3D comparison of low, intermediate, and advanced hippocampal atrophy in MCI.

We applied the hippocampal radial atrophy mapping technique to the baseline and follow-up magnetic resonance image data of 169 amnestic mild cognitive impairment (MCI) participants in the imaging arm of the Alzheimer's Disease Cooperative Study MCI Donepezil/Vitamin E trial. Sixty percent of the subjects with none to mild hippocampal atrophy rated with the visual medial temporal atrophy rating scale (MTA score < 2) and 33.8% of the subjects with moderate to severe (MTA > or = 2) hippocampal atrophy converted to Alzheimer's disease (AD) during 3-year follow-up.

Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders.

Background: Immunization of patients with Alzheimer's disease (AD) with synthetic amyloid-beta peptide (Abeta(42)) (AN1792) was previously studied in a randomized, double-blind, placebo-controlled phase 2a clinical trial, Study AN1792(QS-21)-201. Treatment was discontinued following reports of encephalitis. One year follow-up revealed that AN1792 antibody responders showed improvements in cognitive measures as assessed by the neuropsychological test battery (NTB) and a decrease in brain volume compared with placebo.

Visuospatial deficits predict rate of cognitive decline in autopsy-verified dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is often characterized by pronounced impairment in visuospatial skills, attention, and executive functions. However, the strength of the phenotypic expression of DLB varies and may be weaker in patients with extensive concomitant Alzheimer's disease (AD). To determine whether strength of the DLB clinical phenotype impacts cognitive decline, visuospatial and language tests were retrospectively used to predict 2-year rate of global cognitive decline in 22 autopsy-confirmed DLB patients (21 with concomitant AD) and 44 autopsy-confirmed "pure" AD patients.

High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial.

Context: Blood levels of homocysteine may be increased in Alzheimer disease (AD) and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B(6) and B(12). Prior studies of B vitamins to reduce homocysteine in AD have not had sufficient size or duration to assess their effect on cognitive decline.

Periventricular white matter hyperintensities increase the likelihood of progression from amnestic mild cognitive impairment to dementia.

Background: White matter hyperintensities (WMH) have an effect on cognition and are increased in severity among individuals with amnestic mild cognitive impairment (aMCI). The influence of WMH on progression of aMCI to Alzheimer's disease (AD) is less clear.

Methods: Data were drawn from a three-year prospective, double blind, placebo controlled clinical trial that examined the effect of donepezil or vitamin E on progression from aMCI to AD.

Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease.

Objective: To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease.

Design: Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial.

Setting: Community-based clinical research centers.

Cognitive discrepancies versus APOE genotype as predictors of cognitive decline in normal-functioning elderly individuals: a longitudinal study.

Objectives: Cognitive-discrepancy analysis has been shown to be a useful technique for detecting subtle cognitive deficits in normal-functioning elderly individuals who are genetically at-risk for Alzheimer disease (AD). However, studies that have used cognitive-discrepancy measures to date have used retrospective or cross-sectional designs, and the utility of this approach to predict cognitive decline has not been examined in a prospective investigation.

Design: Longitudinal study.

Rofecoxib in patients with mild cognitive impairment: further analyses of data from a randomized, double-blind, trial.

A recent clinical trial in patients with Mild Cognitive Impairment (MCI) found an increased rate of possible or probable Alzheimer's disease (AD) diagnoses in patients assigned to rofecoxib compared to placebo. This unexpected finding was difficult to interpret due to methodological issues and a lack of confirmation on secondary endpoints, as well as a lack of confirmation in trials in related populations. We performed additional post hoc analyses to explore explanations for the finding based on possible neuropathological, cardiovascular/cerebrovascular, or cognitive effects of rofecoxib.

Evidence that common variation in NEDD9 is associated with susceptibility to late-onset Alzheimer's and Parkinson's disease.

Late-onset Alzheimer's disease (LOAD) and Parkinson's disease (PD) are the most common neurodegenerative disorders and in both diseases susceptibility is known to be influenced by genes. We set out to identify novel susceptibility genes for LOAD by performing a large scale, multi-tiered association study testing 4692 single nucleotide polymorphism (SNPs). We identified a SNP within a putative transcription factor binding site in the NEDD9 gene (neural precursor cell expressed, developmentally down-regulated), that shows good evidence of association with disease risk in four out of five LOAD samples [N = 3521, P = 5.

APOE genotype predicts depression in women with Alzheimer's disease: a retrospective study.

Objective: The association between the APOE epsilon4 allele and depression was investigated in a retrospective study of 323 AD patients.

Methods: Patients were divided into demographically comparable groups based on the presence or absence of depression.

Results: Results showed that the frequency of APOE epsilon4 allele was significantly higher in the depressed vs non-depressed AD patients (72% and 58%, respectively), and an interaction revealed that women possessing the APOE epsilon4 allele were almost four times more likely to be depressed than those without the epsilon4 allele.

Progressive impairment on neuropsychological tasks in a longitudinal study of preclinical Alzheimer's disease.

Previous research suggests that patients with Alzheimer's disease exhibit cognitive impairment in the years preceding a clinical diagnosis. Memory impairments are particularly pronounced, but the relative degree to which other cognitive functions are impaired and the speed with which they decline during the preclinical years remains unclear. The authors report a detailed neuropsychological evaluation of 11 patients over the course of 3 years up to and including the 1st year of nonnormal diagnosis.

Ways toward an early diagnosis in Alzheimer's disease: the Alzheimer's Disease Neuroimaging Initiative (ADNI).

With the increasing life expectancy in developed countries, the incidence of Alzheimer's disease (AD) and thus its socioeconomic impact are growing. Increasing knowledge over the last years about the pathomechanisms involved in AD allow for the development of specific treatment strategies aimed at slowing down or even preventing neuronal death in AD. However, this requires also that (1) AD can be diagnosed with high accuracy, because non-AD dementias would not benefit from an AD-specific treatment; (2) AD can be diagnosed in very early stages when any intervention would be most effective; and (3) treatment efficacy can be reliably and meaningfully monitored.

Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI.

The vitamin E and donepezil trial for the treatment of amnestic mild cognitive impairment (MCI) was conducted at 69 centers in North America; 24 centers participated in an MRI sub study. The objective of this study was to evaluate the effect of treatment on MRI atrophy rates; and validate rate measures from serial MRI as indicators of disease progression in multi center therapeutic trials for MCI. Annual percent change (APC) from baseline to follow-up was measured for hippocampus, entorhinal cortex, whole brain, and ventricle in the 131 subjects who remained in the treatment study and completed technically satisfactory baseline and follow-up scans.

Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms.

Background: Animal studies suggest that brain apolipoprotein E (apoE) levels influence amyloid-beta (Abeta) deposition and thus risk for Alzheimer's disease (AD). We have previously demonstrated that deletion of the ATP-binding cassette A1 transporter (ABCA1) in mice causes dramatic reductions in brain and cerebrospinal fluid (CSF) apoE levels and lipidation. To examine whether polymorphisms in ABCA1 affect CSF apoE levels in humans, we measured apoE in CSF taken from 168 subjects who were 43 to 91 years old and were either cognitively normal or who had mild AD.

Nerve growth factor promotes survival of new neurons in the adult hippocampus.

Exogenously provided NGF enhances cognitive performance in impaired rodents and humans and is currently a promising compound for the treatment of dementia. To investigate whether NGF-dependent cognitive improvement may be due in part to increased hippocampal neurogenesis, adult and aged male rats were treated with NGF or vehicle intracerebroventricularly for 6 or 20 days followed by evaluation of cholinergic parameters and hippocampal neurogenesis. We show that NGF increases hippocampal cholinergic activity as rapidly as 3 days after initiation of treatment.

Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia.

Background: Individuals diagnosed as having mild cognitive impairment (MCI) have a high likelihood of progressing to dementia within 3 to 5 years, but not all individuals with MCI progress to dementia. Prognostic uncertainty suggests the need for additional measures to assist the clinician.

Objective: To assess the added value of qualitative measures of medial temporal atrophy (MTA) to estimate the relative risk of progressing from MCI to dementia.

Disparate letter and semantic category fluency deficits in autopsy-confirmed frontotemporal dementia and Alzheimer's disease.

Patients with autopsy-confirmed frontotemporal dementia (FTD; n = 16) and Alzheimer's disease (AD; n = 32) were compared on first-letter and semantic category fluency tasks. Despite being matched on age, education, and dementia severity, FTD patients performed worse overall and showed similar impairment in letter and semantic category fluency, whereas AD patients showed greater impairment in semantic category than letter fluency. A measure of the disparity between letter and semantic category fluency (the semantic index) was effective in differentiating FTD from AD patients, and this disparity increased with increasing severity of dementia.

ADCS Prevention Instrument Project: pharmacoeconomics: assessing health-related resource use among healthy elderly.

Background: The Prevention Instrument project of the Alzheimer's Disease Cooperative Study (ADCS) seeks to develop instruments to assess treatment efficacy including potential economic benefit. The Resource Use Inventory (RUI) is an instrument that has been used to capture resource utilization and costs in populations with Alzheimer disease (AD). However, resource utilization and costs for healthy, cognitively intact elderly as they begin to demonstrate cognitive deterioration are not well understood.

ADCS Prevention Instrument Project: development of a brief verbal memory test for primary prevention clinical trials.

The validity and reliability of clinic-based and telephone-based versions of a 4 word delayed recall test were evaluated in nondemented elderly individuals (n=644) participating in a simulated primary prevention clinical trial. There was no significant difference in the average scores achieved by participants tested in clinic (mean=3.40) or by telephone (mean=3.

ADCS Prevention Instrument Project: overview and initial results.

One objective of the Alzheimer's Disease Cooperative Study (ADCS) is to develop new or improved instruments and assessment methods for evaluating treatment efficacy in Alzheimer disease (AD) clinical trials. The ADCS Instrument Committee has previously helped to define the state of the art in assessment for AD and Mild Cognitive Impairment clinical trials. We are now entering an exciting era of primary prevention trials to evaluate promising treatments that may delay disease onset and there is a need to develop appropriate instruments for these trials.

Spanish instrument protocol: new treatment efficacy instruments for Spanish-speaking patients in Alzheimer disease clinical trials.

Objective: To evaluate the feasibility of longitudinal assessment and the psychometric properties of both established and new outcome measures used in clinical trials of patients with dementia in a cohort of Spanish-speaking elders in the United States.

Methods: This is a prospectively collected multicenter study comparing patients with Alzheimer disease (AD) (N=77) and elderly controls (N=17) who are primary Spanish speakers. Spanish-speaking individuals with AD (SSI AD) were selected to represent predefined categories of impairment as determined by a Mini-Mental State Examination score.

Prevention of Alzheimer disease.

The prevention of Alzheimer disease (AD) remains an important goal because of its high prevalence in our society and its associated costs. Two types of primary prevention trials have been conducted in AD to date: trials in independent cohorts specifically recruited for an AD primary prevention trial and cohorts in other studies randomized to a drug of interest where appropriate cognitive measures can be added. There have been numerous difficulties in conducting primary prevention trials in AD because of the need for a large sample size, long length of poor follow up, and adverse event profile or toxicity of the agents being studied.