Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study

Catarina Tristão-Pereira; Valentin Fuster; Belen Oliva; Andrea Moreno-Arciniegas; Ines Garcia-Lunar; Cristina Perez-Herreras; Michael Schöll; Marc Suárez-Calvet; Maria Angeles Moro; Ana Garcia-Alvarez; Antonio Fernandez-Ortiz; Javier Sanchez-Gonzalez; Henrik Zetterberg; Kaj Blennow; Borja Ibanez; Juan D Gispert; Marta Cortes-Canteli

doi:10.1016/S2666-7568(23)00134-4

Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study

Lancet Healthy Longev. 2023 Sep;4(9):e487-e498. doi: 10.1016/S2666-7568(23)00134-4.

Authors

Catarina Tristão-Pereira¹, Valentin Fuster², Belen Oliva¹, Andrea Moreno-Arciniegas¹, Ines Garcia-Lunar³, Cristina Perez-Herreras⁴, Michael Schöll⁵, Marc Suárez-Calvet⁶, Maria Angeles Moro¹, Ana Garcia-Alvarez⁷, Antonio Fernandez-Ortiz⁸, Javier Sanchez-Gonzalez⁹, Henrik Zetterberg¹⁰, Kaj Blennow¹¹, Borja Ibanez¹², Juan D Gispert¹³, Marta Cortes-Canteli¹⁴

Affiliations

¹ Spanish National Center for Cardiovascular Research, Madrid, Spain.
² Spanish National Center for Cardiovascular Research, Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Spanish National Center for Cardiovascular Research, Madrid, Spain; Cardiology Department, La Moraleja University Hospital, Madrid, Spain; Biomedical Research Networking Centers on Cardiovascular Diseases, Madrid, Spain.
⁴ Santander Bank, Madrid, Spain.
⁵ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, UK.
⁶ Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Hospital del Mar Medical Research Institute, Barcelona, Spain; Biomedical Research Networking Centers on Frailty and Healthy Ageing, Madrid, Spain; Neurology Department, Hospital del Mar, Barcelona, Spain.
⁷ Spanish National Center for Cardiovascular Research, Madrid, Spain; Biomedical Research Networking Centers on Cardiovascular Diseases, Madrid, Spain; August Pi i Sunyer Biomedical Research Institute, Clínic Hospital, University of Barcelona, Barcelona, Spain.
⁸ Spanish National Center for Cardiovascular Research, Madrid, Spain; Biomedical Research Networking Centers on Cardiovascular Diseases, Madrid, Spain; Institute for Health Research Clinico San Carlos Hospital, Complutense University of Madrid, Madrid, Spain.
⁹ Philips Healthcare Iberia, Madrid, Spain.
¹⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, UK; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden; UK Dementia Research Institute at University College London, London, UK; Hong Kong Center for Neurodegenerative Diseases, Hong Kong Special Administrative Region, China; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹² Spanish National Center for Cardiovascular Research, Madrid, Spain; Biomedical Research Networking Centers on Cardiovascular Diseases, Madrid, Spain; Cardiology Department, Institute for Health Research Fundación Jiménez Díaz University Hospital, Madrid, Spain.
¹³ Spanish National Center for Cardiovascular Research, Madrid, Spain; Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Hospital del Mar Medical Research Institute, Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine, Madrid, Spain.
¹⁴ Spanish National Center for Cardiovascular Research, Madrid, Spain; Cardiology Department, Institute for Health Research Fundación Jiménez Díaz University Hospital, Madrid, Spain. Electronic address: marta.cortes@cnic.es.

Abstract

Background: Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals.

Methods: The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG)-PET, and annual percentage change in [¹⁸F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach.

Findings: This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [¹⁸F]FDG uptake compared with low risk (β=-0·008 [95% CI -0·013 to -0·002]; p_FDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; p_FDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [¹⁸F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (β=-0·269 [95% CI -0·509 to -0·027]; p=0·029).

Interpretation: Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life.

Funding: Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Atherosclerosis* / epidemiology
Cardiovascular Diseases* / diagnostic imaging
Cardiovascular Diseases* / epidemiology
Carotid Artery Diseases*
Female
Fluorodeoxyglucose F18
Glucose
Heart Disease Risk Factors
Humans
Longitudinal Studies
Male
Middle Aged
Neurodegenerative Diseases*
Prospective Studies
Risk Factors

Substances

Fluorodeoxyglucose F18
Glucose

Associated data

ClinicalTrials.gov/NCT01410318