| dc.description.abstract | Neurodegenerative disorders (NDDs) embody the progressive loss of structure or function of neurons, typically culminating in neuronal cell death and include conditions such as Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and multiple sclerosis (MS). AD is characterized neuropathologically by aggregation and accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFTs), DLB by the presence of α-synuclein Lewy bodies and neurites, and MS by the presence of demyelinating lesions. Despite differences in their underlying neuropathology, they share symptoms of sleep disturbances such as insomnia, sleep apnea, rapid eye movement sleep behaviour disorder, and other sleep-wake cycle disturbances. Moreover, disrupted sleep patterns in NDDs have been shown to worsen existing neurological symptoms, thereby further diminishing patients’ quality of life and potentially accelerating the disease process. Functions such as sleep, wakefulness, memory, and cognition are all in part modulated by the cholinergic system. Acetylcholine (ACh), a key neurotransmitter in the cholinergic system, is synthesized by choline acetyltransferase (ChAT) and interacts with nicotinic and muscarinic acetylcholine receptors before being hydrolyzed by the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The basal forebrain (BF) and brainstem (BS), brain regions crucial for the sleep-wake cycle, exhibit significant expression of ChAT, AChE, and BChE. Cholinergic system changes are prevalent in NDD brains, and appears to exert notable effects on neuroinflammation, neuropathology, neurodegeneration, and cognitive functions. The contribution of neuropathology and neuroinflammation to sleep-wake cycle dysfunction in AD, DLB, and MS is not well known. This study investigated cholinergic, neuropathological, and neuroinflammatory changes in nuclei related to sleep in the basal forebrain (BF) and brainstem (BS) in AD, DLB, MS and cognitively normal (CN) brains. Formalin-fixed human tissue blocks from AD, DLB, MS, and CN brains containing the medial septum, vertical limb of the diagonal band of Broca, and nucleus basalis of Meynert of the BF and the pedunculopontine nucleus, laterodorsal tegmental nucleus, dorsal raphe nucleus, and locus coeruleus (LC) of the BS were utilized in this study. BF and BS sections were examined with histochemical and immunohistochemical techniques to evaluate for cholinergic, neuroinflammatory, and neuropathological markers. Results showed significant reductions in ChAT-, AChE-, and NADPH-diaphorase- positive neurons, and LC pigmented neurons in AD and DLB brains, but not MS. Aβ- and cholinesterase-positive plaques as well as tau NFTs were observed frequently in AD but sparsely in DLB, which also exhibited moderate α-synuclein pathology. pTDP-43 pathology was identified in just one case among all the brains examined, specifically within the AD group, with no significant difference observed when compared to CN brains. MS cases showed several demyelinated lesions throughout varying regions of the BF and BS. Elevated neuroinflammation was noted in all NDD brains. Results demonstrated that cholinergic, neuropathological, and neuroinflammatory changes are observed in BF and BS nuclei involved in sleep in many NDD brains and may underlie sleep-wake disturbances. Investigating the intricate mechanisms and contributors of sleep dysfunction in NDDs could help facilitate better understanding of these conditions and provide new avenues for development of novel curative and diagnostic approaches. | en_US |
