Links between cardiovascular disease and cognitive decline may begin in midlife before the first clinical symptoms of either condition appear, cross-sectional data from a cohort study suggested.
Middle-age cardiovascular risk — largely driven by hypertension — was associated with brain hypometabolism, an imaging marker of neurodegeneration, according to Valentin Fuster, MD, PhD, of Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, Spain, and Mount Sinai Hospital in New York City, and colleagues.
Subclinical carotid plaque burden also was tied to reduced brain metabolism independent of diabetes, hypertension, dyslipidemia, and smoking, they reported in the Journal of the American College of Cardiology.
“When brain metabolism declines, the brain’s ability to handle adverse events can be compromised. Depending on the brain area affected, this can lead to a range of distinct problems,” co-author Marta Cortes-Canteli, PhD, also of CNIC, said in a statement.
“We found that a higher cardiovascular risk in apparently healthy middle-aged individuals was associated with lower brain metabolism in parietotemporal regions involved in spatial and semantic memory and various types of learning,” she added. “The next step will be to determine whether individuals with subclinical atherosclerosis in the carotid arteries and low brain metabolism at the age of 50 go on to experience cognitive decline 10 years later.”
The study used data from the PESA (Progression of Early Sub-clinical Atherosclerosis) study of white employees, ages 40 to 54, of a Madrid bank with no clinically apparent cardiovascular disease. From 2010 to 2014, participants had assessments to determine 30-year Framingham cardiovascular risk scores, coronary artery calcification imaging, and 3D vascular ultrasound carotid and femoral artery atherosclerotic plaque measurements.
Of 946 participants with evidence of asymptomatic atherosclerosis, the researchers evaluated 547 people with full brain 18F-fluorodeoxyglucose (FDG) PET to assess cerebral hypometabolism. Most (82.5%) were men and mean age was 50. Their most prevalent risk factor was dyslipidemia (60%), followed by smoking (27.1%), hypertension (19.7%), and diabetes (4.6%).
Median 30-year Framingham risk score was 24.2%. Mean carotid and femoral artery plaque burdens were 4 and 46 mm3, respectively.
Adjusted for age, sex, and blood glucose at the time of PET, two main findings emerged:
- Higher Framingham risk scores were associated with global brain hypometabolism (β= -0.15, P<0.001), driven mainly by hypertension (d=0.36, P<0.001)
- Carotid artery atherosclerosis burden, but not femoral artery burden, was inversely associated with global brain FDG uptake (β= -0.16, P<0.001), even after adjusting for 30-year Framingham scores
Brain hypometabolism in parietotemporal regions (angular, supramarginal, and inferior/middle temporal gyri) and the cingulate gyrus was associated with 30-year Framingham scores, hypertension, and carotid plaque burden.
This hypometabolism pattern implicates midlife cardiovascular risk factors and carotid atherosclerosis in Alzheimer’s disease decades before the typical age of symptom onset, noted Neal Parikh, MD, of Weill Cornell Medicine in New York City, and Rebecca Gottesman, MD, PhD, of Johns Hopkins University in Baltimore, in an accompanying editorial.
“Furthermore, these data suggest that carotid atherosclerosis — carotid atherosclerosis alone, and above and beyond comorbid cardiovascular risk factors — may be detrimental to brain health even when it is subclinical and nonstenosing,” they wrote.
By assessing cerebral hypometabolism, this study “filled important gaps in the emerging paradigm by which midlife cardiovascular risk factors influence brain health and may cause cognitive impairment and dementia,” the editorialists added.
But FDG-PET also is a limitation, Parikh and Gottesman noted: the tracer has relatively low specificity for Alzheimer’s disease. “This, combined with the cross-sectional design of the study and lack of actual cognitive measures, precluded making causal inferences from these data,” they wrote. The study’s high proportion of males, racial homogeneity, and inclusion only of people with atherosclerosis also limited generalizability.
The PESA study is co-funded equally by CNIC and Banco Santander, Madrid, Spain. The study also receives funding from the Instituto de Salud Carlos III, Madrid, Spain, the European Regional Development Fund, and the European Social Fund.
Researchers disclosed relevant relationships with Fondo de Investigación Sanitaria, Iniciativa de Empleo Juvenil of the Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid, Ministerio de Ciencia e Innovación, European Research Council, la Caixa Foundation, EU/EFPIA Innovative Medicines Initiative Joint Undertaking, European Union Horizon, Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, ProMIS Neurosciences, General Electric, Phillips, and Biogen.
Gottesman disclosed serving as the former associate editor of Neurology. Parikh disclosed support from the Leon Levy Fellowship in Neuroscience.