Alzheimer disease neuropathology:understanding autonomic dysfunction

Abstract

Alzheimer’s disease is a widely studied disorder with research focusing on cognitive and functional impairments, behavioral and psychological symptoms, and on abnormal motor manifestations. Despite the importance of autonomic dysfunctions they have received less attention in systematic studies. The underlying neurodegenerative process of AD, mainly affecting cortical areas, has been studied for more than one century. However, autonomic-related structures have not been studied neuropathologically with the same intensity. The autonomic nervous system governs normal visceral functions, and its activity is expressed in relation to homeostatic needs of the organism’s current physical and mental activities. The disease process leads to autonomic dysfunction or dysautonomy possibly linked to increased rates of morbidity and mortality.ObjectiveThe aim of this review was to analyze the cortical, subcortical, and more caudal autonomic-related regions, and the specific neurodegenerative process in Alzheimer’s disease that affects these structures.MethodsA search for papers addressing autonomic related-structures affected by Alzheimer’s degeneration, and under normal condition was performed through MedLine, PsycInfo and Lilacs, on the bibliographical references of papers of interest, together with a manual search for classic studies in older journals and books, spanning over a century of publications.ResultsThe main central autonomic-related structures are described, including cortical areas, subcortical structures (amygdala, thalamus, hypothalamus, brainstem, cerebellum) and spinal cord. They constitute autonomic neural networks that underpin vital functions. These same structures, affected by specific Alzheimer’s disease neurodegeneration, were also described in detail. The autonomic-related structures present variable neurodegenerative changes that develop progressively according to the degenerative stages described by Braak and Braak.ConclusionThe neural networks constituted by the central autonomic-related structures, when damaged by progressive neurodegeneration, represent the neuropathological substrate of autonomic dysfunction. The presence of this dysfunction and its possible relationship with higher rates of morbidity, and perhaps of mortality, in affected subjects must be kept in mind when managing Alzheimer’s patients.

Unsuspected Involvement of Spinal Cord in Alzheimer Disease

“…The hippocampi have been proposed as in vivo non-invasive imaging biomarkers of AD while other structures may be useful in distinguishing between different subtypes of dementia (Palesi et al, 2018). Only far and few old studies have looked at the spinal cord in AD, from a postmortem histochemical analysis and with reference to the autonomic system, but results were never reproduced or follow through as they focused on tau pathology, which was only sporadically reported (Engelhardt and Laks, 2016).…”

Vascular Risk Factors and Cognitive Function

“…Insular cortex, in particular, is a frequent site of vascular damage, and may be involved in a brain-heart axis increasing the risk of future brain vascular damage [60]. Moreover, amygdala is affected by AD neuropathology early in the neurodegenerative process (Braak stages II-III), possibly before the onset of overt cognitive impairment, and insula and anterior cingulate cortex are involved too, in a slightly later stage (Braak stages III-IV) [61]. As an alternative explanation, higher heart rate variability might be a marker of healthier cardiovascular system, which is a protective factor for brain aging and functional decline.…”

Dysautonomia in Alzheimer's Disease

“…Autonomic nervous system (ANS) mediates homeostasis by controlling several visceral systems and providing specific responses (i.e., autonomic behaviors) that accompany and adjust in relation to physical efforts and mental activities (e.g., emotions, cognitive challenge) [ 4 ]. Damage to the ANS that impairs function beyond compensatory mechanisms leads to dysautonomia [ 4 ].…”

“…Autonomic nervous system (ANS) mediates homeostasis by controlling several visceral systems and providing specific responses (i.e., autonomic behaviors) that accompany and adjust in relation to physical efforts and mental activities (e.g., emotions, cognitive challenge) [ 4 ]. Damage to the ANS that impairs function beyond compensatory mechanisms leads to dysautonomia [ 4 ]. The spectrum of dysautonomia manifestations ranges from asymptomatic (detectable only on clinical examination or autonomic testing) to disabling symptoms (orthostatic hypotension, syncope) [ 4 ].…”