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Recessive mutations in PRKN, PARK7, and PINK1 are established causes of early-onset Parkinson's disease (EOPD). Previous studies have interrogated the role of heterozygous variants in these genes but mainly focused on rare (minor allele frequency [MAF]lt;1%) damaging variants or established mutations. Here, we assessed heterozygous private PRKN, PARK7 and PINK1 variants in PD risk in four large-scale PD case-control datasets by performing gene-wise burden analyses using sequencing data totaling 5,829 PD cases and 7,221 controls, and summary allele counts from 9,501 PD cases and 48,207 controls. Results showed no significant burden in all three genes after meta-analyses. Burden in EOPD (age at onsetlt;50 years) and late-onset PD (≥50 years) remained nonsignificant. In summary, we found no evidence to support the association of the excess burden of heterozygous private variants in PRKN, PARK7, and PINK1 with PD risk in the European population. Larger, more diverse cohorts are needed to accurately determine their role in PD.

Background: The purpose of this study is to explore changes in blood-brain barrier (BBB) function and volumetry associated with Parkinson’s disease (PD) levodopa-induced-dyskinesia (LID). Methods: Twenty-six PD patients [matched pairs, 13 with LID (LID+) and 13 without (LID-)], performed high resolution 3D FSPGR MRI, applying a novel methodology developed for calculating delayed- enhancement-subtraction-maps, representing BBB function. Segmentation software calculated volumes of pre-determined brain structures and the mean BBB function was calculated for each structure. Comparisons between the LID+ and LID- paired patients and within patient, between the more and less affected hemisphere (MAH, LAH) and correlation tests with lateralized UPDRS motor scores were performed. Results: There were no significant differences in volumetric or BBB map characteristics between the matched LID+ and LID- patients regarding most brain areas except for the inferior parietal cortex (IPC) of the MAH that displayed a higher BBB disruption in LID+ vs. LID- patients. A positive correlation was found with the motor score of the side contralateral to the MAH(r = 0.58, p

BackgroundSeveral lysosomal genes are associated with Parkinson’s disease (PD), yet the association between PD andARSA, which encodes for the enzyme arylsulfatase A, remains controversial.ObjectivesTo evaluate the association between rareARSAvariants and PD.MethodsTo study possible association of rare variants (minor allele frequencyARSAwith PD, we performed burden analyses in six independent cohorts with a total of 5,801 PD patients and 20,475 controls, using optimized sequence Kernel association test (SKAT-O), followed by a meta-analysis.ResultsWe found evidence for an association between functionalARSAvariants and PD in four independent cohorts (P≤0.05 in each) and in the meta-analysis (P=0.042). We also found an association between loss-of-function variants and PD in the UKBB cohort (P=0.005) and in the meta-analysis (P=0.049). However, despite replicating in four independent cohorts, these results should be interpreted with caution as no association survived correction for multiple comparisons. Additionally, we describe two families with potential co-segregation of theARSAvariant p.E384K and PD.ConclusionsRare functional and loss-of-functionARSAvariants may be associated with PD. Further replication in large case-control cohorts and in familial studies is required to confirm these associations.

Botulinum toxin (BT) injections into the cervical muscles are an effective and commonly practiced treatment approach for cervical dystonia. In this retrospective longitudinal study, we collected data from the Sheba electronic medical records on consecutive patients with idiopathic cervical dystonia (ICD), treated regularly with periodic BT injections between the years 2008–2020. All treatment visits were analyzed regarding type of toxin, dose injected, and clinical outcomes. The vast majority of patients were treated with abobotulinum toxin A. Sixty-four ICD patients (51 (79.7%) females, onset at age 45.8 ± 13.7 years) were treated over 17.1 ± 13.9 (range 3 to 49) visits per patient; BT treatment efficacy increased gradually from initial treatment sessions to visit 13, when it achieved a steady state. While the subjective report of percentage improvement and its duration were around 78.9 ± 17.1% for 2.8 ± 1.0 months, respectively, the dose of BT increased significantly over the years (p = 0.006). Side effects (SE) were not rare, and commonly recurred after subsequent sessions and were usually mild and short-lasting, with dysphagia being the most common (~17.5%), followed by neck/arm weakness (11.9%) and cervical pain (8.9%). Repeated injections of BT for ICD remain beneficial for patients over several years of therapy, and despite mild SE, patients tend to adhere to a 3–4 months interval schedule.

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.

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.

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.

The association between glucocerebrosidase (GCase), encoded byGBA, and Parkinson’s disease highlights the role of the lysosome in Parkinson’s disease pathogenesis. Genome-wide association studies (GWAS) in Parkinson’s disease have revealed multiple associated loci, including theGALClocus on chromosome 14.GALCencodes the lysosomal enzyme galactosylceramidase (GalCase), which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whetherGALCis the gene driving the association in the chromosome 14 locus, and if so, by which mechanism.We first aimed to examine whether variants in theGALClocus and across the genome are associated with GalCase activity. We performed a GWAS in two independent cohorts from a)Columbia University and b)the Parkinson’s Progression Markers Initiative study, followed by a meta-analysis with a total of 976 Parkinson’s disease patients and 478 controls with available data on GalCase activity. We further analyzed the effects of commonGALCvariants on expression and GalCase activity using genomic colocalization methods. Mendelian randomization was used to study whether GalCase activity may be causal in Parkinson’s disease. To study the role of rareGALCvariants we analyzed sequencing data from 5,028 Parkinson’s disease patients and 5,422 controls. Additionally, we studied the functional impact ofGALCknock-out on alpha-synuclein accumulation and on GCase activity in neuronal cell models and performedin silicostructural analysis of commonGALCvariants associated with altered GalCase activity.The top hit in Parkinson’s disease GWAS in theGALClocus, rs979812, is associated with increased GalCase activity (b=1.2; se=0.06; p=5.10E-95). No other variants outside theGALClocus were associated with GalCase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased GalCase expression. Mendelian randomization suggested that increased GalCase activity may be causally associated with Parkinson’s disease (b=0.025, se=0.007, p=0.0008). We did not find an association between rareGALCvariants and Parkinson’s disease.GALCknockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced GalCase levels may be associated with Parkinson’s disease. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of GalCase affecting its activity.Our results nominateGALCas the gene associated with Parkinson’s disease in this locus and suggest that the association of variants in theGALClocus may be driven by their effect of increasing GalCase expression and activity. Whether altering GalCase activity could be considered as a therapeutic target should be further studied.

The association between glucocerebrosidase, encoded by GBA, and Parkinson’s disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson’s Progression Markers Initiative study, followed by a meta-analysis with a total of 976 PD patients and 478 controls with available data on galactosylceramidase activity. We further analysed the effects of common GALC variants on expression and galactosylceramidase activity using genomic colocalization methods. Mendelian randomization was used to study whether galactosylceramidase activity may be causal in PD. To study the role of rare GALC variants, we analysed sequencing data from 5028 PD patients and 5422 controls. Additionally, we studied the functional impact of GALC knockout on alpha-synuclein accumulation and on glucocerebrosidase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered galactosylceramidase activity. The top hit in PD genome-wide association study in the GALC locus, rs979812, is associated with increased galactosylceramidase activity (b = 1.2; SE = 0.06; P = 5.10 × 10−95). No other variants outside the GALC locus were associated with galactosylceramidase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased galactosylceramidase expression. Mendelian randomization suggested that increased galactosylceramidase activity may be causally associated with PD (b = 0.025, SE = 0.007, P = 0.0008). We did not find an association between rare GALC variants and PD. GALC knockout using CRISPR–Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced galactosylceramidase levels may be associated with PD. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of galactosylceramidase affecting its activity. Our results nominate GALC as the gene associated with PD in this locus and suggest that the association of variants in the GALC locus may be driven by their effect of increasing galactosylceramidase expression and activity. Whether altering galactosylceramidase activity could be considered as a therapeutic target should be further studied.

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.

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.

We previously reported on interhemispheric cortical hyper synchronization in PD. The aim of the present study was to address the hypothesis that increased interhemispheric cortical synchronization in PD is related to dopamine deficiency and is correlated with motor function.We studied participants with PD and characterized cortical synchronization with reference to brain regions. Electroencephalography (EEG) was recorded from 20 participants with PD while OFF and ON their dopaminergic medications (two separate visits), during quiet standing and straight-line walking. Cortical interactions in the theta, alpha, beta, and gamma brain wave frequency bands were evaluated using interhemispheric phase synchronization (inter-PS).Inter-PS values were found to be significantly higher during the OFF state as compared to the ON state in standing and walking trials for theta, alpha and beta bands. In addition, inter-PS reduction from OFF to ON was associated with mobility improvement evaluated by the Timed Up and Go test, and with daily levodopa equivalent dose across individuals. Higher differences in inter-PS values between OFF and ON states were evident mainly in the occipital-parietal cortex.Persons with PD have increased inter-PS during the OFF state compared to their ON state, and this increase in inter-PS is associated with the clinical improvement between OFF and ON. We speculate that these findings, together with previous evidence of higher inter-PS in PD as compared to healthy older adults, reflect neuronal processes consequential to asymmetric subcortical dopamine deficiency.

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.

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.

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.

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 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?).

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.

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. (c) 2019 International Parkinson and Movement Disorder Society

Background: People with Parkinson's disease (PD) treated with deep brain stimulation (DBS) with non-rechargeable implantable pulse generators (IPGs) require elective IPG replacement operations involving surgical and anesthesiologic risk. Life expectancy and the number of replacements per patient with DBS are increasing. Objective: To determine whether IPG longevity is influenced by stimulation parameters alone or whether there is an independent effect of the number of battery replacements and IPG model. Methods: PD patients treated with bilateral subthalamic DBS were included if there was at least one IPG replacement due to battery end of life. Fifty-five patients had one or two IPG replacements and seven had three or four replacements, (80 Kinetra® and 23 Activa-PC®). We calculated longevity corrected for total electrical energy delivered (TEED) and tested for the effect of IPG model and number of previous battery replacements on this measure. Results: TEED-corrected IPG longevity for the 1st implanted IPG was 51.3 months for Kinetra® and 35.6 months for Activa-PC®, which dropped by 5.9 months and 2.8 months, respectively with each subsequent IPG replacement (p

The clinical characteristics of Parkinson's disease (PD) associated with both the LRRK2 p.G2019S mutation and a GBA variant (LRRK2-GBA-PD) have not yet been determined.In this retrospective observational study of Ashkenazi-Jewish (AJ) PD patients, we describe the clinical course and characteristics of LRRK2-GBA-PD and estimate the risk to develop PD for the double mutation carriers. Odds ratios (OR) were estimated using published data on frequencies of GBA and LRRK2 mutations. Demographic and clinical data was retrieved from medical records and from rating at last visit.Our analysis included 236 PD patients, divided into four groups: LRRK2-PD (n = 66), GBA-PD (n = 78), GBA-LRRK2-PD (n = 12) and mutation-negative PD (MNPD, n = 80 randomly selected). The estimated ORs in different models for GBA-LRRK2 PD were 15-28 (95% CI 6.7-72.0, p 0.0001), compared to AJ controls. Using logistic regression (while controlling for sex, age at onset and PD duration), we found that probable REM-sleep behavior disorder (RBD) was significantly more common for GBA-PD than for LRRK2-PD, while none of the GBA-LRRK2-PD patients reported RBD. Dementia was significantly more common for GBA-PD than for the LRRK2-PD and MNPD. Psychosis was the most common for GBA-PD and least common for LRRK2-GBA-PD.While GBA-PD is characterized by higher rates of dementia, probable RBD and psychosis, it seems that compared to the other groups, these features are less common for LRRK2-GBA-PD. This may imply to a possible protective effect of LRRK2 p.G2019S mutation among GBA variant carriers.

Background: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD. Methods: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed. Results: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome. Conclusions: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.

Background Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered. Methods GBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PD patients and 662 AJ controls, from Israel and New York. Additional AJ control data (n = 3044) from the Inflammatory Bowel Disease Exome Portal was used. Results Full GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PD patients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PD patients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PD patients and 7.5% of controls (OR = 2.7, 95%CI = 1.9–3.8, p Conclusion Without full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials.

International audience; 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.

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.

BackgroundIncreased 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.ObjectivesWe 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.Methods20 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.ResultsVisual 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=0.002 and pConclusionsThese 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 accounts of increased visual dependence and impaired multisensory integration in PD, and could contribute to gait and balance impairments. Future work should investigate PD confidence in somatosensory function. A better understanding of altered sensory reliance in PD might open up new avenues to treat debilitating symptoms.

The PSAP gene encodes prosaposin, which is later cleaved into four active saposins: saposin A, B, C and D. Mutations in these enzymes have been linked to specific lysosomal storage disorders. Recently, a genetic association between mutations in saposin D and Parkinson’s disease (PD) has been reported. To further examine whether variants in saposin D or the other saposins could be associated with Parkinson’s disease, we performed Optimized Sequence Kernel Association Test (SKAT-O) in 4,132 Parkinson’s disease patients and 4,470 controls. Furthermore, we analyzed data from a PD Genome Wide Association Study (GWAS) to examine the association of common variants in the PSAP locus with Parkinson’s disease risk (analysis on 56,308 patients) and age at onset (analysis on 28,568 patients). We did not find any statistically significant associations between neither rare nor common variants in saposin D, nor any of the other saposins, and PD risk or onset. These results suggest that PSAP variants play either a very minor role, or more likely, no role, in PD.