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Explore the complex relationship between brain aging, cognition, and vascular risk factors in this comprehensive study. Delve into the impact of inflammation and its consequences on brain structure. Discover how vascular risk factors may influence cognitive function and brain health.
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Early Brain Changes of Non-Amyloid Pathways Charles DeCarli, MD Victor and Genevieve Orsi Chair in Alzheimer's Research Director University of California at Davis, Alzheimer’s Disease Center
Acknowledgements • Funded in part by Grant R13 AG030995 from the National Institute on Aging • The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.
Outline • Brain Aging: cognition and structural imaging • Potential Causes of heterogeneity • Amyloidosis (brief) • Vascular risk factors • Time course of vascular risk on brain • Inflammation and brain aging
Cross-sectional and Longitudinal Memory Performance Wilson et al,Psychology and Aging, 2002 Wilson et al, Arch Neuro, 1999
Clinical Consequences Mungas, et al. Psychology and Aging, 2010
Summary • Brain aging is heterogeneous • Cognition • Brain structure
Outline • Brain Aging: cognition and structural imaging • Potential Causes of heterogeneity • Amyloidosis (brief) • Vascular risk factors • Time course of vascular risk on brain • Inflammation and brain aging
Percent PiB+ with Age Morris et al, Annals of Neuro, 2010
Time Dependent Differences Jack, et al. JAMA Neurology, 2015
Prevalence of Vascular Risk Factors among the Framingham Offspring DeCarli, et al. Neurobiology of Aging, 2005
Women Future Risk of Stroke or Dementia at Age 65 Men Seshadri, S. et al. Stroke 2006;37:345-350
Spectrum of CVD Stroke MRI Infarction White Matter Hyperintensities Brain Atrophy
MRI Examples of WMH and SBI Normal WMH Extensive WMH Silent MRI Infarct Debette et al, Stroke, 2010
Age-Specific Prevalence of SBI DeCarli, et al. Neurobiology of Aging, 2005
Aging White Matter Disease 0.30 0.29 0.25 0.23 0.20 Vascular Risk DeCarli, et al. Neurobiology of Aging, 2005
Quantification of age-related differences in WMH • Define Large WMH as 1 sd above age-related mean WMH
Middle Life Vascular Risk Factors and Dementia Risk Whitmer, et al, Neurology, 2005
Increasing odds of Dementia with number of Risk Factors* *~74% Caucasian Whitmer, et al, Neurology, 2005
Dementia Risk with MRI Vascular Measures Debette et al, Stroke, 2010
Impact of Vascular Risk (VR) on White Matter Integrity and Gray Matter Atrophy 0 VR 1 VR 2 VR • Significant change in FA • Significant negative Jacobians • Both 3 VR Maillard et al, Neurobiology of Aging, 2015
Significant Atrophy /year Significant FA loss /year ** ** * * ** Number of VR
Annual change in hippocampus volume *** * * Number of Vascular Risk Factors
Summary II • Vascular risk factors are common • Vascular risk factors affect the brain • Silent brain infarctions • WMH • Cerebral Atrophy • Vascular risk factors affect cognition and brain structure in a dose dependent fashion
Outline • Brain Aging: cognition and structural imaging • Potential Causes of heterogeneity • Amyloidosis (brief) • Vascular risk factors • Time course of vascular risk on brain • Inflammation and brain aging
Impact of Vascular Disease may begin early Maillard, et al, Lancet Neurology, 2013
Hypothetical Consequences Cognition VRF VBI SNAP?
Summary III • Advancing age is associated with co-morbid diseases • Alzheimer’s pathology • Cerebrovascular pathology • Vascular injury may begin early in life • The number of vascular risk factors appears additive to later life dementia risk • Vascular risk may contribute to neurodegeneration in SNAP
Outline • Brain Aging: cognition and structural imaging • Potential Causes of heterogeneity • Amyloidosis (brief) • Vascular risk factors • Time course of vascular risk on brain • Inflammation and brain aging
Inflammation in Younger Individuals Interaction p-value indicates significant differences by younger versus older
GDF-15 in Brain Immunostaining of human cortex from individual who had mixed dementia (AD+vascular dementia). Blue=cell nuclei stained with DAPI. Green=microglia stained with IBA-1. Red =immunostaining for GDF15. Colocalization of GDF15 is noted in microglia (arrows). Bar = 20um.
Summary IV • Aging and atherosclerosis lead to increasing inflammation • Inflammation can lead to brain injury and cognitive decline independent of vascular risk factors • Inflammation may lead to microglial activation with release of harmful cytokines
Conclusions • Brain aging is heterogeneous • Vascular risk factors cause subtle brain injury and cognitive impairment in a dose dependent manner • Cerebral atrophy is a common consequence of vascular risk • Inflammation secondary to systemic atherosclerosis may mediate some of the atrophic process