Le cerveau aux limites du vieillissement: à propos des nonagénaires et centenaires

Abstract

The elderly population represents the fastest growing age group worldwide and there is a growing awareness of age-related diseases such as dementia. By 2020 it is estimated that at least 1 billion people will be older than 60 years representing more than 20% of the total population. However, recent epidemiological studies of very old individuals have shown that prevalence rates of dementia vary from 27 to 62% pointing to the fact that dementia is not inevitable in very old individuals and that the risk of Alzheimer's disease (AD) decreases significantly after age 90, suggesting a relative resistance of centenarians to the degenerative process. Normal brain aging is characterised by the formation of neurofibrillary tangles (NFT) and senile plaques (SP), as well as neuronal and synaptic loss in both cognitively intact individuals and patients with AD. In non-demented cases neurofibrillary tangles are usually restricted to the hippocampal formation, whereas the progressive involvement of the association areas in the temporal neocortex parallels the development of overt clinical signs of dementia. In contrast, there is no correlation between the quantitative distribution of senile plaques and severity of AD. The pattern of lesion distribution and neuronal loss changes in extreme aging. Several neuropathologic analyses postulated that in contrast to younger cases where dementia is mainly related to severe NFT formation within adjacent components of the medial and inferior aspects of the temporal cortex, oldest-old individuals display a preferential involvement of the anterior part of the CA1 field of the hippocampus whereas the inferior temporal and frontal association areas are relatively spared, supposing that the extent of NFT development in the hippocampus is the key determinant of dementia in the very old. In our first series of 12 patients older than 90 years with sterological analysis we found a significant difference in NFT densities, in the anterior CA1 field, but not in the posterior CA1 field and entorhinal cortex (EC), between demented and non-demented very old patients and suggested that nonagenarians and centenarians may show a displacement of subregional distribution of NFT within the CA field. Cortical association areas were relatively preserved. The progression of NFT formation across the different CDR groups was significantly slower in nonagenarians and centenarians compared to younger cases in the CA1 field and EC; even cases with moderate dementia display only mild NFT formation in this area with more than 80% of preserved neurons. The total amyloid and the neuronal loss in the entorhinal cortex and CA1 field in these cases were also significantly lower than that reported in younger AD cases. In a second stereologic study of 19 very old individuals with various degrees of cognitive impairment we also assessed total capillary length, number and length-weighted mean diameters in the CA1 and entorhinal cortex. Both mean diameters and total capillary numbers, but no capillary length, were strongly related to total neuron numbers in the CA1 field and entorhinal cortex. In conclusion, the most intriguing results of these studies were the relative paucity of correlations between AD pathological hallmarks in the hippocampal formation and clinical status after 90 years and the clear dissociation between total neuron numbers and AD-related lesions in the hippocampal formation. Microvascular parameters such as mean capillary diameters may be a key factor to consider for the prediction of cognitive decline in the oldest-old.