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AIMS: While behavioral-based pelvic floor muscle exercise therapy is an effective treatment for overactive bladder in Parkinson disease (PD) patients, cognitive function may be a predictor of rehabilitation outcomes. METHODS: In a planned exploratory analysis, participants who had a Montreal Cognitive Assessment (MoCA) with a score ≥18 who were randomized in a clinical trial to behavioral treatment were classified by perceived improvement (Benefit vs. No Benefit) as reported on a validated Satisfaction and Benefit Questionnaire. General cognition (MoCA), motor procedural learning (Serial Reaction Time Task), verbal memory (Buschke Delayed Recall), spatial memory (Nonverbal/Spatial Selective Reminding Test), and working memory (Wisconsin Card Sorting Task) were compared between the two groups using Wilcoxon Rank Sum Test. RESULTS: Of the 26 participants randomized to behavioral treatment (70% male, mean age 71 ± 6.1 years), 22 participants (85%) reported Benefit and 4 reported No Benefit. General cognition, motor procedural learning, verbal memory, spatial memory, and working memory did not differ between these groups. While the difference between the time to complete the final practiced series and the random series of the Serial Reaction Time Task (SRTT) was statistically similar between the groups, the Benefit group performed the random sequence more quickly (567.0 ± 136.5 msec) compared to the No Benefit group (959.4 ± 443.0 msec (p=0.03)) and trended toward faster performance in the final practiced series. CONCLUSIONS: Perceived benefit from behavioral treatment for overactive bladder was not associated with measures of baseline cognition other than faster completion of the SRTT. This is noteworthy because many behavioral-based therapy studies exclude participants with mild cognitive impairment. Additional studies may evaluate if domain-specific cognitive function, particularly assessment of implicit memory, could lead to individualized behavioral therapy recommendations.

OBJECTIVE: A rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer’s disease, while mixed evidence has been reported for association of the variant with other neurodegenerative diseases. Here, we investigated the frequency of the R47H variant in a diverse and well-characterized multicenter neurodegenerative disease cohort. METHODS: We examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, including a total of 3,058 patients clinically diagnosed with Alzheimer’s disease, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5,089 control subjects. RESULTS: We observed a significant association between the R47H variant and Alzheimer’s disease, while no association was observed with any other neurodegenerative disease included in this study. CONCLUSIONS: Our results support the consensus that the R47H variant is significantly associated with Alzheimer’s disease. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.

Aim Determine the efficacy of behavioral therapy for urinary symptoms in Parkinson's disease. Methods Randomized trial of behavioral therapy compared with control condition among adults (aged 54-85 years, 74% male, 10% Black/ 83% White) with Parkinson's and greater than or equal to 4 incontinence episodes weekly. Behavioral therapy included pelvic floor muscle exercises, bladder training, fluid and constipation management. Both groups completed bladder diary self-monitoring. Outcomes included diary-derived incontinence and ICIQ-overactive bladder (OAB) score (range, 0-16) with bother and quality of life questionnaires (higher scores = worse outcomes). Results Fifty-three participants randomized and 47 reported 8-week outcomes including 26 behavioral therapy and 21 control. Behavioral vs control participants were similar with respect to age (71.0 ± 6.1 vs 69.7 ± 8.2 years), sex (70% vs 78% male), motor score, cognition, mean weekly incontinence episodes (13.9 ± 9.6 vs 15.1 ± 11.1) and OAB symptoms (8.9 ± 2.4 vs 8.3 ± 2.2). Weekly incontinence reduction was similar between behavioral (-6.2 ± 8.7) and control participants (-6.5 ± 13.8) (P = 0.89). After multiple imputation analysis, behavioral therapy participants reported statistically similar reduction in OAB symptoms compared to control (-3.1 ± 2.8 vs -1.9 ± 2.2, P = 0.19); however quality of life (-22.6 ± 19.1 vs -7.0 ± 18.4, P = 0.048) and bother (-12.6 ± 17.2 vs - 6.7 ± 8.8, P = 0.037) improved significantly more with behavioral therapy. Conclusion Self-monitoring resulted in fewer urinary symptoms; however, only multicomponent behavioral therapy was associated with reduced bother and improved quality of life. Providers should consider behavioral therapy as initial treatment for urinary symptoms in Parkinson's disease.

Background: Age-gender-specific prevalence rates for parkinsonism and Parkinson’s disease (PD) are important to guide research, clinical practice and public health planning; however, prevalence estimates in Latin America (LatAm) are limited. We aimed to estimate the prevalence of parkinsonism and PD and examine its risk factors in a cohort of elderly individuals from LatAm. Methods: Data from 11,613 adults (65+ years) who participated in a baseline assessment of the 10/66 study and who lived in six LatAm countries were analyzed to estimate Parkinsonism and PD prevalence. Crude and age-adjusted prevalence were determined by sex and country. Diagnosis of PD was established using the UK Parkinson’s Disease Society Brain Bank’s clinical criteria. Findings: In this cohort, the prevalence of Parkinsonism was 8.0% (95% CI 7.6%-8.5%), and the prevalence of PD was 2.0% (95% CI 1.7%-2.3%). PD prevalence increased with age from 1.0 to 3.5 (65-69 vs. 80 years or older, p

Functional neurological disorder (FND) is a complex neuropsychiatric syndrome with many phenotypes that are commonly encountered in clinical practice. Despite the heterogeneity of FND, the rate of misidentification is consistently low. For the more common motor subtypes, there are clear positive clinical, electrophysiological, and rarely imaging criteria that can establish the diagnosis in the traditional sense. For nonmotor subtypes, the characterization may be less clear. Here, we argue that the current diagnostic criteria are not reflective of the current shared neuropsychiatric understanding of FND, and, as a result, provide an incomplete picture of the diagnosis. We propose a three-step diagnostic triad for FND, in which the traditional neurological diagnosis is only the first element. Other steps include psychiatric/psychological formulation, integration, and follow-up. We advocate that this diagnostic approach should be the shared responsibility of neurology and mental health professionals. Finally, a research agenda is proposed to address the missing factors in the field.

Background Dopamine D2 receptor antagonists used to treat Tourette syndrome may have inadequate responses or intolerable side effects. We present results of a 4-week randomized, double-blind, placebo-controlled crossover study evaluating the safety, tolerability, and efficacy of the D1 receptor antagonist ecopipam in children and adolescents with Tourette syndrome. Methods Forty youth aged 7 to 17 years with Tourette syndrome and a Yale Global Tic Severity Scale - total tic score of ≥20 were enrolled and randomized to either ecopipam (50 mg/day for weight of 34 kg) or placebo for 30 days, followed by a 2-week washout and then crossed to the alternative treatment for 30 days. Stimulants and tic-suppressing medications were excluded. The primary outcome measure was the total tic score. Secondary outcomes included obsessive compulsive and attention deficit/hyperactivity disorder scales. Results Relative to changes in placebo, reduction in total tic score was greater for ecopipam at 16 days (mean difference, -3.7; 95% CI, -6.5 to -0.9; P = 0.011) and 30 days (mean difference, -3.2; 95% CI, -6.1 to -0.3; P = 0.033). There were no weight gain, drug-induced dyskinesias, or changes in laboratory tests, electrocardiograms, vital signs, or comorbid symptoms. Dropout rate was 5% (2 of 40). Adverse events reported for both treatments were rated predominantly mild to moderate, with only 5 rated severe (2 for ecopipam and 3 for placebo). Conclusions Ecopipam reduced tics and was well tolerated. This placebo-controlled study of ecopipam supports further clinical trials in children and adolescents with Tourette syndrome. © 2018 International Parkinson and Movement Disorder Society.

Background Anti-inflammatory drug use, particularly ibuprofen, has been associated with a lower risk of Parkinson's disease. Microglial activation and inflammatory cytokine expression have been shown to be pathological features of progressive supranuclear palsy. We examined the association between NSAID use and risk of PSP, disease severity and age at onset. Methods The ENGENE-PSP multicenter case-control study recruited incident PSP cases who met the NINDS-PSP Society diagnostic criteria and age-, sex- and race-matched controls primarily from the same geographical areas. All subjects underwent standardized interviews to obtain data on demographics, residential history, medication history and lifetime occupational history. NSAID use was specifically queried by telephone interview using a standardized questionnaire. Results Information was obtained on anti-inflammatory drug exposure in 276 cases and 278 controls. No association was found between NSAID exposure and risk of PSP, age at onset or rate of change of UPDRS motor subscale, PSP Rating Scale or Mattis Dementia Rating Scale scores. This lack of association persisted when NSAID exposure was measured considering any NSAIDs, ibuprofen only, ASA only or non-ibuprofen, non-aspirin NSAIDs. Conclusions These results do not suggest an important association between NSAID use and PSP occurrence or expression. Despite the large size of our study, confidence intervals were wide. To rule out small associations, very large sample sizes will be required.

Studies of saccadic eye movements in subjects with Tourette syndrome (TS) have provided additional evidence that there is a link between TS symptoms and deficits in fronto-striato-thalamic networks. These studies revealed impaired timing and inhibition of saccades. We compared fixational eye movements, such as microsaccades and ocular drifts, in subjects with TS and healthy controls.We measured horizontal and vertical eye positions with video-oculography in 14 subjects with Tourette syndrome. We found reduced microsaccade amplitude but increased time between adjacent microsaccades (intersaccadic interval). Hence, the rate of microsaccades was reduced in subjects with TS compared to controls. Measure of ocular stability during intersaccadic intervals revealed increased drift velocity and increased variance in eye position. We hypothesize that increased activity of the direct fronto-striatal pathway and the resulting reduction in basal ganglia outflow targeting the superior colliculus fixation zone affect the rate and amplitudeS of microsaccades in subjects with TS. The resulting impairment in frontal eye field fixation leads to increased drifts during intersaccadic interval in subjects with TS. Possible clinical implication for these results is that fixational eye movements can be objective biological markers of TS.

The International Parkinson Disease and Movement Disorder Society PSP study group (IPMDS-PSP) recently published new clinical diagnostic criteria for progressive supranuclear palsy (PSP). Currently, there is no data regarding the accuracy of these sets of criteria for differentiating various PSP phenotypes. We discuss the accuracy of the IPMDS-PSP criteria for differentiation of patients with the PSP-Richardson phenotype (PSP-RS) from those with the PSP-Parkinsonism (PSP-P) using data from a sample of 274 clinically diagnosed PSP patients participating in the Environmental Genetic PSP (ENGENE-PSP) case control study. Using National Institute of Neurological Disorders and Stroke and the Society for PSP (NINDS-SPSP) criteria and the Williams criteria we categorized 259 of these patients as possible and probable PSP-RS and 15 as PSP-P. The IPD-MDS PSP-RS and PSP-P criteria were unable to distinguish the PSP-RS from the PSP-P phenotypes in this sample. Nearly all (92.6%; 240 out of 259) the PSP-RS patients and over half (60%; 9 out of 15) of the PSP-P patients fulfilled both the IPMDS criteria for PSP-RS and PSP-P. Applying the newly proposed multiple allocation extinction rules decreased the number of overlapping diagnoses among the NINDS-SPSP PSP-RS patients, however problems remained in the PSP-P group. Diagnostic accuracy might be improved by modification of timelines for development of falls and other parkinsonian features.

We hypothesize that swearing is an emotional action that hardly says anything other than expressing and evoking emotions and that studying swearing might shed light on the evolutionary path from motor behavior to language. Our lens is the involuntary swearing—coprolalia—associated with Tourette syndrome (ts). In a qualitative analysis of videotaped interviews with 16 ts sufferers and their families, we arrive at the following findings, of which the first one replicates previous findings, and the following are novel: (i) coprolalia, once believed psychogenic, is embodied; (ii) the pragmatics of swearing obeys the cultural rules of communication while violating the culture’s values; (iii) coprolalia is unique as a speech act as it relies mainly on cultural context rather than semantics; (iv) coprolalia’s sensitivity to culture affords its performative effectiveness in hurting its hearer. Therefore, reducing the automaticity of the hearer’s interpretation of the coprolaliac’s intention can reduce the hurtful effect.

Background The cause of progressive supranuclear palsy (PSP) is largely unknown. Based on evidence for impaired mitochondrial activity in PSP, we hypothesized that the disease may be related to exposure to environmental toxins, some of which are mitochondrial inhibitors. Methods This multicenter case-control study included 284 incident PSP cases of 350 cases and 284 age-, sex-, and race-matched controls primarily from the same geographical areas. All subjects were administered standardized interviews to obtain data on demographics, residential history, and lifetime occupational history. An industrial hygienist and a toxicologist unaware of case status assessed occupational histories to estimate past exposure to metals, pesticides, organic solvents, and other chemicals. Results Cases and controls were similar on demographic factors. In unadjusted analyses, PSP was associated with lower education, lower income, more smoking pack-years, more years of drinking well water, more years living on a farm, more years living 1 mile from an agricultural region, more transportation jobs, and more jobs with exposure to metals in general. However, in adjusted models, only more years of drinking well water was significantly associated with PSP. There was an inverse association with having a college degree. Conclusions We did not find evidence for a specific causative chemical exposure; higher number of years of drinking well water is a risk factor for PSP. This result remained significant after adjusting for income, smoking, education and occupational exposures. This is the first case-control study to demonstrate PSP is associated with environmental factors. © 2016 International Parkinson and Movement Disorder Society

The epidemiologic evidence of whether hypertension is associated with Progressive Supranuclear Palsy (PSP) is inconsistent. The ENGENE-PSP case-control study determined various PSP risk factors including whether hypertension preceded PSP onset.Incident PSP cases per NINDS-PSP criteria and age-, sex-, race- matched controls were recruited from similar North American geographic areas. All study participants were administered standardized interviews to obtain data on demographics, medical history and medications.We used univariate and multivariate conditional logistic regression models to measure the associations between PSP and the following predictor variables: education level, hypertension, comorbid vascular conditions (diabetes mellitus and hyperlipidemia), and classes of anti-hypertensive medications using odds ratios and 95% confidence intervals.There were significant associations seen between PSP and hypertension (OR: 1.569; 95% CI 1.129-2.181; p-value = 0.007), education level (OR: 0.733; 95% CI 0.637-0.843; p-value0.001) and beta-blocker use (OR: 2.000; 95% CI 1.053-3.799; p-value = 0.034). However, in the multi-variate analysis hypertension (OR: 1.492; 95% CI 1.045-2.129; p-value = 0.027) and education level (OR: 0.730; 95% CI 0.633-0.841; p-value0.001) were the only significant associations.These results suggest that there is a modest, yet significant association between hypertension and PSP. Further studies will be needed to better understand the pathophysiological basis for this finding.

Background Although levodopa is considered the most effective pharmacotherapy for motor symptoms of Parkinson’s disease (PD), chronic use is associated with motor complications, including fluctuating response and unpredictable, involuntary movements called dyskinesia. ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRITM) is a recent US FDA-approved treatment for dyskinesia in PD patients. ADS-5102 is a high-dose, ER formulation of amantadine, administered orally once daily at bedtime, that achieves high plasma drug concentrations throughout the day. Objective In this study, we present pooled results from two randomized, double-blind, placebo-controlled, phase III ADS-5102 trials. Patients and Methods The two studies in PD patients with dyskinesia shared design and eligibility criteria, differing only in treatment duration. Results from common assessment time points were pooled. Results At 12 weeks, the least squares (LS) mean change in total score on the Unified Dyskinesia Rating Scale among 100 patients randomized to ADS-5102 and 96 patients randomized to placebo was − 17.7 (standard error [SE] 1.3) vs. − 7.6 (1.3) points, respectively (− 10.1 points, 95% confidence interval [CI] − 13.8, − 6.5; p

Although levodopa is considered the most effective pharmacotherapy for motor symptoms of Parkinson’s disease (PD), chronic use is associated with motor complications, including fluctuating response and unpredictable, involuntary movements called dyskinesia. ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRITM) is a recent US FDA-approved treatment for dyskinesia in PD patients. ADS-5102 is a high-dose, ER formulation of amantadine, administered orally once daily at bedtime, that achieves high plasma drug concentrations throughout the day. In this study, we present pooled results from two randomized, double-blind, placebo-controlled, phase III ADS-5102 trials. The two studies in PD patients with dyskinesia shared design and eligibility criteria, differing only in treatment duration. Results from common assessment time points were pooled. At 12 weeks, the least squares (LS) mean change in total score on the Unified Dyskinesia Rating Scale among 100 patients randomized to ADS-5102 and 96 patients randomized to placebo was − 17.7 (standard error [SE] 1.3) vs. − 7.6 (1.3) points, respectively (− 10.1 points, 95% confidence interval [CI] − 13.8, − 6.5; p

Background and objectives Slowed and curved rapid eye movements, saccades, are the well-known features of progressive supranuclear palsy (PSP). We hypothesized that the saccades in PSP are not only slow and curved, but they are also irregular and have timing deficits. Methods We tested this hypothesis in 12 patients with PSP by measuring vertical and horizontal visually guided saccades using a limbus tracker. Results Both, horizontal and vertical saccades were slow and had irregular trajectory and velocity profiles, but deficits were much more robust in vertical saccades. The irregularity in the saccade velocity was due to premature interruptions that either completely stopped the eyes, or moved the eyes at much slower velocity along or in the opposite direction of the ongoing saccade. The direction of the eyes’ trajectory was often changed after the interruption. We simulated a conductance based single-compartment model of the burst neurons embedded in local feedback circuit for saccade generation. This model mimicked anatomical and physiological realism, while allowing the liberty to selectively change the activation of individual burst neurons or the pause neurons. The PSP saccades were comparable to the simulations during reduced activity of the inhibitory and excitatory burst neurons. Conclusion PSP saccades are due to the paucity in burst generation at the excitatory and imprecise timing signal from the inhibitory burst neurons. Premature discharge of the inhibitory burst neuron further leads to breaks in the saccade trajectory, and maladaptive superior colliculus activity leading to aberrant saccades changing the intended trajectory of the ongoing saccade. This article is protected by copyright. All rights reserved.

Deep brain stimulation (DBS) may improve disabling tics in severely affected medication and behaviorally resistant Tourette syndrome (TS). Here we review all reported cases of TS DBS and provide updated recommendations for selection, assessment, and management of potential TS DBS cases based on the literature and implantation experience. Candidates should have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) diagnosis of TS with severe motor and vocal tics, which despite exhaustive medical and behavioral treatment trials result in significant impairment. Deep brain stimulation should be offered to patients only by experienced DBS centers after evaluation by a multidisciplinary team. Rigorous preoperative and postoperative outcome measures of tics and associated comorbidities should be used. Tics and comorbid neuropsychiatric conditions should be optimally treated per current expert standards, and tics should be the major cause of disability. Psychogenic tics, embellishment, and malingering should be recognized and addressed. We have removed the previously suggested 25-year-old age limit, with the specification that a multidisciplinary team approach for screening is employed. A local ethics committee or institutional review board should be consulted for consideration of cases involving persons younger than 18 years of age, as well as in cases with urgent indications. Tourette syndrome patients represent a unique and complex population, and studies reveal a higher risk for post-DBS complications. Successes and failures have been reported for multiple brain targets; however, the optimal surgical approach remains unknown. Tourette syndrome DBS, though still evolving, is a promising approach for a subset of medication refractory and severely affected patients.

Background We previously screened 400 elderly Costa Ricans for neurodegenerative disease. Those reporting occupational pesticide exposure (18%) had an increased Parkinson׳s disease (PD) risk (OR 2.57, 95% CI 0.91–7.26), and worse cognition (Mini-Mental States Exam (MMSE) 24.5 versus 25.9 points, p=0.01). We subsequently measured long-lasting organochlorine pesticides (β-HCH, DDE, DDT, and dieldrin) in a sub-sample (n=89). Dieldrin and β-HCH have been linked to PD, and DDE to Alzheimer׳s disease. Methods We ran regression models for MMSE and tremor-at-rest to assess associations with pesticides in 89 subjects. Results The percent of β-HCH, DDE, DDT (parent compound for DDE), and dieldrin above their limit of detection (LOD) were 100%, 93%, 75%, and 57%, respectively. Tremor-at-rest was found in 21 subjects, and the mean MMSE was 25. Those who reported occupational pesticide exposure (n=36) had more detectable dieldrin samples (p=0.005), and higher mean levels of dieldrin (p=0.01), than those not reporting exposure. Other pesticides did not differ between those with and without self-reported occupational exposure. There was a positive but non-significant trend of higher risk for tremor-at-rest with higher dieldrin (p=0.10 for linear trend). Neither DDE nor DDT showed a relationship with MMSE. However, after excluding two outliers with the lowest MMSE scores, higher DDT levels showed some modest association with lower MMSE (p=0.09 for linear trend). Conclusions Our data are limited by small sample size. However, dieldrin was high in our population, has been previously linked to PD, and could be partly responsible for the excess PD risk seen in our population.

Aims To compare the prevalence of urinary and bowel symptoms in a sample of adults with early Parkinson's disease (PD) and healthy controls (HC). Methods Data were obtained from the Michael J. Fox Parkinson's Progression Markers Initiative (PPMI). Prevalent bladder (urinary incontinence (UI) and nighttime voiding) and bowel (constipation and fecal incontinence (FI)) symptoms were defined as occurring at least sometimes when queried using the Scale for Outcomes in PD for Autonomic Symptoms. Results The proportion of men (65% vs 64%) and the mean age (61.0 ± 9.7 vs 60.2 ± 11.2 years) was similar between early PD (n = 423) and HC (n = 195). UI and constipation were more prevalent among early PD versus HC (UI: 26.7% vs 8.2%, constipation: 32.4% vs 11.8%; P's

Aim Characterize clinical factors related to nocturia and sleep disruption in Parkinson disease (PD) using polysomnography (PSG). Methods Sixty-three PD patients were recruited regardless of sleep or voiding complaints from a university-based movement disorders clinic for a 48 hr inpatient PSG protocol. Nocturia frequency and bother related to urinary symptoms were assessed using the International Prostate Symptom Score (IPSS) and were corroborated by measurements of PSG-defined sleep made immediately preceding and subsequent to each in-lab voiding episode. PSG measures included whole-night total sleep time (TST), sleep efficiency (SE), apnea/hypopnea index (AHI), and time to PSG-defined sleep following nocturia episodes. Differences between groups were assessed using Mantel–Haenszel chi-square, t-tests, or Wilcoxon signed rank tests. Linear regression was used to assess factors associated with reported nocturia frequency. Results Sixty patients completed the IPSS. Thirty-seven (61%) reported at least two nocturia episodes nightly; those individuals demonstrated lower PSG-defined SE (P = 0.01) and TST (P = 0.02) than patients with 0–1 episodes. Participants reporting 2–3 episodes of nocturia with high bother on the IPSS (n = 12) demonstrated lower whole-night TST (280.5 ± 116.1 min vs. 372.5 ± 58.7 min, P = 0.03) and worse SE (59.2 ± 22.7% vs. 75.9 ± 11.2%, P = 0.04) when compared to participants with 2–3 episodes of nocturia with low bother (n = 13). Conclusions These results verify objectively that PD patients with nocturia have poor sleep. Furthermore, among individuals with comparable levels of reported nocturia, higher bother is associated with poorer sleep as defined on PSG. Neurourol. Urodynam. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. Neurourol. Urodynam. 32:1080–1085, 2013.

Background Recognizing the factors associated with falling in Parkinson's disease (PD) would improve identification of at-risk individuals. Objective To examine frequency of falling and baseline characteristics associated with falling in PD using the National Institute of Neurological Disorders and Stroke (NINDS) Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1) dataset. Methods The LS-1 database included 1741 early treated PD subjects (median 4 year follow-up). Baseline characteristics were tested for a univariate association with post-baseline falling during the trial. Significant variables were included in a multivariable logistic regression model. A separate analysis using a negative binomial model investigated baseline factors on fall rate. Results 728 subjects (42%) fell during the trial, including at baseline. A baseline history of falls was the factor most associated with post-baseline falling. Men had lower odds of post-baseline falling compared to women, but for men, the probability of a post-baseline fall increased with age such that after age 70, men and women had similar odds of falling. Other baseline factors associated with a post-baseline fall and increased fall rate included the Unified PD Rating Scale (UPDRS) Activities of Daily Living (ADL) score, total functional capacity (TFC), baseline ambulatory capacity score and dopamine agonist monotherapy. Conclusion Falls are common in early treated PD. The biggest risk factor for falls in PD remains a history of falling. Measures of functional ability (UPDRS ADL, TFC) and ambulatory capacity are novel clinical risk factors needing further study. A significant age by sex interaction may help to explain why age has been an inconsistent risk factor for falls in PD.

Introduction Progressive supranuclear palsy (PSP) is characterized by frequent falls which worsen with disease progression, causing substantial morbidity and mortality. Few studies have investigated which factors contribute to falls in PSP, and all have involved few participants, thus lacking necessary statistical power. The aim of this study was to identify clinical parameters most significantly associated with increasing falls in PSP, using the largest sample of patients to date. Methods Comprehensive clinical data were collected from 339 not demented PSP patients meeting the NINDS-SPSP criteria, who were divided into two groups – Infrequent Fallers (IF; n = 118) with rare falls, and Frequent Fallers (FF; n = 221) who fell occasionally to multiple times a day. Of 198 clinical parameters, we hypothesized 38 to be correlated with an increasing risk of falls. These 38 parameters were analyzed via univariate regression analysis to determine the strength of their association with fall frequency. Unit odds ratios identified the magnitude with which each parameter resulted in an increasing risk of falls. Results Twenty-five of 38 parameters analyzed were significantly associated with fall frequency based on univariate analysis. Symptom duration, clinical measures of disease severity, and several motoric and oculomotor clinical parameters were associated with FF. Examined cognitive parameters and slowing of vertical saccades were not. Conclusions The clinical parameters identified as associated with increased frequency of falls improve our understanding of why they occur and may help identify not demented PSP patients at risk for increasing falls.

Fragile X-associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by an expansion of a CGG repeat to 55–199 in the FMR1 gene on the X chromosome. Male premutation carriers above age 50 are at higher risk of developing this syndrome, compared to women carriers. FXTAS is characterized by slowly progressive intention/action tremor, gait ataxia, variable frontal-subcortical neuropsychological deficits, and characteristic neuroimaging findings.1–3 In other trinucleotide repeat disorders, such as the spinocerebellar ataxias, and in multiple systems atrophy-C (MSA-C),4,5 olfactory identification defects, as measured by the University of Pennsylvania Smell Identification Test (UPSIT),6 are an established early finding, even in the absence of significant motor or cognitive symptoms. 7–11 The pathophysiologic explanation of these defects remains unclear. Nonetheless, the potential importance of hyposmia as an early marker of neurodegeneration is highlighted by ongoing studies in PD.12 Olfaction defects in degenerative ataxias tend to be less severe than those found in PD and Alzheimer’s disease (AD), but noteworthy compared to age-matched controls.13 Given this coincidence across different forms of neurodegeneration, we examined olfaction identification capacity as a potential clinical marker of neurodegeneration in FXTAS. Olfactory function can be measured by threshold, a function of the integrity of the olfactory bulb, and by the ability to identify and discriminate odorants that also relies on the entorhinal cortices, amygdala, and hippocampus.9,14 The UPSIT has been used extensively in the evaluation of olfaction in patients with different forms of neurodegeneration and levels of cognitive impairment.11,15–17 In this study, we used the UPSIT as a measure of above-threshold central olfactory processing and as a possible window into central neural substrates underlying FXTAS.6

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component., T.G. serves as an editorial board member of Movement Disorders and Parkinsonism and Related Disorders and is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society) and the European Community (MeFoPa, Medndelian Forms of Parkinsonism). T.G. received speakers honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim and Valeant Pharma and royalties for his consulting activities from Cefalon Pharma and Merck-Serono. T.G. holds a patent concerning the LRRK2 gene and neurodegenerative disorders. J.H. is consulting for Merck Serono and Eisai. I.Litvan is the founder of the Litvan Neurological Research Foundation, whose mission is to increase awareness, determine the cause/s and search for a cure for neurodegenerative disorders presenting with either parkinsonian or dementia symptoms (501c3).

Background: Stereotactic thermocoagulative lesions of the subthalamic nucleus (STN) have been shown to induce significant motor improvement in patients with Parkinson’s disease (PD). Patients and methods: 89 patients with PD were treated with unilateral subthalamotomy. 68 patients were available for evaluations after 12 months, 36 at 24 months and 25 at 36 months. Results: The Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores improved significantly contralaterally to the lesion in the “off” and “on” states throughout the follow-up, except for the “on” state at the last evaluation. Axial features and signs ipsilateral to the lesion progressed steadily throughout the study. Levodopa daily doses were significantly reduced by 45%, 36% and 28% at 12, 24 and 36 months post-surgery. 14 patients (15%) developed postoperative hemichorea-ballism which required pallidotomy in eight. These 14 patients had significantly higher dyskinesia scores (levodopa induced) preoperatively than the entire cohort. Conclusion: Unilateral subthalamotomy was associated with significant and sustained motor benefit contralateral to the lesion. Further work is needed to ascertain what factors led to severe, persistent chorea-ballism in a subset of patients. Subthalamotomy may be considered an option in circumstances when deep brain stimulation is not viable.

Individuals diagnosed with Parkinson’s disease (PD) and older adults transitioning to frailty are two specific populations of older adults that are highly susceptible to falls, are known to possess significant fear of falling, and demonstrate disturbances in postural stability and gait abnormalities (Kressig et al., 2004, Wolf et al., 2003, Adkin et al., 2003, Morris et al., 2001, Hass et al., 2004). Adults transitioning to frailty can be defined as those persons not meeting the criteria for either frail or vigorous based on Speechley and Tinetti’s (Speechley and Tinetti, 1991) classification scheme of ten attributes of frail or vigorous adults. Using this classification criteria (Speechley and Tinetti, 1991), Kressig et al. (Kressig et al., 2004) observed that the spatial and temporal features of gait in this population are characterized by reduced gait velocity and stride lengths and greater variability (greater standard deviations in spatiotemporal parameters) compared to robust older adults. Similarly, Hass and colleagues (Hass et al., 2004) observed that adults transitioning to frailty produced anticipatory postural adjustments during gait initiation that were smaller and less forceful than those reported previously for older adults (Halliday et al., 1998, Martin et al., 2002). Persons with PD are also known to exhibit performance decrements during both straight line walking and gait initiation. Compared to healthy older adults, these patients demonstrate reduced gait speed, stride length, abnormal force regulation, and excessive variability during locomotion and reduced magnitudes of center of pressure (COP) displacements during gait initiation (Morris et al., 2001, Halliday et al., 1998, Gantchev et al., 1996, Martin et al., 2002). Thus, both of these populations have demonstrable problems with postural stability during locomotion and during transitions between states of equilibrium, such as gait initiation. Gait initiation is a functional task representing one of the first voluntary destabilizing behaviors observed in the development of a locomotor pattern as the whole body center of mass (COM) transitions from a large to small base of support. This task represents a challenge to the postural control system due to the volitional transition from a condition of relatively static stable support to one of continuously unstable posture during locomotion (Jian et al., 1993, Martin et al., 2002, Polcyn et al., 1998, Halliday et al., 1998, Chang and Krebs, 1999) and one that has been shown to be a sensitive indicator of balance dysfunction (Chang and Krebs, 1999). Indeed, gait initiation has been studied to provide insight into dynamic postural control and the changes that occur in the control system with advancing age and disability (Halliday et al., 1998, Martin et al., 2002, Mbourou et al., 2003, Michel and Do, 2002, Patchay et al., 2002, Fiolkowski et al., 2002, Sasaki et al., 2001). Of note, however, is that studies utilizing gait initiation to study postural control have been limited to straight ahead walking. The fact that the effects of changing direction during gait initiation has been given little attention is surprising considering: many older adults report falling when directing motion laterally; impairments in lateral stability are an important aspect of balance dysfunction and falls (Rogers and Mille, 2003) and older adults and patient populations are known to have difficulty turning and moving laterally. Indeed, in persons with PD twenty percent of falls are directed laterally and the predominance of sway abnormalities is observed in the mediolateral direction (Bloem, 2003 and 2004). Further, changing direction during the initiation of gait is a common skill performed daily such as when walking away from the kitchen sink or after selecting groceries from the grocery aisle. To date, multi-directional gait initiation and direct comparisons between transitionally frail older adults and persons with PD, whose postural and locomotor performance are both degraded, have not been performed. We suggest that the examination of differences in postural control within these two fall prone populations during forward and lateral gait initiation is valuable for several reasons. First, acquiring more information regarding postural control during functional tasks in these groups could add to our understanding of dynamic postural stability in fall prone older populations. An understanding of performance during multidirectional gait initiation may provide insight as to why changing direction has been associated with an increased incidence of falls in older adult populations. Second, these direct comparisons would provide valuable information regarding the degradation in postural control that is observed in elderly or diseased populations and could help partition which decrements result from increasing frailty, alone, or from the motor dysfunction associated with neurodegeneration. These two groups have also been observed to have similar gait performance with differences in magnitude in stride length, velocity, and cadence between groups averaging

Carriers of the FMR1 premutation allele are at a significantly increased risk for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). This disorder is distinct from fragile X syndrome (FXS) with respect to the molecular etiology and clinical presentation. The primary features of FXTAS are late-onset intention tremor and gait ataxia. Associated features include parkinsonism, neuropsychological dysfunction, autonomic dysfunction and peripheral neuropathy. Our primary goal in this work was to investigate the usefulness of a quantitative neurological test battery implemented through the CATSYS instrumentation to identify pre-clinical symptoms of FXTAS. We have tested both premutation carriers with 70-199 repeats (N=62 males) and their low-repeat allele carrier siblings (N=27 males) identified through families with an individual affected with FXS. As expected, due to the sensitivity of the instrument, we were able to identify tremor in 23% of men who had not self-reported tremor, and ataxia in 30% of men who had not endorsed ataxia. Among subjects who self-reported tremor and ataxia, we found significant concordance between measures of the CATSYS system and self-report. Comparison of rates of these traits among premutation carriers and low-repeat allele carrier siblings are presented along with the minimum estimates of age-related prevalence.

Background. Persons with Parkinson disease (PD) exhibit decreased muscular fitness including decreased muscle mass, muscle strength, bioenergetic capabilities and increased fatigability. Objective. This purpose of this investigation was to evaluate the therapeutic effects of resistance training with and without creatine supplementation in patients with mild to moderate PD. Methods. Twenty patients with idiopathic PD were randomized to receive creatine monohydrate supplementation plus resistance training (CRE) or placebo (lactose monohydrate) plus resistance training (PLA), using a double-blind procedure. Creatine and placebo supplementation consisted of 20 g/d for the first 5 days and 5 g/d thereafter. Both groups participated in progressive resistance training (24 sessions, 2 times per week, 1 set of 8-12 repetitions, 9 exercises). Participants performed 1-repetition maximum (1-RM) for chest press, leg extension, and biceps curl. Muscular endurance was evaluated for chest press and leg extension as the number of repetitions to failure using 60% of baseline 1-RM. Functional performance was evaluated as the time to perform 3 consecutive chair rises. Results. Statistical analyses (ANOVA) revealed significant Group × Time interactions for chest press strength and biceps curl strength, and post hoc testing revealed that the improvement was significantly greater for CRE. Chair rise performance significantly improved only for CRE (12%, P = .03). Both PLA and CRE significantly improved 1-RM for leg extension (PLA: 16%; CRE: 18%). Muscular endurance improved significantly for both groups. Conclusions. These findings demonstrate that creatine supplementation can enhance the benefits of resistance training in patients with PD.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

Deep brain stimulation (DBS) may improve disabling tics in severely affected medication and behaviorally resistant Tourette syndrome (TS). Here we review all reported cases of TS DBS and provide updated recommendations for selection, assessment, and management of potential TS DBS cases based on the literature and implantation experience. Candidates should have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) diagnosis of TS with severe motor and vocal tics, which despite exhaustive medical and behavioral treatment trials result in significant impairment. Deep brain stimulation should be offered to patients only by experienced DBS centers after evaluation by a multidisciplinary team. Rigorous preoperative and postoperative outcome measures of tics and associated comorbidities should be used. Tics and comorbid neuropsychiatric conditions should be optimally treated per current expert standards, and tics should be the major cause of disability. Psychogenic tics, embellishment, and malingering should be recognized and addressed. We have removed the previously suggested 25-year-old age limit, with the specification that a multidisciplinary team approach for screening is employed. A local ethics committee or institutional review board should be consulted for consideration of cases involving persons younger than 18 years of age, as well as in cases with urgent indications. Tourette syndrome patients represent a unique and complex population, and studies reveal a higher risk for post-DBS complications. Successes and failures have been reported for multiple brain targets; however, the optimal surgical approach remains unknown. Tourette syndrome DBS, though still evolving, is a promising approach for a subset of medication refractory and severely affected patients.

International audience; Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode beta- and gamma-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.European Journal of Human Genetics advance online publication, 23 July 2014; doi:10.1038/ejhg.2014.95.

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10−7) and MAPT H1c (17q21; rs242557; P=7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein)., Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.

Hass CJ, Waddell DE, Fleming RP, Juncos JL, Gregor RJ. Gait initiation and dynamic balance control in Parkinson's disease. Objective To determine whether the magnitude of the separation between the center of pressure (COP) and the whole-body center of mass (COM) during gait initiation can differentiate patients with varying severity of Parkinson's disease (PD) disability. Design Cross-sectional, intact groups research design. Setting Biomechanics research laboratory. Participants Forty-three patients were stratified into 2 groups based on the Hoehn and Yahr (HY age, 61±10y) or HY age, 70±9y). Interventions Not applicable. Main Outcome Measures The peak COP-COM distance represents the maximum separation between the location of the whole-body COM and the ground reaction force's COP, and thus is an indicator of dynamic balance control. The peak COP-COM was evaluated during 3 phases of the COP trajectory during a gait initiation task. Results The peak magnitude of the COP-COM distance was significantly greater during the end of the single-support phase in the less disabled patients (H&Y score ≤2.0) than in more balance disabled patients (H&Y score ≥2.5) ( P =.004). Conclusions The differences in COP-COM distances between these H&Y groups suggest that patients with PD who have impaired postural control produce shorter COM-COP distances than do persons without clinically detectable balance impairment. This method of evaluation could prove a useful quantitative index to examine the impact of interventions designed to improve ambulation and balance in PD.

We conducted an open label pilot study of the effect of bilateral subthalamotomy in 18 patients with advanced Parkinson's disease. In seven patients, the first subthalamotomy pre-dated the second by 12-24 months ('staged surgery'). Subsequently, a second group of 11 patients received bilateral subthalamotomy on the same day ('simultaneous surgery'). Patients were assessed according to the CAPIT (Core Assessment Program for Intracerebral Transplantation) protocol, a battery of timed motor tests and neuropsychological tests. Evaluations were performed in the 'off' and 'on' drug states before surgery and at 1 and 6 months and every year thereafter for a minimum of 3 years after bilateral subthalamotomy. Compared with baseline, bilateral subthalamotomy induced a significant (P < 0.001) reduction in the 'off' (49.5%) and 'on' (35.5%) Unified Parkinson's Disease Rating Scale (UPDRS) motor scores at the last assessment. A blind rating of videotape motor exams in the 'off' and 'on' medication states preoperatively and at 2 years postoperatively also revealed a significant improvement. All of the cardinal features of Parkinson's disease as well as activities of daily living (ADL) scores significantly improved (P < 0.01). Levodopa-induced dyskinesias were reduced by 50% (P < 0.01), and the mean daily levodopa dose was reduced by 47% at the time of the last evaluation compared with baseline (P < 0.0001). Dyskinesias occurred intraoperatively or in the immediate postoperative hours in 13 patients, but were generally mild and short lasting. Three patients developed severe generalized chorea that gradually resolved within the next 3-6 months. Three patients experienced severe and persistent postoperative dysarthria. In two, this coincided with the patients exhibiting large bilateral lesions also suffering from severe dyskinesias. No patient exhibited permanent cognitive impairment. The motor benefit has persisted for a follow-up of 3-6 years. This study indicates that bilateral subthalamotomy may induce a significant and long-lasting improvement of advanced Parkinson's disease, but the clinical outcome was variable. This variability may depend in large part on the precise location and volume of the lesions. Further refinement of the surgical procedure is mandatory.

Twenty-nine elderly patients who failed treatment with clozapine, risperidone, or olanzapine entered this 24-week, single-center, open-label trial to assess the efficacy of quetiapine (12.5-400 mg/day) for psychosis in patients with Parkinson's disease (PD). Psychiatric, motor, and cognitive assessments were administered at baseline and at periodic intervals for 24 weeks. These included the Brief Psychiatric Rating Scale (BPRS), Neuropsychiatric Inventory (NPI), Unified Parkinson's Disease Rating Scale (UPDRS) and tests of intellectual functioning, attention, and memory. Repeated measures statistical analysis was used to assess change from baseline. The results revealed significant improvements in the 24-week BPRS total score and NPI psychosis subscale scores, with no decline in UPDRS total or motor subscale scores. There was also significant improvement in recall scores on cognitive measures. These results indicate that quetiapine may treat psychotic symptoms and improve cognition without worsening motor function in patients with PD, suggesting that quetiapine is an effective and well-tolerated antipsychotic in this population.

Essential tremor can cause significant functional disability in some patients. The arms are the most common body part affected and cause the most functional disability. The treatment of essential tremor includes medications, surgical options and other forms of therapy. Presently there is no cure for essential tremor nor are there any medications that can slow the progression of tremor. Treatment for essential tremor is recommended if the tremor causes functional disability. If the tremor is disabling only during periods of stress and anxiety, propranolol and benzodiazepines can be used during those periods when the tremor causes functional disability. The currently available medications can improve tremor in approximately 50% of the patients. If the tremor is disabling, treatment should be initiated with either primidone or propranolol. If either primidone or propranolol do not provide adequate control of the tremor, then the medications can be used in combination. If patients experience adverse effects with propranolol, occasionally other beta-adrenoceptor antagonists (such as atenolol or metoprolol) can be used. If primidone and propranolol do not provide adequate control of tremor, occasionally the use of benzodiazepines (such as clonazepam) can provide benefit. Other medications that may be helpful include gabapentin or topiramate. If a patient has disabling head or voice tremor, botulinum toxin injections into the muscles may provide relief from the tremor. Botulinum toxin in the hand muscles for hand tremor can result in bothersome hand weakness and is not widely used. There are other medications that have been tried in essential tremor and have questionable efficacy. These drugs include carbonic anhydrase inhibitors (e.g. methazolamide), phenobarbital, calcium channel antagonists (e.g. nimodipine), isoniazid, clonidine, clozapine and mirtazapine. If the patient still has disabling tremor after medication trials, surgical options are usually considered. Surgical options include thalamotomy and deep brain stimulation of the thalamus. These surgical options provide adequate tremor control in approximately 90% of the patients. Surgical morbidity and mortality for these procedures is low. Deep brain stimulation and thalamotomy have been shown to have comparable efficacy but fewer complications have been reported with deep brain stimulation. In patients undergoing bilateral procedures deep brain stimulation of the thalamus is the procedure of choice to avoid adverse effects seen with bilateral ablative procedures. The use of medication and/or surgery can provide adequate tremor control in the majority of the patients.

The objective of this study was to determine the reliability of a new scale for the clinical assessment of essential tremor. The Essential Tremor Rating Assessment Scale contains 9 performance items that rate action tremor in the head, face, voice, limbs, and trunk from 0 to 4 in half-point intervals. Head and limb tremor ratings are defined by specific amplitude ranges in centimeters.Videos of 44 patients and 6 controls were rated by 10 specialists on 2 occasions 1-2 months apart. Inter- and intrarater reliability was assessed with a 2-way random-effects intraclass correlation, using an absolute agreement definition.Inter- and intrarater intraclass correlations for head and upper-limb tremor ranged from 0.86 to 0.96, and intraclass correlations for total score were 0.94 and 0.96. The intraclass correlations for voice, face, trunk, and leg were less robust.This scale is an exceptionally reliable tool for the clinical assessment of essential tremor.

Background : The integration of mental and neurologic services in healthcare is a global priority. The universal Social Security of Costa Rica aspires to develop national screening of neurodegenerative disorders among the elderly, as part of the non-communicable disease agenda. Objective : This study assessed the feasibility of routine screening for Parkinson’s disease (PD) and Alzheimer’s disease (AD) within the public healthcare system of Costa Rica. Design : The population (aged ≥65) in the catchment areas of two primary healthcare clinics was targeted for motor and cognitive screening during routine annual health check-ups. The screening followed a tiered three-step approach, with increasing specificity. Step 1 involved a two-symptom questionnaire (tremor-at-rest; balance) and a spiral drawing test for motor assessment, as well as a three-word recall and animal category fluency test for cognitive assessment. Step 2 (for those failing Step 1) was a 10-item version of the Unified Parkinson Disease Rating Scale and the Mini-Mental State Examination. Step 3 (for those failing Step 2) was a comprehensive neurologic exam with definitive diagnosis of PD, AD, mild cognitive impairment (MCI), other disorders, or subjects who were healthy. Screening parameters and disease prevalence were calculated. Results : Of the 401 screened subjects (80% of target population), 370 (92%), 163 (45%), and 81 (56%) failed in Step 1, Step 2, and Step 3, respectively. Thirty-three, 20, and 35 patients were diagnosed with PD, AD, and MCI, respectively (7 were PD with MCI/AD); 90% were new cases. Step 1 sensitivities of motor and cognitive assessments regarding Step 2 were both 93%, and Step 2 sensitivities regarding definitive diagnosis 100 and 96%, respectively. Specificities for Step 1 motor and cognitive tests were low (23% and 29%, respectively) and for Step 2 tests acceptable (76%, 94%). Based on international data, PD prevalence was 3.7 times higher than expected; AD prevalence was as expected. Conclusion : Proposed protocol adjustments will increase test specificity and reduce administration time. A routine screening program is feasible within the public healthcare system of Costa Rica. Keywords: Alzheimer’s; Parkinson’s; screening; aging; public health system; Costa Rica (Published: 27 December 2013) Citation: Glob Health Action 2013, 6 : 23061 - http://dx.doi.org/10.3402/gha.v6i0.23061

Characterize clinical factors related to nocturia and sleep disruption in Parkinson disease (PD) using polysomnography (PSG).Sixty-three PD patients were recruited regardless of sleep or voiding complaints from a university-based movement disorders clinic for a 48 hr inpatient PSG protocol. Nocturia frequency and bother related to urinary symptoms were assessed using the International Prostate Symptom Score (IPSS) and were corroborated by measurements of PSG-defined sleep made immediately preceding and subsequent to each in-lab voiding episode. PSG measures included whole-night total sleep time (TST), sleep efficiency (SE), apnea/hypopnea index (AHI), and time to PSG-defined sleep following nocturia episodes. Differences between groups were assessed using Mantel-Haenszel chi-square, t-tests, or Wilcoxon signed rank tests. Linear regression was used to assess factors associated with reported nocturia frequency.Sixty patients completed the IPSS. Thirty-seven (61%) reported at least two nocturia episodes nightly; those individuals demonstrated lower PSG-defined SE (P = 0.01) and TST (P = 0.02) than patients with 0-1 episodes. Participants reporting 2-3 episodes of nocturia with high bother on the IPSS (n = 12) demonstrated lower whole-night TST (280.5 ± 116.1 min vs. 372.5 ± 58.7 min, P = 0.03) and worse SE (59.2 ± 22.7% vs. 75.9 ± 11.2%, P = 0.04) when compared to participants with 2-3 episodes of nocturia with low bother (n = 13).These results verify objectively that PD patients with nocturia have poor sleep. Furthermore, among individuals with comparable levels of reported nocturia, higher bother is associated with poorer sleep as defined on PSG. Neurourol. Urodynam. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

The relationship between depression and disability in idiopathic Parkinson's disease (PD) was examined in 31 outpatients. Thirteen percent had current major depression (MD), 10% dysthymia, and 32% a lifetime history of MD. Depression was significantly related to both illness severity and functional impairment. Male patients with early-onset PD (before age 55) had more mood and anxiety disorders than late-onset male patients. Patients with right-sided PD had significantly more depressive symptoms than those with left-sided PD. On multiple regression analyses, depression predicted impaired social, role, and physical functioning for men (but not for women), independent of the impact of illness severity. The results suggest that treatment of depression may improve function; however, findings of gender differences will require replication.

We describe a case of pseudobulbar crying associated with deep brain stimulation (DBS) in the region of the subthalamic nucleus (STN). Patients with pseudobulbar crying show no other evidence of subjective feelings of depression such as dysphoria, anhedonia, or vegetative signs. This may be accompanied by other symptoms of pseudobulbar palsy and has been reported to occur with ischaemic or structural lesions in both cortical and subcortical regions of the brain. Although depression has been observed to result from DBS in the region of the STN, pseudobulbar crying has not been reported. A single patient who reported the symptoms of pseudobulbar crying after placement of an STN DBS was tested in the off DBS and on DBS conditions. The patient was tested using all four DBS lead contacts and the observations and results of the examiners were recorded. The Geriatric Depression Scale was used to evaluate for depression in all of the conditions. The patient exhibited pseudobulbar crying when on monopolar stimulation at all four lead contacts. The pseudobulbar crying resolved off stimulation. This case describes another type of affective change that may be associated with stimulation in the region of or within the STN. Clinicians should be aware of this potential complication, the importance of differentiating it from stimulation induced depression, and its response to a serotonin reuptake inhibitor, such as sertraline.

Gait dysfunction and postural instability are two debilitating symptoms in persons with Parkinson's disease (PD). Tai Chi exercise has recently gained attention as an attractive intervention for persons with PD because of its known potential to reduce falls and improve postural control, walking abilities, and safety at a low cost. The purpose of this report is to investigate the effect of Tai Chi exercise on dynamic postural control during gait initiation and gait performance in persons with idiopathic PD, and to determine whether these benefits could be replicated in two different environments, as complementary projects. In these two separate projects, a total of 45 participants with PD were randomly assigned to either a Tai Chi group or a control group. The Tai Chi groups in both projects completed a 16-week Tai Chi exercise session, while the control groups consisted of either a placebo (i.e., Qi-Gong) or non-exercise group. Tai Chi did not significantly improve Unified Parkinson's Disease Rating Scale Part III score, selected gait initiation parameters or gait performance in either project. Combined results from both projects suggest that 16 weeks of class-based Tai Chi were ineffective in improving either gait initiation, gait performance, or reducing parkinsonian disability in this subset of persons with PD. Thus the use of short-term Tai Chi exercise should require further study before being considered a valuable therapeutic intervention for these domains in PD.

Background Pesticides have been associated with Parkinson's disease (PD) in many studies, and with Alzheimer's disease (AD) in a few. Methods We conducted screening tests for neurologic disease and occupational pesticide use in a population-based sample of 400 elderly subjects at two government-run clinics in Costa Rica; 361 subjects who failed the initial screen were given both the Mini-mental States Exam (MMSE) and a modified version of a 10-item United Parkinson's Disease Rating Motor Subscale (UPDRS). Among subjects who failed either test, 144 were then examined by a neurologist. Results Past occupational pesticide exposure was reported by 18% of subjects. Exposed subjects performed worse on the MMSE than the non-exposed (mean 24.5 versus 25.9, p =0.01, adjusted for age, sex, and education). The exposed had significantly elevated risks of abnormal scores on two UPDRS items, tremor-at-rest (OR 2.58, 1.28–5.23), and finger-tapping (OR=2.94, 95% CI 1.03–8.41). Thirty-three (23%) of those examined by the neurologist were diagnosed with possible/probable PD, 3–4 times the expected based on international data; 85% of these cases had not been previously diagnosed. Among subjects who took the UPDRS, the exposed had an increased risk of PD (OR=2.57, 95% CI 0.91–7.26). No excess risk was found for a diagnosis of AD or mild cognitive impairment. Conclusions Elderly subjects with past occupational pesticide exposure performed significantly worse on screening tests for dementia and PD, and had an increased risk of an eventual PD diagnosis. Screening may be particularly appropriate among elderly subjects with past pesticide exposure.

Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.