title: Are Major Dementias Triggered by Poor Blood Flow to the Brain? Theoretical Considerations.
abstract: There is growing evidence that chronic brain hypoperfusion plays a central role in the development of Alzheimer's disease (AD) long before dyscognitive symptoms or amyloid-β accumulation in the brain appear. This commentary proposes that dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD) may also develop from chronic brain hypoperfusion following a similar but not identical neurometabolic breakdown as AD. The argument to support this conclusion is that chronic brain hypoperfusion, which is found at the early stages of the three dementias reviewed here, will reduce oxygen delivery and lower oxidative phosphorylation promoting a steady decline in the synthesis of the cell energy fuel adenosine triphosphate (ATP). This process is known to lead to oxidative stress. Virtually all neurodegenerative diseases, including FTD, DLB, and CJD, are characterized by oxidative stress that promotes inclusion bodies which differ in structure, location, and origin, as well as which neurological disorder they typify. Inclusion bodies have one thing in common; they are known to diminish autophagic activity, the protective intracellular degradative process that removes malformed proteins, protein aggregates, and damaged subcellular organelles that can disrupt neuronal homeostasis. Neurons are dependent on autophagy for their normal function and survival. When autophagic activity is diminished or impaired in neurons, high levels of unfolded or misfolded proteins overwhelm and downregulate the neuroprotective activity of unfolded protein response which is unable to get rid of dysfunctional organelles such as damaged mitochondria and malformed proteins at the synapse. The endpoint of this neuropathologic process results in damaged synapses, impaired neurotransmission, cognitive decline, and dementia.
authors.forename: Jack C
authors.initials: JC
authors.lastname: de la Torre
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D003704:Dementia / Q000503:physiopathology*; D006801:Humans
keywords: Alzheimer’s disease; Creutzfeldt-Jakob disease; autophagy; brain hypoperfusion; cerebral blood flow; cognitive decline; dementia with Lewy bodies; frontotemporal dementia; inclusion bodies; prion; protein misfolding; unfolded protein response