Holly Posner

The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function

Background Hypertension at the age of 45 to 50 years may predispose to AD later in life. It is not known whether hypertension after age 65 years also contributes to AD risk, and its effect on cognitive function is also not fully understood. MethodsData were analyzed from 1,259 Medicare recipients free of dementia in a longitudinal study covering a 7-year period (1991 to 1998). The effect of hypertension was first examined in relationship to the risk for incident AD and then to incident vascular dementia (VaD) using Cox proportional hazards models. Changes in performance over time on tasks of memory, language, and visuospatial/cognitive function were compared in those with and without hypertension using generalized estimating equations. ResultsOf the 1,259 subjects, 731 (58.1%) had a history of hypertension associated with diabetes, stroke, and heart disease. A history of hypertension was not associated with an increased risk for AD (rate ratio [RR] 0.9, 95% CI 0.7 to 1.3) but was associated with an increased risk for VaD (1.8 [1.0 to 3.2]). Hypertension was not associated with changes in memory, language, and general cognitive function in normal individuals over time. Compared with individuals with neither hypertension nor heart disease, those with hypertension or heart disease alone had no increase in risk for VaD. However, when both were present, there was a threefold increase in risk for VaD. A sixfold increase in risk was observed when both hypertension and diabetes were present. Conclusions Hypertension after age 65 years is not associated with AD and does not adversely affect memory, language, or general cognitive function. A history of hypertension may be an antecedent to VaD, particularly in the presence of heart disease or diabetes.

Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL

BACKGROUND Cholinergic deficits might contribute to vascular cognitive impairment. Trials of cholinesterase inhibitors in patients with vascular dementia are difficult because of heterogeneous disease mechanisms and overlap between vascular and Alzheimers disease (AD) pathology in the age-group recruited. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a genetic form of subcortical ischaemic vascular dementia. It represents a homogeneous disease process, and because of CADASILs early onset, comorbid AD pathology is rare. We did a multicentre, 18-week, placebo-controlled, double-blind, randomised parallel-group trial to determine whether the cholinesterase inhibitor donepezil improves cognition in patients with CADASIL. METHODS 168 patients with CADASIL (mean age 54.8 years) were assigned to 10 mg donepezil per day (n=86) or placebo (n=82) by a computer-generated randomisation protocol. Inclusion criteria included a mini-mental state examination (MMSE) score of 10-27 or a trail making test (TMT) B time score at least 1.5 SD below the mean, after adjustment for age and education. The primary endpoint was change from baseline in the score on the vascular AD assessment scale cognitive subscale (V-ADAS-cog) at 18 weeks. Secondary endpoints included scores on the ADAS-cog, MMSE, TMT A time and B time, Stroop, executive interview-25 (EXIT25), CLOX, disability assessment for dementia, and sum of boxes of the clinical dementia rating scale. Analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00103948. FINDINGS 161 patients were analysed. There was no significant difference between donepezil (n=84) and placebo (n=77) in the primary endpoint. The least-squares mean change from baseline score was -0.81 (SE 0.59) in the placebo group and -0.85 (SE 0.57) in the donepezil group (p=0.956). There was a significant treatment effect favouring donepezil on the following secondary outcomes: TMT B time (p=0.023), TMT A time (p=0.015), and EXIT25 (p=0.022). Ten donepezil-treated patients discontinued treatment due to adverse events compared to seven placebo-treated patients. INTERPRETATION Donepezil had no effect on the primary endpoint, the V-ADAS-cog score in CADASIL patients with cognitive impairment. Improvements were noted on several measures of executive function, but the clinical relevance of these findings is not clear. Our findings may have implications for future trial design in subcortical vascular cognitive impairment.

The ADAS-cog in Alzheimer's disease clinical trials: psychometric evaluation of the sum and its parts

Background The Alzheimers Disease Assessment Scale Cognitive Behavior Section (ADAS-cog), a measure of cognitive performance, has been used widely in Alzheimers disease trials. Its key role in clinical trials should be supported by evidence that it is both clinically meaningful and scientifically sound. Its conceptual and neuropsychological underpinnings are well-considered, but its performance as an instrument of measurement has received less attention. Objective To examine the traditional psychometric properties of the ADAS-cog in a large sample of people with Alzheimers disease. Methods Data from three clinical trials of donepezil (Aricept) in mild-to-moderate Alzheimers disease (n=1421; MMSE 10–26) were analysed at both the scale and component level. Five psychometric properties were examined using traditional psychometric methods. These methods of examination underpin upcoming Food and Drug Administration recommendations for patient rating scale evaluation. Results At the scale-level, criteria tested for data completeness, scaling assumptions (eg, component total correlations: 0.39–0.67), targeting (no floor or ceiling effects), reliability (eg, Cronbachs α: = 0.84; test-retest intraclass correlations: 0.93) and validity (correlation with MMSE: −0.63) were satisfied. At the component level, 7 of 11 ADAS-cog components had substantial ceiling effects (range 40–64%). Conclusions Performance was satisfactory at the scale level, but most ADAS-cog components were too easy for many patients in this sample and did not reflect the expected depth and range of cognitive performance. The clinical implication of this finding is that the ADAS-cogs estimate of cognitive ability, and its potential ability to detect differences in cognitive performance under treatment, could be improved. However, because of the limitations of traditional psychometric methods, further evaluations would be desirable using additional rating scale analysis techniques to pinpoint specific improvements.

Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic

The last decade has seen a substantial increase in research focused on the identification of blood‐based biomarkers that have utility in Alzheimers disease (AD). Blood‐based biomarkers have significant advantages of being time‐ and cost‐efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood‐based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public‐private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.

Assessment of cognition in early dementia.

Better tools for assessing cognitive impairment in the early stages of Alzheimers disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow for detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimers Association convened a meeting to discuss state‐of‐the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory, and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real‐world situations so as to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally, and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

Putting the Alzheimer's cognitive test to the test II: Rasch Measurement Theory

The Alzheimers Disease Assessment Scale—Cognitive Behavior section (ADAS‐Cog) is the most widely used measure of cognitive performance in AD clinical trials. This key role has rightly brought its performance under increased scrutiny with recent research using traditional psychometric methods, questioning the ADAS‐Cogs ability to adequately measure early‐stage disease. However, given the limitations of traditional psychometric approaches, herein we use the more sophisticated Rasch Measurement Theory (RMT) methods to fully examine the strengths and weaknesses of the ADAS‐Cog, and identify potential paths toward its improvement.

Putting the Alzheimer's cognitive test to the test I: traditional psychometric methods.

The Alzheimers Disease Assessment Scale—Cognitive Behavior section (ADAS‐Cog) is the most commonly used cognitive test in AD clinical trials. However, there are concerns about its use in early‐stage disease. Herein we examine those concerns using traditional psychometric methods.

Efficacy and safety of pregabalin versus levetiracetam as adjunctive therapy in patients with partial seizures: A randomized, double‐blind, noninferiority trial

To assess the comparative efficacy and safety of pregabalin and levetiracetam for the reduction of seizure frequency in patients with partial seizures.

Adjunctive use of controlled‐release pregabalin in adults with treatment‐resistant partial seizures: A double‐blind, randomized, placebo‐controlled trial

To assess the efficacy and tolerability of add‐on pregabalin controlled‐release formulation (PGB‐CR) (doses of 165 or 330 mg/day) in patients with partial‐onset seizures (POS).

Magnetic resonance imaging-measured atrophy and its relationship to cognitive functioning in vascular dementia and Alzheimer’s disease patients

Recent pathological studies report vascular pathology in clinically diagnosed Alzheimers disease (AD) and AD pathology in clinically diagnosed vascular dementia (VaD). We compared magnetic resonance imaging (MRI) measures of vascular brain injury (white matter hyperintensities [WMH] and infarcts) with neurodegenerative measures (medial‐temporal atrophy [MTA] and cerebral atrophy [CA]) in clinically diagnosed subjects with either AD or VaD. We then examined relationships among these measures within and between the two groups and their relationship to mental status.