Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer's disease

Abstract

Cholinergic neurons were studied by immunohistochemistry, with an antiserum against choline acetyltransferase (ChAT), in the basal forebrain (Ch1 to Ch4) of four patients with Alzheimer's disease (AD) and four control subjects. ChAT-positive cell bodies were mapped and counted in Ch1 (medial septal nucleus), Ch2 (vertical nucleus of the diagonal band), Ch3 (horizontal nucleus of the diagonal band) and Ch4 (nucleus basalis of Meynert). Compared to controls, the number of cholinergic neurons in AD patients was reduced by 50% on average. The interindividual variations in cholinergic cell loss were high, neuronal loss ranging from moderate (27%) to severe (63%). Despite the small number of brains studied, a significant correlation was found between the cholinergic cell loss and the degree of intellectual impairment. To determine the selectivity of cholinergic neuronal loss in the basal forebrain of AD patients, NPY-immunoreactive neurons were also investigated. The number of NPY-positive cell bodies was the same in controls and AD patients. The results (1) confirm cholinergic neuron degeneration in the basal forebrain in AD and the relative sparing of these neurons in some patients, (2) indicate that degeneration of cholinergic neurons in the basal forebrain contributes to intellectual decline, and (3) show that, in AD, such cholinergic cell loss is selective, since NPY-positive neurons are preserved in the basal forebrain.

Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain

“…3A in Mufson et al, 1989). The cell group designated as Ch3 in our paper represents a transitory area between the septum-diagonal band complex and the more caudal cell groups of the magnocellular basal forebrain system and may correspond to be part of the anteromedial Ch4 group in some publications (Mesulam et al, 1983;Lehericy et al 1993;Gilmor et al, 1999). We, and others, noted that a separation of the anterior Ch4 group into medial and lateral sectors by a vascular structure, as proposed by Mesulam and his coworkers, is ambiguous due to the variation of the vessels (Halliday et al, 1993;Swaab, 2003).…”

“…Severe involvement of the magnocellular basal complex has been found in Alzheimer's disease, where various studies reported cell loss up to 90% (Whitehouse et al, 1981;Vogels et al, 1990;Lehericy et al, 1993;Cullen and Halliday, 1998). Estimations of the neuronal loss of basal nucleus of Meynert during normal aging also vary greatly from 23% to 50% to no neuronal loss at all (Whitehouse et al, 1981;Chui et al, 1984;De Lacalle et al, 1991).…”

MEG resting state functional connectivity in Parkinson’s disease related dementia

“…A possible common candidate accounting for the loss of synchronization could be the profound loss of cortical cholinergic projections from the basal nucleus of Meynert, since this is a characteristic of AD, DLB and PDD (Braak et al 2003;Londos et al 2002;Lippa et al 1999;Cullen and Halliday 1998;Lehericy et al 1993;Vogels et al 1990;Candy et al 1983). Involvement of the cholinergic system is supported by an animal study, in which lesioning of the cholinergic system resulted in a reduction of long distance intrahemispheric as well as interhemispheric coherence (Holschneider et al 1999).…”

Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer's disease and dementia

“…Initial studies of the basal forebrain in DAT suggested that decrements in cortical ChAT were the result of frank loss of nucleus basalis cholinergic magnocellular neurons (72,73). However, more detailed analyses revealed that cholinergic neurons were generally shrunken and dysfunctional, but not dead, except in late-stage DAT (74)(75)(76)(77)(78)(79). These neuronal phenotypic changes without frank neuronal degeneration also occur early in cognitive decline (80).…”