Normal Aging And Synapse Loss

It has been suggested in the literature that AD-associated cognitive decline may be an inevitable consequence of the aging process. Age-associated changes in neuron number are often cited as the primary reason for age-related cognitive change, yet careful cell counting studies have failed to support this idea9. Recent studies of the entorhinal cortex, an area believed to be an early site of AD-related pathology, shows no significant change in total neuron number as a function of aging10,11. Most notably there does appear to be a significant age-related loss of white matter, suggesting a loss of brain connectivity indicative of a loss of synapses12-15. The loss of such brain connectivity is important since recent work has demonstrated that synaptic loss is strongly associated with cognitive ability and provides a strong correlation with dementia16-23.

Assessing inevitable age-related changes in synaptic connectivity are complicated since the methods for identifying and quantifying synaptic numbers in human tissue are either direct, using labor-intensive electron microscopy (EM), or indirect using immunohistochemical methods or an enzyme-linked immunoassay (ELISA). Relatively few studies have investigated normal age-related changes in the neocortex. Because of its involvement in AD, the frontal region (Brodmann areas 9, 10, 46) was one of the initial areas investigated and reported to undergo some age-related loss of synapses24-27. Other cortical regions, such as the inferior parietal (Brodmann area 39,40), inferior temporal (Brodmann area 20), and posterior cingulate cortex (Brodmann area 23), all with ties to AD, have also been implicated with age-related synaptic loss26. Not all regions of the cortex show such age-related changes. In a rather interesting ultrastructural study, Adams28 reported an age-related loss in the precentral motor cortex (Brodmann area 4) but failed to observe an age-related change in the postcentral gyrus (Brodmann area 3), an area that is primary sensory cortex. An ELISA and immunoblotting study with synaptophysin29 failed to detect any age-related differences in Brodmann area 17, the occipital cortex, the superior temporal cortex (Brodmann area 22), or hippocampus, supporting the idea that different regions of the neocortex age differently.

Most of the human studies assessing possible age-related changes in synaptic numbers have limited number of subjects in part because of restricted access to tissue from individuals without pathology. With the exception of two studies27,30, all of the age-related synapse studies use subject pools with less than 40% of the subjects under the age of 60. One highly cited ultrastructural developmental study of the frontal cortex by Huttenlocher31 used infants and very young children in the assessment. That study reported no age-related changes. When these data are re-evaluated after removing individuals below the age of 10, there is a clear trend toward an age-related loss in synaptic numbers. It is also interesting to note that the post mortem interval (PMI) for this tissue ranged from 0 to 36 h and could have had a significant effect on synaptic recognition. In a rather unprecedented study, we used an ultrastructural approach and sampled two different laminae (III and V) of Brodmann area 930. The reason for examining laminae III and V

stemmed from previous work involving cholinergic circuitry in the frontal cortex. Stereological methods were employed in an attempt to obtain an unbiased estimate of the synaptic packing density. Constraints on tissue acquisition at the time of autopsy precluded estimating total synaptic numbers. This study is unique in that at least five short post mortem cases were obtained for each decade of life. All cases were believed to be from individuals who were considered neurologically normal and without cognitive impairment. The subjects ranged in age from 20-89 years. Individuals 65 years of age and older had been cognitively tested within 1 year prior to death. A previous study has shown that sex of the individual is an important factor in predicting neocortical neuron number and can account for as much as 21% of the variance32. Each age group in our synapse study had almost equal numbers of males and females and almost all of the subjects were well educated.

Frontal Cortex (Area 9)

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