Ageing of the normal brain

Until recently, ageing and senility were considered firm partners. We now know, however, that normal ageing ofthe brain is a process distinct from the degenerative dementias. Early neuropathology studies led to the dogma that up to 40% of neurons inexorably died over the lifespan. That belief was overturned by improved methodology using unbiased stereological techniques (Morrison & Hof 1997). In ageing primates and ageing rodents, rather than a loss of cortical pyramidal cells there is decreased neuronal size and loss of synaptic arborization (Masliah et al 1993, Peters et al 1994). Gomez-Isla et al (1996) found no age-related loss of cells in the entorhinal cortex of the temporal lobe in normal subjects aged from 60 to 90, in contrast to losses up to 65% in early Alzheimer's disease (AD).

A modest loss of brain volume occurs in normal ageing. In men, total brain volume at 60 is 10% less than at 25 years (Murphy et al 1992). This change affects cortical and subcortical white matter rather than grey matter (Guttmann et al 1998, Peters et al 1994) and is associated with myelin pathology in vertical fibres traversing deeper layers of the cortex. This myelin pathology will slow nerve conduction in association pathways, and may lead to functional deficits in reaction time and working memory (Peters 1996, Peters et al 1994, 2000). In the rhesus monkey, neurons of prefrontal cortex and substantia nigra show severe dendritic pathology, with loss of organelles, vacuolation of cytoplasm, membranous whorls and dense inclusion bodies (Siddiqi & Peters 1999, Peters et al 1998). There is a reduction of 30—60% in the density of apical synapses on pyramidal cells in prefrontal cortex. These changes correlate with age-related cognitive impairment (Peters et al 1996, 1998).

It was also accepted wisdom that age-related neuronal loss occurs in subcortical nuclei of the human brainstem, such as locus ceruleus (LC), which project widely to the cerebral cortex and to subcortical limbic system sites, including the hypothalamus (Chan-Palay & Asan 1989). Recent results with unbiased stereological methods are conflicting, with predominantly negative studies (Ohm et al 1997, Kubis et al 2000), though some continue to report substantial cell loss in LC with age (Manaye et al 1995). Whether LC cells do or do not die with age, their forebrain and hypothalamic projections certainly are dystrophic, with reduced terminal arborization, loss of synaptic contacts and abnormal axonal branching (Ishida et al 2000). A similar pattern of preserved neuronal number but aberrant axonal formations with ageing occurs in the serotonin-containing rostral projections of the dorsal raphe nucleus (Nishimura et al 1998, van Luijtelaar et al 1992).

A particular focus of recent work has been the trisynaptic perforant pathway (PP) circuit that projects from layer II of the entorhinal cortex (EC) to granule cells in the dentate gyrus of the hippocampus. These neurons in turn send mossy fibre projections to the CA1 and CA3 regions of Ammon's horn, with further relays to the hippocampal outflow paths via the subiculum and the fimbria-fornix (see Morrison & Hof 1997). This circuit is critical for associative memory, as the EC receives highly processed information from heteromodal cortical association areas, which it funnels into the hippocampus. Layer II of the EC is affected by neurofibrillary tangles (NFTs) very early in AD, but it is minimally affected in normal ageing. Likewise, there is up to a 50% neuronal loss in the EC in early AD but not in normal ageing.

Nevertheless, there is evidence of functional impairment of the perforant pathway in normal ageing. Smith et al (2000) reported that spatial learning deficits in aged rats correlated with reduced synaptophysin staining in the PP entry zone, as well as in the CA3 region, which suggests loss of synaptic integrity between EC and hippocampus via the PP. There is also a significant decrease of N-methyl-D-aspartate (NMDA) receptor subunit 1 (NMDAR1) in the distal dendrites of the dentate gyrus granule cells that receive the PP input (Gazzaley et al 1996) — the inference is that distal dendritic pruning has occurred in the granule cells. It is now clear that glucocorticoid excess and chronic stress produce similar dendritic changes (McEwen 2000). The role of the PP and NMDA receptors in long-term potentiation in the hippocampus is well known, and the changes just described have been suggested as a basis of benign, age-related memory decline (Morrison & Hof 1997).

In the hypothalamus itself, ageing and AD also are quite distinct with respect to NFTs (Swaab et al 1992) and cell survival. Age-related changes of neuronal number in human hypothalamic nuclei are quite variable (Swaab 1995, Hofman 1997). The sexually dimorphic interstitial nucleus of the anterior hypothalamus displays a greater than 80% decrease of cell number in both sexes. In contrast, the vasopressin- and oxytocin-producing cells of the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) remain intact in old age. In the infundibular nucleus there is increased cell number and activity, with hypertrophic neurokinin B neurons in postmenopausal women.

Age-related neuronal dystrophic changes occur in the hypothalamus, similar to those described in EC, hippocampus and cerebral cortex. For example, in the arcuate nucleus the number of dendritic segments, total dendritic length, branching and spine densities are reduced (Leal et al 1998). Likewise, in the SON of the rat, marked dendritic regression is seen even though there is no neuronal loss. The dendritic regression is thought to result from deafferentation due to the preceding age-related loss of the noradrenergic input to the SON from the brainstem (Flood & Coleman 1993). A related contribution is the decrease of a key growth factor, brain-derived neurotrophic factor (BDNF) in ageing (Croll et al 1998). These dystrophic changes in the ageing hypothalamus resemble those seen in the hippocampus and the frontal cortex with stress (see below). The morphologic similarities are accompanied by activation of hypothalamic nitric oxide synthase (NOS) through NMDA receptor activation in both stress and ageing (Kishimoto et al 1996, Vernet et al 1998). This process has been identified as responsible for corticosterone-produced dystrophic dendritic changes in CA3 hippocampal pyramidal cells (Reagan et al 1999), and may be a general mechanism by which stress and glucocorticoids cause neuronal dystrophy. Likewise, both stress and ageing are associated with a decrease of BDNF in hippocampus, hypothalamus and cortex. Furthermore, in ageing rats the dynamic responses of BDNF and its receptor, TrkB, to stress are impaired (Smith et al 1995, Smith & Cizza 1996), a dysregulation that appears to be glucocorticoid-mediated (Cosi et al 1993).

In summary, age-associated changes in the brain are not like the pathology of AD. They more closely resemble the changes caused by stress. There is no marked loss of cortical neurons and only minimal appearance of NFTs in the PP— hippocampal circuit or the hypothalamus. There is significant pathology of myelin and of glial cells, which may slow nerve conduction velocities, reduce the formation of synapses, and impair normal associative functioning. Most striking is the dystrophy of forebrain projections from key brainstem nuclei. Axons display reduced terminal arborization and abnormal branching, which is followed by dendritic atrophy in the terminal fields. This deafferentation and the loss of synapses result in functional disconnection and consequent dysregulation of hypothalamic functions, including the gonadal, growth hormone and hypothalamus—pituitary—adrenal (HPA) axes. Candidate mechanisms for the functional disconnection of the forebrain and hypothalamus in ageing are NMDA receptor—NOS activation, compounded by impaired responsiveness of mRNA for BDNF and TrkB, which would normally counter-regulate the dendritic and axonal dystrophy in brainstem and forebrain sites. Both these neurochemical changes are glucocorticoid-mediated and are seen in chronic stress.

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