Cited by 200Acute Ischemic Stroke ManagementNeurological Disease Mechanisms and TreatmentsDementia and Cognitive Impairment Research

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Serum Brain–Derived Neurotrophic Factor and Vascular Endothelial Growth Factor Levels Are Associated With Risk of Stroke and Vascular Brain Injury: Framingham Study

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Pikula, Aleksandra, Beiser, Alexa S., Chen, Tai C., Preis, Sarah R., Vorgias, Demetrios, DeCarli, Charles, Au, Rhoda, Kelly-Hayes, Margaret, Kase, Carlos S., Wolf, Philip A., Vasan, Ramachandran S., Seshadri, Sudha·2013·Stroke

DOI 10.1161/strokeaha.113.001447PMC PMC3873715

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Abstract

Background and Purpose—: Brain-derived neurotrophic factor (BDNF), a major neurotrophin and vascular endothelial growth factor (VEGF) have a documented role in neurogenesis, angiogenesis, and neuronal survival. In animal experiments, they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample. Methods—: In 3440 Framingham Study participants (mean age, 65±11 years; 56% women) who were free of stroke/transient ischemic attack (TIA), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological tests available (n=1863 and 2104, respectively; mean age, 61±9 years, 55% women, in each), we related baseline BDNF and logVEGF to log-white matter hyperintensity volume on brain MRI, and to visuospatial memory and executive function tests. Results—: During a median follow-up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age, sex, and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (hazard ratio comparing BDNF Q1 versus Q2–Q4, 1.47; 95% confidence interval, 1.09–2.00; P =0.012 and hazard ratio/SD increase in logVEGF, 1.21; 95% confidence interval, 1.04–1.40; P =0.012). Persons with higher BDNF levels had less log-white matter hyperintensity volume (β±SE=−0.05±0.02; P =0.025), and better visual memory (β±SE=0.18±0.07; P =0.005). Conclusions—: Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury.

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Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers
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“These radiographic lessons are thought to be a consequence of neuronal and vascular injury; resulting either from chronic hypoperfusion and ischemia, demyelination, axonal loss, and gliosis in the territory of deep, small perforating cerebral arteries, or through neurodegenerative processes involved in usual brain agi…”
Background
Epidemiological approaches to heart disease: the Framingham study
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“The Framingham Study is a prospective, community-based cohort that enrolled 5209 participants in 1948; these participants have had biennial re-examinations.(15) In 1971, the offspring of the Original cohort and their spouses were enrolled in an Offspring cohort, assessed once every 4 years.”
The Framingham Study
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BackgroundMethodSelf-citation
National Institute of Neurological Disorders and Stroke–Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards
Hachinski, V., Iadecola, C., Petersen, R. C., Breteler, M. M., Nyenhuis, D. L., Black, S. E., Powers, W. J., DeCarli, C., Merino, J. G., Kalaria, R. N., et al. (2006) · Stroke · doi:10.1161/01.str.0000237236.88823.47 · Cited by 1,722 · cited 1×
“Details of the tests administered and normative values for the Framingham Original and Offspring cohorts have been previously published.(18,19) In this study, we selected cognitive domains previously associated with vascular risk factors and vascular brain injury; visuospatial memory (measured by delayed recall on the…”
MethodSelf-citation
AN INVESTIGATION OF CORONARY HEART DISEASE IN FAMILIES
Kannel, W. B., Feinleib, M., McNAMARA, P. M., Garrison, R. J., & Castelli, W. P. (1979) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a112813 · Cited by 1,639 · cited 1×
“In 1971, the offspring of the Original cohort and their spouses were enrolled in an Offspring cohort, assessed once every 4 years.(16) The participants from both cohorts have been under ongoing surveillance for incident stroke and TIA since the inception of the study.”
Method
BRIEF COMMUNICATION.
Beekman, A. T. F., Deeg, D. J. H., van Limbeek, J., Braam, A. W., VRIES, M. Z. D., & van Tilburg, W. (1997) · Psychological Medicine · doi:10.1017/s0033291796003510 · Cited by 1,135 · cited 1×
“Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression scale (CES-D).(20) The physical activity index was calculated as a composite score based on information collected from a structured questionnaire.”
Method
Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery
Cramer, S. C. (2008) · Annals of Neurology · doi:10.1002/ana.21393 · Cited by 875 · cited 1×
“Whereas the burden of cerebrovascular disease may be largely attributed to well-established stroke risk factors, genetic and lifestyle differences and structural and functional brain capacities (such as neural density, synaptic connectivity, and the compensatory ability of existing neural networks) may modulate risk a…”
Background
The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function.
FERRIS, L. T., WILLIAMS, J. S., & SHEN, C.-L. (2007) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e31802f04c7 · Cited by 849

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“BDNF may be involved in neuroprotection due to its role in neuronal development, differentiation, and survival and its involvement in homeostatic interactions in neurovascular units (Pikula et al., 2013; Calabrese et al., 2014).”
Background
Prophylactic Chronic Zinc Administration Increases Neuroinflammation in a Hypoxia-Ischemia Model
Tomás-Sanchez, C., Blanco-Álvarez, V. M., González-Barrios, J. A., Martínez‐Fong, D., Garcia-Robles, G., Soto-Rodríguez, G., Brambila, E., Torres-Soto, M., Gonzalez-Vazquez, A., Aguilar-Peralta, A. K., et al. (2016) · Journal of Immunology Research · doi:10.1155/2016/4039837 · Cited by 15
“At least the increases of VEGFA agree with the association of the risk of incident stroke/transient ischemic attack [79] as well as the occurrence and development of cognitive impairment in stroke [80].”
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“The data obtained here regarding a link between the decrease in VEGF-A a d the formation of a specific neuroimaging profile may explain the contr dictory elationship reported between VEGF-A nd cSVD [17,30,31,45,46].”
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InfluentialSelf-citation
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“Pikula et al. (2013) discovered that higher BDNF levels were associated with a reduced risk of stroke and better outcomes [58].”
Background
Associations between accelerometer‐derived sedentary behavior and physical activity with white matter hyperintensities in middle‐aged to older adults
Raichlen, D. A., Ally, M., Aslan, D. H., Sayre, M. K., Bharadwaj, P. K., Maltagliati, S., Lai, M. H. C., Wilcox, R. R., Habeck, C. G., Klimentidis, Y. C., et al. (2024) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.70001 · Cited by 6
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“, 2019), while the relationship between vascular factors and BDNF is inconsistent and may depend on age and sex (Pikula et al., 2013; Jamal et al., 2015).”
Background
Brain Derived Neurotrophic Factor Interacts with White Matter Hyperintensities to Influence Processing Speed and Hippocampal Volume in Older Adults
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Method
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Retracted
Lower serum BDNF as a predictor of post-stroke cognitive impairment in acute ischemic stroke patients
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“14 For example, BDNF levels in peripheral blood (serum or plasma) were significantly lower in patients with ischaemic heart disease or acute coronary syndrome, 15 with unstable angina, 16 at risk of stroke and vascular brain injury, 17 and with chronic heart failure 18 compared to healthy controls.”
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Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0031 · Cited by 1
Cigarette Smoking
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0017 · Cited by 1
Bipolar Disorder
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0006 · Cited by 1
Peripheral blood diagnostic markers of chronic cerebral hypoperfusion
Zhang, Q. (2024) · American Journal of Translational Research · doi:10.62347/orsn1228 · Cited by 2
Activation of endogenous mechanisms of sanogenesis in cognitive impairment in cerebral small vessel disease
Esin, R. G., Erkinova, D. E., & Esin, O. R. (2024) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro20241241217 · Cited by 1
In Vitro Measurement of the Elastic Properties of the Native Red Blood Cell Membrane
Sergunova, V. A., Kozlova, E. K., Myagkova, E. A., & Черныш, А. М. (2015) · Cited by 1
Copyright Page
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.002.0003 · Cited by 1
Dynamics of serum BDNF After Aerobic Exercise in Subacute Stroke Patients: A Sub-Analysis of the randomized controlled Phys-Stroke trialPreprint
Rackoll, T., Doppelbauer, L., Neumann, K., Nave, A. H., & the Phys-Stroke study group (2024) · medRxiv · doi:10.1101/2024.09.24.24314322 · Cited by 1
ЭКСПРЕССИЯ МОЗГОВОГО НЕЙРОТРОФИЧЕСКОГО ФАКТОРА (BDNF) ПОВЫШАЕТ УСТОЙЧИВОСТЬ НЕЙРОНОВ К ГИБЕЛИ В ПОСТРЕАНИМАЦИОННОМ ПЕРИОДЕ
Ostrova, I. V., & Sh., M. D. (2015)
Poststroke Depression: Contributions From Network Science
Lisle, B., Hurley, R. A., & Taber, K. H. (2018) · Journal of Neuropsychiatry · doi:10.1176/appi.neuropsych.18080188
“Low circulating BDNF levels have been associated with an increased risk of stroke.(51) Low levels of BDNF in the acute stage of stroke have been associated with poor functional outcomes at two-year and seven-year follow ups, independent of stroke severity.”
Background
MEDIATORS OF ENDOTHELIAL DYSFUNCTION IN CEREBRAL ISCHEMIA IN PREMATURE INFANTS
Smirnov, I. E., Кучеренко, А. Г., Belyaeva, I. A., Диевна, Ш. Л., Владимировна, П. Е., Петровна, Б. Е., & Александровна, Х. Н. (2019) · Russian Pediatric Journal · doi:10.18821/1560-9561-2017-20-4-196-201
Brain Derived Neurotrophic Factor Interacts with Diabetes Status to Influence Memory and Hippocampal Volume in Older AdultsPreprint
Brenner, E. K., Weigand, A. J., Edwards, L., Thomas, K. R., Edmonds, E. C., Bondi, M. W., & Bangen, K. J. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4096907
Potential Role of Hypercoagulation in the Onset and Progression of Obesity Induced NeurodegenerationPreprint
Khan, S. I., Hasan, N., Anwar, L., Khan, S., Akhtar, M., Akhtar, M., & Najmi, A. K. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4159332
Summary and Conclusions
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0034
Hypertension
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0021
Suicide
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0007
Depression
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0005 · Cited by 1
Chronic Pain
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0029
Preface
Levin, J. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.002.0007
Health Policy Implications
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0033
Introduction
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.002.0009
Alzheimer’s Disease and Other Dementias
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0023
Immune Function
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0024
Heart Disease
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0020
Cancer
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0026
Disease Prevention, Detection, and Treatment
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0030 · Cited by 1
Diet and Weight
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0019
Dedication
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.002.0004
Personality Traits and Disorders
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0011
Schizophrenia and Other Psychoses
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0009
Coping with Stress
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0004
Exercise
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0018
Research Design
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0003 · Cited by 1
Delinquency and Crime
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0013
Foreword
Koh, H. K. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.002.0006
Physical Disability
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0028
Cerebrovascular Disease
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0022
Studies on Religion and Health
Koenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.005.0001
Systemic Sclerosis and its Cerebral, Neurological, and Psychiatric Impacts: A Narrative ReviewPreprint
Silva, R. C., Arruda, J. D. M., Pereira, M. C., Rêgo, M. J. B. D. M., Pitta, M. G. D. R., & da Rosa, M. M. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5228120
Association Between Physical Activity and Memory Function: The Role of Brain Structural Markers in a Cross‐Sectional Study
Wu, X., Yang, W., Li, Y., Zhang, L., Li, C.-Y., Xu, W., & Ma, F. (2025) · European Journal of Neuroscience · doi:10.1111/ejn.70325
Neurotrophins Plasma Levels Kinetics in Ischemic Stroke Patients—Potential Relation to Outcomes
Opiła, R., Łuczkowska, K., Paczkowska, E., Nowacki, P., Peregud-Pogorzelski, J. W., & Machaliński, B. (2026) · Neurology International · doi:10.3390/neurolint18030051
“Together with previously reported data associating lower BDNF level with overall higher risk of stroke, this implies that the pre-existing status of BDNF in the brain influences its post-stroke measure and, possibly, its relation to outcomes [30].”
Linking inflammatory and structural neuroimaging biomarkers in treatment-resistant depression: Current evidence and emerging hypotheses
Balcioglu, S. S. K., Paolini, M., Baune, B. T., Branchi, I., Cattaneo, A., Leboyer, M., Vai, B., & Picker, L. D. (2026) · Neuroscience Applied · doi:10.1016/j.nsa.2026.107015
“WMH are white matter lesions that appear hyperintense in FLAIR sequences; they are linked to cardiovascular risk factors (albeit their exact etiology and pathophysiology is still controversial) and a regular finding in cerebral small vessel disease (Wardlaw et al., 2015; Koohi et al., 2023).”
Influential
Genetic regulation of platelet-derived BDNF by rs11030119: discrepancy between circulating levels and hemostatic function
Boukhatem, I., Blais, J., Welman, M., Tardif, J., Dubé, M., Jourdi, G., & Lordkipanidzé, M. (2026) · Genes and Immunity · doi:10.1038/s41435-026-00405-2
Nut consumption, cognitive function and brain health markers in individuals with and without stroke: cross-sectional and longitudinal findings from the Framingham heart study
Amanat, S., Dordevic, A. L., Pase, M. P., & Cardoso, B. R. (2026) · Food & Function · doi:10.1039/d6fo00666c

Authors: Pikula, A., Beiser, A. S., Chen, T. C., Preis, S. R., Vorgias, D., DeCarli, C., Au, R., Kelly-Hayes, M., Kase, C. S., Wolf, P. A., Vasan, R. S., & Seshadri, S.
Affiliations: Boston University (US)
From the Boston University Schools of Medicine and Public Health, Boston, MA (A.P., A.S.B., T.C.C., S.R.P., D.V., R.A., M.K.-H., C.S.K., P.A.W., R.S.V., S.S.); Framingham Heart Study, Framingham, MA (A.P., A.S.B., S.R.P., C.D., R.A., M.K.-H., C.S.K., P.A.W., R.S.V., S.S.); and University of California at Davis, Sacramento (C.D.).
ORCID: Pikula, Aleksandra
Beiser, Alexa S.
Chen, Tai C.
Preis, Sarah R.
DeCarli, Charles
Au, Rhoda
Kase, Carlos S.
Wolf, Philip A.
Vasan, Ramachandran S.
Seshadri, Sudha
Venue: Stroke
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2013-10
Volume: 44
Issue: 10
Pages: 2768-2775
ISSN: 0039-2499 (ISSN-L)
1524-4628
DOI: 10.1161/strokeaha.113.001447
PMC: PMC3873715
OpenAlex: W2111149177
Cited by: 200
References: 47
Citations by year: 2026: 5 · 2025: 7 · 2024: 15 · 2023: 51 · 2022: 16 · 2021: 10 · 2020: 18 · 2019: 15 · 2018: 12 · 2017: 15 · 2016: 13 · 2015: 17 · 2014: 6
FWCI: 8.66
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Stroke (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: American Heart Association
National Institutes of Health (UL1TR000157, n01hc25195-41-0-1, n01hv28178-12-0-0)
National Institute on Aging (R01AG031287, AG031287, AG08122, AG033193, R01AG016495, R01AG033193, R01AG008122)
National Heart, Lung, and Blood Institute (N01‐HC25195, K24HL004334, N01-HC-025195, N01-HV-028178, R01HL093029, U01HL096917)
National Institute of Neurological Disorders and Stroke (R01NS017950)
National Center for Research Resources
National Center for Advancing Translational Sciences
Topics: Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: brain-derived neurotrophic factor, vascular endothelial growth factor, stroke risk, transient ischemic attack, white matter hyperintensities, vascular brain injury, visuospatial memory, executive function, serum biomarkers, Framingham Heart Study, angiogenesis, neurogenesis, ischemic brain injury, cognitive function, vascular risk factors, sex differences, neuroinflammation
MeSH terms: Age Factors, Aged, Brain Ischemia, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Radiography, Risk Factors, Sex Factors, Incidence, Brain-Derived Neurotrophic Factor, Stroke, Vascular Endothelial Growth Factor A

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Serum Brain–Derived Neurotrophic Factor and Vascular Endothelial Growth Factor Levels Are Associated With Risk of Stroke and Vascular Brain Injury: Framingham Study

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