early brain changes of non-amyloid pathways charles decarli, md victor and genevieve orsi chair in...

Early Brain Changes of Non-Amyloid Early Brain Changes of Non-Amyloid PathwaysPathways

Charles DeCarli, MDCharles DeCarli, MDVictor and Genevieve Orsi Chair in Alzheimer's

ResearchDirector University of California at Davis,

Alzheimer’s Disease Center

AcknowledgementsAcknowledgements

Funded in part by Grant R13 AG030995 Funded in part by Grant R13 AG030995 from the National Institute on Agingfrom the National Institute on Aging

The views expressed in written conference The views expressed in written conference materials or publications and by speakers materials or publications and by speakers and moderators do not necessarily reflect and moderators do not necessarily reflect the official policies of the Department of the official policies of the Department of Health and Human Services; nor does Health and Human Services; nor does mention by trade names, commercial mention by trade names, commercial practices, or organizations imply practices, or organizations imply endorsement by the U.S. Government.endorsement by the U.S. Government.

OutlineOutline

Brain Aging: cognition and structural Brain Aging: cognition and structural imagingimaging

Potential Causes of heterogeneityPotential Causes of heterogeneity

• Amyloidosis (brief)Amyloidosis (brief)

• Vascular risk factorsVascular risk factorsTime course of vascular risk on brainTime course of vascular risk on brain Inflammation and brain agingInflammation and brain aging

Cross-sectional and Longitudinal Cross-sectional and Longitudinal Memory PerformanceMemory Performance

Cross-sectional and Longitudinal Cross-sectional and Longitudinal Memory PerformanceMemory Performance

Wilson et al, Arch Neuro, 1999Wilson et al, Arch Neuro, 1999 Wilson et al,Psychology and Aging, 2002Wilson et al,Psychology and Aging, 2002

Clinical ConsequencesClinical Consequences

Mungas, et al. Psychology and Aging, 2010

MRI Measures of AtrophyMRI Measures of Atrophy

Variability in Brain AgingVariability in Brain Aging

Hippocampus

Hip

po/t

cv

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

30 35 40 45 50 55 60 65 70 75 80 85 90 95 100AGE

New Gender

FM

Change in Gray Matter Volume

Total-

gray-w

oC

RB

L

300

350

400

450

500

550

0 2 4 6 8 10Time

Subject of Subset of auto hippo with other MRI regions

0-11830-1270-14770-15030-16510-16580-18500-18900-24620-25480-26460-28510-28570-29310-30030-35420-35790-3900-40280-4419

0-44370-46130-50320-52040-53920-955

Hippocampal Rates of Change

auto

4.4

4.6

4.8

5.0

5.2

5.4

5.6

5.8

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0Years

id of Sheet1

0-10380-10650-10780-11130-11350-11830-12020-12060-12200-12310-1270-12820-13500-13590-1380-13800-13960-1450-14550-1477

0-15030-1540-15540-1570-16510-16580-17000-17130-17760-1790-18370-18500-18900-19390-19540-19570-20040-21180-21220-2146

0-21470-21660-22740-23100-23120-2315

SummarySummary

Brain aging is heterogeneousBrain aging is heterogeneous

• CognitionCognition

• Brain structureBrain structure

OutlineOutline





Percent PiB+ with AgePercent PiB+ with Age

Morris et al, Annals of Neuro, 2010

Time Dependent Time Dependent DifferencesDifferences

Jack, et al. JAMA Neurology, 2015

50.00%

55.00%

60.00%

65.00%

70.00%

75.00%

80.00%

85.00%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

35-44 44-54 55-64 65-74 75-84

Age-Specific Prevalence of Vascular Disease and Brain Volume

HTN

CAD

CVA

AD

SBI

Brain Volume

Framingham Heart Study, unpublished data

50.00%

55.00%

60.00%

65.00%

70.00%

75.00%

80.00%

85.00%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

35-44 44-54 55-64 65-74 75-84


HTN

CAD

CVA

AD

Brain Volume

50.00%

55.00%

60.00%

65.00%

70.00%

75.00%

80.00%

85.00%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

35-44 44-54 55-64 65-74 75-84


CVA

AD

Brain Volume

50.00%

55.00%

60.00%

65.00%

70.00%

75.00%

80.00%

85.00%

0%

10%

20%

30%

40%

50%

60%

70%

80%

35-44 44-54 55-64 65-74 75-84


AD

Brain Volume

Prevalence of Vascular Risk Factors Prevalence of Vascular Risk Factors among the Framingham Offspringamong the Framingham Offspring

Measure Result

Age 62 + 10

Percent Obese 33

Percent hypertensive 52

Percent treated hypertensive 40

Percent Diabetic 13

Percent current smoker 14

Percent CAD 17

Percent MI 6

Percent stroke/TIA 4

Percent atrial fibrillation 5

DeCarli, et al. Neurobiology of Aging, 2005

Seshadri, S. et al. Stroke 2006;37:345-350

Future Risk of Stroke or Dementia at

Age 65

Women

Men

Spectrum of CVDSpectrum of CVD

MRI Infarction

Stroke

White Matter Hyperintensities

Brain Atrophy

MRI Examples of WMH and MRI Examples of WMH and SBISBI

NormalWMH

ExtensiveWMH

Silent MRIInfarct

Debette et al, Stroke, 2010

Age-Specific Prevalence of SBIAge-Specific Prevalence of SBI


0

5

10

15

20

25

30

35

5 6 7 8 9

Pre

va

len

ce

of

MR

Infa

rcts

(%

)

Decade of Life

Women

Men

Combined

N=100N=85

N=185 N=400

N=314N=714

N=322

N=300

N=622

N=214N=201

N=415

N=89N=39

N=128

0

10

20

30

40

50

60

70

80

30 40 50 60 70 80 90 100

WM

H v

olu

me

(cc)

Age

Aging White Matter DiseaseAging White Matter Disease

0.30

0.29

0.25

0.23

0.20

Vas

cula

r R

isk


Quantification of age-Quantification of age-related differences in related differences in

WMHWMHDefine Large WMH as 1 Define Large WMH as 1

sd above age-related sd above age-related mean WMHmean WMH

Vascular Risk and WMHVascular Risk and WMH

WomenWomen MenMen

SBPSBP 123 123 ++ 20 20 127 127 ++ 16 16

HTN Rx HTN Rx 15%15% 18%18%

DiabetesDiabetes 4%4% 7%7%

SmokerSmoker 16%16% 17%17%

History of CVDHistory of CVD 4%4% 8%8%

Atrial fibrillationAtrial fibrillation 0.2%0.2% 0.7%0.7%

ECG- LVHECG- LVH 4%4% 14%14%

FSRP score FSRP score 0.023 0.023 ++ 0.034 0.034 0.048 0.048 ++ 0.043 0.043

0.74

0.75

0.76

0.77

0.78

0.79

0.8

Cer

ebru

m %

TC

V

Quartiles of FSRP

Q1 Q2 Q3 Q4

Risk Factors, Age and Brain VolumeRisk Factors, Age and Brain Volume

Cognitive ConsequencesCognitive Consequences

Middle Life Vascular Risk Middle Life Vascular Risk Factors and Dementia RiskFactors and Dementia Risk

Whitmer, et al, Neurology, 2005

Increasing odds of Dementia with Increasing odds of Dementia with number of Risk Factors*number of Risk Factors*

Whitmer, et al, Neurology, 2005*~74% Caucasian

Dementia Risk with MRI Dementia Risk with MRI Vascular Measures 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 Annual change in hippocampus volumehippocampus volume

Summary IISummary II

Vascular risk factors are commonVascular risk factors are commonVascular risk factors affect the brainVascular risk factors affect the brain

• Silent brain infarctionsSilent brain infarctions

• WMHWMH

• Cerebral AtrophyCerebral AtrophyVascular risk factors affect cognition Vascular risk factors affect cognition

and brain structure in a dose dependent and brain structure in a dose dependent fashionfashion

OutlineOutline





Impact of Impact of Vascular Vascular

Disease may Disease may begin early begin early

Maillard, et al, Lancet Neurology, 2013

Neurology, 2015

Diabetes and Brain AgingDiabetes and Brain Aging

Cognitive ConsequencesCognitive Consequences

Hypothetical Model of Vascular Hypothetical Model of Vascular Disease and Brain AtrophyDisease and Brain Atrophy

0123456789

10

1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97 101

Amyloid Vascular Risk CVD Brain Injury

Age

Sev

erity

Hypothetical ConsequencesHypothetical Consequences

0

1

2

3

4

5

6

7

8

9

10

1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97 101Age

CognitionVRFVBI

SNAP?

Summary IIISummary III

Advancing age is associated with co-Advancing age is associated with co-morbid diseasesmorbid diseases

• Alzheimer’s pathologyAlzheimer’s pathology

• Cerebrovascular pathologyCerebrovascular pathologyVascular injury may begin early in lifeVascular injury may begin early in life

• The number of vascular risk factors The number of vascular risk factors appears additive to later life dementia appears additive to later life dementia riskrisk

Vascular risk may contribute to Vascular risk may contribute to neurodegeneration in SNAPneurodegeneration in SNAP

OutlineOutline





Atheroscler, Thromb, Vasc, Bio, 2011

Inflammation in Younger Inflammation in Younger IndividualsIndividuals

Interaction p-value indicates significant differences by younger versus older

Inflammation and Inflammation and CognitionCognition

GDF-15 in BrainGDF-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 Model of Inflammation and Brain Pathology in AgingBrain Pathology in Aging

Summary IVSummary IV

Aging and atherosclerosis lead to Aging and atherosclerosis lead to increasing inflammationincreasing inflammation

Inflammation can lead to brain injury Inflammation can lead to brain injury and cognitive decline independent of and cognitive decline independent of vascular risk factorsvascular risk factors

Inflammation may lead to microglial Inflammation may lead to microglial activation with release of harmful activation with release of harmful cytokinescytokines

ConclusionsConclusions

Brain aging is heterogeneousBrain aging is heterogeneousVascular risk factors cause subtle brain Vascular risk factors cause subtle brain

injury and cognitive impairment in a injury and cognitive impairment in a dose dependent mannerdose dependent manner

Cerebral atrophy is a common Cerebral atrophy is a common consequence of vascular riskconsequence of vascular risk

Inflammation secondary to systemic Inflammation secondary to systemic atherosclerosis may mediate some of atherosclerosis may mediate some of the atrophic processthe atrophic process

UC Davis Alzheimer’s Disease CenterUC Davis Alzheimer’s Disease Center

Supported by NIH: Supported by NIH: P30 AG10129,P30 AG10129, P01 AG12435,P01 AG12435,R01 AG010220, R01 AG021028,R01 AG010220, R01 AG021028,R01 AG031252, R01 AG 031563,R01 AG031252, R01 AG 031563,DHS 98-14970, K01 AG030514DHS 98-14970, K01 AG030514

http://alzheimer.ucdavis.edu/

• Charles DeCarliCharles DeCarli• Dan MungasDan Mungas• John OlichneyJohn Olichney• Sarah FariasSarah Farias• Berneet KaurBerneet Kaur• Bruce ReedBruce Reed• Ladson HintonLadson Hinton• Laurel BeckettLaurel Beckett• Danielle HarveyDanielle Harvey• Cam CarterCam Carter• Owen CarmichaelOwen Carmichael• Lee-Way JinLee-Way Jin• Joshua MillerJoshua Miller

IDeA Lab IDeA Lab Owen CarmichaelOwen Carmichael Evan FletcherEvan Fletcher Baljeet SinghBaljeet Singh Noel SmithNoel Smith Alexandra RoachAlexandra Roach Samuel LockhartSamuel Lockhart Jing HeJing He Pauline MaillardPauline Maillard

Supported by NIH and the Dana Supported by NIH and the Dana FoundationFoundation

http://neuroscience.ucdavis.edu/idealab/

early brain changes of non-amyloid pathways charles decarli, md victor and genevieve orsi chair in...

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