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Objective: To assess for TDP-43 deposits in brains with and without a LRRK2 G2019S mutation., Background: LRRK2 G2019S mutations have been associated with parkinsonism and a wide range of pathological findings. There are no systematic studies examining the frequency and extent of TDP-43 deposits in neuropathological samples from LRRK2 G2019S carriers., Methods: Twelve brains with LRRK2 G2019S mutations were available for study from the New York Brain Bank at Columbia University; 11 of them had samples available for TDP-43 immunostaining. Clinical, demographic, and pathological data are reported for 11 brains with a LRRK2 G2019S mutation and compared to 11 brains without GBA1 or LRRK2 G2019S mutations with a pathologic diagnosis of Parkinson's disease (PD) or diffuse Lewy body disease. They were frequency matched by age, gender, parkinsonism age of onset, and disease duration., Results: TDP-43 aggregates were present in 73% (n = 8) of brains with a LRRK2 mutation and 18% (n = 2) of brains without a LRRK2 mutation (P = 0.03). In one brain with a LRRK2 mutation, TDP-43 proteinopathy was the primary neuropathological change., Conclusions: Extranuclear TDP-43 aggregates are observed with greater frequency in LRRK2 G2019S autopsies compared to PD cases without a LRRK2 G2019S mutation. The association between LRRK2 and TDP-43 should be further explored. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Genetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct-to-consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene-targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long-term outcomes of consumer- and research-based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost-benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: There is growing clinical and research utilization of genetic testing in Parkinson's disease (PD), including direct-to-consumer testing., Objectives: The aim is to determine the international landscape of genetic testing in PD to inform future worldwide recommendations., Methods: A web-based survey assessing current practices, concerns, and barriers to genetic testing and counseling was administered to the International Parkinson and Movement Disorders Society membership., Results: Common hurdles across sites included cost and access to genetic testing, and counseling, as well as education on genetic counseling. Region-dependent differences in access to and availability of testing and counseling were most notable in Africa. High-income countries also demonstrated heterogeneity, with European nations more likely to have genetic testing covered through insurance than Pan-American and Asian countries., Conclusions: This survey highlights not only diversity of barriers in different regions but also the shared and highly actionable needs for improved education and access to genetic counseling and testing for PD worldwide. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited., Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD., Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed., Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published., Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Age of manifest Huntington's disease (HD) onset correlates with number of CAG repeats in the huntingtin gene. Little is known about onset with 36 to 39 repeats, the "reduced penetrance" (RP) range., Objectives: We provide allele-specific estimates of HD penetrance (diagnostic confidence level of 4) for RP allele carriers., Methods: We analyzed 431 pre-manifest RP allele carriers from Enroll-HD, the largest prospective observational HD study. Cumulative penetrance (CP) was estimated from Kaplan-Meier curves., Results: No one with 36 repeats (n = 25) phenoconverted. CP for 38 repeats (n = 120) was 32% (95% confidence interval [CI] 0%-55%) and 51% (CI, 10%-73%) by ages 70 and 75, respectively, and 68% (CI, 46%-81%) and 81% (CI, 58%-92%) by ages 70 and 75 for 39 repeats (n = 253). CP was not estimable at those ages for 37 repeats (n = 33)., Conclusions: Differences by RP-range repeat length did not reach significance with a 3-year median follow-up duration among censored individuals. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease., Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers., Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset., Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls., Methods: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients., Results: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients., Conclusions: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Background: In 2015, the International Parkinson and Movement Disorder Society Task Force recommended research criteria for the estimation of prodromal PD., Objectives: We aimed to evaluate, for the first time, the criteria in first-degree relatives of Ashkenazi Jewish G2019S-LRRK2 PD patients, who are considered a population at risk for developing PD, and assess the sensitivity and specificity of the criteria in identifying phenoconverters., Methods: Participants were evaluated longitudinally over a period of 5 years (average follow-up: 49.2 ± 12.3 months). Likelihood ratios and probability estimations were calculated based on the International Parkinson and Movement Disorder Society Research Criteria for Prodromal Parkinson's Disease markers and examined for each assessment point., Results: One hundred twenty healthy carriers (49.53 ± 13.4 years; 54% female) and 111 healthy noncarriers (48.43 ± 15.79 years; 49% female) participated in this study. Probability scores were significantly higher in healthy carriers than healthy noncarriers (P < 0.0001). Of the 20 participants (8.6%) who met criteria for probable prodromal PD at baseline, 17 were healthy carriers. Participants who reached the threshold were older (P < 0.0001), had higher UPDRS-III (P < 0.001), lower cognitive function (P = 0.001), and more nonmotor symptoms (P < 0.0001), compared to those who did not. Ten participants were diagnosed with incident PD within 5 years from baseline resulting in a specificity of 91.82% (95% confidence interval: 86.69-96.94), sensitivity of 80% (95% confidence interval: 55.21-100), positive predictive value of 47.06% (95% confidence interval: 23.33-70.79), and negative predictive value of 98.06% (95% confidence interval: 95.39-100). All 10 phenoconvertors were G2019S-LRRK2 carriers., Conclusions: The results showed the utility of using the criteria and high sensitivity and specificity in identifying prodromal PD in this high-risk unique cohort. These results may be valuable for future disease modification clinical trials. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: In Huntington's disease, 60% of the variance in onset age is not explained by the huntingtin gene mutation. Huntington's disease onset was earlier in caffeine users., Objective: The objective of this study was to assess the relationship of lifestyle factors with motor phenoconversion among persons at risk for Huntington's disease., Methods: The associations of motor phenoconversion and exposure to selected lifestyle and health factors were examined using Cox proportional hazards analyses adjusted for age, gender, and repeat length., Results: Of 247 participants, 36 (14.6%) phenoconverted. Mean follow-up was 4.2 years. Greater caffeinated soda use was associated with an increased hazard of phenoconversion: moderate use hazard ratio 2.26 (95% confidence interval 0.59-8.71), high use hazard ratio 4.05 (95% confidence interval 1.18-13.96)., Conclusions: Huntington's disease onset was earlier among consumers of caffeinated soda, but not other caffeinated beverages. This finding may be spurious or not related to caffeine. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%-100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80., Methods: The kin-cohort method was used to estimate penetrance in 474 first-degree relatives of 69 non-Ashkenazi Jewish LRRK2 p.G2019S carrier probands at 8 sites from the Michael J. Fox LRRK2 Cohort Consortium. An identical validated family history interview was administered to assess age at onset of PD, current age, or age at death for relatives in different ethnic groups at each site. Neurological examination and LRRK2 genotype of relatives were included when available., Results: Risk of PD in non-Ashkenazi Jewish relatives who carry a LRRK2 p.G2019S mutation was 42.5% (95% confidence interval [CI]: 26.3%-65.8%) to age 80, which is not significantly higher than the previously estimated 25% (95% CI: 16.7%-34.2%) in Ashkenazi Jewish carrier relatives. The penetrance of PD to age 80 in LRRK2 p.G2019S mutation carrier relatives was significantly higher than the noncarrier relatives, as seen in Ashkenazi Jewish relatives., Conclusions: The similar penetrance of LRRK2 p.G2019S estimated in Ashkenazi Jewish carriers and non-Ashkenazi Jewish carriers confirms that p.G2019S penetrance is 25% to 42.5% at age 80 in all populations analyzed. © 2017 International Parkinson and Movement Disorder Society., (© 2017 Internationalnternational Parkinson and Movement Disorder Society.)

Background: Rapid eye movement sleep behavior disorder occurs with idiopathic Parkinson's disease (PD) and often precedes PD. Its frequency in LRRK2-PD and utility as a preclinical marker has not been established., Methods: One hundred forty-four idiopathic PD, 142 LRRK2 G2019S mutation PD, 117 non-manifesting carriers, 93 related noncarriers, and 40 healthy controls completed the Rapid eye movement sleep Behavior Disorder Screening Questionnaire., Results: Cut scores were met by 30.6% idiopathic PD, 19.7% LRRK2-PD, 6% nonmanifesting carriers, 20.4% related noncarriers, and 15% controls. The likelihood of abnormal scores was decreased in LRRK2-PD versus idiopathic PD (odds ratio = 0.55, P = 0.03), nonmanifesting carriers versus related noncarriers (OR = 0.25, P < 0.01), and PD of less than 3 years' duration, 1 of 19 LRRK2-PD versus 14 of 41 idiopathic PD (P < 0.05)., Conclusions: A lower frequency of abnormal questionnaire scores is seen in LRRK2-PD, especially in early LRRK2-PD, and in nonmanifesting carriers. Therefore, the Rapid eye movement sleep Behavior Disorder Questionnaire is unlikely to serve as a preclinical marker for phenoconversion to PD., (© 2015 International Parkinson and Movement Disorder Society.)

Background: The asymptomatic carriers of the Leucine rich repeat kinase 2 (LRRK2) G2019S mutation represent a population at risk for developing PD. The aim of this study was to assess differences in nonmotor symptoms between nonmanifesting carriers and noncarriers of the G2019S mutation., Methods: Two hundred fifty-three subjects participated in this observational cross-sectional multicenter study. Standard questionnaires assessing anxiety, depression, cognition, smell, nonmotor symptoms, and rapid eye movement (REM) sleep behavior were administered. Analyses were adjusted for age, sex, family relations, education, and site., Results: One hundred thirty-four carriers were identified. Carriers had higher nonmotor symptoms score on the Nonmotor symptoms (NMS) questionnaire (P = 0.02). These findings were amplified in carriers older than age 50 y, with higher nonmotor symptoms scores and trait anxiety scores (P < 0.03)., Conclusions: In this cross-section study, carriers of the G2019S LRRK2 mutation endorsed subtle nonmotor symptoms. Whether these are early features of PD will require a longitudinal study. © 2015 International Parkinson and Movement Disorder Society., (© 2015 International Parkinson and Movement Disorder Society.)

Background: Patients with Parkinson's disease have reduced gray matter volume and fractional anisotropy in both cortical and sub-cortical structures, yet changes in the pre-motor phase of the disease are unknown., Methods: A comprehensive imaging study using voxel-based morphometry and diffusion tensor imaging tract-based spatial statistics analysis was performed on 64 Ashkenazi Jewish asymptomatic first degree relatives of patients with Parkinson's disease (30 mutation carriers), who carry the G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene., Results: No between-group differences in gray matter volume could be noted in either whole-brain or volume-of-interest analysis. Diffusion tensor imaging analysis did not identify group differences in white matter areas, and volume-of-interest analysis identified no differences in diffusivity parameters in Parkinson's disease-related structures., Conclusions: G2019S carriers do not manifest changes in gray matter volume or diffusivity parameters in Parkinson's disease-related structures prior to the appearance of motor symptoms., (© 2014 International Parkinson and Movement Disorder Society.)

The Unified Huntington's Disease Rating Scale is used to characterize motor impairments and establish motor diagnosis. Little is known about the timing of diagnostic confidence level categories and the trajectory of motor impairments during the prodromal phase. Goals of this study were to estimate the timing of categories, model the prodromal trajectory of motor impairments, estimate the rate of motor impairment change by category, and provide required sample size estimates for a test of efficacy in clinical trials. In total, 1010 gene-expanded participants from the Neurobiological Predictors of Huntington's Disease (PREDICT-HD) trial were analyzed. Accelerated failure time models were used to predict the timing of categories. Linear mixed effects regression was used to model the longitudinal motor trajectories. Age and length of gene expansion were incorporated into all models. The timing of categories varied significantly by gene expansion, with faster progression associated with greater expansion. For the median expansion, the third diagnostic confidence level category was estimated to have a first occurrence 1.5 years before diagnosis, and the second and first categories were estimated to occur 6.75 years and 19.75 years before diagnosis, respectively. Motor impairments displayed a nonlinear prodromal course. The motor impairment rate of change increased as the diagnostic confidence level increased, with added acceleration for higher progression scores. Motor items can detect changes in motor impairments before diagnosis. Given a sufficiently high progression score, there is evidence that the diagnostic confidence level can be used for prodromal staging. Implications for Huntington's disease research and the planning of clinical trials of efficacy are discussed., (© 2013 International Parkinson and Movement Disorder Society.)

Patients with Parkinson's disease (PD) who carry the G2019S mutation (a glycine to serine substitution at amino acid 2019) in the leucine-rich repeat kinase 2 (LRRK2) gene are generally believed to be clinically indistinguishable from patients with sporadic PD. There are, however, conflicting reports on the relationship between the mutation and the motor phenotype. We quantitatively compared gait and mobility in patients with PD carriers of the G2019S mutation to non-carrier patients with PD to better understand the genotype-phenotype relationship. Fifty patients with PD carriers of the G2019S LRRK2 mutation and 50 age, disease duration, and disease severity matched PD non-carriers were studied. An accelerometer quantified gait under three walking conditions: usual-walking, dual-tasking, and fast-walking. The Unified Parkinson's Disease Rating Scale classified patients into PD sub-types and the Timed Up and Go quantified mobility and fall risk. In all three walking conditions, gait variability was larger and the walking pattern was less consistent among the PD mutation carriers (P < 0.016). The PD carriers also took longer to complete the Timed Up and Go (P = 0.011) and were more likely to report having fallen in the previous year (P = 0.018). 64% of the PD carriers were classified as belonging to the postural-instability-gait-difficulty (PIGD) sub-type compared to only 17% of the PD non-carriers (P < 0.0001). Among patients with PD, the G2019S mutation in the LRRK2 gene is apparently associated with increased gait variability, an increased fall risk, and the PIGD sub-type. Therapeutic approach specifically designed to delay gait disturbances and falls may be justified in patients who carry the G2019S mutation., (© 2013 Movement Disorder Society.)

Objective: Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility., Methods: A 2-stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 single-nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls)., Results: Genome-wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio [OR]=1.37; p=9.3×10(-21)), MAPT (rs242559; C: OR=0.78; p=1.5×10(-10)), GAK/DGKQ (rs11248051; T: OR=1.35; p=8.2×10(-9)/rs11248060; T: OR=1.35; p=2.0×10(-9)), and the human leukocyte antigen (HLA) region (rs3129882; A: OR=0.83; p=1.2×10(-8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5×10(-8) Combined Sample) (N370; OR=3.08; p=7×10(-5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5×10(-5) Discovery Sample; p=1.52×10(-7) Replication sample; p=2×10(-10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes., Interpretation: We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA., (Copyright © 2012 American Neurological Association.)

Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage., (Copyright © 2012 Movement Disorder Society.)

Over the last decade, the importance of cognitive impairment and dementia in Parkinson's disease (PDD) has been increasingly recognized. Investigators have proposed criteria for PD dementia, and mild cognitive impairment. Risk profiles associated with the development of dementia based on demographic, neurological, neuropsychological, imaging, and genetic investigations have been delineated. The FDA has approved a treatment for PDD, and efforts now are directed toward intervention at earlier stages of cognitive impairment.

Objective: To report a novel prion disease characterized by distinct histopathological and immunostaining features, and associated with an abnormal isoform of the prion protein (PrP) that, contrary to the common prion diseases, is predominantly sensitive to protease digestion., Methods: Eleven subjects were investigated at the National Prion Disease Pathology Surveillance Center for clinical, histopathological, immunohistochemical, genotypical, and PrP characteristics., Results: Patients presented with behavioral and psychiatric manifestations on average at 62 years, whereas mean disease duration was 20 months. The type of spongiform degeneration, the PrP immunostaining pattern, and the presence of microplaques distinguished these cases from those with known prion diseases. Typical protease-resistant PrP was undetectable in the cerebral neocortex with standard diagnostic procedures. After enrichment, abnormal PrP was detected at concentrations 16 times lower than common prion diseases; it included nearly 4 times less protease-resistant PrP, which formed a distinct electrophoretic profile. The subjects examined comprised about 3% of sporadic cases evaluated by the National Prion Disease Pathology Surveillance Center. Although several subjects had family histories of dementia, no mutations were found in the PrP gene open reading frame., Interpretation: The distinct histopathological, PrP immunohistochemical, and physicochemical features, together with the homogeneous genotype, indicate that this is a previously unidentified type of disease involving the PrP, which we designated "protease-sensitive prionopathy" (or PSPr). Protease-sensitive prionopathy is not rare among prion diseases, and it may be even more prevalent than our data indicate because protease-sensitive prionopathy cases are likely also to be classified within the group of non-Alzheimer's dementias.

Mild Parkinsonian signs (MPS, impaired gait, rigidity, bradykinesia, rest tremor) are commonly found during the clinical examination of older people and may be a precursor to Parkinson's disease (PD) or Alzheimer's disease (AD). Marked deficits in olfaction occur in PD and AD. The objective of this study was to determine whether University of Pennsylvania Smell Test (UPSIT) scores were lower in nondemented community-dwelling elderly with versus without MPS. Nondemented persons age >or=65 years without PD in Washington Heights-Inwood, NY were evaluated with an abbreviated motor Unified PD Rating Scale and a 40-item UPSIT. Lower UPSIT and higher transformed UPSIT score (square root [UPSIT - 41]) indicated greater olfactory dysfunction. One-hundred-seventy-seven (16.4%) of 1,078 participants had MPS. Mean UPSIT scores (MPS vs. without MPS) were 24.3 +/- 7.1 versus 26.4 +/- 6.8, P < 0.001. In a logistic regression analysis adjusting for age and education, transformed UPSIT score was associated with MPS (OR 1.25, 95% CI 1.04-1.52, P = 0.02). In an adjusted logistic regression analysis, participants with higher transformed UPSIT scores (based on a median split) were 1.55 times more likely to have MPS than were those with lower scores (P = 0.01). Within transformed UPSIT score quartiles, the odds of having MPS were 1.0 (reference), 1.35, 2.02, and 2.20 (P < 0.05). The association with transformed UPSIT scores was similar across MPS subtypes (axial dysfunction, rigidity, tremor).MPS were associated with a mild reduction in olfactory function. These observations further support the view of MPS as a marker of emerging degenerative brain pathologies., (c) 2007 Movement Disorder Society.)

There are no standardized diagnostic criteria for psychosis associated with Parkinson's disease (PDPsy). As part of an NIH sponsored workshop, we reviewed the existing literature on PDPsy to provide criteria that distinguish PDPsy from other causes of psychosis. Based on these data, we propose provisional criteria for PDPsy in the style of the Diagnostic and Statistical Manual of Mental Disorders IV-TR. PDPsy has a well-characterized temporal and clinical profile of hallucinations and delusions, which is different than the pattern seen in other psychotic disorders such as substance induced psychosis or schizophrenia. PDPsy is associated with a poor prognosis of chronic psychosis, nursing home placement, and death. Medications used to treat Parkinson's disease (PD) contribute to PDPsy but may not be sufficient or necessary contributors to PDPsy. PDPsy is associated with Lewy bodies pathology, imbalances of monoaminergic neurotransmitters, and visuospatial processing deficits. These findings suggest that PDPsy may result from progression of the disease process underlying PD, rather than a comorbid psychiatric disorder or drug intoxication. PDPsy is not adequately described by existing criteria for psychotic disorders. We established provisional diagnostic criteria that define a constellation of clinical features not shared by other psychotic syndromes. The criteria are inclusive and contain descriptions of the full range of characteristic symptoms, chronology of onset, duration of symptoms, exclusionary diagnoses, and associated features such as dementia. These criteria require validation and may be refined, but form a starting point for studies of the epidemiology and pathophysiology of PDPsy, and are a potential indication for therapy development.

Parkin mutations account for the majority of familial and sporadic early onset Parkinson's disease (EOPD) cases with a known genetic association. More than 100 mutations have been described in the Parkin gene that includes homozygous, compound heterozygous, and single heterozygous mutations. We have designed a Parkin mutation genotyping array (gene chip) that includes published Parkin sequence variants and allows their simultaneous detection. The chip was validated by screening 85 PD cases and 47 controls previously tested for Parkin mutations. Similar genotyping microarrays have been developed for other genetically heterogeneous diseases including age-related macular degeneration. Here, we show the utility of a genotyping array for Parkinson's disease by analysis of 60 subjects from the Genetic Epidemiology of Parkinson Disease (GEPD) study that includes 15 early-onset PD case probands and 45 relatives., ((c) 2007 Movement Disorder Society.)

Mild tremor, rigidity, and bradykinesia (mild parkinsonian signs, MPS) are commonly detected during the clinical examination of elderly people without known neurological disease. The functional correlates of these incidental findings are not well understood. Balance and ability to ambulate independently are important functions in the elderly. The objective of this study is to examine whether MPS were associated with impaired balance. Balance was assessed using a subjective measure (complaint of poor balance) and a functional measure (the need to use a walker, cane, or wheelchair). Our methods included the neurological evaluation of nondemented older people in Washington Heights-Inwood, NY. Of 2,251 participants, 527 (23.4%) complained of poor balance; 538 (23.9%) required a cane, walker, or wheelchair; and 363 (16.1%) had MPS. In adjusted logistic regression analyses, MPS were associated with a complaint of poor balance (OR=1.5, 95% CI=1.1-2.0) and the need to use a cane, walker, or wheelchair (OR=1.9, 95% CI=1.4-2.6). The need to use a cane, walker, or wheelchair was associated with changes in axial function (OR=5.5, 95% CI=2.6-11.6) as well as rigidity (OR=1.5, 95% CI=1.07-2.2). Although they are incidental and subtle, signs of bradykinesia, rigidity, and tremor are associated with impaired function. The elderly in whom these signs have been detected are 50% more likely to complain of poor balance and 90% more likely to require a cane, walker, or wheelchair than are their counterparts without these signs., ((c) 2005 Movement Disorder Society.)

University of Pennsylvania Smell Identification Test data from control subjects (n = 63), patients with mild cognitive impairment (n = 147), and patients with Alzheimer's disease (n = 100) were analyzed to derive an optimal subset of items related to risk for Alzheimer's disease (ie, healthy through mild cognitive impairment to early and moderate disease stages). The derived 10-item scale performed comparably with the University of Pennsylvania Smell Identification Test in classifying subjects, and it strongly predicted conversion to Alzheimer's disease on follow-up evaluation in patients with mild cognitive impairment. Independent replication is needed to validate these findings.

Complications from human immunodeficiency virus (HIV)/acquired immune deficiency syndrome are notorious for mimicking other neurological diseases. We describe a case of HIV encephalitis presenting with the classic clinical features of Huntington's Disease in a woman without known HIV risk factors or other clinical stigmata suggestive of immunosuppression. This case reminds us that HIV should be part of the differential diagnosis in unexplainable neurological diseases., (Copyright 2004 Movement Disorder Society.)

A 42-year-old, left-handed woman first noted impaired dexterity of the dominant hand, soon followed by dysarthria and cognitive decline. Over a 4-year period, she developed severe left-sided apraxia with eventual neglect of the left arm and progressive extrapyramidal signs. Cognitive testing showed progressive executive, visuospatial, fluency, and naming impairment with relative preservation of memory. Single-photon emission computed tomography demonstrated asymmetric right posterior frontal and superior parietal hypoperfusion. The clinical impression was corticobasal degeneration. At autopsy, severe atrophy was seen in the perirolandic and frontal regions. There was marked neuronal loss and gliosis in the posterior frontal and precentral regions and less severe pathology in prefrontal, temporal, and parietal areas. Mild to moderate gliosis and neuronal loss were also seen in the putamen, globus pallidus, subthalamic, and dentate nuclei. Gallyas silver stain revealed numerous inclusions adjacent to oligodendrocyte nuclei in white and gray matter of affected cortical and subcortical regions. The gracile inclusions were wavy, slender, and stained positively with antibodies to ubiquitin and alphaB-crystallin but not to microtubule-associated proteins (tau, MAP1B, MAP2), tubulin, neurofilaments, glial fibrillary acidic protein, or alpha-synuclein. The argyrophilic inclusions identified in this case are distinct from those previously described in neurodegenerative diseases., (Copyright 2005 Movement Disorder Society.)

Purpose: To evaluate single-voxel proton magnetic resonance spectroscopy (SV-MRS) and magnetic resonance spectroscopic imaging (MRSI) metabolite results in individuals with HIV dementia., Materials and Methods: Twenty HIV-positive (HIV+) individuals underwent SV-MRS (TE 35 msec) and MRSI (TE 280 msec). Results were stratified according to serostatus, dementia severity, psychomotor speed performance, and functional impairment., Results: HIV+ individuals with psychomotor slowing had an increased myoinositol/creatine (mI/Cr) ratio (0.63 vs. 0.45) in the frontal white matter using SV-MRS and an increased choline (Cho)/Cr ratio (1.88 vs. 1.41) in the mesial frontal gray matter using MRSI compared to HIV+ individuals without psychomotor slowing. Using MRSI, subjects with HIV dementia also had a decreased N-acetyl aspartate (NAA)/Cho ratio (1.55 vs. 2.53) compared to HIV+ individuals without cognitive impairment in the mesial frontal gray matter. Both techniques detected metabolite ratio abnormalities associated with abnormal functional performance., Conclusion: SV-MRS and MRSI offer complementary roles in evaluating individuals with HIV dementia. Short TE SV-MRS measures mI, which may be elevated in early HIV dementia, whereas MRSI provides wider spatial coverage to examine specific regional changes., (Copyright 2005 Wiley-Liss, Inc.)

With prospects improving for experimental therapeutics aimed at postponing the onset of illness in preclinical carriers of the Huntington's disease (HD) gene, we assessed agreement among experienced clinicians with respect to the motor manifestations of HD, a relevant outcome measure for preventive trials in this population. Seventy-five clinicians experienced in the evaluation of patients with early HD and six non-clinicians were shown a videotape compiled from the film archives of the United States-Venezuela Collaborative HD Research Project. Observers were asked to rate a 2-3-minute segment of the motor examination for each of 17 at-risk subjects. The rating scale ranged from 0 (normal) to 4 (unequivocal extrapyramidal movement disorder characteristic of HD). As measured by a weighted kappa statistic, there was substantial agreement among the 75 clinicians in the judgment of unequivocal motor abnormalities comparing scale ratings of 4 with ratings that were not 4 (weighted kappa = 0.67; standard error (SE) = 0.09). Agreement among the non-clinicians was only fair (weighted kappa = 0.28; SE = 0.10). Even under the artificial conditions of a videotape study, experienced clinicians show substantial agreement about the signs that constitute the motor manifestations of illness in subjects at risk for HD. We expect these findings to translate to a similar level of interobserver agreement in the clinical trial setting involving experienced investigators examining live patients., (2005 Movement Disorder Society.)

Although little is known regarding potential socioeconomic or racial bias in the recording of Parkinson's disease (PD) on death certificates, studies of incidence, prevalence, and the etiology of PD frequently rely on this type of data. A national population-based survey was linked to death certificate data to investigate the concordance of PD reported on death certificates for persons reporting PD during life. Logistic regression was used to identify independent factors associated with differential reporting of PD at death. Among decedents with PD reported during life, 54.8% had PD recorded on the death certificate. Nearly 70% of persons in higher income categories had PD recorded at death compared to 35.4% for those earning $10,000 or less. Age and gender adjusted odds of having PD recorded at death was 2.3 (1.1-3.9), for those with an annual income of $35,000 or more. Income differences remain significant in multivariable models after controlling for age, gender, race, census region, family size, rural residence, and number of chronic medical conditions. In conclusion, this study found socioeconomic bias in the reporting of PD at death. This bias is large enough to confound death certificate-based investigations of incidence, prevalence, and risk factors that differ across socioeconomic strata., (2004 Movement Disorder Society.)

Mutations in the beta-glucocerebrosidase gene cause Gaucher's disease, one of the most common lysosomal lipid storage diseases in the Ashkenazi Jewish population. The occurrence of parkinsonism in patients with Type 1 Gaucher's disease has been noted previously. In this pilot study, we evaluated a possible association between Parkinson's disease (PD) and the beta-glucocerebrosidase gene N370S allele (nt.1226 A>G) in 160 Parkinson's disease patients and 92 controls of Jewish ethnicity. We observed a higher frequency of the N370S genotype in PD cases (NS and SS, 10.7%) compared to controls (NS and SS 4.3%); however, the difference was not statistically significant (chi(2) = 3.4, P = 0.2). A total of 17 PD cases carry the N370S allele, including 2 homozygotes and 15 heterozygotes. The N370S allele (nt.1226 A>G) may be associated with PD in patients of Jewish ethnicity and should be examined in a larger study., ((c) 2004 Movement Disorder Society.)

Early-onset Parkinson's disease (PD) has been associated with different mutations in the Parkin gene (PARK2). To study distribution and type of Parkin mutations, we carried out a comprehensive literature review that demonstrated two prominent types of mutations among 379 unrelated mutation carriers: exon rearrangements involving exon 3, 4, or both, and alterations in exons 2 and 7, suggesting mutational hot spots or founders. To elucidate the origin of 14 recurrent Parkin mutations in our samples, we carried out a detailed haplotype analysis at the PARK2 locus. Thirty-eight mutation-positive individuals, available family members, and 62 mutation-negative individuals were genotyped. We determined allele frequencies and linkage disequilibrium (LD) to evaluate the significance of shared haplotypes. We observed no LD between markers at PARK2. Our data support a common founder for the most frequent Parkin point mutation (924C>T; exon 7) and indicate a mutational hot spot as cause of a common small deletion (255/256delA; exon 2). Furthermore, the most frequent Parkin exon deletion (Ex4del) arose independently in 2 of our subjects. However, it also occurred as the result of a founder mutation in 2 cases that shared identical deletion break points. This study provides evidence for both mutational hot spots and founder mutations as a source of recurrent mutations in Parkin, regardless of the mutation type., ((c) 2004 Movement Disorder Society.)

The frequency and relative contribution of DJ-1 mutations in early-onset Parkinson's disease (EOPD) is currently unknown. We analyzed a cohort of 89 EOPD patients (mean age at onset of PD +/- SD, 41.5 +/- 7.2 years), ascertained independent of family history, who participated in a study of the genetic epidemiology of PD. This study includes sequence analysis of the DJ-1 gene in addition to assaying the 14,082-bp deletion spanning exons 1 to 5, previously identified in a Dutch kindred, in 89 EOPD cases. A heterozygous missense mutation in exon 5 (A104T) was identified in an EOPD case of Asian ethnicity; this sequence variant was absent in 308 control chromosomes. We identified additional sequence variation in the DJ-1 gene, including a polymorphism in the coding region in exon 5 (R98Q), three polymorphisms in the 5' untranslated region (exon 1A/1B), and two polymorphisms in intronic regions (IVS1 and IVS5). Mutations in the DJ-1 gene are rare in EOPD in both sporadic and familial cases., (Copyright 2004 Movement Disorder Society)

We compared the clinical and neuropsychological pattern of dementia with Lewy bodies (DLB) to Alzheimer's disease (AD) and Parkinson's disease with dementia (PD-d). Sixteen patients clinically diagnosed with DLB were compared with two groups of patients with PD-d (n = 15) and AD (n = 16) matched for level of dementia. Isolated cognitive impairment was the most common form of presentation in AD (93.8%) and DLB (31.3%) groups, while parkinsonism was in 100% of PD-d subjects. Psychoses associated with cognitive impairment at the beginning of the disease were more frequent in DLB patients (31.3%) than in AD (6.3%) and PD-d (0%) groups. There were no significant differences in Unified Parkinson Disease Rating Scale motor-subscale scores between DLB and PD-d patients. DLB and PD-d patients performed significantly worse on attentional functions and better on memory tests than AD. DLB patients also showed lower scores than AD subjects on visual memory, visuoperceptive, and visuoconstructive tests. No significant differences were found between PD-d group and DLB subjects on any neuropsychological test. We were unable to find any differences in cognitive tasks between PD-d and DLB subjects. Clinical features and neuropsychological deficiencies of DLB (attentional, visuoperceptive, and visuoconstructive deficits) and PD (attentional deficits) compared to AD (amnesic syndrome) can contribute to accurate identification of these entities and to the understanding of the neuropathological and neurochemical substrate underlying these diseases., (Copyright 2003 Movement Disorder Society)

The role of heredity in early- versus late-onset Parkinson's disease (PD) is controversial. We estimated the degree of increased risk of PD in first-degree relatives of 221 PD probands with age of onset 50 years or younger and 266 PD probands with age of onset older than 50 years compared with the first-degree relatives of 409 control probands. Risk of PD was similar among first-degree relatives of early-onset PD probands (risk ratio [RR], 2.9; 95% confidence interval [CI], 1.6-5.0; p = 0.0002) and late-onset PD probands (RR, 2.7; 95% CI, 1.6-4.4; p = 0.0002) when each was compared with first-degree relatives of controls. However, siblings of early-onset PD probands were at markedly increased risk of PD compared with siblings of controls (RR, 7.9; 95% CI, 2.5-25.5; p = 0.0005), whereas parents of early-onset PD probands were not at significantly increased risk compared with parents of controls (RR, 1.7; 95% CI, 0.9-3.3; p = 0.2). In late-onset families, both siblings (RR, 3.6; 95% CI, 1.3-10.3; p = 0.02) and parents (RR, 2.5; 95% CI, 1.4-4.6; p = 0.003) were at increased risk compared with control relatives. This pattern is consistent with an autosomal recessive contribution to the inheritance of early but not late-onset PD. Genetic factors are important in both early- and late-onset PD, but specific genes and mode of inheritance may differ between the two groups.

We analyzed the association of neuropsychological test impairment at baseline with the development of dementia in idiopathic Parkinson's disease (PD) patients. A cohort of nondemented PD patients from northern Manhattan, NY was followed annually with neurological and neuropsychological evaluations. The neuropsychological battery included tests of verbal and nonverbal memory, orientation, visuospatial ability, language, and abstract reasoning. The association of baseline neuropsychological tests scores with incident dementia was analyzed using Cox proportional hazards models. The analysis controlled for age, gender, education, duration of PD, and the total Unified Parkinson's Disease Rating Scale motor score at baseline. Forty-five out of 164 patients (27%) became demented during a mean follow-up of 3.7 +/- 2.3 years. Four neuropsychological test scores were significantly associated with incident dementia in the Cox model: total immediate recall (RR: 0.92, 95% CI: 0.87-0.97, P = 0.001) and delayed recall (RR: 0.73, 95% CI: 0.59-0.91, P = 0.005) of the Selective Reminding Test (SRT), letter fluency (RR: 0.87, 95% CI: 0.77-0.99, P = 0.03), and Identities and Oddities of the Mattis Dementia Rating Scale (RR: 0.85, 95% CI: 0.73-0.98, P = 0.03). When the analysis was performed excluding patients with a clinical dementia rating of 0.5 (questionable dementia) at baseline evaluation, total immediate recall and delayed recall were still predictive of dementia in PD. Our results indicate that impairment in verbal memory and executive function are associated with the development of dementia in patients with PD., (Copyright 2002 Movement Disorder Society)

Age and severity of extrapyramidal signs have been consistently associated with incident dementia in Parkinson's disease. We evaluated the separate and combined effects of age and severity of extrapyramidal signs on the risk of incident dementia in Parkinson's disease in the setting of a population-based prospective cohort study. Age and the total Unified Parkinson's Disease Rating Scale motor score at baseline evaluation were dichotomized at the median. Four groups of Parkinson's disease patients were defined: younger age/low severity (reference), younger age/high severity, older age/low severity, and older age/high severity. Risk ratios for incident dementia were calculated with Cox proportional hazards models controlling for gender, education, ethnicity, and duration of Parkinson's disease. Of 180 patients, 52 (28.9%) became demented during a mean follow-up period of 3.6 +/- 2.2 years. The median age at baseline of the Parkinson's disease patients was 71.8 years (range, 38.5-95.9 years), and the median total Unified Parkinson's Disease Rating Scale motor score was 24 (range, 2-65). The group with older age/high severity had a significantly increased risk of incident dementia (relative risk, 9.7; 95% confidence interval, 3.9-24.4) compared with the group with younger age/low severity (reference), whereas the groups with older age/low severity (relative risk, 1.6; 95% confidence interval, 0.5-4.8) and younger age/high severity (relative risk, 1.2; 95% confidence interval, 0.5-3.2) did not. These findings suggest that the increased risk of incident dementia in Parkinson's disease associated with age and severity of extrapyramidal signs is related primarily to their combined effect rather than separate effects.

Field work is commonly required in movement disorders research. Sending neurologists into the field can be logistically challenging and costly. Alternatively, neurological examinations may be videotaped and reviewed later. There is little knowledge of the validity of the videotaped neurological examination in the diagnosis of Parkinson's disease (PD). We examined the validity of the videotaped Unified Parkinson's Disease Rating Scale (UPDRS) motor examination in the diagnosis of PD, and sought to determine which factors are associated with incorrect diagnoses. PD patients and controls were enrolled in a familial aggregation study between August of 1998 and June of 2000, and as part of that study each was examined by a physician who performed an in-person UPDRS motor examination. Each also underwent a second, videotaped UPDRS motor examination. Based on the review of this videotape, a neurologist, who was blinded to the previous clinical diagnosis, assigned a diagnosis of PD or normal. A total of 211 of 231 PD patients (sensitivity = 91.3%), and 170 of 172 controls (specificity = 98.8%) were correctly identified based on the videotape. True positives had a higher mean rest tremor score (1.7 vs. 0.3; P < 0.001), action tremor score (0.9 vs. 0.3; P < 0.001), bradykinesia score (11.2 vs. 7.4; P = 0.02), and disease of longer mean duration (8.9 vs. 5.8 years; P = 0.001) than false negatives. False negatives did not differ from true positives in terms of age, total dose of levodopa, Hoehn and Yahr score, or rigidity, gait and posture, or facial masking scores (each assessed during the in-person examination). The videotaped UPDRS motor examination is a useful means of diagnosing PD and provides an alternative approach for the diagnosis of PD in field studies. A limitation is that patients with milder PD of shorter duration may not be recognized as PD., (Copyright 2002 Movement Disorder Society)

The extent to which concomitant Alzheimer's disease (AD) is etiologically related to the development of dementia in Parkinson's disease (PD) remains controversial. We explored the association of four risk factors associated with AD, including head injury, smoking, hypertension, and diabetes mellitus, with incident dementia in PD. A cohort of 180 nondemented PD patients from the Washington Heights community in northern Manhattan, New York, completed a risk factor questionnaire at baseline and was followed annually with neurological and neuropsychological evaluations. The association of baseline variables with incident dementia was analyzed by using Cox proportional hazards models. All analyses controlled for age at baseline, gender, years of education, duration of PD, and total Unified Parkinson's Disease Rating Scale (UPDRS) motor score at baseline. Of 180 patients (mean age, 71.0 +/- 10.3 years), 52 (29%) became demented during a mean follow-up period of 3.6 +/- 2.2 years. Head injury risk ratio ([RR] 0.9; 95% confidence interval [CI], 0.4-2.2; P = 0.9), hypertension (RR, 0.7; 95% CI, 0.4-1.4, P = 0.3), and diabetes mellitus (RR, 0.8; 95% CI, 0.3-2.3; P = 0.7) were not significantly associated with incident dementia in the Cox models. Patients who reported having ever smoked were at increased risk for the development of dementia compared with nonsmokers (RR, 2.0; 95% CI, 1.0-3.9; P = 0.05). Current smoking was significantly associated with incident dementia (RR, 4.5; 95% CI, 1.2-16.4; P = 0.02), whereas past smoking approached significance (RR, 1.9; 95% CI, 0.9-3.7; P = 0.07). Although an inverse association between smoking and PD has been reported in several studies, our study showed a positive association between smoking and dementia in the setting of PD. The association of smoking with incident dementia in PD deserves further study., (Copyright 2002 Movement Disorder Society.)

Individuals with Huntington's Disease (HD) have difficulty grasping and transporting objects, however, the extent to which specific impairments affect their performance is unknown. The present study examined the kinematics and force coordination during transport of an object in 12 subjects with HD and 12 age-matched controls. Subjects grasped an object between their thumb and index finger, transported it 25 cm forward, replaced and released it while their fingertip forces and the object's position were recorded. Five trials were performed with each of three weights (200 g, 400 g, and 800 g). While bradykinesia was evident in subjects with HD, this slowness was not consistently observed in all phases of the movement. The slowness of movement seen during the task appears to be due to impairments in sequencing and the movement strategies selected by the subjects. Compared to control subjects, subjects with HD produced highly curvilinear hand paths and more variable grip forces that were dependent on the weight of the object. Isometric force development and movement speed during transport were unaffected by the disease. The results suggest that prolonged task durations in subjects with HD are not necessarily due to slowness of movement, per se. These findings have clinical implications for understanding the task-specific nature of movement impairments in HD and developing effective intervention strategies., (Copyright 2001 Movement Disorder Society.)

Background: The prevalence and clinical characteristics of dystonia in Huntington's disease (HD) have not been formally assessed., Objectives: To study (1) the prevalence of dystonia in HD in a clinic population, (2) the clinical features of dystonia, and (3) clinical correlates of dystonia (for example, age, disease duration)., Methods: Patients with HD attending the HD Center at the New York State Psychiatric Center were administered the Unified HD Rating Scale and underwent a standardized 5.5-minute videotaped examination. Two neurologists reviewed the videotaped examination and rated the severity and constancy of dystonia, calculating a total dystonia score for each patient., Results: Prevalence of dystonia of any severity was 95.2%. Twenty-four of 42 (57.1%) had dystonia in at least one body region that was moderate and present more than half of the time, and seven of 42 (16.7%) had dystonia that was severe and constant. The most prevalent types of dystonia were internal shoulder rotation (64.3%), sustained fist clenching (47.1%), excessive knee flexion (42.9%), and foot inversion (42.9%). In 37 of 42 (88.1%) patients, there were more than two types of dystonia, and in the average patient, three to four types of dystonia. The mean severity was between 1 (mild) and 2 (moderate), and the mean constancy was between 2 (present less than half of the time) and 3 (present more than half of the time). Multivariate linear regression revealed that disease duration (p = 0.0005) and taking an antidopaminergic agent (p = 0.03) were positively associated with the total dystonia score., Conclusions: The majority of patients in this HD clinic exhibited some dystonia. The dystonia was present in several body regions and manifested by a variety of movements and postures not typical of idiopathic torsion dystonia. The dystonia was not bothersome to most patients, and its severity was a function of disease duration and use of an antidopaminergic agent.

Background: Recent studies have proposed a role for diet in Parkinson's disease (PD). PD is characterized by a high deposition of iron and a low concentration of ferritin in the substantia nigra. Few data in the literature are available on the possible role of dietary iron in the development of PD., Methods: In a population-based, case-control study, we addressed the hypothesis that high dietary iron intake was associated with PD. We assessed dietary iron intake with a semiquantitative food-frequency questionnaire in 104 PD patients and 352 control subjects, frequency matched for age and gender. We also studied the association of PD and dietary iron and animal fat intake in the presence of different iron stores measured by transferrin saturation., Results: No significant differences were observed between patients' and control subjects' dietary intake of iron from food or supplements (odds ratio [OR] for the highest quartile of intake, 0.9; 95% confidence interval [95% CI], 0.6, 1.3; p for trend = 0.60). Among those with low transferrin saturation levels (lower 50%), the odds ratio for PD associated with animal fat intake was ninefold higher than the risk of those with low intake (OR, 9.0; 95% CI, 2.7-29.9). Among those with high transferrin saturation, risk of PD was two times higher (relative risk, 1.9; 95% CI, 0.5-7.2) for those who reported high intake of animal fat compared with those who reported low intake., Conclusion: Dietary iron intake after caloric adjustment was not associated with an increased risk of PD. However, the previously described association between animal fat intake and PD was modified by iron level stores as measured by transferrin saturation. These observations suggest that dietary fat and a systemic defect in iron metabolism may act synergistically in the process of lipid peroxidation in PD.

We examined 180 siblings of 127 probands with probable or possible Alzheimer's dementia (AD) in a family study of AD. The overall sensitivity of a simple family history questionnaire was 64% and the specificity was 84%. Sensitivity improved 90-100% with minimal decline in specificity when we considered clinic-based vs. population survey patients. Higher education among informants and the availability of a spouse or a sibling as informant significantly increased sensitivity. Awareness of such factors may improve the yield of the family history in AD using a simple questionnaire.