To what degree is the neurodegeneration of Alzheimer’s disease driven by reduced blood flow to brain tissue? This is as compared to the contributions of the well-studied aggregation of amyloid-β and tau proteins, or the neuroinflammation driven by senescent cells, persistent viral infection, and various forms of molecular damage in and around cells. One of the challenges inherent in investigations of aging and age-related disease is that it is very hard to determine the relative importance of the range of mechanisms likely involved in producing pathology, loss of function, and eventual mortality. Here, however, the data suggests that vascular dysfunction may indeed be more important than protein aggregation, at least in the earlier stages of Alzheimer’s disease.
Instead of looking at the brain’s amyloid plaques, researchers focused on the way blood flow through the brain is autoregulated in order to oxygenate the brain tissue, and whether possible dysregulation may cause cognitive impairment. The study harnessed data from 200 participants over five years, investigating the intricate dynamic relationship between natural changes in arterial blood pressure, carbon dioxide (CO2) levels in the blood, and the resulting fluctuations of cerebral blood flow and cortical tissue oxygenation. “When we exert cognitive effort, we generate CO2 from the metabolism in our cerebral cells, which obviously has to be taken away by our blood to avoid acidosis. Our body is endowed with this regulatory mechanism called vasomotor reactivity, which dilates (widens) our cerebral vessels when CO2 goes up in the blood, so that more blood can go through and the excess CO2 be washed out.”
Fifteen years ago, researchers made a serendipitous observation: Alzheimer’s patients show impaired vasomotor reactivity. “They cannot dilate the cerebral vessels to bring more blood in and provide adequate blood perfusion to the brain. This means they don’t get the oxygen, nutrients, and glucose that we need for cognition in a timely manner.” In the new study, researchers tested this observation, developing a novel marker called the Cerebrovascular Dynamics Index (CDI). This non-invasive test uses non-invasive Doppler ultrasound to measure blood flow velocity in some main arteries of the brain, and near-infrared spectroscopy to measure oxygenation in the front part of the brain’s cortex. This quantifies how quickly and effectively the brain’s blood supply responds to subtle changes in pressure and CO2.
The research team obtained some encouraging results – The CDI showed excellent diagnostic performance, differentiating individuals with mild cognitive impairment (MCI) or Alzheimer’s from cognitively normal control subjects with an Area Under the Curve (AUC) of 0.96. AUC is a common statistical measure of diagnostic performance; a value of 1.0 is perfect, and 0.5 is random chance. For context, the amyloid PET test achieved an AUC of only 0.78, while the Montreal Cognitive Assessment (MoCA) and mini-mental state examination (MMSE) cognitive tests were 0.92 and 0.91, respectively. The difference between 0.78 and 0.96 translated to a “very substantial improvement” in the test’s ability to correctly identify those with and without the condition.
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