Brain's Metabolic Run-up to Dementia Directly Linked to Hypertension, Carotid Disease

March 02, 2021

What could be early metabolic signs of future dementia, as seen by PET, were closely associated with standard cardiovascular (CV) disease risk factors, some modifiable, in a study of middle-aged people in the community.

The PET scans showed deficient glucose metabolism, which may signal early neurodegeneration, concentrated in specific brain regions closely linked to dementia, including Alzheimer's disease (AD), the team reports. The results are based on assessment of asymptomatic participants, 40 to 54 years of age, in the PESA prospective cohort study.

The regions of glucose hypometabolism were independently correlated with preclinical carotid artery disease and even more so with 30-year Framingham Risk Score (FRS), the latter association driven by the eminently treatable hypertension.

"Our data suggest that brain metabolism may be affected from the earliest stages of exposure to CV risk factors," conclude the researchers, who predict that primary-preventive therapies could potentially "delay or even stop downstream brain alterations" that can lead to neurocognitive decline and dementia.

Their report was published in the February 23 issue of the Journal of the American College of Cardiology, with lead author Marta Cortes-Canteli, PhD, Spanish National Cardiovascular Research Center, Madrid.

Brain hypometabolism on 18F-fluorodeoxyglucose (FDG) PET scans was "present in parietotemporal areas critical for spatial and semantic memory, language and visual processing, and learning and memory retrieval; most of these regions form part of a specific hypometabolic AD signature predictive of future cognitive deterioration," they write.

"Therefore, in middle-aged individuals, hypometabolism in these brain areas may be interpreted as a marker of increased vulnerability to future cognitive decline due to AD."

The findings "suggest that the interplay between CV risk factors, atherosclerosis, and altered brain metabolism starts early in life," and support the use of primary CV prevention measures "early in midlife" as a strategy for cutting risk for later dementia, the group concludes.

"Most studies that utilize FDG PET use it as a downstream marker for neuronal injury, so in this study, it is possible that the poor FDG uptake in those specific brain regions may be markers of new neurodegeneration," observed Alifiya Kapasi, PhD, Rush Medical College and Alzheimer's Disease Center, Chicago, for theheart.org | Medscape Cardiology.

It's also known that that beta amyloid and tau tangles, "which are the pathologic hallmarks of Alzheimer's disease, can accumulate in these regions." That's especially true for beta amyloid, "which studies have shown is the first pathologic change in the AD continuum," said Kapasi, a research neuropathologist not associated with the current report. "They've been shown to accumulate even in preclinical AD patients."

But despite the strong evidence linking such hypometabolism to neurodegeneration, "we have to consider there may be other factors at play, and one of them could be inflammation, which could have an impact on glucose uptake," she said.

"The study filled important gaps in the emerging paradigm by which midlife cardiovascular risk factors influence brain health and may cause cognitive impairment and dementia," states an accompanying editorial from Neal S. Parikh, MD, Weill Cornell Medicine, New York City, and Rebecca F. Gottesman, MD, PhD, Johns Hopkins University, Baltimore.

The associations seen between the observed regional hypometabolism pattern with FRS and carotid atherosclerosis burden, they write, "implicates these factors in AD decades before the typical age of symptom onset."

The study further suggests that carotid atherosclerosis, independently of other CV risk factors, "may be detrimental to brain health even when it is subclinical and non-stenosing."

The analysis involved 547 PESA participants, evaluated from 2010 to 2014, who had imaging evidence of atherosclerosis and whose vascular PET scans included the entire brain; their mean age was 50.3 years.

Global cerebral FDG uptake was inversely correlated with 30-year FRS, with a beta coefficient of 0.15, driven by the hypertension component that had an effect size of 0.36 (< .001 for both coefficients), the group reports. But it wasn't significantly associated with the study's proxy for total atheroma plaque burden, that is, the combination of carotid arterial plaque and femoral arterial plaque burdens by 3-dimensional vascular ultrasound.

Nor was brain FDG uptake correlated with plaque burden in the femoral arteries by themselves. However, it was inversely correlated with carotid plaque burden, with a beta of 0.16 (P < .001) unadjusted, and 0.13 (< .002) after adjustment for 30-year FRS.

Areas of the brain with the most impaired FDG uptake associated with FRS, hypertension, and carotid plaque burden, the report notes, were the parietotemporal regions — including the angular, supramarginal, and inferior and middle temporal gyri — and the cingulate gyrus.

The study highlights "the potential damaging effects of unmitigated cardiovascular risk factors and subclinical atherosclerosis on brain health in people as young as 40 years of age," write Parikh and Gottesman. "Longitudinal assessments of cognitive measures, in addition to vascular and AD biomarkers, are needed to comprehensively grasp the role and mechanisms of cardiovascular risk factors in dementia."

It's "plausible" that impairment of glucose uptake as shown by FDG PET represents "a link between vascular disease and neurodegeneration," Kapasi said in an interview. But, "they don't include any clinical measures, so to really understand how their vascular risk factors are related to glucose metabolism — and down the road, dementia — would be vary hard to interpret from this study," she said. "Further studies are warranted to really tease out the causal relationship."

PESA is partially funded by Banco Santander , Madrid , Spain . Cortes-Canteli had no relevant conflicts; disclosures for the other authors are in the report. Kapasi, Gottesman, and Parikh had no relevant disclosures.

J Am Coll Cardiol. 2021;77:888-898, 899-901. Full text, Editorial

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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