Publications by authors named "Sharon Hassin-Baer"

92 Publications

Investigation of Autosomal Genetic Sex Differences in Parkinson's disease.

Ann Neurol 2021 Apr 26. Epub 2021 Apr 26.

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.

Objective: Parkinson's disease (PD) is a complex neurodegenerative disorder. Males are on average ~ 1.5 times more likely to develop PD compared to females with European ancestry. Over the years genome-wide 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 two 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 genome-wide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWASes was 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 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 females. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.26090DOI Listing
April 2021

Neuro-Ophthalmic Phenotype of OPA3.

J Neuroophthalmol 2021 Apr 14. Epub 2021 Apr 14.

Neuro-Ophthalmology Unit (RH-B), Goldschleger Eye Institute Chaim Sheba Medical Center, Tel-Hashomer, Israel; Department of Neurology (GY, SH-B), Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Movement Disorders Clinic and Department of Neurology (GY), Shaare Zedek Medical Center, Jerusalem, Israel; Metabolic Disease Unit Edmond and Lily Safra Children's Hospital (YA), Chaim Sheba Medical Center, Tel-Hashomer, Israel; Pediatric Neurology Unit (BBZ), Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Radiology Department (CH), Chaim Sheba Medical Center, Tel-Hashomer, Israel; and Sackler Faculty of Medicine (RH-B, YA, BBZ, CH, SH-B), Tel-Aviv University, Tel-Aviv, Israel.

Background: Type III 3-methylglutaconic aciduria (OPA 3) is a neuro-ophthalmologic syndrome consisting of early-onset bilateral optic atrophy. Since Costeff described the phenotype of 19 patients in 1989, several reports described approximately 50 patients, but most of them lack details about neuro-ophthalmic phenotype. Our aim was to characterize the clinical neuro-ophthalmic phenotype of this syndrome.

Methods: Nine patients underwent meticulous visual function history and medical documents' review. Results of best-corrected visual acuity (VA), color vision, visual field (VF), ocular motility, pupillary reaction, slit-lamp, and dilated fundus examinations were recorded. Optical coherence tomography (OCT) was performed whenever possible.

Results: The average VA was 1.4 ± 0.8 logarithm of the minimum angle of resolution. Poor vision was the presenting symptom in 5 patients. Six patients had decreased VA and variable degrees of optic atrophy. Humphrey VF testing of 7 patients revealed generalized depression in 5 and a cecocentral defect in 2. All patients demonstrated dysmetric saccades. Four patients had strabismus, 3 with exotropia, and one with esotropia. Seven patients had nystagmus. Ocular motility abnormality is possibly the result of cerebellar atrophy that was found in MRI studies of our patients. OCT of the retina was possible in 6 patients and revealed retinal nerve fiber layer (RNFL) thinning as well as average retinal thinning. Three patients, in whom ganglion cell layer-inner plexiform layer (IPL) measurement was possible, also showed diffused thinning.

Conclusions: This study compiled data regarding neuro-ophthalmic manifestation of OPA 3 Type III patients. Contrary to established literature, poor vision was the presenting symptom in only 50% of our patients. This is the first report of OCT findings in 3MGA patients. The results demonstrated diffused thinning of the RNFL and ganglion cell complex-IPL with correlation to VA, which is in contrast to OPA1 patients in whom the most severe thinning is at the level of the papillomacular bundle. Average retinal thinning was identified at second and third decades of life, possibly resulting from early ganglion cell loss. These results may contribute to visual prognosis, and OCT may help monitor experimental therapies.
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http://dx.doi.org/10.1097/WNO.0000000000001249DOI Listing
April 2021

DailyCog: A Real-World Functional Cognitive Mobile Application for Evaluating Mild Cognitive Impairment (MCI) in Parkinson's Disease.

Sensors (Basel) 2021 Mar 4;21(5). Epub 2021 Mar 4.

Movement Disorders Institute, Sheba Medical Center, Ramat-Gan 5262000, Israel.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder affecting patient functioning and quality of life. Aside from the motor symptoms of PD, cognitive impairment may occur at early stages of PD and has a substantial impact on patient emotional and physical health. Detecting these early signs through actual daily functioning while the patient is still functionally independent is challenging. We developed DailyCog-a smartphone application for the detection of mild cognitive impairment. DailyCog includes an environment that simulates daily tasks, such as making a drink and shopping, as well as a self-report questionnaire related to daily events performed at home requiring executive functions and visual-spatial abilities, and psychomotor speed. We present the detailed design of DailyCog and discuss various considerations that influenced the design. We tested DailyCog on patients with mild cognitive impairment in PD. Our case study demonstrates how the markers we used coincide with the cognitive levels of the users. We present the outcome of our usability study that found that most users were able to use our app with ease, and provide details on how various features were used, along with some of the difficulties that were identified.
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http://dx.doi.org/10.3390/s21051788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961428PMC
March 2021

Exploring the perceptions and stigmatizing experiences of Israeli family caregivers of people with Parkinson's disease.

J Aging Stud 2021 Mar 24;56:100910. Epub 2020 Dec 24.

Department of Community Mental Health, University of Haifa, Israel. Electronic address:

Providing care to people with Parkinson's disease (PD) poses challenges for family carers, including experiencing stigmatic beliefs -i.e., family stigma. However, to the best of our knowledge, there is no empirical study examining the stigmatic experiences of family members of people with PD. This was the aim of the present study. Three focus groups with 22 Israeli spouses of people with PD were conducted. Data were analyzed using theory-led thematic analysis. Overall, the spouses in our study shared mainly experiences of the stigma attached to the illness and/or to their loved ones, and not to themselves as carers. Three major themes emerged: the stereotypes that typify PD, stigmatizing behaviors towards the person with the disease, and structural stigma. Our findings highlight the profound stigma confronting carers of persons with PD, particularly when it comes to structural stigma.
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http://dx.doi.org/10.1016/j.jaging.2020.100910DOI Listing
March 2021

Markers for neural degeneration and regeneration: novel highly sensitive methods for the measurement of thrombin and activated protein C in human cerebrospinal fluid.

Neural Regen Res 2021 Oct;16(10):2086-2092

Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan; Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Inflammation and coagulation are tightly interconnected in the pathophysiology of neuronal diseases. Thrombin, a pro-coagulant serine protease is associated with neurodegeneration and its indirect inhibitor, activated protein C (aPC), is considered neuroprotective. While levels of thrombin and aPC activity are readily measured in the blood, similar assays in the cerebrospinal fluid (CSF) have not been described. The aim of this study was to establish a specific and sensitive enzymatic assay to measure both thrombin and aPC activity in the CSF. CSF was collected from 14 patients with suspected normal pressure hydrocephalus served as a control group, while seven patients with central nervous system infections served as an acute neuro-inflammatory study group and one sample of CSF following traumatic lumbar puncture served as a positive control. Thrombin and aPC activities were measured by fluorescence released by specific proteolytic cleavage in the presence of endopeptidase and amino-peptidase inhibitors to ensure specificity. Specificity of the method was verified by thrombin and serine-protease inhibitors N-alpha-((2-naphthylsulfinyl)glycyl)-DL-p-amidinophenylalanylpiperidine and phenylmethanesulfonyl fluoride. Inhibition of thrombin activity by CSF samples and levels of specific thrombin inhibitors were also assessed. Thrombin and aPC activities were reliably measured and were significantly higher in the CSF of patients with central nervous system infections compared to normal pressure hydrocephalus controls, suggesting the involvement of these factors in neuro-inflammation. CSF thrombin activity levels in the presence of known thrombin concentration were high in patients with central nervous system infections, and low in normal pressure hydrocephalus patients. Quantification of endogenous thrombin inhibitors protease nexin 1, amyloid precursor protein and anti-thrombin III in CSF by western blot indicated a significant elevation of amyloid precursor protein in infectious CSF. In conclusion, this study describes a novel and sensitive assay aimed at the detection of thrombin and aPC activity in CSF. This method may be useful for measuring these factors that reflect degenerative and protective influences of coagulation on neurological disorders. The study procedure was approved by the Ethics Committee of the Chaim Sheba Medical Center (approval No. 4245-17-SMC) on October 18, 2018.
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http://dx.doi.org/10.4103/1673-5374.308098DOI Listing
October 2021

Overconfidence in visual perception in parkinson's disease.

Eur J Neurosci 2021 Mar 12;53(6):2027-2039. Epub 2021 Jan 12.

Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel.

Increased dependence on visual cues in Parkinson's disease (PD) can unbalance the perception-action loop, impair multisensory integration, and affect everyday function of PD patients. It is currently unknown why PD patients seem to be more reliant on their visual cues. We hypothesized that PD patients may be overconfident in the reliability (precision) of their visual cues. In this study we tested coherent visual motion perception in PD, and probed subjective (self-reported) confidence in their visual motion perception. Twenty patients with idiopathic PD, 21 healthy aged-matched controls and 20 healthy young adult participants were presented with visual stimuli of moving dots (random dot kinematograms). They were asked to report: (1) whether the aggregate motion of dots was to the left or to the right, and (2) how confident they were that their perceptual discrimination was correct. Visual motion discrimination thresholds were similar (unimpaired) in PD compared to the other groups. By contrast, PD patients were significantly overconfident in their visual perceptual decisions (p = .002 and p < .001 vs. the age-matched and young adult groups, respectively). These results suggest intact visual motion perception, but overestimation of visual cue reliability, in PD. Overconfidence in visual (vs. other, e.g., somatosensory) cues could underlie increased visual dependence and impaired multisensory/sensorimotor integration in PD. It could thereby contribute to gait and balance impairments, and affect everyday activities, such as driving. Future work should investigate and compare PD confidence in somatosensory function. A better understanding of altered sensory reliance might open up new avenues to treat debilitating PD symptoms.
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http://dx.doi.org/10.1111/ejn.15093DOI Listing
March 2021

Targeted sequencing of Parkinson's disease loci genes highlights SYT11, FGF20 and other associations.

Brain 2021 03;144(2):462-472

Department of Human Genetics, McGill University, Montréal, QC, H3A 1A1, Canada.

Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (P = 5.23 × 10-5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson's disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (odds ratio 0.73, 95% confidence interval 0.60-0.89, P = 1.161 × 10-3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.
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http://dx.doi.org/10.1093/brain/awaa401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940168PMC
March 2021

Implicit sequence learning in individuals with Parkinson's disease: The added value of using an ocular version of the serial reaction time (O-SRT) task.

Brain Cogn 2021 02 24;147:105654. Epub 2020 Nov 24.

Movement Disorders Institute and Department of Neurology, Sheba Medical Center, Tel HaShomer, Israel Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Introduction: Though the majority of studies reported impaired sequence learning in individuals with Parkinson's disease (PD) tested with the Serial Reaction Time (SRT) task, findings are inconclusive. To elucidate this point, we used an eye tracker in an ocular SRT task version (O-SRT) that in addition to RT, enables extraction of two measures reflecting different cognitive processes, namely, Correct Anticipation (CA) and number of Stucks.

Methods: Individuals with PD (n = 29) and matched controls (n = 31) were tested with the O-SRT task, consisting of a repeated sequence of six blocks, then a block with an interference sequence followed by an original sequence block.

Results: Unlike controls, patients with PD did not improve in CA rate across learning trials, did not show an increase in RT when presented with the interference sequence, and showed a significantly higher rate of Stucks.

Conclusions: Low CA rate and high Stucks rate emerge as the cardinal deficits leading to impaired sequence learning following PD. These are viewed as reflecting difficulty in exploration for an efficient learning strategy. This study highlights the advantage in using the O-SRT task, which enables the generation of several informative measures of learning, allowing better characterization of the PD effect on sequence learning.
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http://dx.doi.org/10.1016/j.bandc.2020.105654DOI Listing
February 2021

Association study of DNAJC13, UCHL1, HTRA2, GIGYF2, and EIF4G1 with Parkinson's disease.

Neurobiol Aging 2021 Apr 31;100:119.e7-119.e13. Epub 2020 Oct 31.

Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, Quebec, Canada. Electronic address:

Rare mutations in genes originally discovered in multigenerational families have been associated with increased risk of Parkinson's disease (PD). The involvement of rare variants in DNAJC13, UCHL1, HTRA2, GIGYF2, and EIF4G1 loci has been poorly studied or has produced conflicting results across cohorts. However, they are still being often referred to as "PD genes" and used in different models. To further elucidate the role of these 5 genes in PD, we fully sequenced them using molecular inversion probes in 2408 patients with PD and 3444 controls from 3 different cohorts. A total of 788 rare variants were identified across the 5 genes and 3 cohorts. Burden analyses and optimized sequence Kernel association tests revealed no significant association between any of the genes and PD after correction for multiple comparisons. Our results do not support an association of the 5 tested genes with PD. Combined with previous studies, it is unlikely that any of these genes plays an important role in PD. Their designation as "PARK" genes should be reconsidered.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940813PMC
April 2021

Restricted Mouth Opening in Head and Neck Cancer: Etiology, Prevention, and Treatment.

JCO Oncol Pract 2020 10;16(10):643-653

Sheba Medical Center at Tel HaShomer, Tel Aviv, Israel.

Restricted mouth opening or trismus is often encountered in patients with head and neck cancer. The restriction may be the presenting sign of malignancy, a sequela of tumor site or growth, an adverse effect of oncologic treatment, or a first sign of tumoral recurrence. In general, any insult to the temporomandibular joint, masticatory muscles, or their neural innervation may cause limitation in mouth opening. The etiologies leading to trismus are as follows: myospasm secondary to tumor infiltration; reflectory myospasm; radiation-induced myositis and myofibrosis; temporomandibular joint involvement with tumor; unfavorable postsurgical scarring; muscle and joint atrophy secondary to immobilization; pain; jaw fracture and hardware failure; and infection. Preventive measures should be implemented before, during, and after treatment. These measures include identification of high-risk patients, utilization of dose-sculpting radiation techniques whenever possible, performing reconstruction at the same time of resective surgery whenever feasible, and initiating mobilization exercises as early as possible. When trismus develops, treatments are often challenging and disappointing. These include physical therapy, mouth opening appliances, drug therapy, and release surgery. All medical specialties dealing with head and neck cancer should be familiar with the diagnosis and prevention of trismus and make an effort to ensure patients are referred to the appropriate care when needed. Trismus should not be considered a trivial sequela of head and neck cancer.
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http://dx.doi.org/10.1200/OP.20.00266DOI Listing
October 2020

Analysis of Heterozygous PRKN Variants and Copy-Number Variations in Parkinson's Disease.

Mov Disord 2021 01 24;36(1):178-187. Epub 2020 Sep 24.

Department of Human Genetics, McGill University, Montréal, Quebec, Canada.

Background: Biallelic PRKN mutation carriers with Parkinson's disease (PD) typically have an earlier disease onset, slow disease progression, and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous PRKN variants in the risk of PD is controversial.

Objectives: Our aim was to examine the association between heterozygous PRKN variants, including single-nucleotide variants and copy-number variations (CNVs), and PD.

Methods: We fully sequenced PRKN in 2809 PD patients and 3629 healthy controls, including 1965 late-onset (63.97 ± 7.79 years, 63% men) and 553 early-onset PD patients (43.33 ± 6.59 years, 68% men). PRKN was sequenced using targeted next-generation sequencing with molecular inversion probes. CNVs were identified using a combination of multiplex ligation-dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single-nucleotide variants and CNVs in PRKN are associated with PD risk and onset, we used optimized sequence kernel association tests and regression models.

Results: We did not find any associations between all types of PRKN variants and risk of PD. Pathogenic and likely-pathogenic heterozygous single-nucleotide variants and CNVs were less common among PD patients (1.52%) than among controls (1.8%, false discovery rate-corrected P = 0.55). No associations with age at onset and in stratified analyses were found.

Conclusions: Heterozygous single-nucleotide variants and CNVs in PRKN are not associated with PD. Molecular inversion probes allow for rapid and cost-effective detection of all types of PRKN variants, which may be useful for pretrial screening and for clinical and basic science studies targeting specifically PRKN patients. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28299DOI Listing
January 2021

Visual self-motion cues are impaired yet overweighted during visual-vestibular integration in Parkinson's disease.

Brain Commun 2020 31;2(1):fcaa035. Epub 2020 Mar 31.

Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan 5290002, Israel.

Parkinson's disease is prototypically a movement disorder. Although perceptual and motor functions are highly interdependent, much less is known about perceptual deficits in Parkinson's disease, which are less observable by nature, and might go unnoticed if not tested directly. It is therefore imperative to seek and identify these, to fully understand the challenges facing patients with Parkinson's disease. Also, perceptual deficits may be related to motor symptoms. Posture, gait and balance, affected in Parkinson's disease, rely on veridical perception of one's own motion (self-motion) in space. Yet it is not known whether self-motion perception is impaired in Parkinson's disease. Using a well-established multisensory paradigm of heading discrimination (that has not been previously applied to Parkinson's disease), we tested unisensory visual and vestibular self-motion perception, as well as multisensory integration of visual and vestibular cues, in 19 Parkinson's disease, 23 healthy age-matched and 20 healthy young-adult participants. After experiencing vestibular (on a motion platform), visual (optic flow) or multisensory (combined visual-vestibular) self-motion stimuli at various headings, participants reported whether their perceived heading was to the right or left of straight ahead. Parkinson's disease participants and age-matched controls were tested twice (Parkinson's disease participants on and off medication). Parkinson's disease participants demonstrated significantly impaired visual self-motion perception compared with age-matched controls on both visits, irrespective of medication status. Young controls performed slightly (but not significantly) better than age-matched controls and significantly better than the Parkinson's disease group. The visual self-motion perception impairment in Parkinson's disease correlated significantly with clinical disease severity. By contrast, vestibular performance was unimpaired in Parkinson's disease. Remarkably, despite impaired visual self-motion perception, Parkinson's disease participants significantly overweighted the visual cues during multisensory (visual-vestibular ) integration (compared with Bayesian predictions of optimal integration) and significantly more than controls. These findings indicate that self-motion perception in Parkinson's disease is affected by impaired visual cues and by suboptimal visual-vestibular integration (overweighting of visual cues). Notably, vestibular self-motion perception was unimpaired. Thus, visual self-motion perception is specifically impaired in early-stage Parkinson's disease. This can impact Parkinson's disease diagnosis and subtyping. Overweighting of visual cues could reflect a general multisensory integration deficit in Parkinson's disease, or specific overestimation of visual cue reliability. Finally, impaired self-motion perception in Parkinson's disease may contribute to impaired balance and gait control. Future investigation into this connection might open up new avenues of alternative therapies to better treat these difficult symptoms.
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http://dx.doi.org/10.1093/braincomms/fcaa035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425426PMC
March 2020

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

Neurobiol Aging 2021 01 13;97:148.e17-148.e24. Epub 2020 Jul 13.

Research Unit U1127 at INSERM, Research Unit UMR 7225 at the French National Centre for Scientific Research (CNRS) Research Unit UMR_1127 at Sorbonne Université, Institutet du Cerveau et de la Moëlle épinière (ICM), Paris, France.

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762821PMC
January 2021

The Montreal Cognitive Assessment: Is It Suitable for Identifying Mild Cognitive Impairment in Parkinson's Disease?

Mov Disord Clin Pract 2020 Aug 25;7(6):648-655. Epub 2020 Jun 25.

Movement Disorders Institute Sheba Medical Center Ramat-Gan Israel.

Background: Administering an abbreviated global cognitive test, such as the Montreal Cognitive Assessment (MoCA), is necessary for the recommended first-level diagnostic criteria for mild cognitive impairment (MCI) in Parkinson's disease (PD). Level II requires administering cognitive functioning neuropsychological tests. The MoCA's suitability for identifying PD-MCI is questionable and, despite the importance of cognitive deficits reflected through daily functioning in identifying PD-MCI, knowledge about it is scarce.

Objectives: To explore neuropsychological test scores of patients with PD who were categorized based on their MoCA scores and to analyze correlations between this categorization and patients' self-reports about daily functional-related cognitive abilities.

Methods: A total of 78 patients aged 42 to 78 years participated: 46 with low MoCA scores (22-25) and 32 with high MoCA scores (26-30). Medical assessments and level II neuropsychological assessment tools were administered along with standardized self-report questionnaires about daily functioning that reflects patients' cognitive abilities.

Results: A high percentage of the low MoCA group obtained neuropsychological test scores within the normal range; a notable number in the high MoCA group were identified with MCI-level scores on various neuropsychological tests. Suspected PD-MCI according to the level I criteria did not correspond well with the level II criteria. Positive correlations were found among the 3 self-report questionnaires.

Conclusions: These results support the ongoing discussion of the complexity of capturing PD-MCI. Considering the neuropsychological tests results, assessments that reflect cognitive encounters in real life daily confrontations are warranted among people diagnosed with PD who are at risk for cognitive decline.
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http://dx.doi.org/10.1002/mdc3.12969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396845PMC
August 2020

Prevalence of -mediated spinocerebellar ataxia in a North American ataxia cohort.

Neurol Genet 2020 Jun 20;6(3):e440. Epub 2020 May 20.

Department of Neurology (D.A.S., D.W., Y.M., S.P., B.L.F.), Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles; Department of Neurology (D.W., B.L.F.), Clinical Neurogenomics Research Center, David Geffen School of Medicine, University of California, Los Angeles; Department of Human Genetics (S.A., M.S., S.D.), University of Chicago, IL; Department of Neurology (C.M.D.G., V.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Neurology (G.G., C.M.G.), University of Chicago, IL; Bruce Lefroy Centre (P.J.L.), Murdoch Children's Research Institute; Department of Paediatrics (P.J.L.), University of Melbourne, Parkville, Australia; Sackler Faculty of Medicine (S.H.-B.), Tel-Aviv University, Tel-Aviv, Israel; and Department of Human Genetics (B.L.F.), David Geffen School of Medicine, University of California, Los Angeles.

Objective: We evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 () and disabled adaptor protein 1 in an undiagnosed ataxia cohort from North America.

Methods: A cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in (AAGGG) and (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for , resulting in a combined 911 subjects tested.

Results: In the initial cohort, 41 samples were identified with 1 expanded allele in the gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the gene (spinocerebellar ataxia type 37).

Conclusions: In a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.
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http://dx.doi.org/10.1212/NXG.0000000000000440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274910PMC
June 2020

Variants in the Niemann-Pick type C gene NPC1 are not associated with Parkinson's disease.

Neurobiol Aging 2020 09 8;93:143.e1-143.e4. Epub 2020 Apr 8.

Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada. Electronic address:

Biallelic variants in NPC1, a gene coding for a lysosomal transmembrane protein involved in cholesterol trafficking, may cause Niemann-Pick disease type C (NPC). A few cases of NPC1 variant carriers with Parkinson's disease (PD) have been reported. In addition, pathologic studies have demonstrated phosphorylated alpha-synuclein and Lewy pathology in brains of NPC patients. Therefore, we aimed to examine whether NPC1 genetic variants may be associated with PD. Full sequencing of NPC1 was performed in 2657 PD patients and 3647 controls from 3 cohorts, using targeted sequencing with molecular inversion probes. A total of 9 common variants and 126 rare variants were identified across the 3 cohorts. To examine their association with PD, regression models adjusted for age, sex, and origin were performed for common variants, and optimal sequence Kernel association test (SKAT-O) was performed for rare variants. After correction for multiple comparisons, common and rare NPC1 variants were not associated with PD. Our results do not support a link between heterozygous variants in NPC1 and PD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302975PMC
September 2020

Age at Onset of Parkinson's Disease Among Ashkenazi Jewish Patients: Contribution of Environmental Factors, LRRK2 p.G2019S and GBA p.N370S Mutations.

J Parkinsons Dis 2020 ;10(3):1123-1132

Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel.

Background: Both genetic and environmental factors contribute to Parkinson's disease (PD) risk.

Objective: We investigated the potential association of several relevant variables with PD age at onset (AAO), focusing on LRRK2 p.G2019S and GBA p.N370S mutations.

Methods: Ashkenazi Jewish (AJ) PD patients, screened for LRRK2 and GBA mutations, underwent an interview regarding exposure to the following environmental and lifestyle factors: cigarette smoking, consumption of coffee, tea and alcohol, head injury and rural living. Multivariate linear regression (adjusted for sex) was used to examine the association with AAO, and models included LRRK2 p.G2019S and GBA p.N370S mutation status (carrier/non-carriers), single environmental variable and their interactions terms, as independent variables.

Results: 225 Israeli AJ PD patients were enrolled: 65 LRRK2 p.G2019S mutation carriers, 60 GBA p.N370S carriers and 100 non-carries of these mutations. In the dichotomized exposure/non-exposure analyses, positive LRRK2 p.G2019S status was associated with younger AAO in all models, at nominal or near significant levels (p = 0.033-0.082). Smoking was associated with older AAO (p = 0.032), and the interaction between GBA p.N370S and history of head injury was associated with younger AAO (p = 0.049), both at nominal significance. There was no indication of a consistent main effect for GBA p.N370S status or significant LRRK2 p.G2019S-environmental factor interaction. In the dose-dependent analyses, increased coffee and tea consumption levels were associated with older AAO (p = 0.001 and p = 0.002, respectively).

Conclusions: Our results suggest that genetic and environmental factors may affect AAO in PD patients, but validation in additional samples is required.
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http://dx.doi.org/10.3233/JPD-191829DOI Listing
January 2020

Self-motion perception in Parkinson's disease.

Eur J Neurosci 2021 Apr 20;53(7):2376-2387. Epub 2020 Mar 20.

Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel.

Parkinson's disease (PD), best characterized by its classic motor symptoms, also manifests non-motor symptoms including perceptual impairments. Normal motor and perceptual brain functions interact continuously in an action-perception loop; hence, perceptual and motor dysfunction in PD are likely also intertwined. A vital skill in order to maintain balance, and to move around in the environment is the ability to perceive one's own motion in space (self-motion perception). Self-motion perception is a complex brain process, that requires the integration of information from visual (optic flow), vestibular (gravito-inertial), and somatosensory senses. Yet, not much is known about self-motion perception or multisensory integration in PD. In this review, we highlight the need to better study these important functions in PD. We review perceptual deficits in underlying functions required for adept self-motion perception (visual, vestibular and somatosensory, as well as multisensory integration) and address how these might affect self-motion perception and motor function in PD. We propose that dysfunction of central brain mechanisms, implicated in impaired visual, vestibular and somatosensory function, likely impact self-motion perception in PD. Recent evidence suggests that visual and multisensory integration mechanisms of self-motion perception are indeed impaired in PD. This can affect motor control, gait and balance. Future research is needed to better investigate this important topic. A better understanding of self-motion perception and multisensory integration in PD may aid diagnosis and subtyping and may open new avenues for novel therapies to treat debilitating motor symptoms, including gait and balance impairment, using sensory augmentation devices or sensory retraining.
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http://dx.doi.org/10.1111/ejn.14716DOI Listing
April 2021

Analysis of common and rare variants in late-onset Parkinson disease.

Neurol Genet 2020 Feb 9;6(1):385. Epub 2020 Jan 9.

Department of Human Genetics (U.R., L.K., G.A.R, Z.G.-O.), McGill University, Montréal; Montreal Neurological Institute (U.R., J.A.R., L.K., S.B.L., D.S., G.A.R., E.A.F.Z.G.-O.), McGill University; Department of Neurology and Neurosurgery (J.A.R., S.B.L., D.S., G.A.R., E.A.F., Z.G.-O.), McGill University, Montréal, Québec, Canada; The Danek Gertner Institute of Human Genetics, Sheba Medical Center (L.G.); The Joseph Sagol Neuroscience Center (L.G., S.H.-B.), Sheba Medical Center, Tel Hashomer, Ramat Gan; Sackler School of Medicine (L.G., G.Y., S.H.-B.), Tel-Aviv University; Department of Neurology (G.Y., S.H.-B.), Sheba Medical Center; Movement Disorders Institute (G.Y., S.H.-B.), Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Centre d'Études Avancées en Médecine du Sommeil (A.D., J.Y.M.), Hôpital du Sacré-Cœur de Montréal; Department of Neurosciences (A.D.), Université de Montréal; Department of Psychiatry (J.Y.M.), Université de Montréal, Québec, Canada; Department of Neurology (S.F., C.H.W., O.L., C.M.K., S.N., R.N.A.), College of Physicians and Surgeons, Columbia University Medical Center, New York; Department of Neurology (Y.D.), National Reference Center for Narcolepsy, Sleep Unit, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm, France; Division of Neurosciences (N.D.), CHU de Québec, Université Laval; Department of Medicine (N.D.), Faculty of Medicine, Université Laval, Québec City, Canada; and Taub Institute for Research on Alzheimer's Disease and the Aging Brain (R.N.A.), College of Physicians and Surgeons, Columbia University Medical Center, New York.

Objective: We aimed to study the role of coding variants in a large cohort of patients with late-onset Parkinson disease (PD) (LOPD).

Methods: and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 patients with PD and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis.

Results: No biallelic carriers of rare variants were found among patients, and 2 carriers of compound heterozygous variants were found in 2 controls. There was no statistically significant burden of rare (minor allele frequency [MAF] <1%) or very rare (MAF <0.1%) coding variants in PD. A haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V [odds ratio = 0.48, 95% confidence interval = 0.28-0.82, = 0.0052]). This haplotype was not in linkage disequilibrium with the known genome-wide association study top hit.

Conclusions: Our results do not support a role for rare heterozygous or biallelic variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD.
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http://dx.doi.org/10.1212/NXG.0000000000000385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984134PMC
February 2020

Smartphone Based Timed Up and Go Test Can Identify Postural Instability in Parkinson's Disease.

Isr Med Assoc J 2020 Jan;22(1):37-42

Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel.

Background: There is a need for standardized and objective methods to measure postural instability (PI) and gait dysfunction in Parkinson's disease (PD) patients. Recent technological advances in wearable devices, including standard smartphones, may provide such measurements.

Objectives: To test the feasibility of smartphones to detect PI during the Timed Up and Go (TUG) test.

Methods: Ambulatory PD patients, divided by item 30 (postural stability) of the motor Unified Parkinson's Disease Rating Scale (UPDRS) to those with a normal (score = 0, PD-NPT) and an abnormal (score ≥ 1, PD-APT) test and a group of healthy controls (HC) performed a 10-meter TUG while motion sensor data was recorded from a smartphone attached to their sternum using the EncephaLog application.

Results: In this observational study, 44 PD patients (21 PD-NPT and 23 PD-APT) and 22 HC similar in age and gender distribution were assessed. PD-APT differed significantly in all gait parameters when compared to PD-NPT and HC. Significant difference between PD-NPT and HC included only turning time (P < 0.006) and step-to-step correlation (P < 0.05).

Conclusions: While high correlations were found between EncephaLog gait parameters and axial UPDRS items, the pull test was least correlated with EncephaLog measures. Motion sensor data from a smartphone can detect differences in gait and balance measures between PD with and without PI and HC.
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January 2020

Psychiatric Patients on Neuroleptics: Evaluation of Parkinsonism and Quantified Assessment of Gait.

Clin Neuropharmacol 2020 Jan/Feb;43(1):1-6

Department of Neurology and Sagol Neuroscience Center and the Movement Disorders Institute, Chaim Sheba Medical Center, Tel-Hashomer.

Objectives: We aimed to characterize parkinsonian features and gait performance of psychiatric patients on neuroleptics (PPN) and to compare them to Parkinson's disease (PD) and healthy controls (HC).

Methods: Hospitalized PPN (n = 27) were recruited, examined, and rated for parkinsonian signs according to the motor part of the Movement Disorders Society Unified Parkinson's Disease Rating Scale and performed a 10-m "timed-up-and-go" (TUG) test with a smartphone-based motion capture system attached to their sternum. Gait parameters and mUPDRS scores were compared to those of consecutive age-matched PD patients (n = 18) and HC (n = 27).

Results: Psychiatric patients on neuroleptics exhibited parkinsonism (mUPDRS score range: 8-44) but less than that of PD patients (18.2 ± 9.2 vs 29.8 ± 10.3, P = 0.001). TUG times were slower for PPN and PD versus HC (total: 30.6 ± 7.6 seconds vs 30.0 ± 7.3 seconds vs 20.0 ± 3.2 seconds, straight walking: 10.6 ± 2.7 seconds vs 10.6 ± 2.4 seconds vs 6.8 ± 1.2 seconds) (P < 0.001), and cadence and step length were similar among PPN and PD and different from HC as well. Although their gait speed was slower than HC but similar to PD, PPN had lower mediolateral sway (4.3 ± 1.1 cm vs 6.7 ± 2.9 cm vs 6.9 ± 2.9 cm, respectively, P < 0.001) than both.

Conclusions: Parkinsonism is very common in hospitalized PPN, but usually milder than that of PD. It seems that wearable sensor-based technology for assessing gait and balance may present a more sensitive and quantitative tool to detect clinical aspects of neuroleptic-induced parkinsonism than standard clinical ratings.
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http://dx.doi.org/10.1097/WNF.0000000000000371DOI Listing
December 2020

Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia.

Brain 2020 01;143(1):234-248

Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland.

Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.
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http://dx.doi.org/10.1093/brain/awz350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935749PMC
January 2020

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders.

Hum Mutat 2020 02 25;41(2):487-501. Epub 2019 Nov 25.

Department of Neurology, Program in Neurogenetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.
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http://dx.doi.org/10.1002/humu.23946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182470PMC
February 2020

Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies.

Ann Neurol 2020 01 18;87(1):139-153. Epub 2019 Nov 18.

Center for Advanced Research in Sleep Medicine, Sacred Heart Hospital of Montreal, Montreal, Quebec, Canada.

Objective: The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications.

Methods: Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function.

Results: Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants.

Interpretation: Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.
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http://dx.doi.org/10.1002/ana.25629DOI Listing
January 2020

Excessive phase synchronization in cortical activation during locomotion in persons with Parkinson's disease.

Parkinsonism Relat Disord 2019 08 22;65:210-216. Epub 2019 May 22.

Center of Advanced Technologies in Rehabilitation, Sheba Medical Center, Tel Hashomer, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel; Gonda Brain Research Center, Bar Ilan University, Ramat-Gan, Israel. Electronic address:

Introduction: Parkinson's disease (PD) is characterized by gait disturbances, which become severe during the advanced stages of the disease. Though gait impairments in Parkinson's disease have been extensively described in terms of spatiotemporal gait parameters, little is known regarding associated patterns of cortical activity. The objective of the present study is to test if interhemispheric synchronization differs between participants with PD and healthy elderly controls (NPD). We analyzed electroencephalography (EEG) signals recorded during bilateral movements, i.e., locomotion and hand tapping.

Methods: Fifteen participants with PD ('OFF' their anti-parkinsonian medications) and eight NPD were assessed during quiet standing, straight-line walking, turning, and hand tapping tasks. Using a 32-electrode EEG array, we quantified the synchronization in periodic cortical activation between the brain hemispheres (interhemispheric phase synchronization; inter-PS). Theta, alpha, beta, and gamma bands were evaluated.

Results: In all bands, inter-PS was significantly higher for the PD group as compared with the NPD group during standing and walking (p < 0.001) and during bimanual tasks (p = 0.026).

Conclusions: Persons with PD exhibit increased inter-PS as compared with NPD participants. These findings support previous evidence from animal studies, that bilateral cortical hypersynchronization emerges from the asymmetric neural degeneration that is at the base of the disease. Future studies should elucidate the long-term temporal development of this hypersynchronization and its clinical relevance (e.g., can it 'serve' as prodromal marker?).
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http://dx.doi.org/10.1016/j.parkreldis.2019.05.030DOI Listing
August 2019

Coupling Between Leg Muscle Activation and EEG During Normal Walking, Intentional Stops, and Freezing of Gait in Parkinson's Disease.

Front Physiol 2019 12;10:870. Epub 2019 Jul 12.

Institute of Physics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.

In this paper, we apply novel techniques for characterizing leg muscle activation patterns via electromyograms (EMGs) and for relating them to changes in electroencephalogram (EEG) activity during gait experiments. Specifically, we investigate changes of leg-muscle EMG amplitudes and EMG frequencies during walking, intentional stops, and unintended freezing-of-gait (FOG) episodes. FOG is a frequent paroxysmal gait disturbance occurring in many patients suffering from Parkinson's disease (PD). We find that EMG amplitudes and frequencies do not change significantly during FOG episodes with respect to walking, while drastic changes occur during intentional stops. Phase synchronization between EMG signals is most pronounced during walking in controls and reduced in PD patients. By analyzing cross-correlations between changes in EMG patterns and brain-wave amplitudes (from EEGs), we find an increase in EEG-EMG coupling at the beginning of stop and FOG episodes. Our results may help to better understand the enigmatic pathophysiology of FOG, to differentiate between FOG events and other gait disturbances, and ultimately to improve diagnostic procedures for patients suffering from PD.
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http://dx.doi.org/10.3389/fphys.2019.00870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639586PMC
July 2019

Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls.

Mov Disord 2019 09 26;34(9):1392-1398. Epub 2019 Jul 26.

Department of Neurology, Mount Sinai Beth Israel Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls.

Methods: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients.

Results: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients.

Conclusions: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754269PMC
September 2019

The spectrum of tremor among carriers of the FMR1 premutation with or without the fragile X-associated tremor/ataxia syndrome (FXTAS).

Parkinsonism Relat Disord 2019 08 7;65:32-38. Epub 2019 May 7.

Movement Disorders Institute and Department of Neurology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a genetically determined neurodegenerative disease which is caused by a 55-200 expansion of CGG repeat element in the promoter region of the fragile X mental retardation 1 (FMR1) gene. The major clinical manifestations are tremor and cerebellar ataxia. Different types of tremor are described in patients with FXTAS: essential tremor-like, rest tremor and cerebellar tremor, and the different tremor types may coexist. There is no effective disease modifying therapy for FXTAS, but troublesome tremor may be treated by pharmacological and surgical approaches used for other more common disorders such as essential tremor and Parkinson's disease.
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http://dx.doi.org/10.1016/j.parkreldis.2019.05.010DOI Listing
August 2019

Catastrophizing mediates the relationship between non-motor symptoms and quality of life in Parkinson's disease.

Disabil Health J 2019 10 19;12(4):673-678. Epub 2019 Mar 19.

Movement Disorders Institute, Department of Neurology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.

Background: The non-motor symptoms of Parkinson's disease (PD), pain, depression, anxiety and sleep disturbances are highly prevalent in persons with PD and have a profound impact on their quality of life (QOL). Catastrophizing is a negative coping style known to influence individuals' ability to cope with their medical symptoms and contributes to negative health-related outcomes, yet, it has not been studied in persons with PD.

Objective: The objectives of this study were to measure catastrophizing in PD and explore its role as a mediator of the relationship between non-motor symptoms and QOL.

Methods: One-hundred and three individuals diagnosed with PD completed questionnaires regarding pain catastrophizing, QOL and non-motor symptoms: pain, depression, anxiety and sleep disturbances.

Results: More than half of the sample exhibited high levels of pain, anxiety and sleep disturbances. Catastrophizing was significantly correlated with QOL and with all of the non-motor symptoms. Catastrophizing mediated the relationship between all of non-motor symptoms and QOL as well as the relationship between age and QOL.

Conclusions: Negative psychologic coping, specifically catastrophizing, has an important role in determining how destructive non-motor symptoms can be on the QOL of persons with PD. This is the first study to measure catastrophizing in this population and demonstrate its negative impact on QOL. Our findings emphasize the need to identify persons at risk for poor QOL and referrer them to appropriate psychological care. Evidence based interventions that target catastrophizing should be tested for their efficacy in persons with PD.
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http://dx.doi.org/10.1016/j.dhjo.2019.03.006DOI Listing
October 2019