Thomas McRae

Potential ethnic modifiers in the assessment and treatment of Alzheimer's disease: challenges for the future

OBJECTIVE Despite numerous clinical trials, it is unknown whether ethnicity affects treatment response to cognitive enhancers in Alzheimers disease (AD). There is convincing evidence of ethnic and genetic variability in drug metabolism. This article reviews the available data on ethnicity in clinical trials for AD to answer two questions: (1) what are the challenges to diagnose and treat AD across different ethnic groups, and (2) are there differences in response to pharmacologic interventions for AD across these different ethnic groups? METHOD Available data from Alzheimers Disease Cooperative Study (ADCS) randomized controlled clinical trials and from randomized controlled industry-sponsored trials for four cognitive enhancers (donepezil, galantamine, rivastigmine and sabeluzole) were pooled to assess the numbers of non-Caucasian participants. RESULTS The participation of ethnic minority subjects in clinical trials for AD was dependent on the funding source, although Caucasian participants were over-represented and non-Caucasian participants were under-represented in the clinical trials. Because of the low participation rate of ethnic minorities, there were insufficient data to assess any differences in treatment outcome among different ethnic groups. Strategies to improve diversity in clinical trials are discussed. CONCLUSION Greater participation of ethnically diverse participants in clinical trials for AD would generate additional information on possible differences in metabolism, treatment response, adverse events to therapeutic agents, and could foster the investigation of genetic variability among ethnic groups.

A brief instrument to assess treatment response in the patient with advanced Alzheimer disease.

The availability of effective treatments for severe Alzheimer disease (AD) has accentuated the need for brief, simple tools to evaluate treatment response in busy clinical settings for patients with advanced dementia. To develop such a tool, data on 875 patients from 4 double-blind–randomized studies of donepezil in severe AD [Mini-Mental State Examination (MMSE) 0 to 12 inclusive] were pooled and analyzed to identify Severe Impairment Battery (SIB) items, which are sensitive to change over time. Eight of the 51 SIB items were chosen based on effect sizes and relative ease of administration. The resulting SIB-8 was then applied to a validation data set (not used to generate the short form) to characterize its usefulness. The items, Month, Months of Year, Write Name, Sentence, Fluency, Confrontational Naming–Spoon, Using Spoon–Photograph, and Digit Span, were sensitive to change with treatment (P<0.0001) and easy to administer. Baseline SIB-8 scores were correlated with baseline MMSE and full-scale SIB scores, and provided a good distribution of scores in patients at the lower end of the MMSE. The SIB-8 is a brief (≤3 min) assessment for patients with severe AD that is sensitive to change and able to detect treatment response.

The Early Detection of Brain Pathology in Alzheimer’s Disease

Studies of aged animals and aging humans have revealed numerous age — associated decrements in brain functioning. Foremost among behavioral changes are the declines in memory functioning. While animal studies have linked many of these aging changes to brain alterations, very little direct evidence is available for the human. By and large, our current understandings suggest that damage to the hippocampus is at least in part related to these age-related memory changes. In Alzheimer’s disease (AD) many of these age-related behavioral changes are markedly exacerbated and there is clear evidence for extensive neuropathological involvement of the hippocampus and associated regions.

CT, MRI, and PET Studies of Hippocampal Pathology in Alzheimer’s Disease

Postmortem studies reveal numerous biochemical and neurotransmitter deficits in Alzheimer’s disease (AD) patients relative to elderly controls. Many of these deficits are more pronounced in the hippocampus; than in the neocortex (for a review see Selkoe and Kosik, 1983). There are many structural hippocampal abnormalities documented in AD. They include neuronal loss, granulovacuolar degeneration, neurofibrillary tangles, and neuritic plaques (Kemper, 1984). In AD these neuropathological findings show a consistent topography with respect to the hippocampal formation and its projections. Pyramidal cells are the primary neuronal population involved. These affected cells are located within the entorhinal cortex (the neurons of origin of the perforant pathway), the subiculum, CA1 of the hippocampus, and the temporal association cortex. This pattern of degeneration results in the “isolation” of the hippocampal formation from its neocortical association areas (Hyman et al., 1984).