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

“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…”

“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.”

“with hypertension, type 2 diabetes mellitus, smoking, obesity, and coronary artery disease,(9,10) all risk factors associated with stroke.(11) Interestingly, under hypoxic and ischemic condi-”

“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…”

“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.”

“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.”

“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…”

“As mentioned earlier, BDNF is highly expressed in neuronal and vascular tissue.(25,27,37) Low levels have been observed in patients with vascular risk factors,(7) and in the present study with increased risk of stroke/TIA.”

“MRI acquisitions and measurement techniques and inter-rater reliability scores have been previously published.(17) In summary, digital MRI information once acquired on a 1 or 1.”

“In previous reports, WMHs were strongly related to stroke risk factors(35) and incident stroke, minimal cognitive impairment, and dementia.(14,36) As mentioned earlier, BDNF is highly expressed in neuronal and vascular tissue.”

“WMHs are highly prevalent in persons with vascular risk factors and stroke.(34,35) 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 ce…”

“Although VEGF promotes neurogenesis and beneficial angiogenesis, angiogenesis is also a component in the progression of atherosclerosis.(9,33) Moreover, in the acute stroke setting, the major source of the circulating VEGF may not be the ischemic brain tissue, but rather the transient peripheral leukocytosis.”

“Animal studies have established a positive effect of BDNF and VEGF on infarct size and on long-term potentiation, neuronal remodeling, and functional motor recovery after induction of an ischemic brain lesion.(25,26) In addition to being a potent angiogenic Figure.”

“tasks; the cognitive domains previously associated with vascular risk factors and WMHV.(14)”

“2768 Cerebrovascular disease (overt and covert) accounts for a significant proportion of brain aging–related mortality and morbidity.(1,2) Whereas the burden of cerebrovascular disease may be largely attributed to well-established stroke risk factors, genetic and lifestyle differences and structural and functional bra…”

“The activation of astrocytes in the white matter ipsilateral to the injury seemed to contribute to tissue repair and regeneration.(40) It is likely that the state of hypoperfusion and chronic ischemia in oligemic/ischemic tissue that leads to manifestation of WMH on brain MRI also acts as a trigger for upregulation of…”

“Recently, in a prospectively followed aging population (57–79 years), decreased levels of BDNF were also associated with poorer performance on global cognitive testing and in several specific cognitive domains, such as verbal memory and language, but not in executive function tests.(44) Although different cognitive te…”

“Animal studies have established a positive effect of BDNF and VEGF on infarct size and on long-term potentiation, neuronal remodeling, and functional motor recovery after induction of an ischemic brain lesion.(25,26) In addition to being a potent angiogenic Figure.”

“However, higher VEGF levels have been observed in persons with obesity, metabolic syndrome, and markers of atherosclerosis, such as increased carotid intimo-medial thickness, perhaps as a compensation to their subclinical disease.(28)”

“Dysfunction of cerebral vascular BDNF signaling, therefore, may contribute to disruption of the neurovascular unit, hence to an alteration of tissue responses to vascular injury.(30) A small molecule BDNF mimetic (LM22A-4) when administered immediately after an ischemic stroke in adult mice leads to increased neurogen…”

“tions, both BDNF and VEGF and their respective receptors are upregulated in neurons and vascular endothelial cells.(12,13)”

“Decline in cognitive function has been associated with higher FSRP and with the presence of ext-WMH.(14,45) In the present study, we also observed an association between low BDNF levels and (1) stroke/TIA and (2) WMHs, both previously associated with decline in cognitive function, minimal cognitive impairment, and dem…”

“Although VEGF promotes neurogenesis and beneficial angiogenesis, angiogenesis is also a component in the progression of atherosclerosis.(9,33) Moreover, in the acute stroke setting, the major source of the circulating VEGF may not be the ischemic brain tissue, but rather the transient peripheral leukocytosis.”

“BDNF plays a critical role in mediating synaptic transmission and synaptic plasticity, a molecular basis for processing new learning and consolidation of short- and long-term memories.(41) A decline in BDNF levels precedes and parallels the observed decrease in choline acetyltransferase enzyme activity in aging brains…”

“In previous reports, higher serum BDNF levels were found to be associated with better performance on NP testing in healthy older adults.(43) Recently, in a prospectively followed aging population (57–79 years), decreased levels of BDNF were also associated with poorer performance on global cognitive testing and in sev…”

“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…”

“2768 Cerebrovascular disease (overt and covert) accounts for a significant proportion of brain aging–related mortality and morbidity.(1,2) Whereas the burden of cerebrovascular disease may be largely attributed to well-established stroke risk factors, genetic and lifestyle differences and structural and functional bra…”

“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…”

“A small molecule BDNF mimetic (LM22A-4) when administered immediately after an ischemic stroke in adult mice leads to increased neurogenesis and improved functional motor recovery.(31) Studies have also found that exogenous BDNF affects vasodilatation via upregulation of prostacyclin synthesis, and protects against va…”

“Whereas there are no previous community-based studies to evaluate the effect of VEGF levels on the risk of incident stroke/TIA, our findings parallel previous observations that higher VEGF levels are associated with other cardiovascular disease risk factors and outcomes.(9,10,12,13) The biological mechanisms by which…”

“However, only a few studies have explored in humans, the association between BDNF (studying genetic polymorphism rather than gene expression or circulating levels) and white matter abnormalities on brain MRI; these studies were restricted to patients with various psychiatric conditions.(38) In a cross-sectional study…”

“Two small clinical studies related higher VEGF levels in patients with acute stroke to better outcomes.(23,24) However, this upregulation could result in higher VEGF levels serving as a marker of chronic cerebral ischemia, and hence of increased stroke risk.”

“Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), both present during early neuronal development, have also been found to have a role in maintaining neuronal plasticity and in neuronal repair by promoting neurogenesis and angiogenesis.(5,6) Background and Purpose—Brain-derived neu…”

“Possible Mechanisms for Association of BDNF and Stroke/TIA There is experimental evidence that neurons and glial cells act as endogenous sources of BDNF after ischemic and other brain injuries.(25,29) It has been shown that BDNF regulates homeostatic interactions between neurons, glial cells, and the vasculature, join…”

“In a cross-sectional study of older subjects with depression, a specific BDNF genotype (the Val66Met allele) was associated with greater WMHV,(38) whereas in a prospective study the same polymorphism seemed to modify the association between stroke and depression.(39) In a primate model of lacunar stroke, the productio…”

“tions, both BDNF and VEGF and their respective receptors are upregulated in neurons and vascular endothelial cells.(12,13)”

“Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), both present during early neuronal development, have also been found to have a role in maintaining neuronal plasticity and in neuronal repair by promoting neurogenesis and angiogenesis.(5,6) Background and Purpose—Brain-derived neu…”