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Spreading of alpha-synuclein (αSyn) may play an important role in Parkinson’s disease and related synucleinopathies. Passive immunization with anti-αSyn antibodies is a promising method to slow down the spreading process and thereby the progression of synucleinopathies. Currently, it remains elusive which specific characteristics are essential to render therapeutic antibodies efficacious. Here, we established a neuronal co-culture model, in which αSyn species are being released from αSyn-overexpressing cells and induce toxicity in a priori healthy GFP-expressing cells. In this model, we investigated the protective efficacy of three anti-αSyn antibodies. Only two of these antibodies, one C-terminal and one N-terminal, protected from αSyn-induced toxicity by inhibiting the uptake of spreading-competent αSyn from the cell culture medium. Neither the binding epitope nor the affinity of the antibodies towards recombinant αSyn could explain differences in biological efficacy. However, both protective antibodies formed more stable antibody-αSyn complexes than the non-protective antibody. These findings indicate that the stability of antibody-αSyn complexes may be more important to confer protection than the binding epitope or affinity to recombinant αSyn.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral disease of the brain—caused by human polyomavirus 2. It affects patients whose immune system is compromised by a corresponding underlying disease or by drugs. Patients with an underlying lymphoproliferative disease have the worst prognosis with a mortality rate of up to 90%. Several therapeutic strategies have been proposed but failed to show any benefit so far. Therefore, the primary therapeutic strategy aims to reconstitute the impaired immune system to generate an effective endogenous antiviral response. Recently, anti-PD-1 antibodies and application of allogeneic virus-specific T cells demonstrated promising effects on the outcome in individual PML patients. This article aims to provide a detailed overview of the literature with a focus on these two treatment approaches. Supplementary Information The online version contains supplementary material available at 10.1007/s00415-021-10952-5.

ZusammenfassungMehr als 20% der Patienten mit idiopathischem Parkinson-Syndrom (IPS) entwickeln Psychosen. Am häufigsten sind visuelle Halluzinationen. Bei der Entwicklung der Psychosen scheinen die Pathogenese der Parkinson-Erkrankung sowie ihre Dauer ebenso eine Rolle zu spielen wie modulierende Effekte der dopaminergen Therapie. Beim Therapiemanagement steht neben allgemeinen Maßnahmen zunächst die Anpassung der dopaminergen Therapie im Vordergrund. Dies kann zu einer Gratwanderung werden zwischen Besserung der Halluzinationen und Verschlechterung der Motorik. Bei unzureichendem Erfolg kann eine antipsychotische Therapie notwendig werden – dabei ist die Auswahl auf sehr wenige Antipsychotika beschränkt, um nicht ernsthafte motorische Verschlechterungen zu riskieren. In der vorliegenden Arbeit wurden basierend auf dem aktuellen Stand der Literatur sowie empirischen Experten-basierten Erfahrungen aus dem klinischen Alltag relevante Aspekte zu Halluzinationen bei IPS-Patienten in der Praxis zusammengefasst und Empfehlungen zum Therapiemanagement erarbeitet.

Objective In the present work, we aimed to investigate the expression of microRNAs (miRNAs) in routine colonic biopsies obtained from patients with idiopathic Parkinson's disease (PD) and to address their value as a diagnostic biomarker for PD and their mechanistic contribution to PD onset and progression. Methods Patients with PD (n = 13) and healthy controls (n = 17) were prospectively recruited to undergo routine colonic biopsies for cancer screening. Total RNA was extracted from the biopsy material and the expression of miRNAs was quantified by Illumina High-Throughput Sequencing. Results Statistical analysis revealed a significant submucosal enrichment of the miRNA hsa-miR-486–5p in colonic biopsies from PD patients compared to the control subjects. The expression of miR-486–5p correlated with age and disease severity as measured by the UPDRS and Hoehn & Yahr scale. miRNA gene target analysis identified 301 gene targets that are affected by miR-486–5p. A follow-up associated target identification and pathway enrichment analysis further determined their role in distinct biological processes in the enteric nervous system (ENS). Interpretation Our work demonstrates an enrichment of submucosal miR-486–5p in routine colonic biopsies from PD patients. Our results will support the examination of miR-486–5p as a PD biomarker and help to understand the significance of the miR-486–5p gene targets for PD onset and progression. In addition, our data will support the investigation of the molecular and cellular mechanisms of GI dysfunction in PD.

BackgroundThe aim of the study was to determine the role of the Coma Recovery Scale-Revised (CRS-R) in the prediction of functional status at the end of neurological early rehabilitative treatment.MethodsPatients consecutively admitted to intensive or intermediate care units of a neurological rehabilitation center were enrolled in the study. Consciousness and functional status were assessed with the Coma Recovery Scale-Revised (CRS-R) and the Early Rehabilitation Barthel Index (ERBI), respectively. Both assessments were carried out weekly within the first month and at the end of early rehabilitation. Patient and clinical data were entered into a binary logistic regression model to predict functional status at discharge.Results327 patients (112 females, 215 males) with a median age of 63 years (IQR = 53–75) and a median disease duration of 18 days (IQR = 12–28) were included. Most patients suffered from stroke (59 %), followed by traumatic brain injury (31 %), and hypoxic ischemic encephalopathy (10 %). Upon admission, 12 % were diagnosed as comatose, 31 % as unresponsive wakefulness syndrome (UWS), 35 % as minimally conscious state (MCS) and 22 % already emerged from MCS (eMCS). Of all patients undergoing complete early rehabilitative treatment (n = 180), 72 % showed improvements in level of consciousness (LOC). In this group, age, initial CRS-R score and gains in CRS-R score after four weeks independently predicted functional outcome at discharge.ConclusionsThe study confirms the relevance of the CRS-R score for functional outcome prediction. High CRS-R scores and young age facilitate functional improvements and increase the probability to continue treatment in subsequent rehabilitation phases. Moreover, results indicate that recovery might occur over a period of time that extends beyond acute care.

To reduce potentially inappropriate medications, the FORTA (Fit fOR The Aged) concept classifies drugs in terms of their suitability for geriatric patients with different labels, namely A (indispensable), B (beneficial), C (questionable), and D (avoid). The aims of our study were to assess the medication appropriateness in PD inpatients applying the FORTA list and drug-drug interaction software, further to assess the adequacy of FORTA list for patients with PD. We retrospectively collected demographic data, comorbidities, laboratory values, and the medication from the discharge letters of 123 geriatric inpatients with PD at the university hospital of Hannover Medical School. Patients suffered on average from 8.2 comorbidities. The majority of the medication was labeled A (60.6% of PD-specific and 40.9% of other medication) or B (22.3% of PD-specific and 26.9% of other medication). Administered drugs labeled with D were amantadine, clozapine, oxazepam, lorazepam, amitriptyline, and clonidine. Overall, 545 interactions were identified, thereof 11.9% severe interactions, and 1.7% contraindicated combinations. 81.3% of patients had at least one moderate or severe interaction. The FORTA list gives rational recommendations for PD-specific and other medication, especially for general practitioners. Considering the demographic characteristics and the common multimorbidity of geriatric PD patients, this study underlines the importance of awareness, education, and preventive interventions to increase drug safety.

LUHMES cells share many characteristics with human dopaminergic neurons in the substantia nigra, the cells, the demise of which is responsible for the motor symptoms in Parkinson's disease (PD). LUHMES cells can, therefore, be used bona fide as a model to study pathophysiological processes involved in PD. Previously, we showed that LUHMES cells degenerate after 6 days upon overexpression of wild-type alpha-synuclein. In the present study, we performed a transcriptome and proteome expression analysis in alpha-synuclein-overexpressing cells and GFP-expressing control cells in order to identify genes and proteins that are differentially regulated upon overexpression of alpha-synuclein. The analysis was performed 4 days after the initiation of alpha-synuclein or GFP overexpression, before the cells died, in order to identify processes that preceded cell death. After adjustments for multiple testing, we found 765 genes being differentially regulated (439 upregulated, 326 downregulated) and 122 proteins being differentially expressed (75 upregulated, 47 downregulated). In total, 21 genes and corresponding proteins were significantly differentially regulated in the same direction in both datasets, of these 13 were upregulated and 8 were downregulated. In total, 13 genes and 9 proteins were differentially regulated in our cell model, which had been previously associated with PD in recent genome-wide association studies (GWAS). In the gene ontology (GO) analysis of all upregulated genes, the top terms were “regulation of cell death,” “positive regulation of programmed cell death,” and “regulation of apoptotic signaling pathway,” showing a regulation of cell death-associated genes and proteins already 2 days before the cells started to die. In the GO analysis of the regulated proteins, among the strongest enriched GO terms were “vesicle,” “synapse,” and “lysosome.” In total, 33 differentially regulated proteins were associated with synapses, and 12 differentially regulated proteins were associated with the “lysosome”, suggesting that these intracellular mechanisms, which had been previously associated with PD, also play an important role in our cell model.

Sleep complaints are the most prevalent syndromes in older adults, particularly in women. Moreover, they are frequently accompanied with a high level of depression and stress. Although several diffusion tensor imaging (DTI) studies reported associations between sleep quality and brain white matter (WM) microstructure, it is still unclear whether gender impacts the effect of sleep quality on structural alterations, and whether these alterations mediate the effects of sleep quality on emotional regulation. We included 389 older participants (176 females, age = 65.5 ± 5.5 years) from the 1000BRAINS project. Neuropsychological examinations covered the assessments of sleep quality, depressive symptomatology, current stress level, visual working memory, and selective attention ability. Based on the DTI dataset, the diffusion parameter maps, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were calculated and normalized to a population-specific FA template. According to the global Pittsburgh Sleep Quality Index (PSQI), 119 poor sleepers (PSQI: 10∼17) and 120 good sleepers (PSQI: 3∼6) were identified. We conducted a two by two (good sleepers/poor sleepers) × (males/females) analysis of variance by using tract-based spatial statistics (TBSS) and JHU-ICBM WM atlas-based comparisons. Moreover, we performed a voxel-wise correlation analysis of brain WM microstructure with the neuropsychological tests. Finally, we applied a mediation analysis to explore if the brain WM microstructure mediates the relationship between sleep quality and emotional regulation. No significant differences in brain WM microstructure were detected on the main effect of sleep quality. However, the MD, AD, and RD of pontine crossing tract and bilateral inferior cerebellar peduncle were significant lower in the males than females. Voxel-wise correlation analysis revealed that FA and RD values in the corpus callosum were positively related with depressive symptomatology and negatively related with current stress levels. Additionally, we found a significantly positive association between higher FA values in visual-related WM tracts and better outcomes in a visual pattern recognition test. Furthermore, a mediation analysis suggested that diffusion metrics within the corpus callosum partially mediated the associations between poor sleep quality/high stress and depressive symptomatology.

Background The International Parkinson and Movement Disorder Society-endorsed Progressive Supranuclear Palsy Study Group published clinical diagnostic criteria for progressive supranuclear palsy in 2017, aiming to optimize early, sensitive and specific diagnosis. Objective To assist physicians in the application of these criteria, we developed a video-based tutorial in which all core clinical features and clinical clues are depicted and explained. Methods Patients provided written informed consent to the publication of their videos. High-quality videos along with essential descriptions were collected by the study group members. Most educational videos were selected in a structured consensus process. Results We provide 68 videos of all core clinical features and clinical clues defined by the diagnostic criteria, along with instructive descriptions of the depicted patients, examination techniques and clinical findings. Conclusions This comprehensive video-based tutorial will support physicians in the application of the diagnostic criteria of progressive supranuclear palsy.

BACKGROUND: The Movement Disorder Society diagnostic criteria for progressive supranuclear palsy introduced the diagnostic certainty level "suggestive of progressive supranuclear palsy" for clinical conditions with subtle signs, suggestive of the disease. This category aims at the early identification of patients, in whom the diagnosis may be confirmed as the disease evolves. OBJECTIVE: To assess the diagnostic performance of the defined clinical conditions suggestive of progressive supranuclear palsy in an autopsy-confirmed cohort. METHODS: Diagnostic performance of the criteria was analyzed based on retrospective clinical data of 204 autopsy-confirmed patients with progressive supranuclear palsy and 216 patients with other neurological diseases. RESULTS: The conditions suggestive of progressive supranuclear palsy strongly increased the sensitivity compared to the National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy criteria. Within the first year after symptom onset, 40% of patients with definite progressive supranuclear palsy fulfilled criteria for suggestive of progressive supranuclear palsy. Two-thirds of patients suggestive of progressive supranuclear palsy evolved into probable progressive supranuclear palsy after an average of 3.6 years. Application of the criteria for suggestive of progressive supranuclear palsy reduced the average time to diagnosis from 3.8 to 2.2 years. CONCLUSIONS: Clinical conditions suggestive of progressive supranuclear palsy allow earlier identification of patients likely to evolve into clinically possible or probable progressive supranuclear and to have underlying progressive supranuclear palsy pathology. Further work needs to establish the specificity and positive predictive value of this category in real-life clinical settings, and to develop specific biomarkers that enhance their diagnostic accuracy in early disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND AND PURPOSE Knowledge about the seizure prevalence in the whole symptomatic course, from disease onset to death, in neurodegenerative diseases (ND) is lacking. Therefore, the aim was to investigate seizure prevalence and associated clinical implications in neuropathologically diagnosed ND. METHODS Clinical records of cases from the Neurobiobank Munich, Germany, were analyzed. Neuropathological diagnoses of the assessed cases included Alzheimer disease (AD), corticobasal degeneration (CBD), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Seizure prevalence during the whole symptomatic disease phase was assessed and compared amongst ND. Associations between first clinical symptom and seizure prevalence and between seizures and disease duration were examined. RESULTS In all, 454 patients with neuropathologically diagnosed ND and with available and meaningful clinical records were investigated (AD, n = 144; LBD, n = 103; PSP, n = 93; FTLD, n = 53; MSA, n = 36; CBD, n = 25). Seizure prevalence was 31.3% for AD, 20.0% for CBD, 12.6% for LBD, 11.3% for FTLD, 8.3% for MSA and 7.5% for PSP. Seizure prevalence was significantly higher in AD compared to FTLD (p = 0.005), LBD (p = 0.001), MSA (p = 0.005) and PSP (p

The impact of preexisting neurodegenerative diseases on superimposed SARS-CoV-2 infections remains controversial. Here we examined the course and outcome of SARS-CoV-2 infections in patients affected by Parkinson's disease (PD) or dementia compared to matched controls without neurodegenerative diseases in the LEOSS (Lean European Open Survey on SARS-CoV-2-infected patients) cohort, a large-scale prospective multicenter cohort study...

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative condition characterised by a range of motor and cognitive symptoms. Very little is known about the longitudinal change in these symptoms over time. Moreover, the effectiveness of clinical scales to detect early changes in PSP is still a matter of debate.ObjectiveWe aimed to determine longitudinal changes in PSP features using multiple closely spaced follow-up time points over a period of 2 years.Methods28 healthy control and 28 PSP participants, with average time since onset of symptoms of 1.9 years, were prospectively studied every 3 months for up to 24 months. Changes from baseline scores were calculated at each follow-up time point using multiple clinical scales to identify longitudinal progression of motor and cognitive symptoms.ResultsThe Montreal Cognitive Assessment, but not the Mini-Mental State Examination, detected cognitive decline at baseline. Both scales revealed poor longitudinal sensitivity to clinical change in global cognitive symptoms. Conversely, the Movement Disorders Society Unified Parkinson’s disease Rating Scale – part III and the PSP Rating Scale (PSPRS) reliably detected motor decline less than 2 years after disease onset. The ‘Gait/Midline’ PSPRS subscore consistently declined over time, with the earliest change being observed 6 months after baseline assessment.ConclusionWhile better cognitive screening tools are still needed to monitor cognitive decline in PSP, motor decline is consistently captured by clinical rating scales. These results support the inclusion of multiple follow-up time points in longitudinal studies in the early stages of PSP.

BACKGROUND: The Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them. METHODS: We retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations. RESULTS: Comprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1. CONCLUSIONS: The proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society.

Describe PSP Study Group, the ProPSP Study Group, and the Movement Disorder Society–Endorsed PSP Study Group., [Background] The Progressive Supranuclear Palsy Rating Scale is a prospectively validated physician-rated measure of disease severity for progressive supranuclear palsy. We hypothesized that, according to experts' opinion, individual scores of items would differ in relevance for patients' quality of life, functionality in daily living, and mortality. Thus, changes in the score may not equate to clinically meaningful changes in the patient's status., [Objective] The aim of this work was to establish a condensed modified version of the scale focusing on meaningful disease milestones., [Methods] Sixteen movement disorders experts evaluated each scale item for its capacity to capture disease milestones (0 = no, 1 = moderate, 2 = severe milestone). Items not capturing severe milestones were eliminated. Remaining items were recalibrated in proportion to milestone severity by collapsing across response categories that yielded identical milestone severity grades. Items with low sensitivity to change were eliminated, based on power calculations using longitudinal 12-month follow-up data from 86 patients with possible or probable progressive supranuclear palsy., [Results] The modified scale retained 14 items (yielding 0–2 points each). The items were rated as functionally relevant to disease milestones with comparable severity. The modified scale was sensitive to change over 6 and 12 months and of similar power for clinical trials of disease-modifying therapy as the original scale (achieving 80% power for two-sample t test to detect a 50% slowing with n = 41 and 25% slowing with n = 159 at 12 months)., [Conclusions] The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine. © 2021 International Parkinson and Movement Disorder Society., This work was supported by the Munich Cluster for Systems Neurology (Synergy), the Volkswagen Stiftung, the Lower Saxony Ministry for Science, the Niedersächsisches Vorab, and the Petermax-Müller Foundation (Etiology and Therapy of Synucleinopathies and Tauopathies). This project was also supported by the German Center for Neurodegenerative Diseases e.V. (DZNE), German PSP Gesellschaft, and the International Parkinson & Movement Disorder Society.

Background: The German research networks DescribePSP and ProPSP prospectively collect comprehensive clinical data, imaging data and biomaterials of patients with a clinical diagnosis of progressive supranuclear palsy. Progressive supranuclear palsy is a rare, adult-onset, neurodegenerative disease with striking clinical heterogeneity. Since now, prospective natural history data are largely lacking. Clinical research into treatment strategies has been limited due to delay in clinical diagnosis and lack of natural history data on distinct clinical phenotypes.Methods: The DescribePSP network is organized by the German Center for Neurodegenerative Diseases. DescribePSP is embedded in a larger network with parallel cohorts of other neurodegenerative diseases and healthy controls. The DescribePSP network is directly linked to other Describe cohorts with other primary diagnoses of the neurodegenerative and vascular disease spectrums and also to an autopsy program for clinico-pathological correlation. The ProPSP network is organized by the German Parkinson and Movement Disorders Society. Both networks follow the same core protocol for patient recruitment and collection of data, imaging and biomaterials. Both networks host a web-based data registry and a central biorepository. Inclusion/exclusion criteria follow the 2017 Movement Disorder Society criteria for the clinical diagnosis of progressive supranuclear palsy.Results: Both networks started recruitment of patients by the end of 2015. As of November 2020, N = 354 and 269 patients were recruited into the DescribePSP and the ProPSP studies, respectively, and N = 131 and 87 patients received at least one follow-up visit.Conclusions: The DescribePSP and ProPSP networks are ideal resources for comprehensive natural history data of PSP, including imaging data and biological samples. In contrast to previous natural history studies, DescribePSP and ProPSP include not only patients with Richardson's syndrome, but also variant PSP phenotypes as well as patients at very early disease stages, before a diagnosis of possible or probable PSP can be made. This will allow for identification and evaluation of early biomarkers for diagnosis, prognosis, and progression.

Objectives: Autoradiography on brain tissue is used to validate binding targets of newly discovered radiotracers. The purpose of this study was to correlate quantification of autoradiography signal using the novel next-generation tau positron emission tomography (PET) radiotracer [18F]PI-2620 with immunohistochemically determined tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue samples of patients with Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). Methods: We applied [18F]PI-2620 autoradiography to postmortem cortical brain samples of six patients with AD, five patients with PSP and five healthy controls, respectively. Binding intensity was compared between both tissue types and different disease entities. Autoradiography signal quantification (CWMR = cortex to white matter ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining, %-area) for FFPE and frozen tissue samples in the different disease entities. Results: In AD tissue, relative cortical tracer binding was higher in frozen samples when compared to FFPE samples (CWMRfrozen vs. CWMRFFPE: 2.5-fold, p < 0.001), whereas the opposite was observed in PSP tissue (CWMRfrozen vs. CWMRFFPE: 0.8-fold, p = 0.004). In FFPE samples, [18F]PI-2620 autoradiography tracer binding and immunohistochemical tau load correlated significantly for both PSP (R = 0.641, p < 0.001) and AD tissue (R = 0.435, p = 0.016), indicating a high agreement of relative tracer binding with underlying pathology. In frozen tissue, the correlation between autoradiography and immunohistochemistry was only present in AD (R = 0.417, p = 0.014) but not in PSP tissue (R = −0.115, p = n.s.). Conclusion: Our head-to-head comparison indicates that FFPE samples show superiority over frozen samples for autoradiography assessment of PSP tau pathology by [18F]PI-2620. The [18F]PI-2620 autoradiography signal in FFPE samples reflects AT8 positive tau in samples of both PSP and AD patients.

The reactivation of human JC polyoma virus (JCPyV) results in lytic infection of oligodendrocytes and neuronal cells. The corresponding clinical picture is called progressive multifocal leukoencephalopathy (PML) and results mostly from a disease-related or drug-induced immunosuppression. The opportunistic brain infection leads to a progressive demyelination of multiple areas of the central nervous system. Patients can present with various neurological deficits ranging from slight motoric symptoms to marked aphasia or reduced vigilance. Currently, there is no effective causal therapy for PML. Survival depends on the ability to achieve timely immune reconstitution. If the immune system cannot be restored, PML progresses rapidly and often ends fatally within months. Recently, some evidence for positive response has been reported in patients treated with immune checkpoint inhibitor therapy. Here, we provide a case series of three PML patients with underlying hematological malignancies who were treated with anti-PD-1-antibody pembrolizumab at Hannover Medical School. All patients received an extensive diagnostic follow-up including cerebrospinal fluid analysis, brain imaging, and lymphocyte-phenotyping via flow cytometry. Our patients had very different outcomes, with the only patient showing a specific anti-JCPyV immune response in the sense of an increased JCPyV antibody index clearly benefiting most from the treatment. Our results partly support the hypothesis that anti-PD-1 therapy may represent a promising treatment option for patients with PML. However, there is a current lack of pre-therapeutic stratification regarding the therapeutic response rates. Before larger studies can be initiated to further evaluate the efficacy of anti-PD-1 antibodies in PML, it is imperative to develop a reliable strategy for selecting suitable patients.

Tau-Pathologie gilt heute als Hauptverursacher eines breiten Spektrums neurodegenerativer Erkrankungen, die als Tauopathien zusammengefasst werden. Dazu gehoren primare Tauopathien, bei denen Tau die Hauptrolle bei der Pathogenese spielt, sowie sekundare Tauopathien wie die Alzheimer-Krankheit, bei der neben Tau auch Amyloid‑β eine wesentliche Rolle im Krankheitsprozess zukommt. Zu den primaren Tauopathien gehoren unter anderem die progressive supranukleare Blickparese, die kortikobasale Degeneration, die Pick-Krankheit und seltene hereditare Tauopathien, welche als frontotemporale Lobardegeneration mit MAPT(„microtubule-associated protein tau“)-Mutation bezeichnet werden. Tauopathien unterscheiden sich pathologisch durch die betroffenen Hirnregionen und Zelltypen sowie durch die biochemischen Merkmale des aggregierten Tau-Proteins. Verschiedene Tau-zentrierte neuroprotektive Therapieansatze befinden sich aktuell in der praklinischen und klinischen Entwicklung. Dabei werden unterschiedliche Mechanismen, wie die Verringerung der Tau-Expression, die Hemmung der Tau-Aggregation, das Auflosen von Tau-Aggregaten, die Verstarkung der zellularen Mechanismen zur Beseitigung toxischer Formen von Tau, die Stabilisierung von Mikrotubuli und die Hemmung der interzellularen Ausbreitung von Tau, untersucht. In dieser Ubersichtsarbeit geben wir einen Uberblick uber Tauopathien und die aktuellen Konzepte zur Entwicklung krankheitsmodifizierender Therapien.

The novel tau-PET tracer [18F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer’s disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [18F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. [18F]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [18F]PI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR30-60) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1SRTM: 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2SRTM: 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p 30-60 (1.3 ± 0.2 vs. 1.8 ± 0.3, p 9-60: 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p 18F]PI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder that is difficult for primary care physicians to recognize due to its progressive nature and similarities to other neurologic disorders. This case-control study aimed to identify clinical features observed in general practice associated with a subsequent diagnosis of PSP.Methods: We analyzed a de-identified dataset of 152 PSP cases and 3,122 matched controls from electronic medical records of general practices in Germany. We used a random forests algorithm based on machine learning techniques to identify clinical features (medical conditions and treatments received) associated with pre-diagnostic PSP without using an a priori hypothesis. We then assessed the relative effects of the features with the highest importance scores and generated multivariate models using clustered logistic regression analyses to identify a subset of clinical features associated with subsequent PSP diagnosis.Results: Using the random forests approach, we identified 21 clinical features associated with pre-diagnostic PSP (odds ratio ≥2.0 in univariate analyses). From these, we constructed a multivariate model comprising 9 clinical features with ~90% likelihood of identifying a subsequent PSP diagnosis. These features included known PSP symptoms, common misdiagnoses, and 2 novel associations, diabetes mellitus and cerebrovascular disease, which are possible modifiable risk factors for PSP.Conclusion: In this case-control study using data from electronic medical records, we identified 9 clinical features, including 2 previously unknown factors, associated with the pre-diagnostic stage of PSP. These may be used to facilitate recognition of PSP and reduce time to referral by primary care physicians.

BACKGROUND AND PURPOSE Clinical diagnostic criteria for neurodegenerative diseases have been framed based on clinical phenomenology. However, systematic knowledge about the first reported clinical symptoms in neurodegenerative diseases is lacking. Therefore, the aim was to determine the prevalence and clinical implications of the first clinical symptom (FS) as assessed by medical history in neuropathologically proven neurodegenerative diseases. METHODS Neuropathological diagnoses from the Neurobiobank Munich, Germany, were matched with clinical records for analyses of the diagnostic and prognostic values of FSs. RESULTS In all, 301 patients with the neuropathological diagnoses Alzheimer disease (AD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD) including the neuropathologically indistinguishable clinical phenotypes Parkinson disease and dementia with Lewy bodies, multiple system atrophy (MSA) and corticobasal degeneration (CBD) were studied. Memory disturbance was the most common FS in AD (34%), FTLD (19%) and LBD (26%), gait disturbance in PSP (35%) and MSA (27%) and aphasia and personality changes in CBD (20%, respectively). In a model adjusting for prevalence in the general population, AD was predicted by memory disturbance in 79.0%, aphasia in 97.2%, personality changes in 96.0% and by cognitive disturbance in 99.0%. Gait disturbance and tremor predicted LBD in 54.6% and 97.3%, coordination disturbance MSA in 59.4% and dysarthria FTLD in 73.0%. Cognitive FSs were associated with longer survival in AD (12.0 vs. 5.3 years; p

Objective: We report the case of a young woman with postinfectious onset of myasthenia gravis after COVID-19 with mild respiratory symptoms and anosmia/ageusia 1 month before admission to our neurological department. Methods: Patient data were derived from medical records of Hannover Medical School, Germany. Written informed consent was obtained from the patient. Results: The 21-year-old female patient presented with subacute, vertically shifted double vision evoked by right sided partial oculomotor paresis and ptosis. About 4 weeks earlier she had suffered from mild respiratory symptoms, aching limbs and head without fever, accompanied by anosmia/ageusia. During the persistence of the latter symptoms for around 10 days the patient had already noticed “tired eyes” and fluctuating double vision. Clinical assessment including a positive test with edrophonium chloride and increased acetylcholine receptor antibodies related the ocular manifestation etiologically to myasthenia gravis. Antibodies (IgA/IgG) against SARS-CoV-2 using three different serological tests (Abbott, DiaSorin, Euroimmun) were detected in serum suggesting this specific coronavirus as previously infectious agent in our patient. The myasthenic syndrome was treated successfully with intravenous immunoglobulins and oral pyridostigmine. Conclusion: This is the first case presentation of postinfectious myasthenia gravis as neurological complication in a COVID-19 patient.

Background P301S tau transgenic mice show age-dependent accumulation of neurofibrillary tangles in the brainstem, hippocampus, and neocortex, leading to neuronal loss and cognitive deterioration. However, there is hitherto only sparse documentation of the role of neuroinflammation in tau mouse models. Thus, we analyzed longitudinal microglial activation by small animal 18 kDa translocator protein positron-emission-tomography (TSPO μPET) imaging in vivo, in conjunction with terminal assessment of tau pathology, spatial learning, and cerebral glucose metabolism. Methods Transgenic P301S (n = 33) and wild-type (n = 18) female mice were imaged by 18F-GE-180 TSPO μPET at the ages of 1.9, 3.9, and 6.4 months. We conducted behavioral testing in the Morris water maze, 18F-fluordesoxyglucose (18F-FDG) μPET, and AT8 tau immunohistochemistry at 6.3–6.7 months. Terminal microglial immunohistochemistry served for validation of TSPO μPET results in vivo, applying target regions in the brainstem, cortex, cerebellum, and hippocampus. We compared the results with our historical data in amyloid-β mouse models. Results TSPO expression in all target regions of P301S mice increased exponentially from 1.9 to 6.4 months, leading to significant differences in the contrasts with wild-type mice at 6.4 months (+ 11–23%, all p < 0.001), but the apparent microgliosis proceeded more slowly than in our experience in amyloid-β mouse models. Spatial learning and glucose metabolism of AT8-positive P301S mice were significantly impaired at 6.3–6.5 months compared to the wild-type group. Longitudinal increases in TSPO expression predicted greater tau accumulation and lesser spatial learning performance at 6.3–6.7 months. Conclusions Monitoring of TSPO expression as a surrogate of microglial activation in P301S tau transgenic mice by μPET indicates a delayed time course when compared to amyloid-β mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-β mouse models. The contribution of microglial response to pathology accompanying amyloid-β and tau over-expression merits further investigation.

Background: Progressive supranuclear palsy is a rare neurodegenerative movement disorder and little is known about its epidemiology.Objective: Estimate age-adjusted prevalence of progressive supranuclear palsy and describe antecedent diagnoses and progressive supranuclear palsy patient features in the 5 years before first diagnostic code.Methods: In a nested case-control study in the IBM MarketScan Commercial and Medicare Supplemental Databases, a large set of US insurance databases containing medical service and prescription drug claims from employer-based commercial and Medicare supplemental health insurance plans, progressive supranuclear palsy cases (identified via International Statistical Classification of Diseases 9th/10th revision codes) and controls were included if enrollment was ≥1 month in the study period (October 1, 2015–October 31, 2017). Two controls with no diagnosis codes for PSP were matched to cases on birth year, sex, enrollment time in the database, and pharmacy benefit eligibility. Controls were assigned a randomly selected index date from their eligibility period. Prevalence of progressive supranuclear palsy was estimated in 2016 among patients with ≥1 month of continuous enrollment in that year. Prevalence ratios for comorbidities (claim/diagnosis codes) were examined in the ≤ 5 years before index date (first progressive supranuclear palsy claim date).Results: Age-adjusted progressive supranuclear palsy prevalence was 2.95/100,000 in 2016. The most common diagnosis codes in cases vs. controls in the 5 years pre-index were gait abnormalities (79.3 vs. 21.8%), pain in joint (54.9 vs. 36.0%), Parkinson's disease (54.6 vs. 1.0%), fatigue (49.8 vs. 21.6%), and cerebrovascular disease (45.6 vs. 16.4%).Conclusions: In this large database analysis, based on preliminary analyses, the prevalence of diagnosed progressive supranuclear palsy was 2.95/100,000, which is lower than many prior studies. Typical symptoms suggestive of progressive supranuclear palsy were present before index date, indicating a potential delay in time to diagnosis. The identification of diagnostic codes for clinical features of progressive supranuclear palsy that occurred before index date may be used to develop predictive models to identify potential progressive supranuclear palsy patients earlier in their disease course.

The clinical diagnosis of Parkinson's disease (PD) based on motor signs is often preceded by several non-motor symptoms that can indicate early prodromal neurodegenerative processes. Such prodromal symptoms can aid the early detection of PD, but their specificity for prodromal PD in comparison to prodromes of other movement disorders is still largely unclear. We here aim to give a first insight into the published evidence of prodromal non-motor symptoms in PD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Huntington's disease (HD), progressive supranuclear palsy (PSP) and spinocerebellar ataxia (SCA). REM-sleep behavior disorder (RBD) and autonomic dysfunction have been observed in the prodromes of PD, MSA, DLB and SCA. Depression and cognitive decline have been reported for prodromal PD, DLB, HD, SCA, and PSP. Olfactory loss has only been described in prodromal PD/DLB. However, estimating the specificity of prodromal non-motor symptoms in PD is so far complicated by scarce prospective evidence and study limitations. Information on marker specificity is a prerequisite for an accurate early (differential) diagnosis of prodromal diseases, as well as specific recruitment for targeted neuroprotective interventions. We here would like to raise awareness of these issues and encourage further prospective research of prodromal non-motor symptoms in neurodegenerative movement disorders and other diseases.

ObjectiveImpaired lysosomal degradation of α‐synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD.MethodsWe investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next‐generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes.ResultsWe confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C.ConclusionRare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome‐wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society.

http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2330-1619/homepage/mdc312582-sup-v001.htm.

PSP is a pathologically defined neurodegenerative tauopathy with a variety of clinical presentations including typical Richardson's syndrome and other variant PSP syndromes. A large body of neuroimaging research has been conducted over the past two decades, with many studies proposing different structural MRI and molecular PET/SPECT biomarkers for PSP. These include measures of brainstem, cortical and striatal atrophy, diffusion weighted and diffusion tensor imaging abnormalities, [18F] fluorodeoxyglucose PET hypometabolism, reductions in striatal dopamine imaging and, most recently, PET imaging with ligands that bind to tau. Our aim was to critically evaluate the degree to which structural and molecular neuroimaging metrics fulfill criteria for diagnostic biomarkers of PSP. We queried the PubMed, Cochrane, Medline, and PSYCInfo databases for original research articles published in English over the past 20 years using postmortem diagnosis or the NINDS-SPSP criteria as the diagnostic standard from 1996 to 2016. We define a five-level theoretical construct for the utility of neuroimaging biomarkers in PSP, with level 1 representing group-level findings, level 2 representing biomarkers with demonstrable individual-level diagnostic utility, level 3 representing biomarkers for early disease, level 4 representing surrogate biomarkers of PSP pathology, and level 5 representing definitive PSP biomarkers of PSP pathology. We discuss the degree to which each of the currently available biomarkers fit into this theoretical construct, consider the role of biomarkers in the diagnosis of Richardson's syndrome, variant PSP syndromes and autopsy confirmed PSP, and emphasize current shortfalls in the field. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Background: Progressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes. Objective: To identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP. Methods: We performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort. Results: Of 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity. Conclusions: Our results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP.

Diese Ubersicht widmet sich den Aspekten der Arzneimitteltherapiesicherheit in der Pharmakotherapie des Morbus Parkinson, einer der haufigsten chronischen Erkrankungen des Nervensystems. Die Pharmakotherapie des Morbus Parkinson ist beispielhaft fur die Komplexitat im typischerweise neurogeriatrischen Patientenkollektiv. Herausstellung potenzieller Risiken und von Aspekten der Arzneimitteltherapiesicherheit in der Pharmakotherapie des Morbus Parkinson. Selektive Literatur- und Leitlinienrecherche unter Zuhilfenahme von Pubmed sowie der wissenschaftlich-klinischen Erfahrungen der Autoren. Da Parkinson-Patienten meist altere Menschen sind, die infolge von Komorbiditaten mit weiteren Medikamenten therapiert werden, kommt es haufig zu einer komplexen Medikation mit mehr als funf Arzneimitteln. Diese Polymedikation erhoht das Risiko unerwunschter Arzneimittelereignisse, sodass die Medikation der Patienten auf Interaktionen uberpruft und Kontraindikationen ausgeschlossen werden mussen. Damit besteht vermehrter Aufklarungsbedarf bezuglich moglicher arzneimittelbezogener Probleme. Die Komorbiditaten oder die verordneten Arzneimittel konnen Kontrolluntersuchungen erforderlich machen, um arzneimittelbezogene Probleme zu erkennen und die Arzneimitteltherapiesicherheit zu gewahrleisten. Um die gesundheitsbezogene Lebensqualitat und die Qualitat der Arzneimitteltherapie von Parkinson-Patienten zu gewahrleisten, muss die individuell beste Therapie unter Berucksichtigung aller Kontraindikationen, Nebenwirkungen, Kontrolluntersuchungen und Interaktionen gefunden werden. Aufklarungsarbeit kann die Compliance der Patienten erhohen und zur Steigerung der Arzneimitteltherapiesicherheit beitragen.

Background: PSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome. Objective: We aimed to provide an evidence- and consensus-based revision of the clinical diagnostic criteria for PSP. Methods: We searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy-confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in two modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2-day meeting, and refined in three further Delphi rounds. Results: Defined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context-dependent exclusion criteria. We identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features. Conclusions: Here, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence.

Background Two recent, randomized, placebo-controlled phase II/III trials (clinicaltrials.gov: NCT01110720, NCT01049399) of davunetide and tideglusib in progressive supranuclear palsy (PSP) generated prospective, 1-year longitudinal datasets of high-resolution T1-weighted three-dimensional MRI. Objective The objective of this study was to develop a quantitative MRI disease progression measurement for clinical trials. Methods The authors performed a fully automated quantitative MRI analysis employing atlas-based volumetry and provide sample size calculations based on data collected in 99 PSP patients assigned to placebo in these trials. Based on individual volumes of 44 brain compartments and structures at baseline and 52 weeks of follow-up, means and standard deviations of annualized percentage volume changes were used to estimate standardized effect sizes and the required sample sizes per group for future 2-armed, placebo-controlled therapeutic trials. Results The highest standardized effect sizes were found for midbrain, frontal lobes, and the third ventricle. Using the annualized percentage volume change of these structures to detect a 50% change in the 1-year progression (80% power, significance level 5%) required lower numbers of patients per group (third ventricle, n = 32; midbrain, n = 37; frontal lobe, n = 43) than the best clinical scale (PSP rating scale total score, n = 58). A combination of volume changes in these 3 structures reduced the number of required patients to only 20 and correlated best with the progression in the clinical scales. Conclusions We propose the 1-year change in the volumes of third ventricle, midbrain, and frontal lobe as combined imaging read-out for clinical trials in PSP that require the least number of patients for detecting efficacy to reduce brain atrophy. © 2017 International Parkinson and Movement Disorder Society

Background: Several morphometric magnetic resonance imaging parameters may serve for differential diagnosis of parkinsonism. The objective of this study was to identify which performs best in clinical routine. Methods: We acquired multicentric magnetization-prepared rapid gradient echo sequences in patients with Parkinson's disease (n=204), progressive supranuclear palsy (n=106), multiple system atrophy-cerebellar, (n = 21); multiple system atrophy-parkinsonian (n = 60), and healthy controls (n = 73), performed manual planimetric measurements, and calculated receiver operator characteristics with leave-one-out cross-validation to propose cutoff values. Results: The midsagittal midbrain area was reduced in PSP versus all other groups (P

Fifty-five years have passed from the first description of PSP, but it is in the last decade that there has been a revolutionary change in understanding both clinical and pathophysiological aspects of this disease. Ten years ago, our knowledge about the clinical spectrum and pathophysiology of the disease was quite limited, and there was no credible clinical study on any drug treatment for this devastating disease. Today, we have discovered the wide clinical spectrum of PSP, and this led to the development of new diagnostic criteria in 2017, aiming to diagnose the disease earlier and include more phenotypes into clinical studies. Moreover, just over the past 10 years, numerous large, double-blind, clinical trials with disease-modifying agents have been conducted that provided important novel insights into disease biomarkers and progression. These studies were possible because of gained novel insights into pathophysiological processes of the disease and pave the way for the near future. In the next decade, we dare to predict the discovery of biomarkers for PSP, improvements in diagnosis using the new criteria in combination with these biomarkers, and ultimately the development of a neuroprotective therapy that could be applied to patients in a prodromal stage and spare them from this devastating disorder. © 2019 International Parkinson and Movement Disorder Society.

Summary Background Multiple system atrophy is a rare neurodegenerative disease characterised by aggregation of α-synuclein in oligodendrocytes and neurons. The polyphenol epigallocatechin gallate inhibits α-synuclein aggregation and reduces associated toxicity. We aimed to establish if epigallocatechin gallate could safely slow disease progression in patients with multiple system atrophy. Methods We did a randomised, double-blind, parallel group, placebo-controlled clinical trial at 12 specialist centres in Germany. Eligible participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1–3); and were on stable anti-Parkinson's, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype (parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment. Participants were given one hard gelatin capsule (containing either 400 mg epigallocatechin gallate or mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period. The primary endpoint was change in motor examination score of the Unified Multiple System Atrophy Rating Scale (UMSARS) from baseline to 52 weeks. Efficacy analyses were done in all people who received at least one dose of study medication. Safety was analysed in all people who received at least one dose of the study medication to which they had been randomly assigned. This trial is registered with ClinicalTrials.gov ( NCT02008721 ) and EudraCT (2012-000928-18), and is completed. Findings Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned—47 to epigallocatechin gallate and 45 to placebo. Of these, 67 completed treatment and 64 completed the study (altough one of these patients had a major protocol violation). There was no evidence of a difference in the mean change from baseline to week 52 in motor examination scores on UMSARS between the epigallocatechin gallate (5·66 [SE 1·01]) and placebo (6·60 [0·99]) groups (mean difference −0·94 [SE 1·41; 95% CI −3·71 to 1·83]; p=0·51). Four patients in the epigallocatechin gallate group and two in the placebo group died. Two patients in the epigallocatechin gallate group had to stop treatment because of hepatotoxicity. Interpretation 48 weeks of epigallocatechin gallate treatment did not modify disease progression in patients with multiple system atrophy. Epigallocatechin gallate was overall well tolerated but was associated with hepatotoxic effects in some patients, and thus doses of more than 1200 mg should not be used. Funding ParkinsonFonds Deutschland, German Parkinson Society, German Neurology Foundation, Luneburg Foundation, Bischof Dr Karl Golser Foundation, and Dr Arthur Arnstein Foundation.

© 2019 International Parkinson and Movement Disorder Society, Multiple system atrophy (MSA) is an adult-onset progressive neurodegenerative disorder that manifests clinically with autonomic failure, parkinsonism, and ataxia in any combination. Oligodendroglial cytoplasmatic inclusions consisting of misfolded α-synuclein are a pathological hallmark of disease. The clinical diagnosis of MSA is typically delayed as a result of incomplete or nonspecific manifestations during early disease stages. Quinn first published diagnostic criteria for MSA in 1989. Since then, the first consensus criteria in 1998 and their revision in 2008 have been widely accepted as diagnostic guidelines for MSA.

ObjectiveProgressive multifocal leukoencephalopathy (PML) is a devastating demyelinating opportunistic infection of the brain caused by the ubiquitously distributed JC polyomavirus. There are no established treatment options to stop or slow down disease progression. In 2018, a case series of 3 patients suggested the efficacy of allogeneic BK virus-specific T-cell (BKV-CTL) transplantation.MethodsTwo patients, a bilaterally lung transplanted patient on continuous immunosuppressive medication since 17 years and a patient with dermatomyositis treated with glucocorticosteroids, developed definite PML according to AAN diagnostic criteria. We transplanted both patients with allogeneic BKV-CTL from partially human leukocyte antigen (HLA) compatible donors. Donor T cells had directly been produced from leukapheresis by the CliniMACS IFN-γ cytokine capture system. In contrast to the previous series, we identified suitable donors by HLA typing in a preexamined registry and administered 1 log level less cells.ResultsBoth patients' symptoms improved significantly within weeks. During the follow-up, a decrease in viral load in the CSF and a regression of the brain MRI changes occurred. The transfer seemed to induce endogenous BK and JC virus-specific T cells in the host.ConclusionsWe demonstrate that this optimized allogeneic BKV-CTL treatment paradigm represents a promising, innovative therapeutic option for PML and should be investigated in larger, controlled clinical trials.Classification of EvidenceThis study provides Class IV evidence that for patients with PML, allogeneic transplant of BKV-CTL improved symptoms, reduced MRI changes, and decreased viral load.

Background Clinical differentiation of parkinsonian syndromes is still challenging. Objectives A fully automated method for quantitative MRI analysis using atlas-based volumetry combined with support vector machine classification was evaluated for differentiation of parkinsonian syndromes in a multicenter study. Methods Atlas-based volumetry was performed on MRI data of healthy controls (n = 73) and patients with PD (204), PSP with Richardson's syndrome phenotype (106), MSA of the cerebellar type (21), and MSA of the Parkinsonian type (60), acquired on different scanners. Volumetric results were used as input for support vector machine classification of single subjects with leave-one-out cross-validation. Results The largest atrophy compared to controls was found for PSP with Richardson's syndrome phenotype patients in midbrain (−15%), midsagittal midbrain tegmentum plane (−20%), and superior cerebellar peduncles (−13%), for MSA of the cerebellar type in pons (−33%), cerebellum (−23%), and middle cerebellar peduncles (−36%), and for MSA of the parkinsonian type in the putamen (−23%). The majority of binary support vector machine classifications between the groups resulted in balanced accuracies of >80%. With MSA of the cerebellar and parkinsonian type combined in one group, support vector machine classification of PD, PSP and MSA achieved sensitivities of 79% to 87% and specificities of 87% to 96%. Extraction of weighting factors confirmed that midbrain, basal ganglia, and cerebellar peduncles had the largest relevance for classification. Conclusions Brain volumetry combined with support vector machine classification allowed for reliable automated differentiation of parkinsonian syndromes on single-patient level even for MRI acquired on different scanners. © 2016 International Parkinson and Movement Disorder Society

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by postural instability and falls, vertical supranuclear gaze palsy, parkinsonism with poor levodopa response, pseudobulbar palsy, and frontal release signs. The natural history of the disease has been previously described. However, the time frame of appearance of clinical milestones and how these symptoms may relate to survival in PSP are unknown. The primary objective was to determine the prevalence of symptoms at different stages of PSP and to estimate the time of appearance of clinical symptoms characteristic of the disease. Second, we determined the association between clinical symptoms and survival. We prospectively studied 35 PSP patients during assessments scheduled every 6 months for up to 2 years. We estimated symptoms prevalence and the association between symptoms and survival. The median age of onset was 65.9 years (IQR 60.6-70.0), and the median time from onset to first assessment was 3.0 years (IQR 2.4-3.9). The most commonly reported symptoms at baseline were: motor (100%) followed by cognitive/behavioral (89%), systemic and bulbar (80%), and sleep disturbances (60%). Slowness of movement, falls, neck stiffness and difficulty looking up/down had high prevalence from baseline, while balance and gait impairment were less common at baseline but increased in prevalence over time. The presence of sleep disturbances, and possibly hallucinations, was associated with increased death risk. Improved recognition of the clinical spectrum and milestones of PSP advances knowledge of the disease, helps earlier diagnosis, and allows prognostic predictions.

We appreciate the interest in our article, and we thank Prof. Videira and colleagues for commenting on “Copathology in Progressive Supranuclear Palsy: Does It Matter?”1 in their Letter to the Editor.2In line with previous reports, our study has confirmed that copathology is the rule rather than the exception in progressive supranuclear palsy (PSP), for which 92% of cases showed coexistence of different protein alterations and/or cerebrovascular changes, in addition to defining the histopathology of PSP.1 We still do not have an answer to why PSP, among all tauopathies, is found to be most prone to the presence of copathology, and pure PSP represents the minority of cases.3 On the other hand, the copathologies observed in PSP were found to be mild and rarely reached high neuropathological stages.In the second part of our study we addressed the very important question of the clinical significance of such findings in PSP. Our data confirmed that, in terms of progression, 4R tau pathology is still the most relevant for PSP, whereas the impact of copathologies on progression rate appears to be on average of minor importance.Videira et al2 described the case of a 83‐year‐old woman with a clinical presentation of corticobasal syndrome and neuropathological evidence of coinciding PSP, Alzheimer's disease, and Lewy body disease. Thus, they underlined the need to search for subtle clinical signs that could point toward the presence of different coexisting pathologies.Based on our published results,1 we may only conclude that on a group level in cases with a primary neuropathological diagnosis of PSP, the clinical disease manifestation and tempo of progression is largely driven by PSP‐specific pathology, whereas the copathology does not appear to play a major role. On the other hand, we still cannot argue with certainty that copathologies may not influence the complex clinical presentation in PSP and the severity of clinical features in individual cases. Therefore, individual cases as reported by Videira et al2 must not be overlooked. Future studies will need to examine the influence of the interplay of different copathologies on the complexity of clinical presentation. Future developments, such as fluid biomarkers or PET ligands to quantify the relative severity and anatomical distribution of different proteinopathies in vivo,4, 5 will help to sort out much better the relative contribution of mixed pathologies to the clinical presentation and disease progression of individual cases, laying the groundwork for future individualized molecular therapies.