Exploratory evaluation of baseline cognition as a predictor of perceived benefit in a study of behavioral therapy for urinary incontinence in Parkinson disease.

AIMS: While behavior-based pelvic floor muscle exercise therapy is an effective treatment for overactive bladder in Parkinson's 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 four 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 ms) compared to the No Benefit group (959.4 ± 443.0 ms; 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 behavior-based therapy studies exclude participants with mild cognitive impairment. Additional studies may evaluate if domain-specific cognitive function, particularly the assessment of implicit memory, could lead to individualized behavioral therapy recommendations.

Are the International Parkinson disease and Movement Disorder Society progressive supranuclear palsy (IPMDS-PSP) diagnostic criteria accurate enough to differentiate common PSP phenotypes?

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 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.

Frequency of the TREM2 R47H Variant in Various Neurodegenerative Disorders.

OBJECTIVE: A rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer disease (AD), 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 3058 patients clinically diagnosed with AD, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5089 control subjects. RESULTS: We observed a significant association between the R47H variant and AD, 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 AD. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.

Behavioral therapy for urinary symptoms in Parkinson's disease: A randomized clinical trial.

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.

Author Correction to: Pooled Analyses of Phase III Studies of ADS-5102 (Amantadine) Extended-Release Capsules for Dyskinesia in Parkinson's Disease.

An Online First version of this article was made available online at http://link.springer.com/journal/40263/onlineFirst/page/1 on 12 March 2018. An error was subsequently identified in the article, and the following correction should be noted.

Pooled Analyses of Phase III Studies of ADS-5102 (Amantadine) Extended-Release Capsules for Dyskinesia in Parkinson's Disease.

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 < 0.0001). The relative treatment difference between groups was 27.3% (p < 0.0001). At 12 weeks, the LS mean change in OFF time was - 0.59 (0.21) vs. +0.41 (0.20) h/day, a difference of - 1.00 h/day (95% CI - 1.57, - 0.44; p = 0.0006). For both efficacy measures, a significant difference from placebo was attained by two weeks, the first post-baseline assessment, and was maintained throughout 12 weeks. In the pooled ADS-5102 group, the most common adverse events were hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension. CONCLUSIONS: These analyses provide further evidence supporting ADS-5102 as an adjunct to levodopa for treating both dyskinesia and OFF time in PD patients with dyskinesia. Clinicaltrials.gov identifier: NCT02136914 and NCT02274766.

Increased odds of bladder and bowel symptoms in early Parkinson's disease.

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 < 0.0001). Prevalent nighttime voiding was high among both groups, but not significantly different (82.5% vs 84.1%, P = 0.62). FI was infrequent in both. The odds of UI and constipation were significantly higher in early PD even after adjustment for age, sex, cognition, and overactive bladder (UI model only), constipation (UI and constipation models only), depression, and anxiety medication usage (UI: OR: 4.39 [95% CI: 2.92, 5.87]; constipation: 3.34 [2.20, 4.42]; P's < 0.0001). CONCLUSIONS: While constipation is known to precede PD diagnosis, these data suggest that the occurrence of UI is elevated in early PD compared to a well-matched HC population.

Fixational eye movements in Tourette syndrome.

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 amplitude 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.

Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy.

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).

Tourette syndrome deep brain stimulation: a review and updated recommendations.

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.

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

IMPORTANCE: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. OBJECTIVE: To examine whether CoQ10 could slow disease progression in early PD. DESIGN, SETTING, AND PARTICIPANTS: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. INTERVENTIONS: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. MAIN OUTCOMES AND MEASURES: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. RESULTS: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). CONCLUSIONS AND RELEVANCE: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00740714.

The effect of Tai Chi exercise on gait initiation and gait performance in persons with Parkinson's disease.

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.

Nocturia and overnight polysomnography in Parkinson disease.

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.

Parkinson's and Alzheimer's diseases in Costa Rica: a feasibility study toward a national screening program.

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.

Reliability of a new scale for essential tremor.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: This scale is an exceptionally reliable tool for the clinical assessment of essential tremor.

Olfactory dysfunction in fragile X tremor ataxia syndrome.

INTRODUCTION: We investigated olfactory defects in fragile X-associated tremor/ataxia syndrome (FXTAS), a finding reported on in other neurodegenerative disorders with clinical features that overlap those of FXTAS. METHODS: We measured olfactory identification capacity in 41 FMR1 premutation carriers and 42 controls using the University of Pennsylvania Smell Identification Test (UPSIT). Carriers received neurologic evaluations using motor rating scales for tremor, ataxia, and parkinsonism. Cognitive function was measured using the Montreal Cognitive Assessment test. RESULTS: Frequency of olfactory defects was higher in carriers, compared to controls (61% versus 29%; P = 0.003). There was no statistically significant group difference in severity of olfaction defects, after accounting for differences in age, and in rates of head injury and smoking. However, both the frequency (odds ratio = 3.9; 95% confidence interval: 0.81-19.1) and severity (28.6 versus 33.4; P = 0.01) of these defects were greater in cognitively impaired, compared to cognitively intact, carriers. There was no correlation between UPSIT scores and the above-mentioned motor rating scales. CONCLUSIONS: FMR1 premutation carriers are susceptible to olfactory identification defects. The severity of these defects is comparable to that reported in hereditary ataxias, but less than that in PD and Alzheimer's disease. This concurrence across neurodegenerative disorders suggests a shared system vulnerability that correlates with, but is not limited to, cognitive impairment, because it is also found in cognitively intact carriers. These results need to be corroborated in a larger prospective study of FMR1 premutation carriers that extends beyond olfactory identification to include measures of smell thresholds.

Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases.

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.

New clinical findings in the fragile X-associated tremor ataxia syndrome (FXTAS).

The objective of this paper was to assess the phenotypic variance in patients with the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and to further elucidate genotype-phenotype correlations in the illness. A second goal was to generate hypotheses regarding symptom progression based on careful histories in our sample that can now be tested in ongoing longitudinal studies. The variability of clinical signs and symptom progression in FXTAS complicates our understanding of its phenotype and presents a series of problems in clinical trial design. Similarly, pre-motor and non-motor symptoms have not been adequately explored to answer outstanding questions regarding genotype-phenotype associations in FXTAS. This was a cross-sectional study of FMR1 premutation carriers from known fragile X syndrome pedigrees. We report on the first 50 subjects who have completed a full neurologic evaluation and a brain MRI. Subjects were selected on the basis of motor symptoms or abnormal results (>1 SD) on a quantitative instrument designed to detect mild tremor and ataxia (CATSYS 1994). A neuropsychological battery included the WAIS-III, COWA, and WCST. Statistical analysis used ANOVA and Fisher's exact test with p < 0.05. All FMR1 premutation carriers were men of mean age 65 ± 7 years. According to the diagnostic criteria of Jacquemont et al. (Am J Hum Genet 72(4):869-878, 2003), 21 subjects met criteria for definite FXTAS, 10 for probable, 9 for possible, and 10 were indeterminate. Duration of motor symptoms was significantly longer in the definitive group (8.6 ± 6) compared to the other groups (p < 0.01). The presentations in 40 subjects, excluding the indeterminate group, included: tremor 24, ataxia 5, memory symptoms 3, parkinsonism 2, and torticollis 1. The data suggest at least two dominant phenotypic presentations: (a) a tremor-dominant subtype in which the onset of ataxia is delayed; (b) a second in which ataxia is the dominant presentation from the outset. In both subtypes, once ataxia emerges it tends to track frontal cognitive changes (p < 0.01). The data support the view that FXTAS is a late-life neurodegenerative disorder with involvement of motor, non-motor, and cognitive systems. The results suggest at least two presentations with tremor- and ataxia-predominant phenotypes. In both, global cognitive decline appears to track ataxia. Prospective longitudinal studies are needed to validate this proposed evolution of FXTAS and its relevance to future clinical trials design.

Chronic dopaminergic stimulation in Parkinson's disease: from dyskinesias to impulse control disorders.

Dopamine is an essential neurotransmitter for many brain functions, and its dysfunction has been implicated in both neurological and psychiatric disorders. Parkinson's disease is an archetypal disorder of dopamine dysfunction characterised by motor, cognitive, behavioural, and autonomic symptoms. While effective for motor symptoms, dopamine replacement therapy is associated not only with motor side-effects, such as levodopa-induced dyskinesia, but also behavioural side-effects such as impulse control disorders (eg, pathological gambling and shopping, binge eating, and hypersexuality), punding (ie, abnormal repetitive non-goal oriented behaviours), and compulsive medication use. We review clinical features, overlapping molecular mechanisms, and a specific cognitive mechanism of habit learning that might underlie these behaviours. We integrate these mechanisms with the emerging view of the basal ganglia as a distributive system involved in the selection and facilitation of movements, acts, and emotions.