GBA1-Associated Parkinson's Disease Is a Distinct Entity.

GBA1-associated Parkinson's disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson's disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit a broader distribution of Lewy bodies within the brain, accentuating neurodegenerative processes. The pathogenesis of GBA1-PD is closely associated with mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In this review, we discuss two mechanisms by which GBA1 mutations contribute to disease development: 'haploinsufficiency,' where a single functional gene copy fails to produce a sufficient amount of GCase, and 'gain of function,' where the mutated GCase acquires harmful properties that directly impact cellular mechanisms for alpha-synuclein degradation, leading to alpha-synuclein aggregation and neuronal cell damage. Continued research is advancing our understanding of how these mechanisms contribute to the development and progression of GBA1-PD, with the 'gain of function' mechanism appearing to be the most plausible. This review also explores the implications of GBA1 mutations for therapeutic strategies, highlighting the need for early diagnosis and targeted interventions. Currently, small molecular chaperones have shown the most promising clinical results compared to other agents. This synthesis of clinical, pathological, and molecular aspects underscores the assertion that GBA1-PD is a distinct clinical and pathobiological PD phenotype, necessitating specific management and research approaches to better understand and treat this debilitating condition.

A benign course of Parkinson's disease associated with different mutations in the glucocerebrosidase gene - A case series.

BACKGROUND: Subjects carrying mutations in the GBA gene, whether in one or two alleles pose a risk to develop Parkinson's disease (PD). This type of GBA-related PD has usually a severe course, and patients tend to develop cognitive deficits faster. Herein we describe 8 cases of GBA-PD patients with a markedly benign course (bGBA-PD), and compared them to the other regular GBA-PD group (rGBA-PD) and to mutation negative patients (MNP). METHODS: All patients who performed next generation testing were enrolled. We defined bGBA-PD as patients with disease duration of at least 5 years, with Hoehn and Yahr (HY) ≤3 and MoCA score of ≥24. Following a selection of patients with a disease duration of 3 years or longer up to 15 years or shorter, we compared the bGBA-PD group to the rGBA-PD and MNP in terms of demographic and clinical features. RESULTS: 166 patients (58 males) diagnosed with PD were genotyped. Twenty-five patients were GBA-PD, of whom 7 were defined as bGBA-PD. Seventeen patients were LRRK2-PD and 123 patients were MNP. The rate of Rapide Eye Movement Behavioral Disorder (RBD) was highest in the rGBA-PD group and lowest in the bGBA-PD group (100 % vs. 28.6 %) (p < 0.001). The bGBA-PD group scored significantly higher in the Montreal Cognitive Assessment (MoCA) than rGBA-PD and MNP (27.6 ± 2.0 vs. 19.8 ± 3.9 vs. 23.5 ± 3.7, respectively; p = 0.006). There were no significant differences in MDS-UPDRS part-3 among the groups. There was no specific GBA mutation which was more commonly associated with bGBA-PD. CONCLUSION: While GBA-PD has a severe course of disease, a subgroup of which shows a benign course with a relatively preserved cognitive function even years after onset. We might suggest that these cases have other pathomechanisms leading to PD, including an incidental GBA carriership.

A Lower Rate of Hyposmia in Non-Ashkenazi Jewish Patients with Parkinson's Disease: Motor and Non-motor Disease Characteristics in Different Ethnic Groups in Israel.

BACKGROUND: Little is known about phenotypical variations among ethnic groups in patients with Parkinson's disease (PD) in Israel. Clinical characteristics of non-Ashkenazi Jews (NAJ) are scantly described. OBJECTIVES: To describe clinical aspects of PD in ethnic groups in Israel, focusing on NAJ and Ashkenazi Jews (AJ). METHODS: In this cross-sectional retrospective study, we collected demographic, genetic, and clinical characteristics of patients from different ethnic Jewish backgrounds. Ethnic groups included AJ; North African Jews (NAFJ); oriental Jews (OJ) originating from Iran, Iraq, and Buchara; Balkan Jews; Yemenite Jews (YJ); and Jews of mixed origin. Clinical characteristics included hyposmia, urinary complaints, constipation, and rapid eye movement sleep behavioral disorder. Cognitive complaints, motor features, levodopa-induced dyskinesia, and motor fluctuations were collected. Motor part of the MDS-UPDRS and Hoehn and Yahr scores were collected. RESULTS: The study comprised 174 PD Jewish patients (63.2% AJ, 56.4% males). The age at onset was 65.3 ± 10.2 years; 106 patients (60.9%) were genotyped (17 glucocerebrosidase [16.0%], 13 leucine-rich repeat kinase 2 [LRRK2] [12.3%]). Rates of hyposmia were significantly higher in AJ than NAJ (56.6% vs. 39.5%, respectively, P = 0.003). No significant differences were found in motor features in all variables. Of 13 AJ patients carrying the LRRK2 mutation, only one had hyposmia. Three patients with LRRK2 were NAJ. CONCLUSIONS: Hyposmia is less prevalent in PD patients of NAJ origin than in AJ. The rate of hyposmia in NAFJ patients is particularly low. The rate of other non-motor features is similar between NAJ and AJ patients.

The Downside of Botulinum Injections for Anterocollis: A Case Series and a Review of the Literature.

OBJECTIVES: This is a case series and a review of the literature of therapeutic outcomes of botulinum toxin (BT) injections for anterocollis. METHODS: Data collected included gender, age, age at onset, muscles targeted, and doses injected. Routine forms were filled out during each visit: Patient Global Impression of Change, Clinician Global Impression of Severity, Tsui scale. The effect duration and side effects (SEs) of the previous treatment were noted. RESULTS: We described 4 patients (3 men, 13 visits) with anterocollis, as primary postural abnormality of the neck, emphasizing the therapeutic response to BT injection. Mean age at onset was 75.3 ± 7.0 years, age at first injection was 80.7 ± 3.5 years. The mean total dose per treatment was 290.0 ± 95.6 units. Patient Global Impression of Change with any grade of favorable effect was reported in 27.3% of the treatments. In objective assessment, Global Impression of Severity and Tsui scores did not show a consistent tendency of improvement. Neck weakness was prevalent in 18.2% of the visits of the anterocollis group while no other SEs were noted. We found 15 articles describing experience with BT for anterocollis in 67 patients (19 in deep and 48 in superficial neck muscles). CONCLUSIONS: This case series describes the poor outcome of BT treatment for anterocollis, with low efficacy and bothersome SE. Levator scapulae injection for anterocollis is not effective and is highly associated with head drop and should perhaps be abandoned. Injection to the longus colli might give some benefit in non-responders.

Management of advanced Parkinson's disease in Israel: Clinicians viewpoint and action items.

Parkinson's disease (PD) is taking a staggering toll on healthcare systems worldwide, with the bulk of the expenditures invested in the late stages of the disease. Considering the rising life expectancy and the increasing prevalence of PD across the globe, a clear understanding of the early signs and treatment options available for advanced PD (APD), will facilitate tailoring management programs and support services. This task is complicated by the lack of both global consensus in defining APD and standardized care guidelines. This perspective prepared by a panel of movement disorder specialists, proposes to extend and optimize currently accepted PD coding to better reflect the diverse disease manifestations, with emphasis on non-motor features. The panel seeks to promote timely diagnosis by adjustment of evaluation tools for use by community neurologists and suggests modification of eligibility criteria for advanced therapy. Moreover, it advocates multidisciplinary assessments of APD patients to drive personalized, patient-centered and holistic management. Overall, earlier and more targeted intervention is expected to markedly improve patient quality of life.

A Comprehensive Assessment of Qualitative and Quantitative Prodromal Parkinsonian Features in Carriers of Gaucher Disease-Identifying Those at the Greatest Risk.

Carriers of GBA1 gene variants have a significant risk of developing Parkinson's disease (PD). A cohort study of GBA carriers between 40−75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40−74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7−33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14−32%), Unified Parkinson's Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2−26.4%), smell assessment (12.4%, 95% CI 6.6−20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7−19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as "abnormal". Then we calculated the percentage of "abnormal" tests for each subject; the median (range) was 4.55 (0−43.5%). Twenty-two subjects had more than 15% "abnormal" tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD.

Therapeutic Approach to Botulinum Injections for Hemifacial Spasm, Synkinesis and Blepharospasm.

The aim of this study was to show our therapeutic outcome of botulinum injection to the facial muscles and thereby to find the best therapeutic concept which should be embraced. The decision to treat the lower eyelid with 1-point or 2-points injection was randomly taken as there is no consensus regarding this debate. Injections of the lateral end of the upper eyelid were performed more laterally to the conventional injection point, just lateral to the conjunction of the upper and lower eyelids. Twenty-three patients (12 hemifacial spasm, 6 blepharospasm, 5 post facial palsy synkinesis) were enrolled. Data were retrieved from 112 visits between 2019 and 2022. Overall, 84.9% of the treatments had moderate or marked improvement. The most common side effect was facial weakness (11.8%). Neither ptosis nor diplopia were noted. Two-points regimen in the lower eyelid was associated with a lower risk of facial weakness (p = 0.01), compared to 1-point regimen, with a better therapeutic outcome as reflected by more favorable PGI-C scores (p = 0.04). Injection of the pretarsal segment of the upper eyelid, just onto or even lateral to the conjunction of the upper and lower eyelids, lowers the risk of ptosis.

Identification of an early-stage Parkinson's disease neuromarker using event-related potentials, brain network analytics and machine-learning.

OBJECTIVE: The purpose of this study is to explore the possibility of developing a biomarker that can discriminate early-stage Parkinson's disease from healthy brain function using electroencephalography (EEG) event-related potentials (ERPs) in combination with Brain Network Analytics (BNA) technology and machine learning (ML) algorithms. BACKGROUND: Currently, diagnosis of PD depends mainly on motor signs and symptoms. However, there is need for biomarkers that detect PD at an earlier stage to allow intervention and monitoring of potential disease-modifying therapies. Cognitive impairment may appear before motor symptoms, and it tends to worsen with disease progression. While ERPs obtained during cognitive tasks performance represent processing stages of cognitive brain functions, they have not yet been established as sensitive or specific markers for early-stage PD. METHODS: Nineteen PD patients (disease duration of ≤2 years) and 30 healthy controls (HC) underwent EEG recording while performing visual Go/No-Go and auditory Oddball cognitive tasks. ERPs were analyzed by the BNA technology, and a ML algorithm identified a combination of features that distinguish early PD from HC. We used a logistic regression classifier with a 10-fold cross-validation. RESULTS: The ML algorithm identified a neuromarker comprising 15 BNA features that discriminated early PD patients from HC. The area-under-the-curve of the receiver-operating characteristic curve was 0.79. Sensitivity and specificity were 0.74 and 0.73, respectively. The five most important features could be classified into three cognitive functions: early sensory processing (P50 amplitude, N100 latency), filtering of information (P200 amplitude and topographic similarity), and response-locked activity (P-200 topographic similarity preceding the motor response in the visual Go/No-Go task). CONCLUSIONS: This pilot study found that BNA can identify patients with early PD using an advanced analysis of ERPs. These results need to be validated in a larger PD patient sample and assessed for people with premotor phase of PD.

Neuro-Ophthalmic Phenotype of OPA3.

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.

Expert opinion on diagnosing, treating and managing patients with cerebrotendinous xanthomatosis (CTX): a modified Delphi study.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare, chronic, progressive, neurodegenerative disorder requiring life-long care. Patients with CTX often experience a diagnostic delay. Although early diagnosis and treatment initiation can improve symptoms and prognosis, a standardised approach to diagnosis, treatment and management of patients is not yet established. AIM: To assess expert opinion on best care practices for patients with CTX using a modified Delphi method. METHODS: A multidisciplinary group of healthcare professionals with expertise in CTX responded to a 3-round online questionnaire (n = 10 in Rounds 1 and 2; n = 9 in Round 3), containing questions relating to the diagnosis, treatment, monitoring, multidisciplinary care and prognosis of patients with CTX. Determination of consensus achievement was based on a pre-defined statistical threshold of ≥ 70% Delphi panellists selecting 1-2 (disagreement) or 5-6 (agreement) for 6-point Likert scale questions, or ≥ 70% Delphi panellists choosing the same option for ranking and proportion questions. RESULTS: Of the Round 1 (n = 22), Round 2 (n = 32) and Round 3 (n = 26) questions for which consensus was assessed, 59.1%, 21.9% and 3.8% reached consensus, respectively. Consensus agreement that genetic analyses and/or determination of serum cholestanol levels should be used to diagnose CTX, and dried bloodspot testing should facilitate detection in newborns, was reached. Age at diagnosis and early treatment initiation (at birth, where possible) were considered to have the biggest impact on treatment outcomes. All panellists agreed that chenodeoxycholic acid (CDCA) is a lifetime replacement therapy which, if initiated early, can considerably improve prognosis as it may be capable of reversing the pathophysiological process in CTX. No consensus was reached on the value of cholic acid therapy alone. Monitoring patients through testing plasma cholestanol levels and neurologic examination was recommended, although further research regarding monitoring treatment and progression of the disease is required. Neurologists and paediatricians/metabolic specialists were highlighted as key clinicians that should be included in the multidisciplinary team involved in patients' care. CONCLUSIONS: The results of this study provide a basis for standardisation of care and highlight key areas where further research is needed to inform best practices for the diagnosis, treatment and management of patients with CTX.

Botulinum Injections for Idiopathic Cervical Dystonia: a Longitudinal Study.

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.

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

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.

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

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.

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

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.

Analysis of common and rare VPS13C variants in late-onset Parkinson disease.

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] <1%) or very rare (MAF <0.1%) coding 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. CONCLUSIONS: Our 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.

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

BACKGROUND: There is a need for standardized and objective methods to measure postural instability (PI) and gait dysfunction in Parkinson's disease (PD) patients. Recent technological advances in wearable devices, including standard smartphones, may provide such measurements. OBJECTIVES: To test the feasibility of smartphones to detect PI during the Timed Up and Go (TUG) test. METHODS: Ambulatory PD patients, divided by item 30 (postural stability) of the motor Unified Parkinson's Disease Rating Scale (UPDRS) to those with a normal (score = 0, PD-NPT) and an abnormal (score ≥ 1, PD-APT) test and a group of healthy controls (HC) performed a 10-meter TUG while motion sensor data was recorded from a smartphone attached to their sternum using the EncephaLog application. RESULTS: In this observational study, 44 PD patients (21 PD-NPT and 23 PD-APT) and 22 HC similar in age and gender distribution were assessed. PD-APT differed significantly in all gait parameters when compared to PD-NPT and HC. Significant difference between PD-NPT and HC included only turning time (P < 0.006) and step-to-step correlation (P < 0.05). CONCLUSIONS: While high correlations were found between EncephaLog gait parameters and axial UPDRS items, the pull test was least correlated with EncephaLog measures. Motion sensor data from a smartphone can detect differences in gait and balance measures between PD with and without PI and HC.

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

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.

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

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.