Early neurone loss in Alzheimer's disease: cortical or subcortical?
Bottom Line: In all three areas, neurone loss becomes detectable already at preclinical stages and is clearly manifest at prodromal AD/MCI.At more advanced AD, cell loss is most pronounced in the NbM > LC > layer-II EC.During early AD, however, the extent of cell loss is fairly balanced between all three areas without clear indications for a preference of one area.
Alzheimer's disease (AD) is a degenerative disorder where the distribution of pathology throughout the brain is not random but follows a predictive pattern used for pathological staging. While the involvement of defined functional systems is fairly well established for more advanced stages, the initial sites of degeneration are still ill defined. The prevailing concept suggests an origin within the transentorhinal and entorhinal cortex (EC) from where pathology spreads to other areas. Still, this concept has been challenged recently suggesting a potential origin of degeneration in nonthalamic subcortical nuclei giving rise to cortical innervation such as locus coeruleus (LC) and nucleus basalis of Meynert (NbM). To contribute to the identification of the early site of degeneration, here, we address the question whether cortical or subcortical degeneration occurs more early and develops more quickly during progression of AD. To this end, we stereologically assessed neurone counts in the NbM, LC and EC layer-II in the same AD patients ranging from preclinical stages to severe dementia. In all three areas, neurone loss becomes detectable already at preclinical stages and is clearly manifest at prodromal AD/MCI. At more advanced AD, cell loss is most pronounced in the NbM > LC > layer-II EC. During early AD, however, the extent of cell loss is fairly balanced between all three areas without clear indications for a preference of one area. We can thus not rule out that there is more than one way of spreading from its site of origin or that degeneration even occurs independently at several sites in parallel.
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Mentions: In the normal aged brain (mean age 81.3 +/− 4.4 years; see Table 1), we determined the mean number of neurons in the NbM, in the LC and in Layer II of the entorhinal cortex at 168,834+/−25,573, 17,487+/−2,736 and 677,685+/−88,072, respectively. As can be seen in Figure 1, there was, however, a rather large inter-individual variety and neuron count varied from 125,734 to 215,827 in the NbM (CV = 0.15), from 13,371 to 22,712 in the LC (CV = 0.15) and from 512,914 to 810,211 in the entorhinal cortex, layer II (CV = 0.13).Table 1