Developmental malformations in Huntington disease: neuropathologic evidence of focal neuronal migration defects in a subset of adult brains.

Neuropathologic hallmarks of Huntington Disease (HD) include the progressive neurodegeneration of the striatum and the presence of Huntingtin (HTT) aggregates that result from abnormal polyQ expansion of the HTT gene. Whether the pathogenic trinucleotide repeat expansion of the HTT gene causes neurodevelopmental abnormalities has garnered attention in both murine and human studies; however, documentation of discrete malformations in autopsy brains of HD individuals has yet to be described. We retrospectively searched the New York Brain Bank (discovery cohort) and an independent cohort (validation cohort) to determine whether developmental malformations are more frequently detected in HD versus non-HD brains and to document their neuropathologic features. One-hundred and thirty HD and 1600 non-HD whole brains were included in the discovery cohort and 720 HD and 1989 non-HD half brains were assessed in the validation cohort. Cases with developmental malformations were found at 6.4-8.2 times greater frequency in HD than in non-HD brains (discovery cohort: OR 8.68, 95% CI 3.48-21.63, P=4.8 × 10-5; validation cohort: OR 6.50, 95% CI 1.83-23.17, P=0.0050). Periventricular nodular heterotopias (PNH) were the most frequent malformations and contained HTT and p62 aggregates analogous to the cortex, whereas cortical malformations with immature neuronal populations did not harbor such inclusions. HD individuals with malformations had heterozygous HTT CAG expansions between 40 and 52 repeats, were more frequently women, and all were asymmetric and focal, aside from one midline hypothalamic hamartoma. Using two independent brain bank cohorts, this large neuropathologic series demonstrates an increased occurrence of developmental malformations in HD brains. Since pathogenic HTT gene expansion is associated with genomic instability, one possible explanation is that neuronal precursors are more susceptible to somatic mutation of genes involved in cortical migration. Our findings further support emerging evidence that pathogenic trinucleotide repeat expansions of the HTT gene may impact neurodevelopment.

Alpha galactosidase A activity in Parkinson's disease.

Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) [2.85 µmol/l/h versus 3.12 µmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls)], and when including the entire cohort (2.89 µmol/l/h versus 3.10 µmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 µmol/l/h versus 3.10 µmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31-0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.

Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease.

BACKGROUND AND PURPOSE: In 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine animal models of Parkinson's disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association. METHODS: Parkinson's Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Two ADORA2A polymorphisms were inversely associated with PD risk - rs71651683, a 5' variant (adjusted allelic OR = 0.51, 95% CI 0.33-0.80, permutation-adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild-type genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively (permutation-adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (P(interaction) = 0.05) or rs2470890 (P(interaction) = 0.04). CONCLUSION: In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms.

The effect of age of onset of PD on risk of dementia.

BACKGROUND: Dementia occurs in the majority of patients with Parkinson's disease (PD). Late onset of PD has been reported to be associated with a higher risk for dementia. However, age at onset (AAO) and age at baseline assessment are often correlated. The aim of this study was to explore whether AAO of PD symptoms is a risk factor for dementia independent of the general effect of age. METHODS: Two community-based studies of PD in New York (n=281) and Rogaland county, Norway (n=227) and two population-based groups of healthy elderly from New York (n=180) and Odense, Denmark (n=2414) were followed prospectively for 3-4 years and assessed for dementia according to DSM-IIIR. All PD and control cases underwent neurological examination and were followed with neurological and neuropsychological assessments. We used Cox proportional hazards regression based on three different time scales to explore the effect of AAO of PD on risk of dementia, adjusting for age at baseline and other demographic and clinical variables. FINDINGS: In both PD groups and in the pooled analyses, there was a significant effect of age at baseline assessment on the time to develop dementia, but there was no effect of AAO independent of age itself. Consistent with these results, there was no increased relative effect of age on the time to develop dementia in PD cases compared with controls. INTERPRETATION: This study shows that it is the general effect of age, rather than AAO that is associated with incident dementia in subjects with PD.

Multidisciplinary baseline assessment of homosexual men with and without human immunodeficiency virus infection. III. Neurologic and neuropsychological findings.

We explored the possibility that neurologic and neuropsychological changes constitute the earliest detectable manifestations of human immunodeficiency virus (HIV) infection. Without knowledge of HIV status, we assessed neurologic signs and symptoms and administered a battery of neuropsychological tests to 208 homosexual men, of whom 84 were HIV negative, 49 were HIV positive and asymptomatic, 29 were mildly symptomatic, and 46 had significant medical symptoms but not the acquired immunodeficiency syndrome. There was no difference between the HIV-negative and HIV-positive men in the frequency of neurologic signs or of defective or borderline performance on any neuropsychological test. However, HIV-positive men performed slightly but significantly worse than HIV-negative men on tests of verbal memory, executive function, and language. Similar results were obtained when comparisons were limited to HIV-positive medically asymptomatic and HIV-negative men. There was no degradation of neurologic status or neuropsychological performance across stages of HIV severity, but neurologic and neuropsychological summary scores correlated with CD4/CD8 ratios in the HIV-positive group. Ratings of neurologic signs and symptoms correlated with neuropsychological summary scores in the HIV-positive group only. Cognitive complaints were more frequent in the HIV-positive men; they correlated with actual test performance in the HIV-positive but not HIV-negative men. The constellation of subjective and objective neuropsychological and neurologic findings suggests the possibility of a definable syndrome associated with HIV infection in asymptomatic individuals.

The course of psychopathologic features in mild to moderate Alzheimer disease.

BACKGROUND: The onset and course of the psychopathologic features of Alzheimer disease have not been established in prospective, longitudinal studies. METHODS: Two hundred thirty-five patients with early, probable Alzheimer disease were recruited at 3 sites and observed naturalistically for up to 5 years. At 6-month intervals, the Columbia University Scale for Psychopathology in Alzheimer's Disease was administered. Markov analyses were used to predict the probability of a specific symptom developing or being maintained at the next visit. For each symptom category, the maximum frequency of occurrence at 4 consecutive points (duration, 2 years) was calculated. RESULTS: Misidentification, wandering or agitation, and physical aggression increased during follow-up. At any visit, the likelihood of a new symptom developing was greatest for behavioral disturbance, intermediate for paranoid delusions and hallucinations, and least for depressed mood with vegetative features. Wandering or agitation occurred at 3 or more of 4 consecutive visits (duration, 2 years) in the majority of patients, paranoid delusions and hallucinations were intermediate in their degree of persistence, and depressed mood with vegetative signs rarely persisted. CONCLUSIONS: Behavioral disturbance, particularly agitation, is common and persistent in patients with Alzheimer disease. Psychotic symptoms are less common and show moderate persistence over time. Depressed mood with vegetative signs is uncommon and rarely persists. These findings suggest leads about the optimal treatment duration for specific subtypes of psychopathologic features.

The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease.

GBA mutations are among the most common genetic risk factors for Parkinson disease (PD) worldwide. We aimed to identify genetic modifiers of the age at onset (AAO) in GBA-associated PD. The study included a genome-wide discovery phase, including a cohort of 79 patients with the GBA p.N370S mutation, and candidate validation and replication analyses of 8 SNPs in patients with mild (n = 113) and severe (n = 41) GBA mutations. Genotyping was performed using the Affymetrix human SNP 6.0 array and TaqMan assays. In the genome-wide phase, none of the SNPs passed the genome-wide significance threshold. Eight SNPs were selected for further analysis from the top hits. In all GBA-associated PD patients (n = 153), the BIN1 rs13403026 minor allele was associated with an older AAO (12.4 ± 5.9 years later, p = 0.0001), compared to patients homozygous for the major allele. Furthermore, the AAO was 10.7 ± 6.8 years later in patients with mild GBA mutations, (p = 0.005, validation group), and 17.1 ± 2.5 years later in patients with severe GBA mutations (p = 0.01, replication). Our results suggest that alterations in the BIN1 locus, previously associated with Alzheimer disease, may modify the AAO of GBA-associated PD. More studies in other populations are required to examine the role of BIN1-related variants in GBA-associated PD.

HIV-1 reverse transcriptase sequence in plasma and cerebrospinal fluid of patients with AIDS dementia complex treated with Abacavir.

OBJECTIVE: To assess HIV-1 RNA levels and the relationship between HIV-1 reverse transcriptase (RT) genotype from plasma and cerebrospinal fluid (CSF) during treatment with abacavir (Ziagen, ABC) or placebo in combination with stable background therapy (SBG) in subjects with AIDS dementia complex (ADC) (study CNA3001). DESIGN: One-hundred and five HIV-1 infected adults with ADC were randomized to receive either ABC (600 mg twice daily) or ABC-matched placebo (twice daily) in addition to SBG for 12 weeks. METHODS: Plasma and CSF were collected for population sequencing at baseline and week 12 (CSF optional). Sequences were analyzed for mutations associated with resistance to nucleoside reverse transcriptase inhibitors (NRTI). RESULTS: Sixty out of sixty-seven subjects with baseline plasma HIV-RT sequence data harbored virus with > or = 1 NRTI-associated mutations; 50 out of 67 had the M184V mutation. At week 12, more subjects in the ABC group had plasma HIV-1 RNA < or = 400 copies/ml than the SBG group (46% versus 13%, P = 0.002). Non-response to ABC was associated with multiple baseline zidovudine (ZDV)/stavudine (d4T)-associated mutations. Baseline RT mutation patterns differed in 14 out of 21 (67%) paired samples from plasma and CSF. Four subjects experienced > 1 log10 copies/ml reductions in CSF HIV-1 RNA, two in the absence of reductions in plasma HIV-1 RNA and two with undetectable plasma HIV-1 RNA at baseline. CONCLUSIONS: Substantial decreases in plasma and CSF HIV-1 RNA following addition of ABC were not precluded by baseline HIV-1 NRTI-associated mutations, including the M184V mutation, but non-responders commonly harbored multiple ZDV/d4T-associated mutations. HIV-1 RNA responses and RT genotype appear to be discordant between CSF and plasma in some subjects.

Characterization of the human mitochondrial aconitase gene (ACO2).

We have cloned and characterized the ACO2 gene on human chromosome 22q13, which encodes the essential iron-dependent metabolic enzyme mitochondrial aconitase. We determined that the ACO2 gene comprises 18 translated exons distributed over approximately 35 kilobasepairs (kbp) of DNA. We have shown that the ACO2 mRNA is 2.7kb in length and is expressed ubiquitously, and we can detect multiple isoforms of the ACO2 protein. As others had reported the existence of biochemically active electrophoretic variants of mitochondrial aconitase, we wished to find common ACO2 gene allozymes, functional polymorphisms that might be associated with susceptibility to human genetic diseases. We looked for ACO2 allozymes by DNA sequencing and genotyping in a population of 217 subjects, many of which had idiopathic Parkinson's disease (IPD). We studied patients with IPD because this movement disorder is thought to arise from defects in neuronal iron and energy metabolism, two properties with which aconitase is involved. Furthermore, reports of associations between alleles of the CYP2D6 locus (nearby on 22q13) and IPD, although inconsistent, indicated that an IPD susceptibility locus might be in strong linkage disequilibrium with CYP2D6. We found three functionally silent single nucleotide polymorphisms (SNPs) present in transcribed sequences that exist in similar frequencies in IPD patients and healthy controls. These ACO2 SNPs are in linkage disequilibrium with each other, providing evidence for distinct ACO2 haplotypes. We have, as yet, not detected polymorphisms that would lead to ACO2 allozymes, nor have we observed differences in ACO2 isoform prevalence or distribution in our population of IPD patients and controls. We conclude it is unlikely that polymorphism in the ACO2 gene or post-translational modification of the enzyme predispose to IPD.

Cognitive correlates of obsessive and compulsive symptoms in Huntington's disease.

OBJECTIVE: The authors' goal was to examine the frequency and type of obsessive and compulsive symptoms in Huntington's disease. METHOD: The Yale-Brown Obsessive Compulsive Scale was used to assess obsessive and compulsive symptoms in 27 patients with Huntington's disease. The neuropsychological test performance of the 14 patients with at least one obsessive symptom and the seven patients with at least one compulsive symptom was compared with the performance of the patients without such symptoms. RESULTS: More than half of the patients with Huntington's disease endorsed obsessive or compulsive symptoms on the Yale-Brown scale. Patients with obsessive or compulsive symptoms showed significantly greater impairment on neuropsychological tests measuring executive function than those without such symptoms. CONCLUSIONS: Basal ganglia pathology in Huntington's disease may contribute to production of obsessive and compulsive symptoms and to executive performance deficits in these patients.

Association of subjective memory complaints with subsequent cognitive decline in community-dwelling elderly individuals with baseline cognitive impairment.

OBJECTIVE: The validity of subjective memory complaints has been questioned by clinical studies that have shown little relationship between memory complaints and objective memory performance. These studies often have been cross-sectional in design, have excluded individuals with cognitive impairment, or have lacked a comparison group. The authors conducted a study that attempted to avoid these limitations. METHOD: Memory complaints of 364 nondemented, community-dwelling elderly individuals were recorded as present or absent at the baseline evaluation. After 1 year, 169 subjects were reevaluated. Standardized neurologic and neuropsychological evaluations were used at each assessment to classify subjects as normal or cognitively impaired. RESULTS: At baseline, 31% of the normal subjects and 47% of those with cognitive impairment had memory complaints. Subjects with memory complaints had higher Hamilton depression scale scores than subjects without memory complaints but equivalent scores on a measure of total recall. At follow-up, multivariate analyses showed that subjects with baseline memory complaints had significantly greater decline in memory and cognition than subjects without memory complaints. Secondary analyses showed this effect to be confined to subjects with baseline cognitive impairment. CONCLUSIONS: Memory complaints may lack validity in subjects with normal cognition, but in nondemented individuals with cognitive impairment, memory complaints may predict subsequent cognitive decline.

Olfactory deficits in patients with mild cognitive impairment predict Alzheimer's disease at follow-up.

OBJECTIVE: This study evaluated the predictive utility of olfactory identification deficits in patients with mild cognitive impairment for follow-up diagnosis of probable Alzheimer's disease. METHOD: Ninety outpatients with mild cognitive impairment were examined at 6-month intervals. Matched healthy comparison subjects (N=45) were examined annually. The University of Pennsylvania Smell Identification Test was given at baseline. RESULTS: Olfaction scores were lower in patients with mild cognitive impairment than in healthy comparison subjects. Seventy-seven patients were followed up; 19 were diagnosed with Alzheimer's disease by 2 years. Patients with low olfaction scores (< or =34 of 40), and patients with low olfaction scores who reported no subjective problems smelling, were more likely to develop Alzheimer's disease than other patients. In a Cox proportional hazards model adjusted for age, sex, modified Mini-Mental State score, and education, low olfaction scores did not predict time until development of Alzheimer's disease, but low olfaction scores accompanied by lack of awareness of olfactory deficits predicted time to development of Alzheimer's disease. This effect remained when attention or memory measures replaced modified Mini-Mental State score in the model. In patients with high Mini-Mental State scores (> or =27 of 30), low olfaction with lack of awareness remained a significant predictor of Alzheimer's disease. Olfaction scores of 30-35 showed moderate to strong sensitivity and specificity for diagnosis of Alzheimer's disease at follow-up. CONCLUSIONS: In patients with mild cognitive impairment, olfactory identification deficits, particularly with lack of awareness of olfactory deficits, may have clinical utility as an early diagnostic marker for Alzheimer's disease.

A randomized, placebo-controlled dose-comparison trial of haloperidol for psychosis and disruptive behaviors in Alzheimer's disease.

OBJECTIVE: The goal of this study was to compare the efficacy and side effects of two doses of haloperidol and placebo in the treatment of psychosis and disruptive behaviors in patients with Alzheimer's disease. METHOD: In a 6-week random-assignment, double-blind, placebo-controlled trial (phase A), haloperidol, 2-3 mg/day (standard dose), and haloperidol, 0.50-0.75 mg/day (low dose), were compared in 71 outpatients with Alzheimer's disease. For the subsequent 6-week double-blind crossover phase (phase B), patients taking standard- or low-dose haloperidol were switched to placebo, and patients taking placebo were randomly assigned to standard- or low-dose haloperidol. RESULTS: For the 60 patients who completed phase A, standard-dose haloperidol was efficacious and superior to both low-dose haloperidol and placebo for scores on the Brief Psychiatric Rating Scale psychosis factor and on psychomotor agitation. Response rates according to three sets of criteria were greater with the standard dose (55%-60%) than the low dose (25%-35%) and placebo (25%-30%). The advantage of standard dose over low dose was replicated in phase B. In phase A, extrapyramidal signs tended to be greater with the standard dose than in the other two conditions, primarily because of a subgroup (20%) who developed moderate to severe signs. Low-dose haloperidol did not differ from placebo on any measure of efficacy or side effects. CONCLUSIONS: The results indicated a favorable therapeutic profile for haloperidol in doses of 2-3 mg/day, although a subgroup developed moderate to severe extrapyramidal signs. A starting dose of 1 mg/day with gradual, upward dose titration is recommended. The narrow therapeutic window observed with haloperidol may also apply to other neuroleptics used in Alzheimer's disease patients with psychosis and disruptive behaviors.

The frequency and associated risk factors for dementia in patients with Parkinson's disease.

OBJECTIVES: To estimate the frequency and determine the risk factors for incident dementia in community-dwelling patients with Parkinson's disease (PD) and in control subjects. DESIGN: Prospective cohort study. During a 3.5-year period, 140 patients with idiopathic PD without evidence of dementia and 572 nondemented control subjects were identified in the community of Washington Heights-Inwood in New York, NY. All subjects underwent neurological and neuropsychological evaluations and follow-up examinations. RESULTS: Twenty-seven patients with PD (19.2%) became demented throughout 2 years, as compared with 87 (15.2%) of the control subjects. The relative risk (RR) for the development of dementia with PD was 1.7 (95% confidence interval [CI], 1.1 to 2.7) after adjusting for age, education, and gender. Predictive features of incident dementia were an extrapyramidal score greater than 25 (RR, 3.56; 95% CI, 1.4 to 8.9) and a Hamilton Depression Rating Scale score greater than 10 (RR, 3.55; 95% CI, 1.6 to 7.9). CONCLUSION: Patients with PD, especially those with severe extrapyramidal signs, have almost twice the risk for the development of dementia than do community-dwelling control subjects.

The validity of new memory complaints in the elderly.

OBJECTIVE: To determine the validity of new subjective memory complaints (MCs) from individuals who previously, when without dementia, denied having MCs. DESIGN: Prospective cohort. SETTING: Longitudinal, community-based study of aging and dementia. PATIENTS: One hundred thirty-three community-dwelling elderly individuals who were part of a registry for the study of conditions related to aging in North Manhattan, NY. Patients were selected if they were initially without dementia and had completed at least 2 successive annual clinical and neuropsychological evaluations and provided their own medical history. MAIN OUTCOME MEASURES: Performance on memory tests--the Buschke Selective Reminding Test and a visual memory task--and global performance on a neuropsychological test battery and clinical evaluation, by which questionable dementia or dementia was diagnosed according to a well-defined paradigm. RESULTS: Fifty-three subjects with MCs at the initial evaluation performed no worse on the memory test than the 80 subjects who denied MCs initially. There was a weak association between MCs and the diagnosis of questionable dementia at baseline (P = .04), but this was nonsignificant after adjusting for age and education. At 1-year follow-up, 21 of the 80 without baseline MCs now reported MCs. At the follow-up evaluation, these 21 subjects performed significantly worse on the memory tests, were 5 times more likely to have significant cognitive impairment, and had shown significantly greater decline over the preceding year on several of the cognitive measures than the 59 who continued to deny MCs. CONCLUSION: New MCs from individuals, who when without dementia recently denied MCs, may suggest the presence of significant impairment of memory or cognition.

Mortality from Parkinson disease.

BACKGROUND: Levodopa therapy for Parkinson disease (PD) has improved quality of life, but mortality rates remain high. Although the presence of dementia and severity of extrapyramidal signs (EPSs) influence morbidity in PD, it is not known whether these manifestations contribute to mortality. METHODS: Patients with PD were compared with nondemented and demented elderly subjects. Each underwent annual neurological and neuropsychological examinations. Dementia was diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria, and EPSs were rated with the Unified Parkinson's Disease Rating Scale. Survival rates were compared using Kaplan-Meier analysis and Cox proportional hazards models. RESULTS: The risk of mortality, when compared with nondemented elderly subjects, was highest among those with both PD and dementia (rate ratio, 4.9; 95% confidence interval, 3.4-7.1), but also was elevated in patients with PD only (rate ratio, 2.7; 95% confidence interval, 1.7-4.4). Dementia in the absence of PD also was associated with an increased risk of mortality (rate ratio, 1.6; 95% confidence interval, 1.1-2.3). A high baseline total EPS score was associated with significantly earlier mortality. CONCLUSIONS: Compared with nondemented elderly people in the same community, patients with PD have a 2- to 5-fold increased risk of mortality. The risk is strongly related to the presence of severe EPSs, especially bradykinesia. Despite the introduction of levodopa and other advances in the treatment of PD, these factors greatly increase mortality.

Dystonia-predominant adult-onset Huntington disease: association between motor phenotype and age of onset in adults.

BACKGROUND: In juvenile Huntington disease (HD), dystonia as well as parkinsonism and eye movement abnormalities may be the predominant motor signs rather than chorea. Several patients have come to our attention with adult-onset HD in whom there is prominent dystonia and minimal chorea (ie, an adult-onset form of HD that resembles juvenile HD). OBJECTIVES: To estimate the prevalence of these cases of dystonia-predominant HD in a clinic and to study the relationship between the motor phenotype and age of onset in HD. METHODS: The Unified Huntington's Disease Rating Scale (UHDRS) was administered to 127 subjects during their initial visit to the Huntington's Disease Center at the New York State Psychiatric Institute, where dystonia, chorea, bradykinesia, rigidity, and eye movements were rated. The dystonia score was the mean UHDRS rating of dystonia in 5 body regions; the chorea score, the mean rating of chorea in 7 regions; the bradykinesia score, the mean rating of axial and limb bradykinesia; the rigidity score, the mean rating of rigidity in both arms; and the eye movement score, the mean rating of ocular pursuit, saccade initiation, and velocity. Dystonia-predominant HD was defined by the severity of dystonia relative to the severity of chorea. RESULTS: Fifteen (11.8%) of 127 subjects had dystonia-predominant HD. Age of onset correlated negatively (r= -0. 22, P=.02) with the dystonia score divided by the chorea score and negatively (r= -0.28, P=.002) with the severity of dystonia, bradykinesia, and eye movement abnormalities relative to chorea (ie, [(dystonia score + bradykinesia score + eye movement score)/3] - chorea score), suggesting that subjects with younger ages of onset had more severe dystonia, bradykinesia, and eye movement abnormalities relative to chorea. CONCLUSIONS: Cases of adult-onset HD with prominent dystonia and a paucity of chorea may represent 1 in 8 cases in specialty clinics. Age of onset was clearly associated with the motor phenotype. A younger age of onset was associated with more severe dystonia, bradykinesia, and eye movement abnormalities relative to chorea, supporting the notion that in adult-onset HD, the motor phenotype forms a continuum with respect to age of onset.

Interrater reliability of extrapyramidal signs in a group assessed for dementia.

Extrapyramidal signs were rated by three neurologists in 20 patients who had either been diagnosed as having probable Alzheimer's disease or who were being evaluated for dementia. In general, good interrater reliability was found for the presence or absence of extrapyramidal signs, although agreement over the presence of some signs was reduced when distinctions between normality and slight departures from normality were required.

Tritiated imipramine binding. A peripheral marker for serotonin in Parkinson's disease.

Tritiated imipramine binding in platelets has been used to evaluate serotonin activity in depression in previous studies. This article examined this marker as a possible measure of central nervous system serotonergic activity for depression in patients with Parkinson's disease (PD). The number of binding sites was significantly lower in depressed patients with PD than in a healthy control group. Patients with PD who were not depressed had lower values than the comparison group, but this difference was not significant. We also found a significant correlation between the receptor site values in platelets and cerebrospinal fluid levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (r = .59), but this was independent of a diagnosis of depression. Receptor site values were examined to identify appropriate cutoff scores to predict depression in the group of patients with PD. A maximum sensitivity of 50% was achieved with a specificity of 64%. Our results strongly support a generalized alteration in serotonin metabolism in depressed patients with PD, but tritiated imipramine binding in platelets is not a useful diagnostic tool for depression.