Early neurone loss in Alzheimer’s disease: cortical or subcortical?

Abstract

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.

Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology

“…In sum, our findings build on a varied body of histological evidence, which collectively point to both Ch4 and EC as early targets of AD pathology8. The cell groups constituting these structures are among the first to express intraneuronal neurofibrilliary tangles and Aβ-containing plaques in cognitively normal older adults.…”

“…The cell groups constituting these structures are among the first to express intraneuronal neurofibrilliary tangles and Aβ-containing plaques in cognitively normal older adults. They are also among the cell groups most devastated by tangles and plaques in MCI and AD81114. The proliferation of tangles and plaques in these structures leads to depletion of axons and cell loss, both of which contribute to microstructural decreases in volume8151718.…”

“…However, the initial stages of AD pathophysiology remain ill defined89, preventing a clear picture of what regions to target as the earliest points of spread. The prevailing model suggests that amyloid and tau deposition first appear within the transentorhinal and entorhinal cortex (EC)10111213.…”

[P3–379]: Altered Functional Connectivity of the Basal Nucleus of Meynert in Mild Cognitive Impairment: A Resting‐state Fmri Study

“…For instance, volume reduction of the BNM and temporal lobe structures was associated with impairment in delayed recall in MCI patients (Grothe et al, 2010). These findings are consistent with neuronal loss in the BNM during the prodromal stage of AD and greater neuronal loss in the BNM than other cortical and subcortical structures in advanced AD (Arendt et al, 2015).…”

Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease

“…Downregulation of Drd2 and Adra1b may be related to dysfunction and neurodegeneration of catecholaminergic systems, including the ventral tegmental area and locus coeruleus (Bondareff et al, 1987; Gibb et al, 1989; Mann et al, 1980), during the progression of AD, which would cause dysregulation of inputs to the cholinergic nbM (Jones and Cuello, 1989; Smiley and Mesulam, 1999; Smiley et al, 1999; Zaborszky and Cullinan, 1996). In particular, we and others have shown that locus coeruleus noradrenergic neuron loss occurs very early in the disease process (Arendt et al, 1985, 2015; Kelly et al, 2017; Theofilas et al, 2017) and likely contributes to disruptions in cholinergic modulation of attentional function. Glutamate-mediated excitotoxicity has been implicated in AD neuronal dysfunction and cognitive impairment, and dysregulation of the Grin2B -encoded NMDA receptor 2B subunit appears to be a primary pathogenic event in disease progression (Andreoli et al, 2013; Hu et al, 2012; Olney et al, 1997).…”