The neurobiological substrates of depression in older people are poorly understood but studies suggest depression in older people has a different aetiology from depression earlier in life. Stereological studies in depression in younger people have shown glial reduction and some evidence of neuronal shrinkage in both the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC), especially in the lower cortical layers. These findings have been supported by other investigations, such as a proteomic study showing a reduction in glial fibrillary acidic protein (GFAP) isoforms in depression, consistent with a diminution of astrocytic activity. Such glial cell loss may be associated with the elevated levels of corticosteroids which occur in depressive illness. This could lead to a loss of trophic support for neurones, which in turn might impact on neuronal size and neurotransmission. In contrast, in late-life depression there is accumulating evidence that vascular disease might be an important aetiological factor, which leads to ischaemic and inflammatory changes in key brain areas. We have reported increases in the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), markers of inflammation such as that following cerebral ischaemia, in the cerebral microvasculature in the DLPFC. Such increases were found throughout the cortex and subcortical white matter in the DLPFC and we have also found an increase in astrocyte activity in the DLPFC, indicating there may be increased glia in late-life depression, in contrast to the findings in younger adults. Consistent with these findings we examined MRI signal hyperintensities in the deep white matter (DWMH) in depression and found they were due to cerebral ischaemia, especially in the DLPFC. Thus in late-life depression cerebrovascular disease might lead to tissue ischaemia and associated gliosis in the DLFPC whereas in younger adults other mechanisms appear to lead to glial reduction. Whilst the same key prefrontal areas, especially the DLFPC, show pathological changes in adults of all ages, there appear to be different pathological substrates for depression in older and younger adults. This has important implications for treatment. Current therapies are based on assumptions about causation drawn mainly from studies in younger adults and it is important that new treatments and preventative measures are developed which focus on depression as it occurs in older people.
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