Estrogen to treat Alzheimer's disease: too little, too late? So what's a woman to do?
Explore the source record for details and available documents.
Alzheimer Disease↗
Biomedical subjects
K Marder
Publications and source records attributed to K Marder.
Mitochondrial DNA mutations in complex I and tRNA genes in Parkinson's disease.
OBJECTIVE: To identify mitochondrial DNA (mtDNA) mutations that predispose to PD. BACKGROUND: Mitochondrial complex I activity is deficient in PD. mtDNA mutations may account for the defect, but the specific mutations have not been identified. METHODS: Complete sequencing was performed of all mtDNA-encoded complex I and transfer RNA (tRNA) genes in 28 PD patients and 8 control subjects, as well as screening of up to 243 additional PD patients and up to 209 control subjects by restriction digests for selected mutations. RESULTS: In the PD patients, 15 complex I missense mutations and 9 tRNA mutations were identified. After screening additional subjects, rare PD patients were found to carry complex I mutations that altered highly conserved amino acids. However, no significant differences were found in the frequencies of any mutations in PD versus control groups. The authors were unable to confirm previously reported associations of mutations at nucleotide positions (np) 4336, 5460, and 15927/8 with PD. Complex I mutations previously linked to Leber's hereditary optic neuropathy, one of which has been linked to atypical parkinsonism, were not associated with PD. CONCLUSIONS: mtDNA mutations with a high mutational burden (present in a high percentage of mtDNA molecules in an individual) in complex I or tRNA genes do not play a major role in the risk of PD in most PD patients. Further investigations are necessary to determine if any of the rare mtDNA mutations identified in PD patients play a role in the pathogenesis of PD in those few cases.
DNA, Mitochondrial↗
Rate of functional decline in Huntington's disease. Huntington Study Group.
OBJECTIVE: To determine the rate of functional decline in a large cohort of patients with Huntington's disease (HD) followed at 43 sites by the Huntington Study Group (HSG). METHODS: The annual rate of functional decline was measured using the Total Functional Capacity Scale (TFC) and the Independence Scale (IS) in 960 patients with definite HD followed prospectively for a mean of 18.3 months. All patients were rated with the Unified Huntington's Disease Rating Scale (UHDRS). Sample size calculations for hypothetical clinical trials were calculated. RESULTS: A factor analysis of the UHDRS at baseline yielded 15 factors accounting for 77% of the variance. The TFC score declined at a rate of 0.72 units/year (standard error [SE] 0.04) and the IS score declined at a rate of 4.52 units/year (SE 0.23). Lower TFC score at baseline, indicating more severe impairment, was associated with less rapid annual decline in TFC score, perhaps reflecting the floor effect of the scale. The annual rate of decline for 575 patients with baseline TFC scores of 7 to 13 was 0.97 (SE 0.06), was 0.38 (SE 0.08) for 270 patients with baseline TFC scores of 3 to 6, and was 0.06 (SE 0.1) for 101 patients with TFC scores of 0 to 2. In multivariate analysis (n = 960), longer disease duration and better cognitive status at baseline were associated with a less rapid rate of decline in TFC score, whereas depressive symptomatology was the only factor associated with more rapid decline on the IS score. Age at onset of HD, sex, weight, and education did not affect decline on either score. CONCLUSIONS: The comparable rates of decline on the TFC and the IS scores with other published studies suggest that these estimates of functional decline are representative of HD patients who are evaluated at HSG research sites. In longitudinal analysis, longer disease duration and better neuropsychological performance at baseline were associated with a less rapid rate of decline in TFC score, whereas depressive symptomatology at baseline was associated with a more rapid decline in the IS score. These rates of functional decline and the covariates that modify them should be considered in estimating statistical power and designing future therapeutic trials involving HD patients with early or moderately severe disease.
Activities of Daily Living↗
Transdermal selegiline in HIV-associated cognitive impairment: pilot, placebo-controlled study.
The authors conducted a pilot randomized, double-blind, placebo-controlled clinical trial of the transdermal administration of selegiline in HIV+ patients to obtain preliminary data to assess its safety, tolerability, and impact on HIV-associated cognitive impairment. Both selegiline and placebo were well tolerated with few adverse events. Improvements favoring the selegiline group were suggested on single tests of verbal memory and motor/psychomotor performance, warranting a larger study.
Administration, Cutaneous↗
Familial aggregation of Alzheimer disease among whites, African Americans, and Caribbean Hispanics in northern Manhattan.
BACKGROUND: Alzheimer disease (AD) aggregates in families. OBJECTIVE: To compare the familial aggregation and lifetime risk of AD to the age of 90 years in the first-degree relatives of patients with AD and unrelated controls among Caribbean Hispanics, African Americans, and whites in Washington Heights, Manhattan, New York, NY. METHODS: Family history of AD and demographic information were obtained from informants of 435 patients with probable or possible AD concerning 1577 siblings and parents and from 1094 controls without dementia concerning 3952 siblings and parents. RESULTS: Lifetime risk of AD to the age of 90 years was 25.9% in relatives of patients and 19.1% in relatives of controls. Rate ratio (RR) for AD in relatives of patients compared with relatives of controls was 1.5 overall (95% confidence interval [CI], 1.2-1.9), and was greater for siblings (RR, 1.8; 95% CI, 1.2-2.5) than for parents (RR, 1.2; 95% CI, 0.9-1.8). Within ethnic groups, RR for AD among relatives was significantly elevated in whites (RR, 2.0; 95% CI, 1.2-3.3) and Hispanics (RR, 1.5; 95% CI, 1.1-2.1), but the difference did not reach statistical significance in African Americans (RR, 1.4; 95% CI, 0.7-2.7). Risk of AD was greater among relatives who were women compared with men (RR, 1.5; 95% CI, 1.2-1.9). CONCLUSIONS: Familial aggregation of AD was increased among families of patients compared with those of controls in all 3 ethnic groups. Risk of AD was highest among siblings and women relatives.
Aged↗
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.
Adult↗
Coordination of prehensile forces during precision grip in Huntington's disease.
The present study examined the coordination of prehensile forces during precision grip in subjects with Huntington's disease (HD). Fingertip forces were measured in 12 subjects with HD and 12 age-matched controls during the lifting of an instrumented object whose weight and surface texture were varied. The results indicate that subjects with HD have impaired initiation and delayed transitions between movement sequences and produce excessive and variable forces. However, subjects with HD demonstrated anticipatory scaling of force development based on the object's expected physical properties (planning) and adjustment of the force to the object's actual physical properties (sensorimotor integration). The observed findings generally were unrelated to the overall disease severity. However, the variability in forces was correlated with functional capacity and motor performance suggesting that variability is a key feature of the motor deficit. These results provide insights into the impaired hand function observed in individuals with HD.
Adult↗
The role of routine laboratory studies and neuroimaging in the diagnosis of dementia: a clinicopathological study.
OBJECTIVE: To determine the neuropathological diagnoses of longitudinally followed patients with potentially reversible causes of dementia and to examine the results of the "dementia work-up," especially neuroimaging, by comparison with the pathological diagnosis. DESIGN: A neuropathologic series of 61 consecutive patients, with review of clinical, laboratory, neuroimaging, and pathological results. RESULTS: Of the 61 patients, forty-eight (79%) had a clinical diagnosis of probable or possible Alzheimer's disease (AD). Compared with the pathological diagnosis, the sensitivity and specificity of the clinical diagnosis of AD were 96% and 79%, respectively. Of the 61 patients, 9 had abnormal laboratory tests, the correction of which did not improve the subsequent course. These patients were found to have AD8 and frontotemporal dementia on pathology. In two patients, neuroimaging was helpful in the clinical diagnoses of frontotemporal dementia and progressive supranuclear palsy (PSP). Neuroimaging revealed cerebrovascular disease in 18 patients, only two of whom were suspected clinically. Pathology confirmed AD in 17 and PSP in 1 of these patients. Sensitivity and specificity for the clinical diagnosis of cerebrovascular disease in comparison with pathology were 6% and 98%, respectively. With the added information from neuroimaging, that sensitivity increased to 59% and specificity decreased to 81%. CONCLUSIONS: All cases with abnormal laboratory or neuroimaging results had AD or some other neurodegenerative disease on pathology. The "dementia work-up" did not reveal any reversible causes for dementia in this group of patients. Neuroimaging may have a role, especially in the diagnosis of possible AD with concomitant cerebrovascular disease.
Aged↗
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.
Aged↗
Pharmacological frontiers in the treatment of AIDS dementia.
Even in the era of highly active antiretroviral therapy, AIDS dementia remains an important and devastating complication of human immunodeficiency virus (HIV-1) infection. Based on the 1997 AIDS case rate of 56 per 100 000 population in the USA, a reasonable estimated incidence of AIDS dementia is 3-8 per 100000, similar to that of multiple sclerosis. The pharmacology of AIDS dementia has been dominated by antiretroviral therapies, the best studied of which is azidothymidine. New and specific therapies are needed to treat and prevent brain injury in the setting of HIV infection. Rational therapy has been limited by the absence of large, adequate and well-controlled clinical trials using neuroprotective agents or those with disease-modifying potential, as well as by an incomplete understanding of the pathophysiology of AIDS dementia. In this review, a summary of evidence-based hypotheses of HIV-associated brain injury is followed by information on current nonantiretroviral therapeutic trials and their scientific rationale.
AIDS Dementia Complex↗
Influence of APOE genotype on familial aggregation of AD in an urban population.
OBJECTIVE: To examine the influence of the proband's APOE genotype on AD among first-degree relatives in a community-based study of African Americans, whites, and Caribbean Hispanics. METHODS: History of AD and demographic information were obtained on 1,073 siblings and parents of 312 patients with AD and 2,722 siblings and parents of 802 nondemented controls. APOE genotyping was performed on all 1,114 patients and controls. RESULTS: A higher proportion of patients with AD (35%) than controls (27%) had one or more APOE-epsilon4 alleles (p = 0.03). When compared with relatives of controls without an APOE-epsilon4 allele, the risk for AD was increased in first-degree relatives of both patients (rate ratio [RR] = 1.9, 95% confidence interval [CI] = 1.2 to 3.1) and controls (RR = 1.8, 95% CI = 1.2 to 2.6) with one or more APOE-epsilone alleles, regardless of ethnic group. There was a similar trend of increased risk in relatives of patients without an APOE-epsilon4 allele, but this was limited to Hispanics and African Americans. CONCLUSIONS: The presence of an APOE-epsilon4 allele increases risk for AD among first-degree relatives, regardless of the probands' disease status, among all ethnic groups. Relatives of patients without an APOE-epsilon4 allele were also at increased risk for AD among Hispanics and African Americans, suggesting that other genes or risk factors may influence risk.
Aged↗
Randomized trial of the platelet-activating factor antagonist lexipafant in HIV-associated cognitive impairment. Neurological AIDS Research Consortium.
OBJECTIVE: To assess the safety and tolerability of lexipafant in HIV-associated cognitive impairment. BACKGROUND: Cognitive impairment is the most common neurologic complication of advanced HIV-1 infection. There is evidence that a variety of inflammatory mediators, including platelet-activating factor (PAF), may contribute to neuronal injury. We hypothesized that lexipafant, a PAF antagonist, might improve cognitive dysfunction in HIV-infected people. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the safety and tolerability of lexipafant 500 mg/day. The primary outcome measure for tolerability was the ability to complete the study on the originally assigned dosage of medication. Thirty patients with cognitive impairment were enrolled. RESULTS: Lexipafant was safe and well tolerated. Ninety-three percent in the placebo group and 88% in the lexipafant group completed the study at the originally assigned dosage. Trends toward improvement were seen in neuropsychological performance, especially verbal memory, in the lexipafant treatment group. CONCLUSIONS: This study shows that lexipafant, the first PAF antagonist used in HIV-associated cognitive impairment, is a safe and well tolerated compound. The observed trends toward improvement in neuropsychological test scores warrant the pursuit of a larger and longer efficacy trial to assess the impact of lexipafant on cognitive performance.
Adult↗
Assessment of cognition in advanced AD: the test for severe impairment.
The Test for Severe Impairment (TSI) was compared with the Mini-Mental State Examination (MMSE) and a modified MMSE (mMMSE) in a multisite, longitudinal study of AD. The TSI correlated highly with the MMSE (r = 0.83) and the mMMSE (r = 0.82), but was not redundant. There was a wide range of scores on the TSI among those scoring in the severely impaired range on the MMSE and mMMSE. The slope of cognitive change over time detected by the TSI was greater than that revealed by the MMSE or the mMMSE. Performance on the TSI was a significant predictor of survival. The TSI is a valid measure that is sensitive to cognitive change over time in severely demented patients with AD.
Aged↗
Risk of Alzheimer's disease in relatives of Parkinson's disease patients with and without dementia.
OBJECTIVE: To determine whether first-degree relatives of PD patients with dementia were at increased risk for the development of AD compared with first-degree relatives of nondemented PD patients and nondemented normal subjects from the community. METHODS: A structured family history interview was administered to 146 nondemented PD patients, 120 patients with PD and dementia, and 903 normal subjects from the community to ascertain the presence of AD among parents and siblings of these subjects. Cox proportional hazards models with double censoring techniques for missing information were used to model the risk of AD among relatives. RESULTS: No increase in risk of AD was found among parents of patients with PD and dementia or parents of nondemented PD patients compared with parents of normal subjects. However, siblings of demented PD patients were three times as likely (relative risk [RR] = 3.2, 95% confidence interval [CI] = 1.1 to 9.4, p < 0.04) as siblings of normal subjects to develop AD. When only siblings >65 years of age were considered, there was a fivefold increase in risk of AD among siblings of demented PD patients compared with siblings of normal subjects (RR = 4.9, 95% CI = 1.1 to 21.4, p < 0.03). The risk of AD was also increased for female relatives, regardless of whether the woman was a relative of a demented PD patient, a nondemented PD patient, or a normal subject. Ethnicity and APOE genotype did not affect dementia status among relatives. CONCLUSIONS: The increased risk of AD in siblings of demented PD patients compared with siblings of normal subjects supports the possibility of familial aggregation of AD and PD with dementia.
Aged↗
Progression of parkinsonian signs in Parkinson disease.
BACKGROUND: Current knowledge about the rate of progression of extrapyramidal signs (EPSs) in Parkinson disease (PD) is derived largely from cross-sectional studies comparing subjects at various stages of illness rather than longitudinal studies in which the subjects were followed up over time. OBJECTIVE: To longitudinally study the progression of EPSs in PD by quantifying the rate of change of EPSs and by examining each EPS (rigidity, bradykinesia, tremor, and postural instability) separately. METHODS: A community-based cohort of 237 patients with PD living in Washington Heights-Inwood in Manhattan, NY, was evaluated at baseline and at yearly intervals. The EPSs were rated using the motor portion of the Unified Parkinson's Disease Rating Scale Motor Examination. Analyses of longitudinal data were performed by applying generalized estimating equations to regression analyses. RESULTS: The total EPS score increased at an annual rate of 1.5 points (1.5%), but, among those who died, the total EPS score increased at an annual rate of 3.6 points (3.6%). Bradykinesia, rigidity, and gait and balance subscores worsened at similar annual rates of 2.0% to 3.1%, whereas the tremor subscore did not clearly worsen with time. Patients with a shorter disease duration (< or =3 years) may have progressed more rapidly than patients with longer disease duration (annual rate of change, 1.9% vs 1.4%, respectively), although this did not reach statistical significance. A high total EPS score was independently associated with dementia, low Activities of Daily Living score, and long disease duration at baseline. CONCLUSIONS: In this cohort, the progression of EPSs in PD occurred at a rate of 1.5% per year and at twice that rate among those who died. Bradykinesia, rigidity, and gait and balance impairment worsened at similar rates, whereas tremor did not, suggesting that tremor may be relatively independent of these other cardinal manifestations of PD.
Age of Onset↗
Dystonia in Huntington's disease: prevalence and clinical characteristics.
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.
Adult↗
Arm elevation in Huntington's disease: dystonia or levitation?
Explore the source record for details and available documents.
Adult↗
Longitudinal changes in sexual risk behavior among HIV+ and HIV- male injecting drug users.
UNLABELLED: Injecting drug users (IDUs) play a prominent role in the transmission of human immunodeficiency virus (HIV), particularly in urban areas such as New York City, where they comprise nearly half of all adult acquired immunodeficiency syndrome (AIDS) cases. Intervention studies have demonstrated that IDUs are responsive to safer sex messages, but sexual behavior appears to be more resistant to change than drug use behavior. This multidisciplinary study (without an intervention component) assesses changes in sexual risk behavior as a function of time, HIV status, and disease progression in a cohort of HIV+ and HIV- male IDUs (N = 144) for 4 years. RESULTS: For HIV+ and HIV- men, there were increases in abstinence and monogamy, with decreases in the frequency of unprotected vaginal/anal sex and sexual risk index scores. With the exception of monogamy, HIV+ men reported lower levels of risk. Although there was also a decline in substance use, this accounted for only some of the decline in sexual risk behavior. Among the HIV+ men, a CD4 level below 200 was associated with more abstinence and monogamy. HIV-related medical symptoms were associated with increased abstinence, less unprotected sex, and lower sexual risk index scores. Lower neuropsychological memory test scores were associated with increased abstinence and lower sexual risk index scores. Neurological impairment and depression were not associated with sexual risk behavior. CONCLUSION: IDU men in New York City have modified their sexual behavior toward safer practices. Lower levels of risk are found among HIV+ men, particularly those with more progressed HIV illness. Nevertheless, a substantial amount of sexual risk behavior remained in this cohort, indicating the continued need for education and intervention.
Adult↗