% CI -0.60 to -0.09)., Conclusion: Cognitive status, but not CSF Aβ42, predicted hippocampal volumes, specifically the CA1 and HATA. Hippocampal subfields were associated with various cognitive domains, as well as with tau pathology., (© 2020 American Academy of Neurology.)

Objective: To characterize peripheral nerve morphology in cerebrotendinous xanthomatosis (CTX) patients using high-resolution ultrasound (HRUS) in vivo. We hypothesized that nerve enlargements might be present in CTX as a result of accumulation of abnormal lipids with deposition also in peripheral nerves., Methods: Four CTX patients were examined using HRUS to assess morphological abnormalities of peripheral nerves as well as cervical nerve roots 5 and 6., Results: HRUS revealed mild to moderate, hypoechogenic thickening of sensorimotor nerves (ulnar nerve in 1/4, tibial nerve in 3/4, median nerve 4/4 patients) as well as mild enlargement of pure sensory nerves (sural nerve in 2/3, superficial FN in 2/4 patients). The vagal nerve was moderately enlarged in one patient, cervical roots showed moderate enlargements of C5 in two patients, one of which also showing thickening of C6 as well as in another patient. UPSS score was slightly to moderately abnormal in all patients. The Homogeneity score was not increased suggesting regional to inhomogeneous nerve enlargement., Conclusions: HRUS shows multifocal, hypoechogenic nerve thickening of peripheral nerves and nerve roots in CTX., Significance: HRUS might serve as a valuable, additive and non-invasive bedside tool to assess peripheral nerve morphology in future clinical studies on CTX patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: With disease-modifying treatment strategies on the horizon, stratification of individual patients at the earliest stages of Parkinson's disease (PD) is key-ideally already at clinical disease onset. Blood levels of neurofilament light chain (NfL) provide an easily accessible fluid biomarker that might allow capturing the conversion from prodromal to manifest PD., Methods: We assessed longitudinal serum NfL levels in subjects converting from prodromal to manifest sporadic PD (converters), at-risk subjects, and matched controls (72 participants with ≈4 visits), using single-molecule array (Simoa) technique., Results: While NfL levels were not increased at the prodromal stage, subjects converting to the manifest motor stage showed a significant intraindividual acceleration of the age-dependent increase of NfL levels., Conclusions: The temporal dynamics of intraindividual NfL blood levels might mark the conversion to clinically manifest PD, providing a potential stratification biomarker for individual disease onset in the advent of precision medicine for PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

The core criterion for Parkinson's disease dementia (PDD) is the impairment in activities of daily living (ADL) function primarily caused by cognitive, not motor symptoms. There is evidence to assume that mild ADL impairments in mild cognitive impairment (PD-MCI) characterize those patients at high risk for dementia. Data of 216 Parkinson's disease (PD) patients assessed with comprehensive motor and neuropsychological assessments were analysed. Based on linear regression models, subscores of the Functional Activities Questionnaire (FAQ) primarily reflecting patients' global cognitive status (FAQ C ) or PD-related motor severity (FAQ M ) were developed. A quotient (FAQ Q ) of both scores was calculated, with values >1 indicating more cognitive- compared to motor-driven ADL impairment. Both FAQ C and FAQ M scores were higher in PD-MCI than cognitively normal (PD-CN) patients, indicating more severe cognitive- and motor-driven ADL impairments in this group. One third (31.6%) of the PD-MCI group had a FAQ Q score >1, which was significantly different from patients with PD-CN (p = .02). PD-MCI patients with an FAQ Q score >1 were more impaired on tests assessing attention (p = .019) and language (p = .033) compared to PD-MCI patients with lower FAQ Q values. The differentiation between cognitive- and motor-driven ADL is important, as the loss of functional capacity is the defining factor for a diagnosis of PDD. We were able to differentiate the cognitive-driven from the motor-driven ADL impairments for the FAQ. PD-MCI patients with more cognitive- compared to motor-driven ADL impairments may pose a risk group for conversion to PDD and can be targeted for early treatments., (© 2018 The British Psychological Society.)

Background: Mutations in the gene glucocerebrosidase (GBA1) are specifically associated with alpha-synucleinopathies, namely, Parkinson's disease (PD) and dementia with Lewy bodies. As disease-modifying treatment options such as alpha-synuclein lowering compounds are under way, patient stratification according to alpha-synuclein-specific enrichment strategies, possibly reflected by cerebrospinal fluid (CSF) profiles, is a much needed prerequisite., Objective: Are GBA1 mutations associated with a CSF alpha-synuclein profile in PD?, Methods: Screening of the GBA1 gene and analysis of CSF levels of total alpha-synuclein were performed in 80 PD GBA , 80 PD GBA _ wildtype and 39 healthy controls cross-sectionally. Subgroup analyses based on mutation severity was done for PD GBA ., Results: Patients carrying severe GBA1 mutations showed (1) an earlier age at onset, (2) more pronounced cognitive decline and higher prevalence of rapid eye movement sleep behavior disorder, and (3) reduced CSF levels of total alpha-synuclein., Conclusion: The effects of GBA1 mutations on CSF alpha-synuclein profiles and phenotypical characteristics seem dependent on GBA1 mutation severity. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

The primary role of magnetic resonance imaging (MRI) in routine diagnostic work-up of motor neuron disease patients is currently still largely limited to exclusion of relevant non-degenerative pathologies. We here present an illustrative case of a 63-year-old woman with early stage Frontotemporal-Dementia-Amyotrophic-Lateral-Sclerosis (FTD-ALS) spectrum disorder showing a striking hypointense signal of the cortical band along the precentral gyrus, termed "motor band sign" (MBS). Based on this finding, we analysed the frequency of the MBS in clinical routine MRIs in a large consecutive series of ALS patients (MRIs available from 157 patients). MBS was present in 5% patients of the total series, but in 78% of patients where susceptibility-weighted images (SWI) were available. These findings suggest that the MBS is a recurrent finding in ALS, which can be identified even on clinical routine 3 T-MRI, and as part of more complex motor neuron syndromes, such as FTD-ALS. Moreover, they indicate that SWI sequences should be considered as part of the clinical routine MRI protocol in the diagnostic work-up of ALS patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Patients with dementia with Lewy bodies reveal a variable pathology including alpha-synuclein, amyloid-beta, and Tau. Mutations in GBA1 are specifically associated with synucleinopathies. PD patients with GBA1 mutations show reduced CSF levels of total alpha-synuclein., Objective: Whether GBA1 mutations are associated with a CSF alpha-synuclein profile in dementia with Lewy bodies., Methods: Screening of the GBA1 gene and single-nucleotide polymorphisms in SNCA rs356220, APOE rs429358, and MAPT rs1052587 as well as CSF levels of total alpha-synuclein, amyloid-beta 1-42 , total-Tau, phospho-Tau, and neurofilament light chain were assessed in 100 dementia with Lewy bodies and 39 controls cross-sectionally., Results: Severity of GBA1 mutations was associated with a younger age at onset and higher prevalence of rapid eye movement sleep behavior disorder. CSF levels of total alpha-synuclein were lowest in DLB GBA_pathogenic compared to DLB GBA_mild and DLB GBA_wildtype ., Conclusion: Similar to PD, pathogenic GBA1 mutations seem to be associated with CSF alpha-synuclein profiles in dementia with Lewy bodies. That might be useful for patient stratification for specific alpha-synuclein-lowering compounds. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Introduction: Impairment of dual-tasking, as an attention-based primary cognitive dysfunction, is frequently observed in Parkinson's Disease (PD). The Training-PD study investigated the efficiency of exergaming, as a novel cognitive-motor training approach, to improve attention-based deficits and dual-tasking in PD when compared to healthy controls. Methods: Eighteen PD patients and 17 matched healthy controls received a 6-week home-based training period of exergaming. Treatment effects were monitored using quantitative motor assessment of gait and cognitive testing as baseline and after 6 weeks of training. Results: At baseline PD patients showed a significantly worse performance in several quantitative motor assessment parameters and in two items of cognitive testing. After 6 weeks of exergames training, the comparison of normal gait vs. dual-tasking in general showed an improvement of stride length in the PD group, without a gait-condition specific improvement. In the direct comparison of three different gait conditions (normal gait vs. dual-tasking calculating while walking vs. dual-tasking crossing while walking) PD patients showed a significant improvement of stride length under the dual-tasking calculating condition. This corresponded to a significant improvement in one parameter of the D2 attention test. Conclusions: We conclude, that exergaming, as an easy to apply, safe technique, can improve deficits in cognitive-motor dual-tasking and attention in PD.

REM sleep behavior disorder (RBD) represents a major and relatively specific prodromal marker for synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies, and multisystem atrophy. Because PD patients primarily suffer from executive dysfunction, we hypothesized that individuals with RBD show an impairment in the nonamnestic executive domain rather than in amnestic domains. To address this question, we investigated a cohort of 1145 healthy elderly (183 with RBD) cross-sectionally and a subgroup of 544 of them longitudinally (144 with RBD) over 6 years. Assessments included the RBD screening questionnaire, the extended Consortium to Establish a Registry for Alzheimer's Disease test battery, and genetic testing for the risk variant rs356219 in the alpha-synuclein gene. In the cross-sectional analysis, the RBD subgroup showed worse performance in the Trail Making Test (TMT) part B and the delta-TMT_B-A when compared to non-RBD subjects. Longitudinal observation revealed a deterioration of TMT-B and delta-TMT_B-A in RBD subjects, a phenomenon that was not observed in the group of non-RBD subjects. These data argue for an early and progressive deterioration of executive dysfunction associated with RBD. Of the total cohort, 18 developed Parkinsonism including 16 with sporadic PD after a mean follow-up of 4.6 years. Of the sporadic PD cases, 4.4% were from the probable RBD group and 0.8% of the non-RBD group. The potential of this dynamic for the detection of prodromal synucleinopathies seems relevant, but has to be determined in studies including converters., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Due to the aging population, dementias represent a growing challenge for the health systems and for the society. This overview summarizes the current state of already practice-relevant therapies and management of dementias. Non-pharmacological approaches have a greater impact than pharmacological treatment. Increasing evidence underlines that consistent management of cardiovascular risk factors has beneficial effects on the progression of at least some, possibly almost all types of dementias. The main pharmacological agents for symptomatic treatment of cognitive deficits in Alzheimer's and Parkinson's disease-associated dementias are cholinesterase inhibitors and memantine. In most other dementias, no specific pharmacological treatment is currently available. There is an urgent need for further research on the effective management of dementias., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To demonstrate that mutations in the phosphatidylglycerol remodelling enzyme SERAC1 can cause juvenile-onset complicated hereditary spastic paraplegia (cHSP) clusters, thus adding SERAC1 to the increasing number of complex lipid cHSP genes., Methods: Combined genomic and functional validation studies (whole-exome sequencing, mRNA, cDNA and protein), biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1), and clinical and imaging phenotyping were performed in six affected subjects from two different branches of a large consanguineous family., Results: 5 of 6 affected subjects shared cHSP as a common disease phenotype. Three subjects presented with juvenile-onset oligosystemic cHSP, still able to walk several miles at age >10-20 years. This benign phenotypic cluster and disease progression is strikingly divergent to the severe infantile phenotype of all SERAC1 cases reported so far. Two family members showed a more multisystemic juvenile-onset cHSP, indicating an intermediate phenotype between the benign oligosystemic cHSP and the classic infantile SERAC1 cluster. The homozygous splice mutation led to loss of the full-length SERAC1 protein and impaired phosphatidylglycerol PG34:1/PG36:1 remodelling. These phosphatidylglycerol changes, however, were milder than in classic infantile-onset SERAC1 cases, which might partially explain the milder SERAC1 phenotype., Conclusions: Our findings add SERAC1 to the increasing list of complex lipid cHSP genes. At the same time they redefine the phenotypic spectrum of SERAC1 deficiency. It is associated not only with the severe infantile-onset 'Methylglutaconic aciduria, Deafness, Encephalopathy, Leigh-like' syndrome (MEGDEL syndrome), but also with oligosystemic juvenile-onset cHSP as part of the now unfolding SERAC1 deficiency spectrum., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1., Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported., Results: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills., Interpretation: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015., (© 2017 American Neurological Association.)

Background: The research criteria for prodromal PD of the MDS propose a new approach for the assessment of the individual probability of prodromal PD. These criteria require a testing of their reliability in different prospective cohorts., Objectives: The objective was to evaluate the MDS prodromal PD criteria in 2 independent prospective studies., Methods: Prodromal PD probabilities of the Tübingen Evaluation of Risk Factors for Early Detection of Neurodegeneration cohort (TREND study, n = 650, recruited by the presence of probable rapid eye movement sleep behavior disorder, depression, and/or hyposmia or none of these at baseline and 2-, 4-, and 6-year follow-up) and the population-based Prospective Evaluation of Risk Factors for Idiopathic Parkinson's Syndrome cohort (PRIPS Tübingen subsample; n = 715, baseline and 3- and 5-year follow-up) were calculated. Baseline posttest probabilities, time to PD diagnosis, marker constellations, and longitudinal changes of prodromal PD probabilities were analyzed., Results: Incident PD cases (TREND, n = 10; PRIPS = 7) showed significantly higher likelihood ratios of risk and prodromal markers at baseline when compared with nonconverters. Only 2 of 17 incident PD cases met the criteria for probable prodromal PD (ie, posttest probability > 80%) and 5 had possible prodromal PD (ie, > 50%) 1.4 to 3.8 years before diagnosis. The criteria showed high specificity and negative predictive values (>98%), but low sensitivity (TREND, 30%; PRIPS, 14%) and positive predictive values (TREND, 19%, PRIPS, 50%). The individual risk for prodromal PD in incident PD cases showed an inverse correlation with the time to conversion (Spearman rho = .80, P = .006) and unlike in nonconverters, increased during follow-up., Conclusion: The MDS prodromal criteria provide a practical framework for the calculation of prodromal PD risk. Although specificity of the criteria is high, most patients will not meet the criteria before diagnosis unless testing is thoroughly performed with numerous and highly specific markers objectively assessed. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.