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BACKGROUND The influence of concomitant brain pathologies on the progression rate in PSP is unclear. OBJECTIVES To analyze the frequency and severity of copathologies and their impact on the progression in PSP. METHODS We analyzed clinic-pathological features of 101 PSP patients. Diagnoses and stages of copathologies were established according to standardized criteria, including Alzheimer's disease-related pathology, argyrophilic grains, Lewy-related pathology, transactive response DNA-binding protein 43 pathology, fused in sarcoma pathology, cerebral amyloid angiopathy, and small vessel disease. Demographic data and major clinical milestones (frequency and latency to onset) were extracted from patients' files. RESULTS Only 8% of 101 patients presented with pure PSP pathology without any copathology. Alzheimer's disease-related pathology was the most frequent (84%), followed by argyrophilic grains (58%), both occurring as single copathology or in combination with other proteinopathies or cerebrovascular disease. Lewy-related and transactive response DNA-binding protein 43 copathology occurred rarely (8% and 6%, respectively). Fused in sarcoma-positive cases were not found. While being common, copathology was mostly mild in severity, with the exception of frequently widespread argyrophilic grains. Small vessel disease was also frequent (65%). Cerebral amyloid angiopathy occurred only in the presence of Alzheimer's disease-related changes (25%). The copathologies did not have major impact on prevalence and time frame of major disease milestones. CONCLUSIONS In PSP, concomitant neurodegenerative proteinopathies or cerebrovascular diseases are frequent, but generally mild in severity. Our data confirmed that four repeat tau is still the most relevant target for PSP, whereas the impact of copathologies on progression rate appears to be of less importance. This is relevant information for the development of disease-modifying therapies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development., There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.

OBJECTIVE: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner. METHODS: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases. RESULTS: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%). INTERPRETATION: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. ANN NEUROL 2021;90:41-48.

Background: Studies on olfaction in LRRK2-associated Parkinson's disease (LRRK2-PD) have yielded variable results. The impact of smell dysfunction upon daily life activities have been rarely assessed in PD. Objective: To characterize the olfactory deficit in LRRK2-PD and its impact on daily life activities. Methods: Twenty-four LRRK2-PD, 40 idiopathic PD (IPD), and 49 age-sex-matched controls were interviewed about olfactory characteristics and the impact of smell on daily life activities. The Barcelona Smell Identification test (BAST-24) and the Spanish-version of the 40-item University of Pennsylvania smell test (UPSIT) were applied. Results: Nineteen (79.2%) LRRK2-PD patients reported subjective smell impairment with a low impact upon daily living activities. UPSIT score was higher in LRRK2-PD than in IPD (22.54 +/- 7.98 vs 18.84 +/- 6.03; p = 0.042). All IPD and 95.8% LRRK2-PD patients had hyposmia/anosmia, assessed by means of the UPSIT. No differences were found between LRRK2-PD and IPD regarding smell detection, memory or forced-choice identification. Conclusion: Most LRRK2-PD patients reported subjective smell impairment and presented hyposmia, according to validated smell tests, with a low impact of the smell dysfunction on daily life activities.

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. © 2020

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. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

OBJECTIVE: The study of cortical gyrification in Alzheimer's disease (AD) could help to further understanding of the changes undergone in the brain during neurodegeneration. Here, we aimed to study brain gyrification differences between healthy controls (HC), mild cognitive impairment (MCI) patients, and AD patients, and explore how cerebral gyrification patterns were associated with memory and other cognitive functions. METHODS: We applied surface-based morphometry techniques in 2 large, independent cross-sectional samples, obtained from the Alzheimer's Disease Neuroimaging Initiative project. Both samples, encompassing a total of 1,270 participants, were analyzed independently. RESULTS: Unexpectedly, we found that AD patients presented a more gyrificated entorhinal cortex than HC. Conversely, the insular cortex of AD patients was hypogyrificated. A decrease in the gyrification of the insular cortex was also found in older HC participants as compared with younger HC, which argues against the specificity of this finding in AD. However, an increased degree of folding of the insular cortex was specifically associated with better memory function and semantic fluency, only in AD patients. Overall, MCI patients presented an intermediate gyrification pattern. All these findings were consistently observed in the two samples. INTERPRETATION: The marked atrophy of the medial temporal lobe observed in AD patients may explain the increased folding of the entorhinal cortex. We additionally speculate regarding alternative mechanisms that may also alter its folding. The association between increased gyrification of the insular cortex and memory function, specifically observed in AD, could be suggestive of compensatory mechanisms to overcome the loss of memory function. ANN NEUROL 2020 ANN NEUROL 2020;88:67-80.

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/. © 2020, The Author(s).

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD., This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000949

Special Issue: Focused Ultrasound in Parkinson's Disease., [Background] Single nucleotide polymorphisms (SNPs) in the α‐synuclein (SNCA ) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine‐rich repeat kinase 2 (LRRK2)‐associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored., [Objectives] The mechanistic target of rapamycin (mTOR ) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO., [Methods] Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium., [Results] In the discovery series cohort, we found a 4‐loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P, [Conclusions] These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society, Funding Information; Fundació la Marató de TV3. Grant Number: 60510; Michael J. Fox Foundation for Parkinson's Research. Grant Numbers: Dyskinesia Challenge 2014, MJF_PPMI_10_001, PI044024; National Institutes of Health. Grant Number: LM010098; Secretaría de Estado de Investigación, Desarrollo e Innovación. Grant Number: SAF2014‐57160R and SAF2017‐88812R.

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. © 2019 International Parkinson and Movement Disorder Society

Background Leucine-rich kinase 2 (LRRK2)-linked Parkinson's disease (PD) is clinically indistinguishable from idiopathic PD (IPD). A pleiotropic neuropathology has been recognized but the majority of studies in LRRK2 p.G2019S patients reveal Lewy-type synucleinopathy as its principal histological substrate. To date no in vivo biomarkers of synucleinopathy have been found in LRRK2 mutation carriers. Objectives We used real-time quaking-induced conversion (RT-QuIC) technique to assess the presence of alpha-synuclein (a-syn) aggregates in cerebrospinal fluid (CSF) of LRRK2 p.G2019S carriers. Methods CSF samples of 51 subjects were analyzed: 15 LRRK2 p.G2019S PD, 10 IPD, 16 LRRK2 p.G2019S nonmanifesting carriers (NMC) and 10 healthy controls. The presence of parkinsonism and prodromal symptoms was assessed in all study subjects. Results Forty percent (n = 6) LRRK2-PD, and 18.8% (n = 3) LRRK2-NMC had a positive a-syn RT-QuIC response. RT-QuIC detected IPD with 90% sensitivity and 80% specificity. No clinical differences were detected between LRRK2-PD patients with positive and negative RT-QuIC. A positive RT-QuIC result in LRRK2-NMC occurred in a higher proportion of subjects meeting the Movement Disorder Society research criteria for prodromal PD. Interpretation RT-QuIC detects a-syn aggregation in CSF in a significant number of patients with LRRK2-PD, but less frequently than in IPD. A small percentage of LRRK2-NMC tested also positive. If appropriately validated in long-term studies with large number of mutation carriers, and hopefully, postmortem or in vivo confirmation of histopathology, RT-QuIC could contribute to the selection of candidates to receive disease modifying drugs, in particular treatments targeting a-syn deposition.

Background Single nucleotide polymorphisms (SNPs) in the alpha-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. (c) 2019 International Parkinson and Movement Disorder Society

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. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society

Introduction: The finding of mutations of the COQ2 gene and reduced coenzyme Q10 levels in the cerebellum in multiple system atrophy (MSA) suggest that coenzyme Q10 is relevant to MSA pathophysiology. Two recent studies have reported reduced coenzyme Q10 levels in plasma and serum (respectively) of MSA patients compared to Parkinson's disease and/or control subjects, but with largely overlapping values, limited comparison with other parkinsonisms, or dependence on cholesterol levels. We hypothesized that cerebrospinal fluid (CSF) is reliable to assess reductions in coenzyme Q10 as a candidate biomarker of MSA. Methods: In this preliminary cross-sectional study we assessed CSF coenzyme Q10 levels in 20 patients with MSA from the multicenter Catalan MSA Registry and of 15 PD patients, 10 patients with progressive supranuclear palsy (PSP), and 15 control subjects from the Movement Disorders Unit Biosample Collection of Hospital Clinic de Barcelona. A specific ELISA kit was used to determine CSF coenzyme Q10 levels. CSF coenzyme Q10 levels were compared in MSA vs. the other groups globally, pair-wise, and by binary logistic regression models adjusted for age, sex, disease severity, disease duration, and dopaminergic treatment. Results: CSF coenzyme Q10 levels were significantly lower in MSA than in other groups in global and pair-wise comparisons, as well as in multivariate regression models. Receiver operating characteristic curve analyses yielded significant areas under the curve for MSA vs. PD, PSP and controls. Conclusions: These findings support coenzyme Q10 relevance in MSA. Low CSF coenzyme Q10 levels deserve further consideration as a biomarker of MSA. (C) 2017 Elsevier Ltd. All rights reserved.

Objective: To analyze the clinical utility of 3 CSF biomarkers and their structural imaging correlates in a large cohort of patients with different dementia and parkinsonian syndromes within the spectrum of frontotemporal lobar degeneration (FTLD). Methods: We analyzed 3 CSF biomarkers (YKL-40, soluble ß fragment of amyloid precursor protein [sAPPß], neurofilament light [NfL]) and core Alzheimer disease (AD) biomarkers (ß-amyloid 1-42, total tau, phosphorylated tau) in patients with FTLD-related clinical syndromes (n = 159): behavioral variant of frontotemporal dementia (n = 68), nonfluent (n = 23) and semantic (n = 19) variants of primary progressive aphasia, progressive supranuclear palsy (n = 28), and corticobasal syndrome (n = 21). We also included patients with AD (n = 72) and cognitively normal controls (CN; n = 76). We compared cross-sectional biomarker levels between groups, studied their correlation with cortical thickness, and evaluated their potential diagnostic utility. Results: Patients with FTLD-related syndromes had lower levels of sAPPß than CN and patients with AD. The levels of sAPPß showed a strong correlation with cortical structural changes in frontal and cingulate areas. NfL and YKL-40 levels were high in both the FTLD and AD groups compared to controls. In the receiver operating characteristic analysis, the sAPPß/YKL-40 and NfL/sAPPß ratios had areas under the curve of 0.91 and 0.96, respectively, distinguishing patients with FTLD from CN, and of 0.84 and 0.85, distinguishing patients with FTLD from patients with AD. Conclusions: The combination of sAPPß with YKL-40 and with NfL in CSF could be useful to increase the certainty of the diagnosis of FTLD-related syndromes in clinical practice. Classification of evidence: This study provides Class III evidence that CSF levels of sAPPß, YKL-40, and NfL are useful to identify patients with FTLD-related syndromes. © 2017 American Academy of Neurology.

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. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society