ABSTRACT
OBJECTIVE: To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials. METHODS: We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up. RESULTS: The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy. CONCLUSIONS: Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures.
Subject(s)
Cognitive Dysfunction/physiopathology , Huntington Disease/physiopathology , Adult , Apathy , Cognitive Dysfunction/psychology , Disease Progression , Emotions , Facial Recognition , Female , Humans , Huntington Disease/drug therapy , Huntington Disease/psychology , Longitudinal Studies , Male , Middle Aged , Motor Skills , Neuropsychological Tests , Prospective Studies , Randomized Controlled Trials as Topic , Reproducibility of Results , Signal-To-Noise Ratio , Social Perception , Stroop Test , Ubiquinone/analogs & derivatives , Ubiquinone/therapeutic use , Vitamins/therapeutic useABSTRACT
We explored the association of Alzheimer's disease (AD) Assessment Scale (ADAS-Cog) item scores with AD severity using cross-sectional and longitudinal data from the same study. Post hoc analyses were performed using placebo data from a 12-month trial of patients with mild-to-moderate AD (N =281 randomized, N =209 completed). Baseline distributions of ADAS-Cog item scores by Mini-Mental State Examination (MMSE) score and Clinical Dementia Rating (CDR) sum of boxes score (measures of dementia severity) were estimated using local and nonparametric regressions. Mixed-effect models were used to characterize ADAS-Cog item score changes over time by dementia severity (MMSE: mild =21-26, moderate =14-20; global CDR: mild =0.5-1, moderate =2). In the cross-sectional analysis of baseline ADAS-Cog item scores, orientation was the most sensitive item to differentiate patients across levels of cognitive impairment. Several items showed a ceiling effect, particularly in milder AD. In the longitudinal analysis of change scores over 12 months, orientation was the only item with noticeable decline (8%-10%) in mild AD. Most items showed modest declines (5%-20%) in moderate AD.
Subject(s)
Alzheimer Disease/psychology , Cognition Disorders/psychology , Cognition , Neuropsychological Tests , Aged , Aged, 80 and over , Alzheimer Disease/diagnosis , Cognition Disorders/diagnosis , Cross-Sectional Studies , Data Interpretation, Statistical , Female , Humans , Longitudinal Studies , Male , Mental Status Schedule , Neuropsychological Tests/statistics & numerical data , Regression Analysis , Severity of Illness IndexABSTRACT
The purpose of the Alzheimer's Association Research Roundtable meeting was to discuss the potential of finding diagnostic tools to determine the earliest risk factors for Alzheimer's disease (AD). Currently, drugs approved for AD address symptoms which are generally manifest after the disease is already well-established, but there is a growing pipeline of drugs that may alter the underlying pathology and therefore slow or halt progression of the disease. As these drugs become available, it will become increasingly imperative that those at risk for AD be detected and possibly treated early, especially given recent indications that the disease process may start decades before the first clinical symptoms are recognized. Early detection must go hand-in-hand with qualified tools to determine the efficacy of drugs in people who may be asymptomatic or who have only very mild symptoms of the disease. Devising strategies and screening tools to identify and monitor those at risk in order to perform "prevention" trials is seen by many as a top public-health priority, made all the more urgent by an impending growth in the elderly population worldwide.
Subject(s)
Alzheimer Disease/diagnosis , Alzheimer Disease/drug therapy , Mass Screening/methods , Risk Reduction Behavior , Aged , Aging/pathology , Alzheimer Disease/prevention & control , Biomarkers/analysis , Clinical Trials as Topic/methods , Clinical Trials as Topic/standards , Disease Progression , Early Diagnosis , Humans , Mass Screening/trends , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/standardsABSTRACT
BACKGROUND: Several markers of immune activation have been identified as potential prognostic markers for human immunodeficiency virus (HIV)-associated morbidity and mortality, but the results from studies are conflicting. OBJECTIVE: To evaluate whether neurocognitive status and baseline levels of plasma and cerebrospinal fluid tumor necrosis factor alpha (TNF-alpha), macrophage chemoattractant protein 1 (MCP-1), matrix metalloproteinase 2 (MMP-2), or macrophage colony-stimulating factor (M-CSF) are associated with time to death in a cohort with advanced HIV infection. DESIGN: Cohort study. SETTING: Enrollees in the Northeast AIDS Dementia Study. PARTICIPANTS: Three hundred twenty-nine subjects who were positive for HIV-1 and had a CD4 cell count of less than 200/microL (or <300/microL but with cognitive impairment at baseline) were assessed for CD4 cell count, neurocognitive status, pertinent demographic and clinical variables, and plasma and cerebrospinal fluid HIV RNA, TNF-alpha, MCP-1, MMP-2, and M-CSF levels. MAIN OUTCOME MEASURES: Cox proportional hazards regression models were used to examine the associations between the variables of interest (using time-dependent covariates, where applicable) and time to death, adjusting for possible confounders. RESULTS: There were 50 deaths in the cohort after a median of 25.2 months of follow-up. The cumulative incidences of death were 7% at 1 year and 16% at 2 years. In Cox proportional hazards regression analyses adjusting for demographic, clinical, and immunological variables, HIV-associated dementia (hazard rate, 6.10; P = .001) was significantly associated with time to death; (log) plasma MCP-1 level (hazard rate, 3.38; P = .08) trended toward significance. CONCLUSION: In patients with advanced HIV infection, HIV-associated dementia is an independent predictor of time to death.
Subject(s)
Diagnostic Imaging , HIV Infections/immunology , HIV Infections/mortality , HIV Infections/pathology , Adult , CD4 Lymphocyte Count , Chemokine CCL2/blood , Chemokine CCL2/cerebrospinal fluid , Cohort Studies , Disease Progression , Female , HIV Infections/epidemiology , Humans , Male , Matrix Metalloproteinase 2/blood , Matrix Metalloproteinase 2/cerebrospinal fluid , Middle Aged , Morbidity , Proportional Hazards Models , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/cerebrospinal fluidABSTRACT
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.