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Imaging the Earliest Stages of

Alzheimer’s Disease

MRI PET Amyloid  PET Tau 


Plaques Tangles

Susan M. Resnick, Ph.D.
Chief, Lab of Behavioral Neuroscience
NIA
Joint Effects of Aging, Vascular Changes
and AD Pathology

Aging

AD Pathology Vascular 
Disease
Plaque Tangles

WMH
Increasing Focus on the Earliest Stages of AD

Alzheimer’s & Dementia ‐ (2011) 1–13
Brain Aging: BLSA Neuroimaging Study
Early Markers of Alzheimer’s Disease and Cognitive Decline
Annual/Biennial Evaluation over 23 Years   
158 Men and Women (Age 55+)
Without Prior Neurologic or 
Severe Cardiovascular Disease

2009 – present: > 1000 MRI participants

MRI PET Cognitive


2005 2016
Testing

Volumes Ischemic CBF Amyloid Tau


Lesions >500 scans N>100
Variability in BLSA Brain Morphology (N = 18)
Annual Rates of Cortical Thinning Over 8 Years in
Normal Aging and Subsequent Cognitive Impairment
MRI Scans Cognitive Impairment

Baseline 1 2 3 4 5 6 7 8 9 10 11 12 … 18

Cognitively Normal (n=96) Cognitively Impaired (n=25)

-0.04 -0.01 0.01 0.04 -0.04 -0.01 0.01 0.04

SI> CN

-4 -2 2 4
Pacheco et al. 
Neurobiology of Aging 2015
Imaging Amyloid Plaques in Living People
Alzheimer’s Mild Cognitive
Disease Impairment Normal

Wolk et al. Annals of Neurology 2009
Amyloid Build-Up Precedes Memory Problems

• Memory
Problems 4
Years Later

• Stable
Memory

Baltimore Longitudinal Study of Aging
Amyloid Accumulation by Age and Over Time
Updated from NeuroImage 134 (2016) 658–670
DVR Increasing Amyloid

190 Participants (Baseline Age 76.3)


500 PET Scans
Amyloid Accumulation by Age and Over Time
Updated from NeuroImage 134 (2016) 658–670
DVR Increasing Amyloid

190 Participants (Baseline Age 76.3) At Last Visit:


500 PET Scans 158 CN
7 MCI
12 AD
13 Other Impaired
Tracking Amyloid Progression Over Time

Baltimore Longitudinal Study of Aging
Risk Factors for Amyloid Build-Up
Ɛ4‐ Ɛ4+
Genetics
APOE
Resnick, BLSA

Sleep 
Duration
Spira et al. JAMA 
Neurol. 2013

> 7 hrs 6 to 7 hrs < 6 hrs

Baltimore Longitudinal Study of Aging
Amyloid Build‐Up Predicts Motor Decline in Aging
Greater Amyloid Burden is Associated with
Longitudinal Slowing of Walking Speed

Gait maintainers      Gait decliners
0.7   0.8   0.9   1.0   1.1   1.2   1.3   1.4
Predicted gait speed, m/s

PiB+: 
amyloid positivity

PiB‐: 
amyloid negativity 
PET Scan Imaging of Plaques and Tangles

Amyloid 
PiB

Tau
AV‐1451

Normal  Alzheimer’s
Cognition Disease
Sperling et al., Neuron 2014
Stay Tuned for Next 
Generation Tau Tracers

AV‐1451
RO‐948
MK‐6240
PI‐2620 
JNJ‐64349311 
GTP‐1
THK‐5351
Hypothetical Model of Pathophysiology
Leading to Cognitive Decline and Impairment

Sperling et al., Neuron 2014
Hypothetical Model of Pathophysiology
Leading to Cognitive Decline and Impairment
?  
Vascular Risk
?  ?  
Stress Sensorimotor 
?  Function
Inflammation
Questions and
Many Thanks for Visiting!