Contrasting Metabolic Insufficiency in Aging and Dementia

Abstract

Metabolic insufficiency and neuronal dysfunction occur in normal aging but is exaggerated in dementia and Alzheimer's disease (AD). Metabolic insufficiency includes factors important for both substrate supply and utilization in the brain. Metabolic insufficiency occurs through a number of serial mechanisms, particularly changes in cerebrovascular supply through blood vessel abnormalities (ie, small and large vessel vasculopathy, stroke), alterations in neurovascular coupling providing dynamic blood flow supply in relation to neuronal demand, abnormalities in blood brain barrier including decreased glucose and amino acid transport, altered glymphatic flow in terms of substrate supply across the extracellular space to cells and drainage into CSF of metabolites, impaired transport into cells, and abnormal intracellular metabolism with more reliance on glycolysis and less on mitochondrial function. Recent studies have confirmed abnormal neurovascular coupling in a mouse model of AD in response to metabolic challenges, but the supply chain from the vascular system into neurons is disrupted much earlier in dementia than in equivalently aged individuals, contributing to the progressive neuronal degeneration and cognitive dysfunction associated with dementia. We discuss several metabolic treatment approaches, but these depend on characterizing patients as to who would benefit the most. Surrogate biomarkers of metabolism are being developed to include dynamic estimates of neuronal demand, sufficiency of neurovascular coupling, and glymphatic flow to supplement traditional static measurements. These surrogate biomarkers could be used to gauge efficacy of metabolic treatments in slowing down or modifying dementia time course.

Regional Glymphatic Abnormality in Behavioral Variant Frontotemporal Dementia

“…Metabolic insufficiency in disease-related regions may be explained by neuronal loss due to the regional accumulation of metabolic waste and toxic proteins. 52 Cortical hypometabolism was reported to reflect tau pathology and predict TDP-43 status. 53,54 Thus, taken together, these findings suggests that regional glymphatic dysfunction may account more for the pathophysiology of bvFTD.…”

“…This study also showed that aDTI‐ALPS was associated with metabolic activity in the anterior brain regions, including the frontal lobe, OFC, and rectus gyrus. Metabolic insufficiency in disease‐related regions may be explained by neuronal loss due to the regional accumulation of metabolic waste and toxic proteins 52 . Cortical hypometabolism was reported to reflect tau pathology and predict TDP‐43 status 53,54 .…”

Modeling CSF circulation and the glymphatic system during infusion using subject specific intracranial pressures and brain geometries

“…In 2012 Iliff et al [2012] the glymphatic pathway for cerebrospinal fluid flow through the murine brain was identified and suggested to be important for clearance of metabolic waste. Accumulation of metabolic waste is common in dementia Turner [2021], Jack Jr et al 2018] and is suggested to be caused by a malfunctioning glymphatic pathway. The glymphatic system and its pathways have been detailed in mice.…”

Frequency of Dementia in Type II Diabetes Mellitus

“…15 An important early change in dementia is the decreased uptake and utilization of glucose by the brain. Greater insulin resistance is associated with decrease in memory and learning capabilities 16 .…”