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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.

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 2,657 patients and 3,647 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 (SKAT-O). 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=5.23E-05 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 nonsynonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in ten 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 (LD) 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 (OR 0.73, 95% CI 0.60-0.89, p=1.161E-03). This variant is not in LD 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.

BackgroundBiallelic 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.ObjectivesWe aimed to examine the association between heterozygous PRKN variants, including single nucleotide variants and copy-number variations, and PD.MethodsWe fully sequenced PRKN in 2,809 PD patients and 3,629 healthy controls, including 1,965 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. Copy-number variations were identified using a combination of multiplex ligation-dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single nucleotide variants and copy-number variations in PRKN are associated with PD risk and onset, we used optimized sequence kernel association tests and regression models.ResultsWe did not find any associations between all types of PRKN variants and risk of PD. Pathogenic and likely-pathogenic heterozygous single nucleotide variants and copy-number variations 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.ConclusionsHeterozygous single nucleotide variants and copy-number variations in PRKN are not associated with Parkinson’s disease. Molecular inversion probes allow for rapid and cost-effective detection of all types of PRKN variants, which may be useful for pre-trial screening and for clinical and basic science studies specifically targeting PRKN patients.

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.

Biallelic variants in NPC1, a lysosomal gene coding for a transmembrane protein involved in cholesterol trafficking, may cause Niemann-Pick disease type C (NPC). A few cases of NPC1 mutation carriers have been reported with a Parkinson’s disease (PD) presentation. In addition, pathological studies 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 2,657 PD patients and 3,647 controls from three cohorts, using targeted sequencing with molecular inversion probes. A total of 9 common variants and 126 rare variants were identified across the three cohorts. To examine 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.

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.

To study the effects of a repetitive deep transcranial magnetic stimulation (rDTMS) in patients with Parkinson disease using the H5 coil for the low-frequency stimulation of the primary motor cortex, followed by the high-frequency rDTMS of the prefrontal cortex.The main outcome measures were the total and motor scores of the Unified Parkinson's Disease Rating Scale (UPDRS). Secondary measures included rating of depression and quantitative motor tasks.Forty-eight patients were randomized 1:1 into real or sham rDTMS treatment arms. Analyses (n = 42) of both UPDRS scores revealed a significant main effect for time between baseline and day 90 (end of treatment), indicating that there was an improvement of both scores over time in the whole sample. Although effects of treatment and time-by-treatment were insignificant, simple effects analysis of both measures was significant in the rDTMS group and reached a P-value of 0.06 in the sham group. The response rate was higher in patients with longer disease duration and higher motor UPDRS scores. Side effects were more common in the rDTMS group but were transient and tolerable.Although rDTMS treatment exhibited some motor improvements, we could not demonstrate an advantage for real treatment over sham. Further research is required to establish stimulation parameters that may induce potentially more beneficial outcomes, probably in patients with longer and more sever disease.

Date Presented Accepted for AOTA INSPIRE 2021 but unable to be presented due to online event limitations. The current guideline criteria for diagnosing people with Parkinson's disease with mild cognitive impairment include neuropsychological tests to assess cognitive functioning. Assessments that reflect real-life confrontations can identify functional cognitive decline. OTs can contribute in implementing evaluations and developing performance-based interventions to promote daily life performance and quality of life and prevent the onset of increased disability. Primary Author and Speaker: Sonya Meyer Additional Authors and Speakers: Sara Rosenblum Contributing Authors: Netta Gemerman, Ariella Richardson, Tal Nevo, and Sharon Hassin-Baer

Myofascial pain of the muscles of mastication is a common temporomandibular disorder. Patients unresponsive to conservative treatment modalities pose a therapeutic challenge to the treating clinician. The efficacy of intramuscular botulinum toxin injections for recalcitrant cases is still not well established due to mixed results from clinical trials. The Diagnostic Criteria of Temporomandibular Disorders (DC/TMD) classified chronic muscle pain broadly into a localized pattern (when pain is localized to the site of palpation or the muscle palpated) and a referring pattern (when the pain spreads beyond the boundary of the muscle being palpated). The medical records of 25 consecutive patients treated with botulinum were analysed retrospectively. Significant pain reduction was achieved in 69.2% of the patients with localized myofascial pain and 16.7% of the patients with referring myofascial pain (P=0.015). Seventy-seven per cent of the patients with localized myofascial pain reported using less analgesic throughout the follow-up period, whereas only 25% of the patients with referring myofascial pain (P=0.017). The effects of botulinum toxin in responsive patients subsided after a mean of 3.21 months. Patients with localized myofascial pain benefited from botulinum toxin injections, but patients with referring myofascial pain responded poorly to this treatment.

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.To test the feasibility of smartphones to detect PI during the Timed Up and Go (TUG) test.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.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 (P0.006) and step-to-step correlation (P0.05).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.

ObjectiveWe aimed to study the role of coding VPS13C variants in a large cohort of patients with late-onset Parkinson disease (PD) (LOPD).MethodsVPS13C 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.ResultsNo biallelic carriers of rare VPS13C 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] VPS13C variants in PD. A VPS13C 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, p = 0.0052]). This haplotype was not in linkage disequilibrium with the known genome-wide association study top hit.ConclusionsOur results do not support a role for rare heterozygous or biallelic VPS13C 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.

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., Motor functions, affected in Parkinson’s disease, rely on the ability to perceive one’s own motion in space. Here, we found impaired visual perception of self-motion in Parkinson’s disease, and visual overweighting during visual–vestibular integration. This may contribute to impaired motor control and can aid Parkinson’s disease diagnosis or subtyping., Graphical Abstract Graphical Abstract

BackgroundParkinson’s disease (PD) is prototypically a movement disorder. Although perceptual and motor functions are interdependent, much less is known about perceptual dysfunction in PD. Perceptual deficits can impact activities of daily living, and contribute to motor symptoms, but might go unnoticed if not tested directly. Posture, gait and balance, affected in PD, rely on veridical perception of one’s own motion in space. Yet it is unknown whether self-motion perception is impaired in PD.ObjectivesTo test self-motion perception in PD, separately for visual and vestibular cues (unisensory), and multisensory integration thereof.MethodsParticipants (19 early stage PD, 23 age-matched and 20 young adult controls) experienced vestibular (motion platform), visual (optic flow), and combined visual-vestibular self-motion stimuli, and discriminated whether the stimulus headings were rightward or leftward of straight ahead. PD participants and age-matched controls were tested on two visits (PD on and off medication).ResultsPD participants had significantly impaired visual self-motion perception, both on and off medication. This deficit correlated significantly with clinical disease severity. By contrast, their vestibular performance was unimpaired. Remarkably, despite impaired visual self-motion perception, PD participants significantly over-weighted visual cues during multisensory (visual-vestibular) integration.ConclusionsSelf-motion perception is affected already in early stage PD, specifically by impaired visual (vs. vestibular) function, and by suboptimal visual-vestibular integration. This may contribute to impaired balance and gait control. Future investigation into this connection might open up new avenues for alternative therapies to better treat these symptoms. Furthermore, these results may also impact early PD diagnosis and subtyping.

ObjectiveRepeat expansions in RFC1 and DAB1 have recently been identified as causing cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) and spinocerebellar ataxia 37 (SCA37), respectively. We evaluated the prevalence of these repeat-expansions in an undiagnosed ataxia cohort from the United States.MethodsA cohort of 596 patients with undiagnosed familial or sporadic cerebellar ataxia were 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 RFC1 (AAGGG) and DAB1 (ATTTC) using fluorescent repeat primed polymerase chain reaction (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 96 and 13 patients respectively, were subsequently screened for RFC1 resulting in a combined 705 subjects tested.ResultsIn the initial cohort, 42 samples were identified with one expanded allele in the RFC1 gene (7.0%), and 9 had two expanded alleles (1.5%). For the additional cohorts, we found 12 heterozygous samples (12.5%) and 7 biallelic samples (7.3%) in the larger cohort, and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 19 patients were identified with biallelic repeat expansions in RFC1 (2.7%). Of these 19 patients, 6 (32%) had a clinical diagnosis of CANVAS, 10 had cerebellar ataxia with neuropathy (53%), and 3 had spinocerebellar ataxia (16%). No patients were identified with expansions in the DAB1 gene.ConclusionIn a large undiagnosed ataxia cohort from the United States, biallelic pathogenic repeat expansion in RFC1 was observed in 2.7%. Testing should be strongly considered in ataxia patients, especially those with CANVAS or neuropathy.

Objective We aimed to study the role of coding VPS13C variants in a large cohort of patients with late-onset Parkinson disease (PD) (LOPD). Methods VPS13C 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 VPS13C 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]

ObjectiveWe aimed to study the role of coding VPS13C variants in a large cohort of late-onset PD (LOPD) patients.MethodsVPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 PD patients 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.ResultsNo bi-allelic carriers of rare VPS13C variants were found among patients and two carriers of compound heterozygous variants were found in two controls. There was no statistically significant burden of rare (MAFVPS13C variants in PD. A VPS13C 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 (OR=0.48, 95%CI=0.28-0.82, p=0.0052). This haplotype was not in linkage disequilibrium (LD) with the known genome-wide association study (GWAS) top hit.ConclusionsOur results do not support a role for rare heterozygous or bi-allelic VPS13C 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.

This study describes the development of DailyCog: an accessible, practical smartphone application for the detection of mild cognitive impairment in Parkinson’s disease. Cognitive impairment in Parkinson’s has been capturing researchers interest lately, as it may occur at early stages of the disease, and has a substantial impact on quality of life. In order to find the best markers of the initial stage of the cognitive decline we developed DailyCog - a smartphone application for the detection of mild cognitive impairment. This work focuses on the design considerations while working in a multidisciplinary team, building a common understanding, and bringing together knowledge from Occupational Therapy, Neurology and Computer Science to build an application for evaluating Mild Cognitive Impairment (MCI) in Parkinson’s Disease.

ObjectiveTo assess genetic modifiers of Parkinson’s disease (PD) age at onset (AAO) penetrance in individuals carrying common and rare LRRK2 risk allelesMethodsWe analysed reported genetic modifier DNM3 rs2421947 in 724 LRRK2 p.G2019S heterozygotes using linear regression of AAO. We meta-analysed our data with previously published data (n=754). VAMP4 is in close proximity to DNM3 and is associated with PD. We analysed the effect of the rs11578699 VAMP4 variant on pG2019S penetrance in 786 LRRK2 p.G2019S heterozygotes. We also evaluated the impact of VAMP4 variants using AAO regression in 4882 patients with PD carrying a common LRRK2 risk variant (rs10878226).ResultsThere was no evidence for linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699. Our linear regression AAO of 724 p.G2019S carriers showed no relationship between DNM3 rs2421947 and AAO (beta = −1.19, p = 0.55, n =708). Meta-analysis with previously published data did not indicate a significant effect on AAO (beta = −2.21, p = 0.083, n = 1304), but there was significant heterogeneity in the analyses of new and previously published data. VAMP4 rs11578699 was nominally associated with AAO in patients dichotomized by the common LRRK2 risk variant rs10878226 (beta=1.68, se=0.81 p=0.037).InterpretationAnalysis of DNM3 in previously unpublished data does not show an interaction between DNM3 and LRRK2 G2019S for AAO, however the inter-study heterogeneity may indicate ethnic-specific effects of DNM3 rs2421947. Analysis of sporadic PD patients stratified by the PD risk variant rs10878226 indicates a possible interaction between LRRK2 and VAMP4.

International audience; 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.

Drooling is the unintentional loss of saliva from the mouth, usually caused by poor coordination of the swallowing mechanism. It is commonly seen in patients with chronic neurologic disorders, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), cerebral palsy, and stroke, as well as in patients with cognitive impairment and dementia.To evaluate the efficacy and safety of ultrasound-guided botulinum toxin injections into the parotid and submandibular salivary glands for the treatment of drooling.We conducted a retrospective analysis of the medical records of 12 consecutive patients treated with botulinum toxin injections into the parotid and submandibular glands for the first time. The primary outcome variable was the subjective improvement of drooling on a 5-point scale. Secondary outcome variables were duration of the therapeutic effect, request to undergo additional treatment, and adverse events.Of 12 patients, 8 (67%) reported considerable improvement after treatment, 3 reported slight improvement, and 1 reported development of dry mouth. All patients stated that they felt the effects 1 week after the injections; the mean duration of the therapeutic effect was 4.5 months (range 3-9 months). One patient suffered from local hematoma and ecchymosis that did not require medical care. Another patient complained of difficulty swallowing, which did not require medical treatment and resolved spontaneously within 1 month.Ultrasound-guided botulinum toxin injections into the parotid and submandibular glands seem to be a safe and effective therapy for the treatment of drooling. Further long-term prospective studies with varying doses are warranted.

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.

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.

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.

Long-term levodopa therapy in patients with Parkinson’s disease (PD) is associated with motor complications including motor fluctuations (MF) and levodopa-induced dyskinesias (LID). The time to appearance of MF and LID is apparently related to both the timing and the duration of levodopa therapy, but is highly variable. We performed a retrospective analysis of all levodopa-treated PD patients to explore the effect of time from PD onset to levodopa initiation on time to MF or LID. We used a Cox multivariate regression model after stratifying patients into four quartiles, according to the time to levodopa initiation. Data from 170 PD patients (117 males, age at onset: 65.1 ± 11.6 years, time to levodopa treatment: 23.8 ± 28.4 months) was included in the analysis. Early levodopa administration was associated with a shorter time from diagnosis to both MF (p

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, pathological 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 2,657 PD patients and 3,647 controls from three cohorts, using targeted sequencing with molecular inversion probes. A total of 9 common variants and 126 rare variants were identified across the three 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.

Date Presented 03/27/20 The current guideline criteria for diagnosing people with PD with MCI include neuropsychological tests to assess cognitive functioning. Assessments that reflect real-life confrontations can identify functional cognitive decline. OTs can contribute in implementing evaluations and developing performance-based interventions to promote daily life performance and quality of life and prevent the onset of increased disability. Primary Author and Speaker: Sonya Meyer Additional Authors and Speakers: Sara Rosenblum Contributing Authors: Netta Gemerman, Lilia Mentzer, Ariella Richardson, Simon Israeli-Korn, Vered Livneh, Tsvia Fay Karmon, Tal Nevo, Gilad Yahalom, Sharon Hassin-Baer

ObjectiveWe evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 (RFC1) and disabled adaptor protein 1 (DAB1) in an undiagnosed ataxia cohort from North America.MethodsA 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 RFC1 (AAGGG) and DAB1 (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 RFC1, resulting in a combined 911 subjects tested.ResultsIn the initial cohort, 41 samples were identified with 1 expanded allele in the RFC1 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 RFC1 (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 DAB1 gene (spinocerebellar ataxia type 37).ConclusionsIn a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in RFC1 was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.

Deep sequencing was used to determine complete nucleotide sequences of echovirus 11 (EV11) strains isolated from a chronically infected patient with CVID as well as from cases of acute enterovirus infection. Phylogenetic analysis showed that EV11 strains that circulated in Israel in 1980-90s could be divided into four clades. EV11 strains isolated from a chronically infected individual belonged to one of the four clades and over a period of 4 years accumulated mutations at a relatively constant rate. Extrapolation of mutations accumulation curve into the past suggested that the individual was infected with circulating EV11 in the first half of 1990s. Genomic regions coding for individual viral proteins did not appear to be under strong selective pressure except for protease 3C that was remarkably conserved. This may suggest its important role in maintaining persistent infection., Author summary We describe evolution of Echovirus 11 genome in chronically infected immunodeficient patient over a period of several years and compare it with the evolution of circulating echoviruses from which it originated. Ratio of silent to missense mutations in protein coding regions suggests that chronic virus was under lower selective pressure than circulating viruses, except for a region coding for viral protease that may participate in neutralizing host cell anti-viral defense mechanisms. This suggests that adaptation to persistence in immunodeficient host may require maintaining functional viral counter-defense mechanisms.

Objectives Repetitive transcranial magnetic stimulation (rTMS), using standard coils, provided modest symptomatic benefits in patients with Parkinson's disease (PD). In our previous exploratory studies, using the newly developed Hesed coil (providing deeper rTMS; rDTMS) high frequency (HF), excitatory rDTMS over the primary motor cortex (M1), did not achieve sufficient beneficial effect for PD symptoms, while low frequency (LF) inhibitory stimulation, was mildly beneficial. To further investigate the optimal rDTMS stimulation parameters for PD patients, and to assess whether there is an added value for dual stimulation, consisting of HF rDTMS over the prefrontal cortex (PFC) along with LF M1 rDTMS. The rational for the selection of the current stimulation parameters and sites lies on the previous studies that demonstrated an inhibitory effect of 1 Hz rTMS on the increased cortical activity in PD as well as dopamine release by PFC stimulation. Patients and methods An open comparative active study of one month duration (12 sessions) of LF rDTMS over M1 alone (n = 9) or combined with HF PFC rDTMS (M1-PFC, n = 10). Outcome measures included the total and motor Unified Parkinson's Disease Rating Scale scores (T-UPDRS and M-UPDRS) and other variables, were collected at baseline and on days 30 and 60. Results For the M1 + PFC group, T-UPDRS score improved from baseline to day 30, by 15% (median: 52 points, decreased to 44, p = 0.02, effect size: 0.51) and M-UPDRS score improved by 24% (median: 37 points decreased to 28, p = 0.04, effect size: 0.47). The corresponding results for the M1 group were insignificant. Additionally, the between groups comparison, was insignificant. Conclusion rDTMS, consisting of M1 excitation with PFC inhibition improved PD motor symptoms but was not significantly superior to M1 rDTMS alone. rDTMS stimulation protocols for M1 should be further evaluated in larger scale controlled studies.

Parkinson's disease (PD) displays an individually variable rate of progression, of which the underlying mechanisms are largely unknown, but may involve genetic factors. In this study, we aimed to explore the effect of ethnic origin on PD progression rate in Israeli Jews, as expressed by time from onset until reaching Hoehn and Yahr stage 3 (HY3).Consecutive patients with PD followed bi-annually at the Movement Disorders Institute at Sheba Medical Center, were included. Demographic data and clinical information, including age at PD onset (AO), HY staging, and family history of PD, were collected. Ethnicity was determined based on the parents' origin and was categorized as Ashkenazi Jews (AJ), Yemenite Jews (YJ), North African Jews (NAJ) and Oriental Jews (OJ) excluding YJ. Associations between the above variables and the time to HY3 were determined using Cox proportional hazards model. Survival curves were derived from the model.Of 707 patients [430 males, AJ: 458, YJ: 37, NAJ: 75 and OJ: 137] included in the analysis, 343 had reached HY3. In a multivariate analysis, a longer time to HY3 was significantly associated with a younger AO (HR = 1.07, p0.001). YJ showed a significantly shorter time to HY3 compared to AJ and OJ, but not compared to NAJ. Time to HY3 was significantly shorter for NAJ than for OJ.Jewish PD patients of Yemenite and North African origin may have a more rapid progression of PD, compared to those of Ashkenazi and Oriental origin, suggesting distinctive genetic influences.

Costeff syndrome is a rare genetic neuro-ophthalmological syndrome consisting of early-onset bilateral optic atrophy along with a progressive complex motor disorder with elevated levels of urinary 3-methylglutaconic acid and 3-methylglutaric acid. While borderline to mild cognitive deficits have been considered to be common in patients with this syndrome, a comprehensive cognitive assessment has never been performed. The aim of the current study was to explore the cognitive profile associated with Costeff syndrome. Sixteen adult patients diagnosed with Costeff syndrome were administered a neuropsychological test battery that was composed of standardized verbal tests adapted for the blind. General intelligence ranged from average to borderline, with a group mean consistent with intact general cognitive functioning (VIQmean = 85, z = -1) in the low-average range of the general population. The auditory immediate and delayed memory indexes were in the average range and were significantly higher than the general cognitive functioning, whereas the working memory index was significantly lower than the general cognitive functioning. Adult patients with Costeff syndrome have intact global cognition and learning abilities and strong auditory memory performance. © 2015 Wiley Periodicals, Inc.

Stimulation settings of deep brain stimulation (DBS) have evolved empirically within a limited parameter space dictated by first generation devices. There is a need for controlled clinical studies, which evaluate efficacy and safety of established programming practice against novel programming options provided by modern neurostimulation devices.Here, we tested a polarity reversal from conventional monopolar cathodic to anodic stimulation in an acute double-blind, randomized, cross-over study in patients with PD implanted with bilateral STN DBS. The primary outcome measure was the difference between efficacy and side-effect thresholds (current amplitude, mA) in a monopolar review and the severity of motor symptoms (as assessed by MDS-UPDRS III ratings) after 30 min of continuous stimulation in the medication off-state.Effect and side effect thresholds were significantly higher with anodic compared to cathodic stimulation (3.36 ± 1.58 mA vs. 1.99 ± 1.37 mA; 6.05 ± 1.52 mA vs. 4.15 ± 1.13 mA; both p 0.0001). However, using a predefined amplitude of 0.5 mA below the respective adverse effect threshold, blinded MDS-UPDRS-III-ratings were significantly lower with anodic stimulation (anodic: median 17 [min: 12, max: 25]; cathodic: 23 [12, 37]; p 0.005).Effective anodic stimulation requires a higher charge injection into the tissue, but may provide a better reduction of off-period motor symptoms within the individual therapeutic window. Therefore, a programming change to anodic stimulation may be considered in patients suffering from residual off-period motor symptoms of PD despite reaching the adverse effect threshold of cathodic stimulation in the subthalamic nucleus.

Premature ejaculation (PE) has been reported in 40.6–51.5% of men affected by Parkinson’s disease (PD), however, this non-motor sexual complaint has not been studied in detail. We describe eight PD patients who asked for a sexological consultation between 2008 and 2014 because of a new-onset of PE. They were diagnosed with acquired PE (APE) according to the DSM-V criteria and the International Society for Sexual Medicine (ISSM) committee. Patients’ demographic, medical and sexual related data were retrieved and studied. The average age of onset of PD was 53.3 ± 12.7 years (range 38–77 years) and the sexual problem appeared 4.0 ± 3.1 years later. The mean intravaginal ejaculation latency (IELT) before APE onset was 7.3 (range 2–20) min. Interestingly, the ejaculatory disorder appeared abruptly, characterized by a dramatically shortened IELT in all patients, while in three of the cases ejaculation occurred before vaginal penetration, hampering sexual intercourse. Some patients had 2 additional sexual problems, (four with erectile dysfunctions, five with libido changes: increased desire in four and reduced in one). In this case series of PD patients with APE, the ejaculatory dysfunction developed when patients were on antiparkinsonian medications, suggesting a possible medication effect.

Costeff syndrome (CS) is a rare autosomal-recessive neurological disorder, which is known almost exclusively in patients of Iraqi Jewish descent, manifesting in childhood with optic atrophy, ataxia, chorea and spastic paraparesis. Our aim was to study the clinical spectrum of CS and natural history using a cross-sectional study design. Consecutive patients with CS were recruited to the study. Patients were diagnosed based on clinical features, along with elevated urinary levels of methylglutaconic and methylglutaric acid, and by identification of the disease-causing mutation in the OPA3 gene in most. All patients were examined by a neurologist and signs and symptoms were rated. 28 patients with CS (16 males, 21 families, age at last observation 28.6 ± 16.1 years, range 0.5-68 years) were included. First signs of neurological deficit appeared in infancy or early childhood, with delayed motor milestones, choreiform movements, ataxia and visual disturbances. Ataxia and chorea were the dominant motor features in childhood, but varied in severity among patients and did not seem to worsen with age. Pyramidal dysfunction appeared later and progressed with age (r = 0.71, p < 0.001) leading to spastic paraparesis and marked gait impairment. The course of neurological deterioration was slow and the majority of patients could still walk beyond the fifth decade. While visual acuity seemed to deteriorate, it did not correlate with age. CS is a rare neurogenetic disorder that causes serious disability and worsens with age. Spasticity significantly increases over the years and is the most crucial determinant of neurological dysfunction.

Cardiac sympathetic denervation is an early nonmotor feature of Parkinson's disease (PD). The aim of the current study was to trace evidence for cardiac dysfunction abnormalities in the premotor phase of PD. We retrospectively reviewed treadmill ergometric tests of a large cohort (n 5 16,841) between 2000 and 2012, that attended the Executive Screening Survey (ESS) at Sheba Medical Center. Heart rate and blood pressure profiles as well as exercise capacity were compared between subjects who later developed PD and age- and sex-matched subjects (ratio 1:2) who did not. We identi- fied 28 subjects (24 males) who developed PD at follow- up. The PD group was older than the group of subjects who did not develop PD on first ergometric test (64.82 6 8.82 vs. 48.91 6 10.60 years, P < 0.001). The time between the first ergometri ct est and motor symptoms onset was 4.64 6 2.86 years. Patients who later devel- oped PD had lower maximal heart rate (P < 0.001) and lower heart rate reserve than healthy controls (P < 0.001); however, compared with age- and sex-matched subjects, subjects who developed PD had similar exercise capacity and heart rate profile during rest, exercise, and recovery, even 1 year before diagnosis. In this study, we did not detect significant signs of sympathetic dysfunction during the premotor phase of PD. V C 2014 International Parkinson and Movement Disorder Society

Introduction In this retrospective study, we compared motor disease progression in Ashkenazi-Jewish (AJ) Parkinson's disease (PD) patients carrying the LRRK2*G2019S mutation with that of noncarriers. Methods Consecutive PD patients were recruited between 2004 and 2011. Disease progression of carriers versus noncarriers was compared using survival analysis, where the end-point was the time from PD onset to reaching Hoehn and Yahr stage 3 (HY3). Results Overall, 405 AJ PD patients (males = 241[60%]) were genotyped, of whom 60 (males = 30) were LRRK2*G2019S mutation carriers. Time to HY3 did not differ significantly between mutation carriers and noncarriers (hazard ratio = 1.21, 95%CI = 0.83-1.77, P = 0.33). Age at PD onset was younger for carriers than for noncarriers (59.1 ± 9.8 vs. 63.2 ± 12.0 years, respectively; P = 0.005). In both groups, young age at onset was strongly associated with longer time to HY3, (P

Objective Creative thinking requires a combination of originality, flexibility, and usefulness. Several reports described enhanced artistic creativity in Parkinson disease (PD) patients treated with dopaminergic agents. We aimed to examine PD patients' ability to perform creativity tasks compared to healthy controls and to verify whether creativity is related to an impulse control disorder (ICD) as a complication of dopaminergic therapy. Methods Right-handed PD patients treated with dopamine agonists and/or levodopa, and age- and education- matched neurologically healthy controls were assessed using the Montreal Cognitive Assessment, semantic verbal fluency, Beck Depression Inventory, and Questionnaire for Impulsive–Compulsive Disorders in Parkinson Disease Rating Scale (QUIP-RS). Creativity assessment included Comprehension of Novel Metaphors (CNM), Remote Association Test, and Tel Aviv Creativity Test (TACT). Groups were compared using analyses of variance, t tests, and correlation analyses. Results Twenty-seven PD patients (age, mean ± standard deviation = 62 ± 7 years; education = 16 ± 3 years; disease duration = 5.8 ± 3.9 years) and 27 controls (age = 59 ± 9 years; education 17 ± 3 years) participated. PD patients performed significantly better than controls in divergent thinking tasks; specifically, the TACT-Visual for both fluency (33.48 ± 11.83 vs 25.59 ± 10.27, p = 0.034) and quality (15.78 ± 7.6 vs 11.19 ± 6.22, p = 0.025). Comprehension of Novel Metaphors was better in PD patients vs controls (0.71 ± 0.23 vs 0.55 ± 0.29, p = 0.04). QUIP-RS scores did not correlate with creativity measures. Interpretation PD patients treated with dopaminergic drugs demonstrated enhanced verbal and visual creativity as compared to neurologically healthy controls. This feature was unrelated to ICD. Dopaminergic agents might act through the reduction of latent inhibition, resulting in widening of the associative network and enriched divergent thinking. Ann Neurol 2014;75:935–942

Levodopa-induced dyskinesias (LID) present a common but elusive complication of levodopa therapy in Parkinson's disease (PD). In order to identify genetic factors associated with LID, 352 (213 males) levodopa-treated Israeli PD patients were genotyped for 34 polymorphisms within three candidate genes affecting dopaminergic activity and synaptic plasticity: dopamine transporter gene (DAT1 or SLC6A3) [14 single nucleotide polymorphisms (SNPs) and 40-bp variable number tandem repeat (VNTR)], DRD2 [11 SNPs and dinucleotide CA short tandem repeat (STR)], and BDNF (7 SNPs). A comparison of patients with and without LID was performed by applying a time-oriented approach, with survival analyses evaluating LID development hazard rate over time [Cox proportional hazards and accelerated failure time (AFT) lognormal models]. Overall, 192 (54.5 %) participants developed LID, with a mean latency of 5.0 (±4.5) years. After adjusting for gender, age at PD onset, duration of symptoms prior to levodopa exposure, and multiple testing correction, one SNP in SLC6A3 (with 81 % genotyping success) was significantly associated with LID latency: the C allele of the rs393795 extended the time to LID onset, time ratio = 4.96 (95 % CI, 2.3-10.9; p = 4.1 × 10(-5)). This finding should be validated in larger, ethnically diverse PD populations, and the biological mechanism should be explored.

Introduction: Onabotulinum toxin A is an effective treatment for a variety of movement disorders; yet, results of efficacy in patients with medically-resistant tic disorders are insufficient. We aimed to assess the efficacy of Onabotulinum toxin A in patients with ocular tics in an observational study. Methods: Patients with ocular tics, regularly treated with Onabotulinum toxin A injections at our clinic, were enrolled for 2 visits, one of which was for baseline assessment and a single injection session and the second -a follow-up visit one month after treatment for evaluation of outcome. The assessment tools consisted of a 10-minute videotape recording which was scored later by a blinded rater. The calculated ocular tic frequency was the primary end-point of this study. Secondary outcome measures consisted of additional items obtained from the video recording as well as the motor subset of the Yale Global Tic Severity Scale (YGTSS-M) and the Clinical Global Impression of change (CGI-C). Results: Six patients were enrolled.Video recordings and rating of the ocular tics before and after treatment revealed a 37% reduction in mean tic frequency, a 2.18-fold prolongation of the time to the first tic following suppression and a reduction in tic frequency during and after suppression by 45% and 52%, respectively. The mean YGTSS-M decreased by 39%. Five patients reported an improvement in CGI-C while one reported no change. Conclusions: In this observational study, Onabotulinum toxin A was found to be an effective treatment for ocular tics, providing both subjective and objective benefit for a subset of patients.

The onset and progression of Parkinson's disease (PD) motor symptoms is generally asymmetric, reflecting differential extent of nigral pathology and resulting dopamine depletion in each of the hemispheres. Given the role of dopamine in processing rewarding and aversive events, and considering findings associating asymmetric neural activity with differential sensitivity to positive and negative stimuli, the current study examined the possibility that dopamine asymmetry in PD is related to differential approach and avoidance tendencies. An original task assessing and comparing sensitivity to positive and negative probabilistic feedback was administered to 29 right-handed participants with idiopathic PD, 16 with predominant right-side and 13 with predominant left-side motor symptoms, to compare the two groups. As dopamine replacement therapy (DRT) has shown different effects on reward and punishment processing, all participants were assessed in both off- and on-medication states. As predicted, when off medication, participants with relatively greater dopamine deficit in the left hemisphere minimized losses better than they increased gains, while those with a greater right hemisphere deficit showed a trend toward the opposite pattern. Medication reversed the relationship between gain and loss sensitivity in the left-hemisphere PD group, but not in the right-hemisphere group. Particularly in the left-hemisphere PD group, findings support the possibility that subcortical dopaminergic asymmetry is reflected in behaviorally-expressed approach and avoidance tendencies. Furthermore, the effects of DRT on approach and avoidance appear to interact with asymmetry, shedding light on previous conclusions regarding the role of dopamine in reinforcement processing.

People with Parkinson's disease (PD) present with problematic sexual behaviors that are often misunderstood or ignored. Sexual problems in PD are part of a non-motor syndrome, and they play a prominent role in the life of affected individuals and their partners. Based on our considerable clinical experience, we describe four common types of sexual preoccupation behaviors in people with PD: (1) sexual behavior with underlying sexual dysfunction, (2) sexual desire discrepancy with partner after restored desire, (3) hypersexuality and compulsive sexual behavior, and (4) sexual behavior with underlying restless genital syndrome. We also suggest methods of assessing and diagnosing these sexual behaviors, and propose alternative possible treatments for people with PD and their partners/caregivers. Understanding these four behavioral types will assist healthcare professionals in explaining and educating people with PD and their partners, contribute to decreased stress and tension between them, and help them manage these sexual issues.

Frontal-type cognitive deficits are common in patients with Parkinson disease (PD). The Frontal Assessment Battery (FAB) was developed to assess frontal lobe functions. However, many studies found that it also correlated with a variety of other general neuropsychological tests.To evaluate whether the FAB has an added value over the Mini-Mental State Examination (MMSE) and other bedside neuropsychological tests in reflecting cognitive deficits in patients with PD.Seventy-two consecutive patients with PD underwent cognitive assessment including the FAB, the MMSE, and a variety of other neuropsychological tests. Correlations were examined using the Spearman's r.Highly significant correlations were found between the total FAB score and tests of attention, executive functions, and memory. To evaluate the contribution of the FAB beyond that of the MMSE, partial correlation was used. Analyses revealed that the FAB still correlated with most of the tests. Dividing the patients according to the median MMSE score revealed that the high correlation between the FAB and the MMSE was preserved in the low MMSE group, while in the high MMSE group the correlation was relatively low. In the high MMSE group, the FAB correlated with 11 tests compared to the MMSE that correlated with one (P.001), while in the low MMSE group the number of correlations was 13 versus 7, respectively (P = .05).In our sample of patients with PD, the FAB correlated with dysfunction in a variety of cognitive domains including attention, memory, and executive functions. The FAB has an added value over the MMSE, particularly among nondemented patients, an advantage that can be used in clinical practice.

Ataxia-telangiectasia is a cerebellar neurodegenerative disorder presenting with ataxia, chorea, myoclonus, and bradykinesia. Literature on treatment of movement disorders is scarce. We treated 17 children (aged 11.2 ± 3.9 years) for 8 weeks with the dopaminergic and anti-N-methyl-d-aspartate (NMDA) agent amantadine sulfate 6.3 ± 0.87 mg/kg/d. Ataxia was assessed by using the International Cooperative Ataxia Scale, parkinsonism by the Unified Parkinson Disease Rating Scale, and chorea/myoclonus by the Abnormal Involuntary Movement Scale. Responders were considered those patients who had at least 20% improvement in the summation of the 3 scales. Overall, 76.5% of patients were responders, with a mean 29.3% improvement. Ataxia, involuntary movements, and parkinsonism improved significantly (25.3%, 32.5%, and 29.5%, respectively); (P < .001, t test). Side effects were mild and transient, and they did not lead to drug discontinuation. Amantadine is a well-tolerated and effective treatment for motor symptoms in ataxia telangiectasia. Assessment of long-term effects and a double-blind study should follow.

Objective: In view of the fact that cancer patterns in patients with Parkinson disease (PD) differ from the general population, we aimed to verify whether patients with PD with LRRK2 mutations have an increased risk for particular cancer types. Methods: In this cross-sectional study, eligible consenting Jewish patients with PD were genotyped for the predominant LRRK2 G2019S mutation. Oncologic data were obtained by personal interview and reviewing patients9 files. Stepwise logistic regression was applied to model the probability of cancer occurrence in carriers vs noncarriers. Results: Overall, 79/490 (16.1%) genotyped patients carried the G2019S mutation. Seventy-seven (16%) were diagnosed with cancer; of those, 67 (14%) with a non-skin cancer. Eighteen (23%) carriers vs 49 (12%) noncarriers had a non-skin cancer ( p = 0.01, odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.19–3.99). A significant ethnicity effect was noted ( p = 0.045, OR = 1.84, 95% CI 1.02–3.34). Among Ashkenazi patients, age and LRRK2 emerged as significant using stepwise logistic regression including age, gender, and LRRK2 status as explanatory variables. The OR for LRRK2 mutation carriers adjusted for age was 3.38 (95% CI 1.64–6.97, p = 0.0009). Conclusions: Ashkenazi Jewish patients with PD who harbor the G2019S LRRK2 mutation are more likely to have a concomitant non-skin cancer than noncarriers.

Background A range of impulse control disorders has been described in Parkinson's disease, including compulsive sexual behavior. Excessive sexual demands of parkinsonian men can lead to considerable tension within the couple. Thorough sexual interviews reveal that these cases may reflect various types of sexual dysfunctions that present as hypersexuality. Objective This study aims to analyze cases of presumed and true compulsive male sexual behavior, and to propose a practical tool for clinicians, assisting them with the diagnosis and management of compulsive sexual behavior and other sexual dysfunctions in parkinsonian patients. Methods We describe four male patients with Parkinson's disease from the movement disorders clinic, which were referred to the sex therapist as suspected hypersexuality. Results The sexual assessment revealed that only one of the cases involved true hypersexuality due to compulsive sexual behavior. The other three presented with erectile dysfunction, difficulties reaching orgasm (delayed ejaculation), and a gap in desire within the couple. Conclusions Complaints about hypersexual behavior in patients with Parkinson's disease must be carefully evaluated, involving a multidisciplinary team. A comprehensive diagnostic and therapeutic algorithm is suggested.

The risk of melanoma is higher in patients with Parkinson's disease (PD) than in the general population. Whether the association is disease related or treatment related is unclear. The objective of this study was to assess melanoma prevalence in PD patients in Israel using active dermatologic screening. Consecutive patients with idiopathic PD were recruited by 12 Israeli centers. A movement disorder specialist assessed the severity of PD and obtained a medical, neurological, and medication history. Subsequently, a dermatologist assessed melanoma risk factors, recorded a dermatologic history, proactively performed a whole-body skin examination, and biopsied suspicious skin lesions. Of the enrolled patients (n = 1,395, mean age 69.5 ± 10.6 years, mean PD duration 7.3 ± 6.0 years), 95.3% were treated with dopaminergic agents. Biopsies revealed 8 patients with melanoma in situ and 1 with invasive malignant melanoma; 14 patients reported a melanoma prior to enrollment. The observed 5-year limited duration prevalence of melanoma in PD patients was 4.4 times greater (95% CI 2.6-7.6) than expected from melanoma prevalence in an age- and sex-matched cohort from the Israel National Cancer Registry. The increase was accounted for by an elevated prevalence of melanoma in situ [relative risk 12.5 (95% CI 6.7-23.2)]. Occurrence of melanoma did not correlate with levodopa therapy or time of onset of PD. Melanoma prevalence in PD patients was higher than expected in the general Israeli population. This was not related to levodopa treatment. PD patients should be actively screened for melanoma on a routine basis.