KENNETT SQUARE, PA — Why have nearly all clinical trials failed for drugs that prevent or halt Alzheimer’s (AD), Parkinson’s (PD), and other related neurological brain diseases? Why is the primary research focused on secondary disease progression rather than on the initial triggers for these diseases? What triggers these diseases? Why are these diseases so complex?
A unique hypothesis entitled “An Alzheimer’s Disease Mechanism Based on Early Pathology, Anatomy, Vascular-Induced Flow, and Migration of Maximum Flow Stress Energy Location with Increasing Vascular Disease” by Conrad Trumbore and Aditya Raghunandan has recently been open-source published in the Journal of Alzheimer’s Disease. It proposes a trigger hydrodynamic-induced chemical mechanism that suggests answers to the above questions.
The proposed mechanism suggests that hydrodynamic forces arising from pulsed cerebrospinal fluid (CSF) flow stretch dissolved protein molecules as they flow through highly confined spaces within the brain. This results in the molecular aggregation of these stressed molecules. Such stretched, aggregated complexes result in “misfolded” proteins that ultimately form the toxic molecular aggregates that have been proposed to initiate multiple brain diseases. The identity of the resulting disease is suggested to be dependent on the types of fluid stresses involved, the energy intensity of fluid pulses, the length of time during which the pulse transfers its energy to the protein molecule, the initial structure of the protein, the opportunity for interaction with other stretched CSF dissolved proteins, and adsorption of the protein complex on surrounding surfaces. Based on MRI studies of the brain, energetic CSF “hot spots” in and around lower brain cisterns and ventricles are proposed as prime suspects for regions in which flow-stress-induced toxic aggregates are formed. Many of these hot spots are sites of the earliest Alzheimer’s and other disease pathology that share the protein-misfolding motif.
These MRI studies clearly show that all parts of the brain are subjected to pulsed back-and-forth CSF flows. Yet nearly all basic brain neurology laboratory studies are conducted under quiescent conditions, that is, without the actual environmental fluid stresses and strains present in the human brain. Individual neurons and associated cellular structures are also subjected to strong mechanical pulses induced by vascular pulses so that intracellular as well as intercellular fluid flows may be generated within a crowded cellular brain environment that is exposed to strong vascular systolic pulses. Trumbore suggests that such intracellular fluid flows could generate key disease bioindicators such as tau tangles in AD within neurons.
A critical part of this hypothesis is the proposal that the brain location of the maximum high-energy CSF pulse intensity is displaced with increasing age. Early atherosclerosis of arteries near the heart causes this migration away from the heart, exposing everchanging, expanding new brain regions to stronger pulsatory CSF flow. This could explain the highly complex time onset and progression of AD and related neurological diseases. Hydrodynamics depends very much on the shape and absolute size of flow channels and, although humans all share similar anatomical features, their critical hot spot hydrodynamics may vary in subtle ways. Trumbore speculates that although animals used in drug studies may have brain structures that generally parallel those in humans, they also probably have different CSF flow path-stress energy patterns.
Reviewers of this paper describe the proposed theory as “intriguing” and have recommended that laboratory experiments and clinical research projects are needed to test this theory. However, Trumbore reports that because of the multidisciplinary nature of the theory, many basic scientists hesitate to do such experiments because they lack a hydrodynamics background. He suggests that what may be needed are interdisciplinary teams to undertake and help guide such experiments. Trumbore insists that, if the above hypotheses are correct, there is an urgent need for a much wider research program including fundamental pulsatory studies in chemistry, biology, and hydrodynamics as well as greatly expanded lower brain MRI clinical studies.
If the proposed mechanism is correct, what can be done to prevent these devastating neurological diseases? The most obvious precaution would be to prevent atherosclerosis that generates strong CSF pulses further from the heart with aging. Failing that, blunting the strong CSF pulse systolic peak could be a possible goal.
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