From the third decade of life to the beginning of the 10th decade, the average decline in weight of the male brain is from 1,394 to 1,161 g, a loss of 233 g. The pace of this change, very gradual at first, accelerates during the sixth or seventh decades. The loss of brain weight, which correlates roughly with enlargement of the lateral ventricles and widening of the sulci, is presumably the result of neuronal degeneration and replacement gliosis. The counting of cerebrocortical neurons is fraught with technical difficulties, even with the use of computer-assisted automated techniques (see the critical review of neuron-counting studies by Coleman and Flood). Nevertheless, most studies point to a depletion of the neuronal population in the neocortex, especially evident in the seventh, eighth, and ninth decades.
Cell loss in the limbic system (hippocampus, parahippocampal, and cingulate gyri) is of special interest in regard to memory. Ball, who measured the neuronal loss in the hippocampus, recorded a linear decrease of 27 percent between 45 and 95 years of age. Dam reported a similar degree of cell loss and replacement gliosis. These changes seem to proceed without relationship to Alzheimer neurofibrillary changes and senile plaques (Kemper). However, more recent morphologic work, summarized by Morrison and Hof, suggests that cerebral cell loss with aging is less pronounced than previously thought. Furthermore, as pointed out by Morrison, the hippocampus may have only minimal cell loss. Moreover, this is partially a result of neurogenesis in this region. Brain shrinkage is accounted for in part by the reduction in size of large neurons, not their disappearance. There is a more substantial reduction in neuronal number in the substantia nigra, locus ceruleus, and basal forebrain nuclei. It may be possible to differentiate normal aging from disease in the medial temporal lobe by distinguishing between cell loss in specific regions (see Small et al), but novel techniques are required.
Mueller and colleagues employed quantitative volumetric MRI techniques to examine a cohort of 46 nondemented elderly individuals. They found small, constant rates of loss of brain volume with aging. Moreover, the rates of volume loss in the last decades of life were no greater than in the immediately preceding decades, suggesting that large changes in brain volume in the elderly are attributable to the dementing diseases common to this age period. Rusinek and colleagues found that serial MRIs of elderly persons predict which individuals will develop disproportionate atrophy and dementia. In particular, hippocampal atrophy increases at the rate of less than 2 percent per year in healthy elderly people, in comparison to 4 to 8 percent a year in early Alzheimer disease. This longitudinal method of study is more sensitive than cross-sectional population studies.
Among lumbosacral anterior horn cells, sensory ganglion cells, and putaminal and Purkinje cells, neuronal loss amounts to at most 25 percent between youth and old age. Not all neuronal groups are equally susceptible. For example, the locus ceruleus and substantia nigra, as already commented, lose approximately 35 percent of their neurons, whereas the vestibular nuclei and inferior olives maintain a fairly constant number of cells throughout life. A very subtle loss, decade by decade, of the major systems of nerve cells and myelinated fibers of the spinal cord was demonstrated by Morrison. This accelerates after the age of 60 (Tomlinson and Irving).
As described earlier in normal aging, there is a gradual decline in memory and in some cognitive functions. In light of the studies just summarized, it is no longer considered that these changes can be ascribed simply to neuronal loss. Rather, they are probably caused, at least in part, by alterations in synaptic connectivity within critical cortical structures.