Neurochemical Correlates of Dementia Severity in Alzheimer's Disease: Relative Importance of the Cholinergic Deficits

Abstract

Cholinergic markers, neuropeptides, and amines and their metabolites were sampled from identical specimens across 10 neocortical regions in a large sample of Alzheimer's disease (AD) cases and controls. Levels of choline acetyltransferase, acetylcholinesterase, somatostatin, corticotropin‐releasing factor, serotonin, and 5‐hydroxyindoleacetic acid were significantly reduced in AD versus controls. After data reduction, the most descriptive neurochemical indices were used to examine the relationship of neurochemical measures and dementia severity within the AD sample, controlling for age effects. Dementia severity ratings were based on antemortem assessments (46.9% of AD sample) and postmortem chart review (53.1% of the AD sample). Choline acetyltransferase activity was highly correlated with clinical dementia ratings across the neocortex of the AD cases. Somatostatin and corticotropin‐releasing factor levels were correlated with dementia severity only when control cases were included in the analyses. None of the amines, their metabolites, or the neuropeptides quantified related significantly to dementia severity in the AD cohort. These data (a) confirm the strong association of cholinergic deficits with functional impairment in AD and show that this association is independent of age and (b) suggest that of all the neurochemical species quantified, the cholinergic indices may be unique in their association with dementia severity.

Single-Cell Gene Expression Analysis: Implications for Neurodegenerative and Neuropsychiatric Disorders

“…CBF neurons of the nucleus basalis (NB) are selectively vulnerable in AD (72,73), and CBF neuron degeneration correlates with disease duration and cognitive decline (74,75). However, the molecular mechanisms(s) associated with CBF cytopathology and cellular dysfunction is unknown.…”

Human adipose tissue‐derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice

“…Cholinergic nerve cells in the basal forebrain undergo neurodegenerative changes during normal ageing as well as in Alzheimer's disease (AD; Bartus et al, 1982;Grothe et al, 2012). Progressive loss of cholinergic neurons, marked by reduced choline acetyltransferase (ChAT) activity leading to decreased acetylcholine (ACh) release and p75 neurotrophin receptor expression, occurs during ageing and AD (Whitehouse et al, 1982;Bierer et al, 1995;Mufson et al, 2002;Gil-Bea et al, 2005;Roman and Kalaria, 2006;Contestabile et al, 2008). The degree of cholinergic neuron loss is closely associated with the severity of the cognitive deficits (Pizzo et al, 2002).…”

Progression of Tau Pathology in Cholinergic Basal Forebrain Neurons in Mild Cognitive Impairment and Alzheimer's Disease

“…Degeneration of the cholinergic basal forebrain (CBF) neurons, which provide the major cholinergic innervation to the entire cortical mantle, hippocampus, and amygdala 1,2 correlates with dementia severity, disease duration, and cognitive impairment 3,4 in Alzheimer's disease (AD). 3,[5][6][7][8][9] The viability of CBF neurons is dependent on the prototypic neurotrophic substance, nerve growth factor (NGF), 10 which is retrogradely transported to CBF neurons through a complex interaction of its two receptors, the high-affinity NGF-specific cell survival tyrosine kinase (trkA) and the putative cell death associated lowaffinity pan neurotrophin (p75 NTR ) receptor.…”