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The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) is the cause of the COVID-19 pandemic [5]. SARS-Cov-2 demonstrates partial resemblance to SARS-CoV and MERS-CoV in phylogenetic analysis, clinical manifestations, and pathological findings [6, 7]. Reports emerging from China have described ataxia as a neurological symptom of the SARS-CoV-2 infection [5]. Opsoclonus consists of back-to-back multidirectional conjugate saccades without an inter-saccadic interval [8]. Myoclonus is defined as a sudden, brief, "shock-like", nonepileptic involuntary movement [9], which has been described as a symptom of SARS-CoV-2 infection [10]. Opsoclonus-Myoclonus-Ataxia syndrome (OMAS) associated COVID-19 infection has been reported recently [1112].

Background Feedback from wearable biosensors may help assess motor function in Parkinson's disease (PD) patients and titrate medication. Kinesia 360 continuously monitors motor symptoms via wrist and ankle sensors. Methods PD0049 was a 12-week pilot study to investigate whether using Kinesia 360 at home could improve motor symptom management in PD patients starting transdermal dopamine agonist rotigotine. Adults with PD and insufficiently controlled motor symptoms (prescribed rotigotine) were randomized 1:1 to Control Group (CG) or Experimental Group (EG) before starting rotigotine. Motor symptoms were assessed in all patients at baseline and Week 12 (W12) using Unified PD Rating Scale (UPDRS) III and Kinesia ONE, which measures standardized motor tasks via a sensor on the index finger. Between baseline and W12, EG used Kinesia 360 at home; clinicians used the data to supplement standard care in adjusting rotigotine dosage. Results At W12, least squares mean improvements in UPDRS II (−2.1 vs 0.5, p = 0.004) and UPDRS III (−5.3 vs −1.0, p = 0.134) were clinically meaningfully greater, and mean rotigotine dosage higher (4.8 vs 3.9 mg/24 h) in EG (n = 19) vs CG (n = 20). Mean rotigotine dosage increase (+2.8 vs + 1.9 mg/24 h) and mean number of dosage changes (2.8 vs 1.8) during the study were higher in EG vs CG. Tolerability and retention rates were similar. Conclusion Continuous, objective, motor symptom monitoring using a wearable biosensor as an adjunct to standard care may enhance clinical decision-making, and may improve outcomes in PD patients starting rotigotine.

Background Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. Methods We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test–Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections. Results Mutation carriers (n = 60; 4.4%) and E326K carriers (n = 65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio = 5.1; P = 9.7 × 10−6; E326K, odds ratio = 6.4; P = 5.7 × 10−7) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc] = 9.0 × 10−4; E326K, Pc = 0.036), Trail Making B-A (mutations, Pc = 0.018; E326K, Pc = 0.018), and Benton Judgment of Line Orientation (mutations, Pc = 0.0045; E326K, Pc = 0.0013). Conclusions Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits. © 2015 International Parkinson and Movement Disorder Society

Introduction: Research suggests an association between global cognition and postural instability/gait disturbance (PIGD) in Parkinson disease (PD), but the relationship between specific cognitive domains and PIGD symptoms is not clear. This study examined the association of cognition (global and specific cognitive domains) with PIGD symptoms in a large, well-characterized sample of individuals with PD. Methods: Cognitive function was measured with a detailed neuropsychological assessment, including global cognition, executive function, memory, visuospatial function, and language. PIGD symptoms were measured using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, Motor Examination subscale. Multiple linear regression analyses were performed to assess the relationship between cognition and PIGD symptoms with models adjusting for age, sex, education, enrollment site, disease duration, and motor symptom severity. Results: The analysis included 783 participants, with mean (standard deviation) age of 67.3 (9.7) years and median (interquartile range) MDS-UPDRS Motor Subscale score of 26 (17, 35). Deficits in global cognition, executive function, memory, and phonemic fluency were associated with more severe PIGD symptoms. Deficits in executive function were associated with impairments in gait, freezing, and postural stability, while visuospatial impairments were associated only with more severe freezing, and poorer memory function was associated only with greater postural instability. Discussion: While impairments in global cognition and aspects of executive functioning were associated with more severe PIGD symptoms, specific cognitive domains were differentially related to distinct PIGD components, suggesting the presence of multiple neural pathways contributing to associations between cognition and PIGD symptoms in persons with PD.

Author(s): Srivatsal, S; Cholerton, B; Leverenz, JB; Wszolek, ZK; Uitti, RJ; Dickson, DW; Weintraub, D; Trojanowski, JQ; Van Deerlin, VM; Quinn, JF; Chung, KA; Peterson, AL; Factor, SA; Wood-Siverio, C; Goldman, JG; Stebbins, GT; Bernard, B; Ritz, B; Rausch, R; Espay, AJ; Revilla, FJ; Devoto, J; Rosenthal, LS; Dawson, TM; Albert, MS; Mata, IF; Hu, SC; Montine, KS; Johnson, C; Montine, TJ; Edwards, KL; Zhang, J; Zabetian, CP | Abstract: Background: Increasing evidence suggests that genetic factors play a role in the variability associated with cognitive performance in Parkinson's disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2-related PD is not well-characterized. Methods: A cohort of 1,447 PD patients enrolled in the PD Cognitive Genetics Consortium was screened for LRRK2 mutations and completed detailed cognitive testing. Associations between mutation carrier status and cognitive test scores were assessed using linear regression models. Results: LRRK2 mutation carriers (n=29) demonstrated better performance on the Mini Mental State Examination (P=0.03) and the Letter-Number Sequencing Test (P=0.005). A smaller proportion of LRRK2 carriers were demented (P=0.03). Conclusions: Our cross-sectional study demonstrates better performance on certain cognitive tests, as well as lower rates of dementia in LRRK2-related PD. Future longitudinal studies are needed to determine whether LRRK2 mutation carriers exhibit slower cognitive decline.

Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p -value ( P FDR ) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; P FDR = 2.7 × 10 −4 ) for JoLO, PARP4 rs9318600 ( P FDR = 0.006), and rs9581094 ( P FDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 ( P FDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.

The diagnosis of psychogenic (functional) movement disorders (PMD) can be challenging given the phenotypic overlap with organic disorders and the poor diagnostic agreement by clinicians using currently available diagnostic criteria.1 Diagnostic delays result in larger accrual of disability and poor prognosis.2 In order to formulate a positive rather than exclusionary diagnosis of PMD, signs and symptoms unique to these disorders, inconsistent or incongruent with their organic counterparts, are needed.3 We have observed that PMD patients with primary or associated involvement of gait and/or balance tend to exhibit verbal and physical behaviors of effort disproportionate to their disability, particularly when standing or walking. These behaviors appear to be much less prevalent among those with organic gait disorders of comparable or greater severity, such as in advanced Parkinson disease, spinocerebellar ataxia or motor neuron disease. We sought to examine the prevalence, phenotypic range, and diagnostic performance of such a “huffing and puffing” spectrum of behaviors in consecutively examined patients with clinically definite PMD as compared with organic gait disorders.

Objectives The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on gait and balance vary and the underlying mechanisms remain unclear. DBS location may alter motor benefit due to anatomical heterogeneity in STN. The purposes of this study were to (1) compare the effects of DBS of dorsal (D-STN) versus ventral (V-STN) regions on gait, balance and regional cerebral blood flow (rCBF) and (2) examine the relationships between changes in rCBF and changes in gait and balance induced by D-STN or V-STN DBS. Methods We used a validated atlas registration to locate and stimulate through electrode contacts in D-STN and V-STN regions of 37 people with Parkinson's disease. In a within-subjects, double-blind and counterbalanced design controlled for DBS settings, we measured PET rCBF responses in a priori regions of interest and quantified gait and balance during DBS Off, unilateral D-STN DBS and unilateral V-STN DBS. Results DBS of either site increased stride length without producing significant group-level changes in gait velocity, cadence or balance. Both sites increased rCBF in subcortical regions and produced variable changes in cortical and cerebellar regions. DBS-induced changes in gait velocity are related to premotor cortex rCBF changes during V-STN DBS ( r = − 0.40, p = 0.03) and to rCBF changes in the cerebellum anterior lobe during D-STN DBS ( r = − 0.43, p = 0.02). Conclusions DBS-induced changes in gait corresponded to rCBF responses in selected cortical and cerebellar regions. These relationships differed during D-STN versus V-STN DBS, suggesting DBS acts through distinct neuronal pathways dependent on DBS location.

BACKGROUND The substantial proportion of individuals with Parkinson's disease (PD) who have or are expected to develop concomitant cognitive impairment emphasizes the need for large, well-characterized participant cohorts to serve as a basis for research into the causes, manifestations, and potential treatments of cognitive decline in those with PD. OBJECTIVE To establish a multi-site clinical core that cognitively and clinically characterizes patients with PD by obtaining quality longitudinal clinical, neuropsychological, and validated biomarker data. METHODS Six hundred nineteen participants with idiopathic PD (68.0 ± 9.1 years, 7.1 ± 6.2 years since diagnosis, 70% males) were enrolled in the Pacific Northwest Udall Center (PANUC), one of the Morris K. Udall Centers of Excellence for Parkinson's Research, Clinical Consortium and underwent comprehensive clinical and neuropsychological assessment. Participants were diagnosed with no cognitive impairment (PD-NCI), mild cognitive impairment (PD-MCI), or dementia (PDD) at a diagnostic consensus conference. RESULTS A substantial proportion of the overall sample was diagnosed with cognitive impairment at baseline: 22% with PDD and 59% with PD-MCI. A higher rate of cognitive impairment was observed in men than women (87% vs. 68%, p < 0.0001), despite a higher level of education. Most patients older than 50 years at the time of diagnosis and with disease duration greater than 10 years were cognitively impaired or demented. CONCLUSIONS The PANUC Clinical Consortium is a clinically and cognitively well-characterized cohort of patients with PD. Baseline cohort characteristics demonstrate a high rate of cognitive impairment in the sample, as well as potential sex differences with regard to cognitive diagnosis. The PANUC Clinical Consortium, with its access to biomarker, genetic, and autopsy data, provides an excellent foundation for detailed research related to cognitive impairment in PD.

This study examined whether antide- pressants delay the need for dopaminergic therapy or change the degree of motor impairment and disability in a population of early Parkinson's disease (PD) patients. Preclinical studies have indicated that antidepressants modulate signaling pathways involved in cell survival and plasticity, suggesting they may serve to both treat PD-associated depression and slow disease progres- sion. A patient-level meta-analysis included 2064 patients from the treatment and placebo arms of the following trials: FS1, FS-TOO, ELLDOPA, QE2, TEMPO, and PRECEPT. Depression severity was determined at baseline, and antidepressant use was reported in a medication log each visit. Kaplan-Meier curves and time-dependent Cox proportional hazards models determined associations between depression severity and antidepressant use with the primary outcome, time to initiation of dopaminergic therapy. ANCOVAs deter- mined associations with the secondary outcome, degree of motor impairment and disability, reported as annualized change in UPDRS scores from baseline to final visit. When controlling for baseline depression, the initiation of dopaminergic therapy was delayed for sub- jects taking tricyclic antidepressants compared with those not taking antidepressants. No significant differ- ences were found in UPDRS scores for subjects taking antidepressants compared with those not taking antide- pressants. Tricyclic antidepressants are associated with a delay in reaching the end point of need to start dopa- minergic therapy. The lack of change in overall UPDRS scores suggests the delay was not attributable to symptomatic effects. V C 2012 Movement Disorder Society

Summary Background The effects of constant-current deep brain stimulation (DBS) have not been studied in controlled trials in patients with Parkinson's disease. We aimed to assess the safety and efficacy of bilateral constant-current DBS of the subthalamic nucleus. Methods This prospective, randomised, multicentre controlled trial was done between Sept 26, 2005, and Aug 13, 2010, at 15 clinical sites specialising in movement disorders in the USA. Patients were eligible if they were aged 18–80 years, had Parkinson's disease for 5 years or more, and had either 6 h or more daily off time reported in a patient diary of moderate to severe dyskinesia during waking hours. The patients received bilateral implantation in the subthalamic nucleus of a constant-current DBS device. After implantation, computer-generated randomisation was done with a block size of four, and patients were randomly assigned to the stimulation or control group (stimulation:control ratio 3:1). The control group received implantation without activation for 3 months. No blinding occurred during this study, and both patients and investigators were aware of the treatment group. The primary outcome variable was the change in on time without bothersome dyskinesia (ie, good quality on time) at 3 months as recorded in patients' diaries. Patients were followed up for 1 year. This trial is registered with ClinicalTrials.gov, number NCT00552474. Findings Of 168 patients assessed for eligibility, 136 had implantation of the constant-current device and were randomly assigned to receive immediate (101 patients) or delayed (35 patients) stimulation. Both study groups reported a mean increase of good quality on time after 3 months, and the increase was greater in the stimulation group (4·27 h vs 1·77 h, difference 2·51 [95% CI 0·87–4·16]; p=0·003). Unified Parkinson's disease rating scale motor scores in the off-medication, on-stimulation condition improved by 39% from baseline (24·8 vs 40·8). Some serious adverse events occurred after DBS implantation, including infections in five (4%) of 136 patients and intracranial haemorrhage in four (3%) patients. Stimulation of the subthalamic nucleus was associated with dysarthria, fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups. Interpretation Constant-current DBS of the subthalamic nucleus produced significant improvements in good quality on time when compared with a control group without stimulation. Future trials should compare the effects of constant-current DBS with those of voltage-controlled stimulation. Funding St Jude Medical Neuromodulation Division.

Background: There is a paucity of therapies for gait impairment in Parkinson disease (PD). Open-label studies have suggested improved gait after treatment with methylphenidate (MPD). Objective: To evaluate the efficacy of MPD for the treatment of gait impairment in PD. Methods: Twenty-seven subjects with PD and moderate gait impairment were screened for this 6-month placebo-controlled, double-blind study. Subjects were randomly assigned to MPD (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed over after a 3-week washout. The primary outcome measure was change in a gait composite score (stride length + velocity) between groups at 4 and 12 weeks. Secondary outcome measures included changes in motor function, as measured by the Unified Parkinson9s Disease Rating Scale (UPDRS), Freezing of Gait Questionnaire (FOGQ), number of gait-diary freezing episodes, and measures of depression, sleepiness, and quality of life. Three-factor repeated-measures analysis of variance was used to measure changes between groups. Results: Twenty-three eligible subjects with PD were randomized and 17 completed the trial. There was no change in the gait composite score or treatment or time effect for any of the variables. Treatment effect was not modified by state or study visit. Although there was a trend for reduced frequency of freezing and shuffling per diary, the FOGQ and UPDRS scores worsened in the MPD group compared to placebo. There was a marginal improvement in some measures of depression. Conclusions: MPD did not improve gait and tended to worsen measures of motor function, sleepiness, and quality of life. Classification of evidence: This study provides Class III evidence for the lack of benefit of MPD on PD-associated gait impairment. Clinical trial registration: NCT00526630.

A 13-year old girl presented with slowly progressive rest tremor of the hands, bradykinesia, and rigidity. The symptoms improved with dopaminergic medications, but severe drug-induced dyskinesias developed early. She subsequently developed cognitive slowing and difficulty initiating saccadic eye movements. She went on to have deep brain stimulation surgery. Experts discuss the syndromal diagnosis and predict the underlying pathology. The pathological diagnosis is given and clinical learning points are considered.

An informal caregiver (ICG) is a family member and/or friend who provides unpaid care to an individual with a disability or chronic disease. ICGs often put their healthcare second while caring for their loved ones; and this may lead to negative impacts on their well-being. ICGs attended an 8-week therapeutic yoga intervention for their care recipients with Parkinson’s disease. ICGs who participated in the yoga classes were assessed utilizing a retrospective pretest and traditional post-test to determine the presence of depressive symptoms and positive aspects of caregiving. Although the sample size was small, data revealed improvements in depressive symptoms and positive aspects of caregiving. Focus group and individual interview data revealed five qualitative categories: yoga engagement, relationship improvement, psychological improvements, functional improvements, and community engagement. Future research should expand participation of ICGs in yoga trials to determine the extent of changes in psychosocial well-being.

Orthostatic tremor (OT) is a disabling movement disorder associated with postural and gait impairment in the elderly. Medical therapy often yields insufficient benefit. We report the clinical and electrophysiological data on two patients with medication-refractory OT treated with deep brain stimulation of the ventral intermediate thalamic nucleus (Vim DBS). Patient 1 underwent bilateral deep brain stimulation (DBS) and Patient 2 unilateral Vim DBS following 28 and 30 years of disease duration, respectively. Both patients showed increased latency to symptom onset after rising from a seated position, improved tolerance for prolonged standing, and slower crescendo of tremor severity when remaining upright. Postoperative evaluation demonstrated decreased amplitude of electromyographic activity with persistence of well-defined oscillatory behavior showing strong coherence at 15 Hz between all muscles tested in the upper and lower limbs. Postural sway was unchanged. Clinical benefits have been sustained for over 18 months in Patient 1, and receded after 3 months in Patient 2. These findings support the consideration of bilateral Vim DBS implantation as a therapeutic option in patients with medically refractory OT. Further efficacy studies on chronic stimulation to disrupt the abnormal oscillatory activity in this disorder are warranted.

Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor function in Parkinson disease (PD). However, little is known about the quantitative effects on motor behavior of unilateral STN DBS.In 52 PD subjects with STN DBS, we quantified in a double-blinded manner rigidity (n=42), bradykinesia (n=38), and gait speed (n=45). Subjects were tested in four DBS conditions: both on, left on, right on and both off. A force transducer was used to measure rigidity across the elbow, and gyroscopes were used to measure angular velocity of hand rotations for bradykinesia. About half of the subjects were rated using the Unified Parkinson Disease Rating Scale (part III) motor scores for arm rigidity and repetitive hand rotation simultaneously during the kinematic measurements. Subjects were timed walking 25 feet.All subjects had significant improvement with bilateral STN DBS. Contralateral, ipsilateral and bilateral stimulation significantly reduced rigidity and bradykinesia. Bilateral stimulation improved rigidity more than unilateral stimulation of either side, but there was no significant difference between ipsilateral and contralateral stimulation. Although bilateral stimulation also increased hand rotation velocity more than unilateral stimulation of either side, contralateral stimulation increased hand rotation significantly more than ipsilateral stimulation. All stimulation conditions improved walking time but bilateral stimulation provided the greatest improvement.Unilateral STN DBS decreased rigidity and bradykinesia contralaterally as well ipsilaterally. As expected, bilateral DBS improved gait more than unilateral DBS.

OBJECTIVE The aim of this study is to establish the safety and efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients with disabling motor fluctuations performed with an expedient procedure with limited intraoperative mapping. METHODS Bilateral STN DBS systems were implanted in 110 PD patients. Targeting of STN was achieved with T2-weighted magnetic resonance imaging guidance and a stereotactic navigation system confirmed by limited electrophysiological mapping. The safety of the procedure was analyzed in all 110 patients. The efficacy of the procedure was assessed in the practically-defined off medication state in the 72 patients who underwent evaluations 3 to 12 months after electrode implantation. RESULTS Adverse effects were infrequent and transient with no incidence of death, hemiparesis, or seizure. In the 72 patients, STN DBS reduced total Unified Parkinson's Disease Rating Scale motor scores at the time of the follow-up evaluation by 47% from 43.4 +/- 16.1 with stimulators off to 22.8 +/- 11.6 with stimulators on (P < 0.001). The changes in Unified Parkinson's Disease Rating Scale motor subscores improved as follows: rest tremor, 74% (P < 0.001); rigidity, 58% (P < 0.001); bradykinesia, 37% (P < 0.001); pull test, 35% (P < 0.001); gait, 44% (P < 0.001); axial signs, 42% (P < 0.001); and speech, 13% (P = 0.002). The prescribed total daily levodopa-equivalent dose decreased 45 +/- 32%. We averaged 1.3 +/- 0.9 electrodes passes per lead implantation. The mean operating time from the mounting of the stereotactic frame to its removal was 5 hours 42 minutes (median, 5 h 25 min; standard deviation, 1 h 12 min). CONCLUSION This STN DBS surgical technique for PD is expedient with effective outcomes and low complication rates.

A 56-year-old woman experienced progressive stiffness and painful spasms in the right arm leading to a frozen arm within 2 years. She had previously developed cerebellar ataxia (anti–glutamic acid decarboxylase [GAD] antibodies, 1,550 nmol/L; age 52 years). Examination showed marked rigidity and decreased movement range of the right arm with generalized hyperreflexia (figure and video). There were no antiamphiphysin or other paraneoplastic antibodies. Search for malignancies was negative. Diabetes was ruled out. The patient benefited from diazepam and IV immunoglobulin. Stiff-person syndrome (SPS) affects predominantly the trunk and lower limbs.1 This case illustrates that the cerebellar ataxia-SPS spectrum of anti-GAD autoimmunity may occur sequentially rather than concurrently, and a stiff arm, a variant of paraneoplastic SPS,2 may rarely be a focal form of anti-GAD-mediated (nonparaneoplastic) SPS.

Objective To identify the causal gene in a multi-incident U.S. kindred with Parkinson’s disease (PD). Methods We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. Results We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. Conclusions Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders. Electronic supplementary material The online version of this article (doi:10.1186/s13024-015-0045-4) contains supplementary material, which is available to authorized users.

Objective Pilot study to evaluate computer-guided deep brain stimulation (DBS) programming designed to optimize stimulation settings using objective motion sensor-based motor assessments. Materials and Methods Seven subjects (five males; 54–71 years) with Parkinson's disease (PD) and recently implanted DBS systems participated in this pilot study. Within two months of lead implantation, the subject returned to the clinic to undergo computer-guided programming and parameter selection. A motion sensor was placed on the index finger of the more affected hand. Software guided a monopolar survey during which monopolar stimulation on each contact was iteratively increased followed by an automated assessment of tremor and bradykinesia. After completing assessments at each setting, a software algorithm determined stimulation settings designed to minimize symptom severities, side effects, and battery usage. Results Optimal DBS settings were chosen based on average severity of motor symptoms measured by the motion sensor. Settings chosen by the software algorithm identified a therapeutic window and improved tremor and bradykinesia by an average of 35.7% compared with baseline in the “off” state (p < 0.01). Conclusions Motion sensor-based computer-guided DBS programming identified stimulation parameters that significantly improved tremor and bradykinesia with minimal clinician involvement. Automated motion sensor-based mapping is worthy of further investigation and may one day serve to extend programming to populations without access to specialized DBS centers.

A substantial body of evidence has accumulated regarding the efficacy and safety of neurosurgery for Parkinson's disease, essential tremor, and dystonia. Surgery for movement disorders (thalamotomy, pallidotomy, and subthalamic nucleotomy or subthalamotomy) was largely ablative (lesion-based). Given the safety and anatomy-preservation advantage, long-term electrical stimulation of these same targets (thalamus, globus pallidus, and subthalamic nucleus) is discussed as the treatment of choice. High-frequency deep brain stimulation procedures replicate the effects of ablative interventions, but do not require making a destructive brain lesion. This article outlines patient eligibility for surgery, targeting techniques, intraoperative findings, and potential complications and discusses the outcomes expected for each of the major interventions for which clinical trial data are available.

Parkinson's disease (PD) patients vary widely in their response to levodopa treatment, and this variation may be partially genetic in origin. We determined whether particular dopamine and opioid receptor polymorphisms were associated with risk of earlier onset of dyskinesia side effects during levodopa therapy. Smoking status was also examined. The 92 subjects were recruited from the movement disorders clinic of a neurology practice associated with a medical school. All were adult-onset PD patients who had been taking levodopa at least 5 years and/or had developed levodopa-induced dyskinesia. Carrying the G-allele of the A118G single nucleotide coding region polymorphism of the mu opioid receptor, as well as a history of never smoking, were independently associated with increased risk of earlier onset of dyskinesia (P=0.05 and 0.02, respectively). One genotype of the D2 dopamine receptor intronic dinucleotide repeat polymorphism (14 repeats/15 repeats, with frequency of 6%) was also associated with earlier dyskinesia (P=0.003). History of smoking has previously been associated with reduced risk of developing PD. Our results suggest that smoking history may also influence the response to levodopa, with contribution comparable to those of individual genes including the mu opioid receptor and D2 dopamine receptor.

We sought to determine the effect of deep brain stimulation (DBS) frequency on tremor suppression in essential tremor (ET) patients with deep brain stimulators implanted in the ventral intermediate nucleus (VIM) of the thalamus. A uniaxial accelerometer was used to measure tremor in the right upper extremity of subjects with a diagnosis of ET who had DBS electrodes implanted in the left VIM. The root-mean-square acceleration was used as the index of tremor magnitude and normalized to the OFF DBS condition. There was a highly significant inverse sigmoidal relationship between stimulation frequency and normalized tremor acceleration (X2/DoF = 0.42, r2 = 0.997). Tremor acceleration had a nearly linear response to stimulation frequencies between 45 and 100 Hz with little additional benefit above 100 Hz. These findings have two important implications. Clinically, frequency of thalamic stimulation is an important variable for optimal tremor control with maximal benefit achieved with 100 to 130 Hz in most patients. Second, thalamic DBS provides tremor benefit in a graded manner and is not an all-or-nothing phenomenon. © 2004 Movement Disorder Society

The putamen has a somatotopic organization of neurons identified by correspondence of firing rates with selected body part movements, as well as by complex, but organized, differential cortical projections onto putamen. In isolated focal dystonia, whole putaminal binding of dopamine D2-like receptor radioligands is quantitatively decreased, but it has not been known whether selected parts of the putamen are differentially affected depending upon the body part affected by dystonia. The radioligand [(18)F]spiperone binds predominantly to D2-like receptors in striatum. We hypothesized that the spatial location of [(18)F]spiperone binding within the putamen would differ in patients with dystonia limited to the hand versus the face, and we tested that hypothesis using positron emission tomography and magnetic resonance imaging. To address statistical and methodological concerns, we chose a straightforward but robust image analysis method. An automated algorithm located the peak location of [(18)F]spiperone binding within the striatum, relative to a brain atlas, in each of 14 patients with cranial dystonia and 8 patients with hand dystonia. The mean (left and right) |x|, y, and z coordinates of peak striatal binding for each patient were compared between groups by t test. The location of peak [(18)F]spiperone binding within the putamen differed significantly between groups (cranial dystonia z

Mild cognitive impairment in Parkinson's disease (PD-MCI) is common and increases the risk for dementia. Establishing distinct PD-MCI cognitive subtypes could be valuable for eventually predicting those most likely to convert to dementia. However, the study of PD-MCI subtypes has not yielded consistent results among cohorts. To determine whether there are distinct cognitive subtypes among participants diagnosed with PD-MCI in the Pacific Northwest Udall Center Clinical Consortium, we cognitively subtyped 95 patients with PD-MCI, using the Movement Disorders Society Task Force diagnostic guidelines. Psychometric test scores were then subjected to principle components factor analysis to determine whether similar cognitive subgroups could be identified using statistical methodology. Multiple-domain PD-MCI was diagnosed in 95% of the sample, and a range of cognitive impairments were noted. Factor analysis yielded seven factors and demonstrated overlap of phonemic verbal fluency on two factors, as well as the loading of verbal fluency on the same factor as a visuospatial measure; however, these factors did not partition the sample into distinct cognitive subtypes. Separation of cognitive subtypes based on the current PD-MCI criteria, or via statistical methods, may not provide sufficient information to describe distinct PD groups. Future efforts to validate the PD-MCI criteria and identify combinations of genetic or other risk factors for cognitive impairment are warranted.

Parkinson’s disease (PD) is a neurodegenerative condition with neuronal cell death in the substantia nigra and striatal dopamine deficiency that produces slowness, stiffness, tremor, shuffling gait and postural instability. More than 1 million people in North America are affected by PD resulting in balance problems and falls. It is observed that postural instability and gait problems become resistant to pharmacologic therapy as the disease progresses. Furthermore, studies suggest that postural sway abnormalities are worsened by levodopa, the mainstay of therapy for PD. This paper presents a classification of postural balance test data using Support Vector Machines (SVM) to identify the effect of medicine (levodopa) as well as dyskinesia. It is demonstrated that SVM is a useful tool and can complement the widely accepted (but very resource intensive) Unified Parkinson’s Disease Rating Scale (UPDRS).Copyright © 2013 by ASME

Los síndromes paraneoplásicos se caracterizan por la presencia de signos y síntomas que ocurren lejos del sitio deltumor o de sus metástasis. Muchos de estos síndromes son mediados por hormonas, citoquinas, u otras sustanciassecretadas por células tumorales, así como por una respuesta inmune contra el tumor. La presencia de anticuerposgenerados para combatir el tumor puede resultar en un síndrome neurológico si las células del sistema nervioso sonafectadas. Las primeras descripciones de tales casos datan más de 20 años, cuando los anticuerpos anti-Hu y anti-Yo fueron descritos. Existe una variedad de síndromes paraneoplásicos, incluyendo cuadros neurológicos clásicosy diversos. En este artículo de revisión hemos querido enfatizar un cuadro neuropsiquiátrico que corresponde a unsíndrome paraneoplásico descrito recientemente, aunque también puede ocurrir en pacientes sin presencia tumoralaparente. Se trata de la encefalitis asociada a anticuerpos contra los receptores N-metil-D-aspartato (NMDA).Nuestro interés en dicho síndrome, como especialistas en trastornos del movimiento, se basa en la presencia comúnde movimientos anormales en esta enfermedad. Sin embargo los pacientes afectados, la mayoría mujeres conteratoma ovárico, presentan un cuadro mixto, psiquiátrico inicialmente, seguido por epilepsia, empeoramiento deconciencia, disautonomía y distonía orofacial y truncal. Como resultado, la relevancia de la encefalitis asociada aanticuerpos contra los receptores NMDA abarca una variedad de especialidades incluyendo psiquiatría, neurología,oncología, inmunología, radiología, medicina general y cirugía. (Rev Neuropsiquiatr 2010;73:20-25).

Background: The effect of dopaminergic therapy on balance in Parkinson’s disease (PD) remains unclear, including previous studies that excluded the effect of dyskinesias or other involuntary movements on postural sway. Additionally, medication’s effects may differ between fallers and non-fallers. In this study, the authors quantify the effect of dopaminergic medication on postural balance (sway) in advanced PD, with and without dyskinesias, and consider the patient’s history of falls. Methods: In 24 patients with advanced idiopathic PD, postural balance was measured using a strain-gauge force platform. Before and after taking dopaminergic medication, the patient’s postural sway was measured at 30-second intervals to determine sway length (SL) and sway area (SA). Data analysis included the presence of dyskinesias during "ON" medication condition and history of previous falls.Results: No significant changes occurred in SL or SA with dopaminergic treatment for fallers without dyskinesias or non-fallers with dyskinesias. However, after dopaminergic treatment, SL and SA were 37.8% and 45% lower, respectively, in non-fallers without dyskinesias (indicating better balance) and were 87.4% and 162.8% higher, respectively, in fallers with dyskinesias (indicating poorer balance). In the ON medication condition, SL and SA were larger in patients with dyskinesias when compared with patients without dyskinesias; SL was larger in fallers than non-fallers in both groups with or without dyskinesias. Conclusions: Dopaminergic medication effects on postural sway could be a predictive factor for fall risk in PD patients with and without dyskinesias: specifically, decreased sway could indicate minimal fall risk whereas no change or increased postural sway could indicate a high risk.

Importance Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. Objective To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. Design, Setting, and Participants Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. Interventions Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. Main Outcomes and Measures Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form– physical functioning subscale score (SF-36), and the change in the Berg Balance Test. Results Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was –2.5 units (95% CI, –3.7 to –1.3) ( P P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group ( P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) ( P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, –0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. Conclusions and Relevance Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety. Trial Registration clinicaltrials.gov Identifier:NCT01795859

Although movement impairment in Parkinson's disease includes slowness (bradykinesia), decreased amplitude (hypokinesia), and dysrhythmia, clinicians are instructed to rate them in a combined 0-4 severity scale using the Unified Parkinson's Disease Rating Scale motor subscale. The objective was to evaluate whether bradykinesia, hypokinesia, and dysrhythmia are associated with differential motor impairment and response to dopaminergic medications in patients with Parkinson's disease. Eighty five Parkinson's disease patients performed finger-tapping (item 23), hand-grasping (item 24), and pronation-supination (item 25) tasks OFF and ON medication while wearing motion sensors on the most affected hand. Speed, amplitude, and rhythm were rated using the Modified Bradykinesia Rating Scale. Quantitative variables representing speed (root mean square angular velocity), amplitude (excursion angle), and rhythm (coefficient of variation) were extracted from kinematic data. Fatigue was measured as decrements in speed and amplitude during the last 5 seconds compared with the first 5 seconds of movement. Amplitude impairments were worse and more prevalent than speed or rhythm impairments across all tasks (P < .001); however, in the ON state, speed scores improved exclusively by clinical (P < 10(-6) ) and predominantly by quantitative (P < .05) measures. Motor scores from OFF to ON improved in subjects who were strictly bradykinetic (P < .01) and both bradykinetic and hypokinetic (P < 10(-6) ), but not in those strictly hypokinetic. Fatigue in speed and amplitude was not improved by medication. Hypokinesia is more prevalent than bradykinesia, but dopaminergic medications predominantly improve the latter. Parkinson's disease patients may show different degrees of impairment in these movement components, which deserve separate measurement in research studies. © 2011 Movement Disorder Society.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor function, including gait and stability, in people with Parkinson's disease (PD) but differences in DBS contact locations within the STN may contribute to variability in the degree of improvement. Based on anatomical connectivity, dorsal STN may be preferentially involved in motor function and ventral STN in cognitive function.To determine whether dorsal DBS affects gait and balance more than ventral DBS, a double blind evaluation of 23 PD patients with bilateral STN DBS was conducted. Each participant underwent gait analysis and balance testing off Parkinson's medication under three DBS conditions (unilateral DBS in the dorsal STN region, unilateral DBS in the ventral STN region and both stimulators off) on 1 day.Improvements were seen in Unified Parkinson's Disease Rating Scale (UPDRS)-III scores and velocity in walking trials as fast as possible (Fast gait) and preferred pace (Pref gait), as well as stride length for Fast and Pref gait, with dorsal and ventral stimulation compared with the off condition (post hoc tests, p0.05). However, there were no differences with dorsal compared to ventral stimulation. Balance, assessed using the multi-item mini-Balance Evaluation Systems Test (mini-BESTest), was similar across conditions.Absence of differences in gait and balance between the dorsal and ventral conditions suggests motor connections involved in gait and balance may be more diffusely distributed in STN than previously thought, as opposed to neural connections involved in cognitive processes, such as response inhibition, which are more affected by ventral stimulation.

Bradykinesia encompasses slowness, decreased movement amplitude, and dysrhythmia. Unified Parkinson’s Disease Rating Scale–based bradykine-sia-related items require that clinicians condense abnormalities in speed, amplitude, fatiguing, hesitations, and arrests into a single score. The objective of this study was to evaluate the reliability of a modified bradykinesia rating scale, which separately assesses speed, amplitude, and rhythm and its correlation with kinematic measures from motion sensors. Fifty patients with Parkinson’s disease performed Unified Parkinson’s Disease Rating Scale–directed finger tapping, hand grasping, and pronation–supination while wearing motion sensors. Videos were rated blindly and independently by 4 clinicians. The modified bradykinesia rating scale and Unified Parkinson’s Disease Rating Scale demonstrated similar inter- and intrarater reliability. Raters placed greater weight on amplitude than on speed or rhythm when assigning a Unified Parkinson’s Disease Rating Scale score. Modified bradykinesia rating scale scores for speed, amplitude, and rhythm correlated highly with quantitative kinematic variables. The modified bradykinesia rating scale separately captures bradykinesia components with interrater and intrarater reliability similar to that of the Unified Parkinson’s Disease Rating Scale. Kinematic sensors can accurately quantify speed, amplitude, and rhythm to aid in the development and evaluation of novel therapies in Parkinson’s disease.

Shuffling and freezing while walking can impair function in patients with Parkinson disease (PD). Open-loop devices that provide fixed-velocity visual or auditory cues can improve gait but may be unreliable or exacerbate freezing of gait in some patients. We examined the efficacy of a closed- loop, accelerometer-driven, wearable, visual-auditory cueing device in 13 patients with PD with off-state gait impairment at baseline and after 2 weeks of twice daily (30 minute duration) at-home use. We measured gait velocity, stride length, and cadence using a validated electronic gait-analysis system. Sub- jects underwent standard motor assessment and completed a self-administered Freezing of Gait Questionnaire (FOGQ) (range 0-24; lower is better). After training, device use enhanced walking velocity (61.6 ± 20.1 cm/s to 72.6 ± 26.5 cm/s, p = 0.006) and stride length (74.3 ± 16.4 cm to 84.0 ± 18.5 cm, p = 0.004). Upon device removal, walking velocity (64.5 ± 21.4 cm/s to 75.4 ± 21.5 cm/s, p < 0.001) and stride length (79.0 ± 20.3 cm to 88.8 ± 17.7 cm, p = 0.003) exhibited a greater magnitude of change, suggesting immediate residual benefits. Also upon device removal, nearly 70 percent of sub- jects improved by at least 20 percent in either walking velocity, stride length, or both. An overall improvement in gait was measured by the FOGQ (14.2 ±1.9 to 12.4 ± 2.5, p = 0.02). Although issues related to compliance and response variability render a definitive interpretation of study outcome difficult, devices using closed-loop sensory feedback appear to be effec- tive and desirable nonpharmacologic interventions to improve walking in selected individuals with PD.

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale-Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale-Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2-6 and 9-15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2-6 months and 25.7% at 9-15 months. At 9-15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9-15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2-6 months; this failed to reach significance at 9-15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

Deep brain stimulation of the subthalamic nucleus (STN DBS) improves motor symptoms in idiopathic Parkinson's disease, yet the mechanism of action remains unclear. Previous studies indicate that STN DBS increases regional cerebral blood flow (rCBF) in immediate downstream targets but does not reveal which brain regions may have functional changes associated with improved motor manifestations. We studied 48 patients with STN DBS who withheld medication overnight and underwent PET scans to measure rCBF responses to bilateral STN DBS. PET scans were performed with bilateral DBS OFF and ON in a counterbalanced order followed by clinical ratings of motor manifestations using Unified Parkinson Disease Rating Scale 3 (UPDRS 3). We investigated whether improvement in UPDRS 3 scores in rigidity, bradykinesia, postural stability and gait correlate with rCBF responses in a priori determined regions. These regions were selected based on a previous study showing significant STN DBS-induced rCBF change in the thalamus, midbrain and supplementary motor area (SMA). We also chose the pedunculopontine nucleus region (PPN) due to mounting evidence of its involvement in locomotion. In the current study, bilateral STN DBS improved rigidity (62%), bradykinesia (44%), gait (49%) and postural stability (56%) (paired t-tests: P < 0.001). As expected, bilateral STN DBS also increased rCBF in the bilateral thalami, right midbrain, and decreased rCBF in the right premotor cortex (P < 0.05, corrected). There were significant correlations between improvement of rigidity and decreased rCBF in the SMA (r(s) = -0.4, P < 0.02) and between improvement in bradykinesia and increased rCBF in the thalamus (r(s) = 0.31, P < 0.05). In addition, improved postural reflexes correlated with decreased rCBF in the PPN (r(s) = -0.38, P < 0.03). These modest correlations between selective motor manifestations and rCBF in specific regions suggest possible regional selectivity for improvement of different motor signs of Parkinson's disease.

A 41-year-old patient developed diplopia, imbalance, and weight loss. Examination showed pendular vergence oscillations of the eyes and synchronous contractions of the masticatory but not palatal muscles, i.e., oculomasticatory myorhythmia (OMM; figure). There was complete supranuclear vertical and, to a …

Objective: To test the hypothesis that subthalamic nucleus (STN) stimulation in Parkinson disease (PD) patients affects working memory and response inhibition performance, particularly under conditions of high demand on cognitive control.Methods: To test this hypothesis, spatial working memory (spatial delayed response [SDR]) and response inhibition (Go–No–Go [GNG]) tasks requiring varying levels of cognitive control were administered to patients with PD with previously implanted bilateral STN stimulators (n = 24). Patients did not take PD medications overnight. Data were collected while bilateral stimulators were on and off, counterbalancing the order across subjects.Results: On the SDR task, STN stimulation decreased patients’ working memory performance under a high but not low memory load condition (effect of stimulator condition on high load only and condition × load interaction, p < 0.05). On the GNG task, STN stimulation reduced discriminability on a high but not medium inhibition condition (effect of stimulator condition on high inhibition level only, p = 0.05; condition × inhibition level interaction, p = 0.07).Conclusion: STN stimulation reduces working memory and response inhibition performance under conditions of greater challenge to cognitive control despite significant improvement of motor function.

The purpose of this study was to determine the effects of unilateral versus bilateral subthalamic nucleus (STN) stimulation on quantitative measures of walking and reaching in Parkinson's disease (PD). We used kinematic measures and the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale (subscale III) to evaluate the movement of 6 people with PD who had bilateral STN stimulators implanted for at least 6 months and withheld their anti-parkinson medication for at least 8 hours. Subjects were studied with both stimulators off, one on, and both on. Kinematic data were collected as subjects walked, reached to a target, and were rated using the UPDRS motor subscale. STN stimulation improved walking speed and stride length, with the greatest benefit from bilateral stimulation. Reaching speed was improved by unilateral STN stimulation alone, with no additive effect of bilateral stimulation. UPDRS motor subscale ratings paralleled the kinematic findings. STN stimulation did not restore PD subjects' movements to the level of age-matched controls. Overall, these results provide further evidence that the basal ganglia pathways involved in control of walking and reaching may be distinct. We speculate that basal ganglia may influence walking through bilateral pedunculopontine projections and reaching through ipsilateral thalamocortical projections. Our findings also suggest that maximal improvement of walking requires bilateral rather than unilateral STN stimulation.

Glutamate-mediated excitotoxicity might contribute to the pathogenesis of Huntington's disease and other polyglutamine repeat disorders. We used murine neocortical cultures derived from transgenic and knock-in mice to test the effect of expression of expanded polyglutamine-containing huntingtin on neuronal vulnerability to excitotoxins or other insults. Neurons cultured from mice expressing either a normal length (Hdh(Q20)) or expanded (Hdh(Q111)) CAG repeat as a knock-in genetic alteration in exon one of the mouse Hdh gene [Hum Mol Genet 8 (1999) 115] had similar vulnerability to N-methyl-D-aspartate (NMDA) and kainate-mediated excitotoxicity. These neurons also exhibited similar vulnerability to oxidative stress (24 h exposure to 10-100 microM paraquat or 1-10 microM menadione), apoptosis (48 h exposure to 30-100 nM staurosporine or 1 microM dizocilpine maleate (MK-801) and proteasome inhibition (48 h exposure to 0.3-3 microM MG-132). Neocortical neurons cultured from mice transgenic for an expanded CAG repeat-containing exon 1 of the human HD gene (Mangiarini et al., 1996, R6/2 line) and non-transgenic littermate controls also had similar vulnerability to NMDA and kainate-mediated excitotoxicity. These observations suggest that expression of expanded polyglutamine-containing huntingtin does not acutely alter the vulnerability of cortical neurons to excitotoxic, oxidative or apoptotic insults.

Importance Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature. Objective To determine whether common variation in the APOE , MAPT , and SNCA genes is associated with cognitive performance in patients with PD. Design, Setting, and Participants We studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test–Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE e2/e3/e4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene. Main Outcomes and Measures Nine variables derived from 7 psychometric tests. Results The APOE e4 allele was associated with lower performance on the HVLT-R Total Recall ( P = 6.7 × 10 −6 ; corrected P [ Pc ] = 6.0 × 10 −5 ), Delayed Recall ( P = .001; Pc = .009), and Recognition Discrimination Index ( P = .004; Pc = .04); a semantic verbal fluency test ( P = .002; Pc = .02); the Letter-Number Sequencing Test ( P = 1 × 10 −5 ; Pc = 9 × 10 −5 ); and Trail Making Test B minus Trail Making Test A ( P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE e4 allele was associated with lower scores on the HVLT-R Total Recall ( P = .005; Pc = .045) and the semantic verbal fluency ( P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests. Conclusions and Relevance Our data indicate that the APOE e4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE e4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.

A 49-year-old wheelchair-bound man was rendered left hemi-paretic, dysarthric, and diplopic after a brainstem hemorrhage. Several months later he developed a progressively disabling left arm tremor. Examination showed skew deviation, left hemipare-sis, left hemianesthesia, truncal ataxia, and a postural and action proximal left arm tremor (video). Brain MRI demonstrated a cavernous malformation in the right …