In the past half century, new genetic, biochemical, neuropathological, neurocognitive, and neuroimaging methods have led to a better understanding of brain disease and have allowed us to distinguish such disease from the aging of a healthy brain. Functional Neurobiology of Aging, a comprehensive, multiauthored book, critically examines the details and implications of these approaches. The book should be read by anyone interested in the structure and function of aging and diseased nervous systems, in humans and in animals. The book's 64 chapters are conveniently arranged in four integrated categories: memory and cognition, the senses (e.g., vision and hearing), movement and movement disorders, and neuroendocrine regulation.
The initial chapters consider, among other disorders, Alzheimer's disease, vascular dementia, Parkinson's disease, frontotemporal dementia, and Lewy body disease -- the last two have only recently been characterized. On occasion, the neuropathological and neurochemical characteristics of different diagnostic entities may be found in the same patient, perhaps because there are a limited number of brain responses to environmental, senescent, or genetic stresses. Overlapping pathological features and highly variable rates of progression in Alzheimer's disease may explain why large numbers of patients are needed to prove efficacy in cross-sectional drug trials.
Recent findings have identified common disease paths in Alzheimer's disease that might be targeted by new drugs. Alzheimer's disease can arise from mutations in amyloid precursor protein, presenilin 1 and 2, or such risk factors as the apolipoprotein E4 allele. The disorder is characterized by the presence of senile plaques, neurofibrillary tangles with hyperphosphorylated tau protein, and marked synaptic, neuronal, and neurotransmitter losses. Braak and Braak's suggestion that the disease progresses in orderly stages, starting with memory changes and limbic abnormalities, appears to be contradicted by evidence of pathological and clinical heterogeneity, as discussed by Vogt.
A complete animal model of Alzheimer's disease does not exist. Hof notes that the disease may be distinctly human, affecting a brain association network that expanded and differentiated during the evolution of primates. In this regard, Erwin shows that spindle cells in the cingulate cortex, which are affected in Alzheimer's disease, appeared only during speciation of the great apes. For want of a natural animal model, considerable effort has been exerted to establish partial animal and cell models of Alzheimer's disease, which are discussed in the chapters by McKeon-O'Malley, Tanzi, Mattson, and Vickers. Genetically engineered mouse models make it possible to establish the connection between a selected genetic defect and a biochemical-neuropathological phenotype. One such model has given rise to a clinical trial of anti-beta-amyloid antibody.
Much of this book concerns the nature of brain aging. Remarkably, many functional and structural imaging studies of brain appear to have been flawed by lack of attention to health status, as noted by Pietrini, even though the importance of controlling for health status was clearly identified some 40 years ago. In carefully screened subjects, regional brain glucose metabolism in the resting state -- the gold-standard marker of functional activity that can be measured with the use of positron-emission tomography -- may decline by only 12 percent between 20 and 70 years of age; the statistical significance of even this small decline disappears after correction for brain atrophy. It is therefore likely that healthy aging is associated with subtle changes in functional interactions among regions of the brain. For example, in vivo neuroimaging in healthy subjects while they perform a cognitive task may demonstrate greater frontal cortical (attentional) activation, or less hippocampal activation, in older subjects than in those who are younger, as Anderson notes. Imaging evidence of circuit reorganization has been correlated with subtle changes in the performance of a task.
The interdisciplinary field of the neurosciences is moving in many directions very rapidly. Functional Neurobiology of Aging provides up-to-date information on brain aging and disease, as well as relevant signposts for directions that are likely to be followed in the future.
Stanley I. Rapoport, M.D.
Copyright © 2001 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.
Ronald Sims, MD, for Doody Publishing Reviews, 2002
"...contains much that is interesting and would provide a dedicated reader a great basic science foundation for patient care."
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