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 AG 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) Amyloidosis (brief) Vascular risk factors Vascular risk factors  Time course of vascular risk on brain  Inflammation and brain aging

Cross-sectional and Longitudinal Memory Performance Wilson et al, Arch Neuro, 1999 Wilson et al,Psychology and Aging, 2002

Clinical Consequences Mungas, et al. Psychology and Aging, 2010

MRI Measures of Atrophy

Variability in Brain Aging

Summary  Brain aging is heterogeneous Cognition Cognition Brain structure Brain structure

Outline  Brain Aging: cognition and structural imaging  Potential Causes of heterogeneity Amyloidosis (brief) Amyloidosis (brief) Vascular risk factors 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

Framingham Heart Study, unpublished data

Prevalence of Vascular Risk Factors among the Framingham Offspring MeasureResult Age Percent Obese33 Percent hypertensive52 Percent treated hypertensive40 Percent Diabetic13 Percent current smoker14 Percent CAD17 Percent MI6 Percent stroke/TIA4 Percent atrial fibrillation5 DeCarli, et al. Neurobiology of Aging, 2005

Seshadri, S. et al. Stroke 2006;37: Future Risk of Stroke or Dementia at Age 65 Women Men

Spectrum of CVD MRI Infarction Stroke 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 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

Vascular Risk and WMH

WomenMenSBP HTN Rx 15%18% Diabetes4%7% Smoker16%17% History of CVD 4%8% Atrial fibrillation 0.2%0.7% ECG- LVH 4%14% FSRP score

Risk Factors, Age and Brain Volume

Cognitive Consequences

Middle Life Vascular Risk Factors and Dementia Risk Whitmer, et al, Neurology, 2005

Increasing odds of Dementia with number of Risk Factors* Whitmer, et al, Neurology, 2005*~74% Caucasian

Dementia Risk with MRI Vascular Measures Debette et al, Stroke, 2010

0 VR 1 VR 2 VR 3 VR  Significant change in FA  Significant negative Jacobians  Both Impact of Vascular Risk (VR) on White Matter Integrity and Gray Matter Atrophy Maillard et al, Neurobiology of Aging, 2015

Significant FA loss /year Significant Atrophy /year ** * Number of VR ** *

*** * * Number of Vascular Risk Factors Annual change in hippocampus volume

Summary II  Vascular risk factors are common  Vascular risk factors affect the brain Silent brain infarctions Silent brain infarctions WMH WMH Cerebral Atrophy 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) Amyloidosis (brief) Vascular risk factors 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

Neurology, 2015

Diabetes and Brain Aging

Cognitive Consequences

Hypothetical Model of Vascular Disease and Brain Atrophy

Hypothetical Consequences Cognition VRF VBI SNAP?

Summary III  Advancing age is associated with co- morbid diseases Alzheimer’s pathology Alzheimer’s pathology Cerebrovascular pathology Cerebrovascular pathology  Vascular injury may begin early in life The number of vascular risk factors appears additive to later life dementia risk 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) Amyloidosis (brief) Vascular risk factors Vascular risk factors  Time course of vascular risk on brain  Inflammation and brain aging

Atheroscler, Thromb, Vasc, Bio, 2011

Inflammation in Younger Individuals Interaction p-value indicates significant differences by younger versus older

Inflammation and Cognition

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.

Model of Inflammation and Brain Pathology in Aging

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

UC Davis Alzheimer’s Disease Center Supported by NIH: P30 AG10129, P01 AG12435, R01 AG010220, R01 AG021028, R01 AG031252, R01 AG , DHS , K01 AG Charles DeCarli Charles DeCarli Dan Mungas Dan Mungas John Olichney John Olichney Sarah Farias Sarah Farias Berneet Kaur Berneet Kaur Bruce Reed Bruce Reed Ladson Hinton Ladson Hinton Laurel Beckett Laurel Beckett Danielle Harvey Danielle Harvey Cam Carter Cam Carter Owen Carmichael Owen Carmichael Lee-Way Jin Lee-Way Jin Joshua Miller Joshua Miller

IDeA Lab  Owen Carmichael  Evan Fletcher  Baljeet Singh  Noel Smith  Alexandra Roach  Samuel Lockhart  Jing He  Pauline Maillard Supported by NIH and the Dana Foundation