Solving the Mysteries of the Aging Brain: Latest Advances in Dementia Research

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Solving the Mysteries of the Aging Brain Latest
Advances in Dementia Research

• Andreana Haley, Ph.D.
• Department of Psychology
• The University of Texas at Austin
• Austin, TX

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Agenda

• Topic
• Neurobiology of Age- and Disease-Related
  Cognitive Impairment
• Diagnosing Dementia
• Assessing Cognition
• Symptoms Diagnoses
• Current State of the Art in the Clinic
• Research Tools
• Neuroimaging MRI, MRS, fMRI
• Latest Research Findings and Future Directions

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Aging A Biological Definition

• aging n.
• 1. The process of growing old or maturing.
• 2. The gradual changes in the structure of a
  mature organism that occur normally over time and
  increase the probability of death.
• declining ability to respond to stress
• increasing homeostatic imbalance
• increased risk of disease
  

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As I get older, I find I rely more and more on
these sticky notes to remind me.
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Source The Silver Book Chronic Disease and
Medical Innovation in an Aging Nation, National
Alliance for Aging Research
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Source The Silver Book Chronic Disease and
Medical Innovation in an Aging Nation, National
Alliance for Aging Research
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The Grim Forecasts

• Population Apocalypse?
• Exponential increase in the number of cognitively
  impaired and severely disabled elderly
  individuals
• Increased societal costs
• Decreased patient quality of life (anxiety,
  depression)
• Increased caregiver burden
• Sky rocketing health care costs

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Possible Solutions

• Treatment
• Study the mechanisms of neurodegenerative
  diseases
• Design and test interventions
• Prevention
• Study age-related changes in
• Glucose regulation
• Vascular health
• Cardiac function
• Design preventive measures

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Defining the Problem

• Neuropsychological Assessment
• Cognition
• Global Cognitive Functioning
• Memory
• Language
• Attention
• Executive Functioning
• Sensory Function
• Activities of Daily Living
• Neurobehavioral Symptoms
• Brain Function

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Localizing Brain Function
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Motor Functions
Sensory Integration
Executive Function
Visual Integration
MEMORY
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Diagnosis

• Dementia vs. Mild Cognitive Impairment
• Impairment in Memory One other area of
  cognition
• Impairment in Activities of Daily Living
• Rule out reversible causes of dementia
• Most Common Dementias
• Alzheimers Disease (AD)
• Vascular Dementia (VaD)
• Dementia with Lewy bodies (DLB)
• Frontotemporal Dementia (FTD)
• Prion Diseases

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Dementia of Alzheimers Type (AD)

• The most common form of dementia (75)
• Affects 30 of all individuals over age 85
• Clinical Symptoms
• Prominent memory impairment
• Followed by language, motor control, gait
  disturbance
• Slow progression
• Pathologic hallmarks atrophy, plaques tangles

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Dementia of Alzheimers Type (AD)
On the Surface
Under the Microscope
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Dementia with Lewy Bodies (DLB)

• Second most common form of dementia (10-15)
• Parkinsons Spectrum Disorder
• Clinical Symptoms
• Persistent memory impairment
• Fluctuating cognition
• Recurrent visual hallucinations
• Spontaneous Parkinsonism
• Pathologic hallmark atrophy, Lewy Bodies

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Dementia with Lewy Bodies (DLB)
On the Surface
Under the Microscope
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Vascular Dementia (VaD)

• Caused by cerebral ischemia (stroke)
• Clinical Symptoms
• Prominent executive dysfunction
• Less language impairment
• Unilateral sensory or motor dysfunction
• Rarely appears in its pure form (3)
• Often contributes to the development of AD
• Pathologic hallmark Cerebrovascular lesions

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Vascular Dementia (VaD)
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Frontotemporal Dementia (FTD)

• Relatively Rare
• Heterogeneous
• Clinical Symptoms
• Profound changes in personality
• Relatively early onset, faster progression
• Pathologic hallmark circumscribed atrophy of the
  frontal lobes, sometimes neuronal inclusions

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Frontotemporal Dementia (FTD)
On the Surface
Under the Microscope
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Prion Diseases (e.g., Mad Cow Disease)

• Extremely rare
• Heterogeneous (BSE, CJD, Juru)
• Infectious
• Clinical Symptoms altered mental state
• Extremely fast progression
• Pathologic hallmark atrophy, spongy appearance
  of the brain matter

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Prion Diseases
On the Surface
Under the Microscope
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State of the Art in the Clinic

• Diagnosis is based on clinical symptoms
• No in vivo biological markers (except for VaD)
• Approximately 90 accurate
• Limited treatments are available for AD, DLB, and
  VaD but not for FTD or CJD
• No cures

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How can Magnetic Resonance (Brain) Imaging Help?

• A window to the living human brain
• Biomarkers of disease and disease progression
• Markers of treatment response
• Understanding disease pathways
• Safe non-invasive
• No radiation
• Contrast agents possible but not necessary
• Good spatial and temporal resolution
• Easy to repeat
• Extremely versatile

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Basic Principles of NMR
Outside magnetic field

• spins randomly oriented

Inside magnetic field
M
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fMRI
MRS
MRI
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BOLD signal
Blood Oxygen Level Dependent signal

• neural activity ? ? blood flow ? ? oxyhemoglobin
  ? ? MR signal

Source fMRIB Brief Introduction to fMRI
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Summary
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Brain Imaging in Dementia Research

• Differential Diagnosis
• Develop non-invasive early biomarkers of disease
• Treatment
• Predict track treatment response
• Prevention
• Study age-related changes in
• Glucose regulation
• Vascular health Cardiac function
• Design preventive measures identify new points
  for intervention

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MRI Biomarkers Atrophy
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MRI Biomarkers Atrophy, Manual Tracing
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MRI Biomarkers Atrophy, Automated Measurements
of Cortical Thickness
AD
FTD
Center for Imaging of Neurodegenerative Disease,
San Francisco, Du et al., Brain, 2007
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fMRI Biomarkers Differences in Brain Activation
During Cognitive Task Performance
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C
x
C
M
X
m
X
R
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fMRI Biomarkers Compensatory Mechanisms
Brain Activation related to performance of a
Verbal Working Memory Task
Dartmouth Medical School, USA, Wishart et al, Am
J Psychiatry, 2006
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fMRI Biomarkers Compensatory Mechanisms
Dartmouth Medical School, USA, Wishart et al, Am
J Psychiatry, 2006
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fMRI Biomarkers Compensatory Mechanisms
Brain Activation related to performance of a
Face-Name Associate Encoding Task
Massachusetts General Hospital, USA Dickerson et
al, Neurology, 2005
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MRS Biomarkers Metabolic Differences
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The Magnetic Resonance Spectrum
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MRS Biomarkers Metabolic Differences
Shonk et al., Radiology, 1995
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MRS Biomarkers Early Neurodegeneration?
University College of London, UK, Godbolt et al.,
Neurology, 2006
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Brain Imaging in Dementia Research

• Differential Diagnosis
• Develop non-invasive early biomarkers of disease
• Treatment
• Predict track treatment response
• Prevention
• Study age-related changes in
• Glucose regulation
• Vascular health Cardiac function
• Design preventive measures identify new points
  for intervention

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Functional Imaging Measuring Treatment Response
to Galantamine in AD
Brain Activation related to performance of a
Semantic Association Task
University of Hull, UK, Shanks et al., MRI, 2007
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Functional Imaging Predicting Treatment Response
to Galantamine in AD
Brown University, Sweet et al.
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Brain Imaging in Dementia Research

• Differential Diagnosis
• Develop non-invasive early biomarkers of disease
• Treatment
• Predict track treatment response
• Prevention
• Study age-related changes in
• Glucose regulation
• Vascular health Cardiac function
• Design preventive measures identify new points
  for intervention

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Glucose Metabolism and Cognitive Function

• Glucose is the primary food source for the brain
• Cerebral glucose stores are limited
• Hypoglycemia results in cognitive impairment
• Glucose facilitates memory in AD
• We can study glucose regulation with glucose
  loading

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Disease Mechanisms Alzheimers Disease
? Acetylcholine
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S. Hoyer J Neural Transm (2002) 109 341-360
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Glucose Metabolism and Cognitive Function
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Rationale

• AD currently has no cure and lacks reliable
  biomarkers
• Disturbances in glucose metabolism can lead to
  neuropathological changes characteristic of AD
• Disturbances in glucose metabolism are treatable
• Understanding cerebral glucose metabolism may
  help identify new treatments and early markers of
  AD

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The Magnetic Resonance Spectrum
MR Signal Intensity (arbitrary units)
Chemical Shift Axis
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Glucose Effect on Brain Glucose Concentrations
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Sources of Detectable Signal in 1H MRS
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Conclusions

• Glucose hypometabolism in AD is related to
  increased cerebral glucose concentration post
  glucose ingestion
• This indicates problems early in the glycolytic
  chain
• Glucose metabolism indexes may provide new early
  markers of AD
• Improving peripheral glucose regulation may be a
  candidate treatment in AD

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Thank you!
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Pittsburgh B Compound for PET
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Methods Design

• Participants
• 15 healthy young (HY)
• 15 healthy elderly (HE)
• 8 AD patients (AD)
• 1H MRS
• short echo time (20 ms)
• right hippocampus
• pre- post-glucose ingestion
• concentrations expressed as mmol/kg of brain
  water
• Repeated measures analysis of variance
• within subjects variable condition (pre-
  post-glucose)
• between subjects variable group (HY, HE, AD)

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Volume of Interest
Post
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Spectral Fitting
Pre Glucose
Post Glucose
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Specific Aims Hypotheses

• To explore the cerebral mechanism behind the
  observed glucose facilitation of memory in
  healthy aging and AD
• We hypothesized that oral glucose ingestion will
  be associated with increased availability of
  glucose to the brain in healthy aging and AD

• Peripheral Glucose ? ? Cerebral Glucose ? ?
  Memory
• Level Concentration