Pathological Evidence for the Common Causation of Cognition, Movement and Mood Disorders David A' Be

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Pathological Evidence for the Common Causation of
Cognition, Movement and Mood Disorders David
A. Bennett, MDRush Alzheimers Disease
CenterRush University Medical CenterChicago, IL
NIA Bedside-to-Bench Conference Thinking, Moving,
Feeling September 5-7, 2007 Bethesda, MD
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THINKING
MOVING
FEELING
DOROTHY
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Rush Memory Aging Project and Religious Orders
Study Participants
Rush University Medical Center Neelum Aggarwal,
MD Zoe Arvanitakis, MD Lisa Barnes, PhD Patricia
Boyle, PhD Julia Bienias, ScD Aron Buchman,
MD Denis Evans, MD Debra Fleischman, PhD Jeremiah
Kelly, MD Sue Leurgans, PhD Carlos Mendes de
Leon, PhD Julie Schneider, MDRaj Shah, MD Robert
Wilson, PhD
University of Pennsylvania Steven Arnold,
MD University of British Columbia William Honer,
MD Drexel University Jonathan Nissanov,
PhD University of California, Davis Laurel
Beckett, PhD University of California, San
Diego Yan Li, PhD Illinois Institute of
Technology Konstantinos Arfanakis, PhD
National Institute on Aging Grants P30AG10161,
R01AG15819, R01AG17917, R01AG24480, R01AG24871,
K08AG0084, K23AG23040, K23AG23675 Alzheimers
Association Illinois Department Public Health
RADC Staff
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Objectives

• Review the design of two large, longitudinal
  epidemiologic studies of aging that include data
  on cognitive and motor function, mood, and organ
  donation at death
• Examine evidence of common causation of
  age-related decline in cognitive and motor
  function
• Relation of change in cognitive function to
  change in motor function
• Common risk factors for change cognitive and
  motor function
• Common neuropathologic indices for cognitive and
  motor function
• Examine relation of mood to decline in cognitive
  and motor function and neuropathologic indices

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Objectives

• Review the design of two large, longitudinal
  epidemiologic studies of aging that include data
  on cognitive and motor function, mood, and organ
  donation at death
• Examine evidence of common causation of
  age-related decline in cognitive and motor
  function
• Relation of change in cognitive function to
  change in motor function
• Common risk factors for change cognitive and
  motor function
• Common neuropathologic indices for cognitive and
  motor function
• Examine relation of mood to decline in cognitive
  and motor function and neuropathologic indices

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The Religious Orders Study

• gt1,100 older nuns, priests, and brothers without
  known dementia from about 40 facilities across
  the U.S.
• All agreed to annual testing of cognition, motor
  function, and mood starting in 1994
• All agreed to brain donation at the time of death
• gt 95 follow-up of survivors
• gt 200 persons have developed incident AD
• gt 90 autopsy rate with 400 brain autopsies

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Religious Orders Study Participating Sites
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The Rush Memory and Aging Project because
memories should last a lifetime

• gt1,200 residents from about 40 retirement
  communities and senior housing from across the
  Chicago area
• All agreed to annual testing of cognition, motor
  function, and mood, and blood draw, starting in
  1997
• All agreed to donate brain, spinal cord, muscle,
  and nerve at the time of death
• gt 95 follow-up of survivors
• gt 150 persons have developed incident AD
• gt 80 autopsy rate with 200 autopsies to date

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Bennett DA, et al. Neuroepidemiology
200525163175.
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Cognitive function
Religious Orders Study Memory and Aging Project
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Motor Function
Religious Orders Study Memory and Aging Project
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Mood
Religious Orders Study Memory and Aging Project
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Objectives

• Review the design of two large, longitudinal
  epidemiologic studies of aging that include data
  on cognitive and motor function, mood, and organ
  donation at death
• Examine evidence of common causation of
  age-related decline in cognitive and motor
  function
• Relation of change in cognitive function to
  change in motor function
• Common risk factors for change cognitive and
  motor function
• Common neuropathologic indices for cognitive and
  motor function
• Examine relation of mood to decline in cognitive
  and motor function and neuropathologic indices

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Religious Orders Study
Wilson RS, et al. Arch Neurol 200360539-44.
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Religious Orders Study
Wilson RS, et al. Arch Neurol 200360539-44.
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Wilson RS, et al. Arch Neurol 200057855-60.
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composite measure based on grip strength
timed walk body composition fatigue
Buchman AS, et al. Psychsomatic Med 200769483-9.
Memory and Aging Project
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Religious Orders Study
Buchman AS, et al. Neuroepidemiology in press.
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Buchman AS, et al. Neurol 2004639961001.
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Parkinsonian signs Physical Frailty Grip
strength Loss of BMI
Odor Identification
Cognitive Decline
Amyloid Tangles
Apolipoprotein E e4
Infarcts Lewy bodies
Apolipoprotein E e4 Diabetes
Unknown neurobiologic indices
Depressive symptoms
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Objectives

• Review the design of two large, longitudinal
  epidemiologic studies of aging that include data
  on cognitive and motor function, mood, and organ
  donation at death
• Examine evidence of common causation of
  age-related decline in cognitive and motor
  function
• Relation of change in cognitive function to
  change in motor function
• Common risk factors for change cognitive and
  motor function
• Common neuropathologic indices for cognitive and
  motor function
• Examine relation of mood to decline in cognitive
  and motor function and neuropathologic indices

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Wilson RS, et al. Arch Neurol 2002591154-1160.
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Memory and Aging Project
Buchman AS, et al. Under review.
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Arvanitakis Z, et al. Archives Neurology
200461661-666.
Religious Orders Study
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Arvanitakis Z, et al. Neurology 200463996-1001.
Religious Orders Study
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Wilson RS, et al. Arch Gen Psych 200764802-808.
Memory and Aging Project
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Wilson RS, et al. Exp Aging Research in press.
Memory and Aging Project
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Parkinsonian signs Physical Frailty Grip
strength Loss of BMI
Odor Identification
Cognitive Decline
Amyloid Tangles
Apolipoprotein E e4
Infarcts Lewy bodies
Apolipoprotein E e4 Diabetes
Unknown neurobiologic indices
Depressive symptoms
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Objectives

• Review the design of two large, longitudinal
  epidemiologic studies of aging that include data
  on cognitive and motor function, mood, and organ
  donation at death
• Examine evidence of common causation of
  age-related decline in cognitive and motor
  function
• Relation of change in cognitive function to
  change in motor function
• Common risk factors for change cognitive and
  motor function
• Common neuropathologic indices for cognitive and
  motor function
• Examine relation of mood to decline in cognitive
  and motor function and neuropathologic indices

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• 141 consecutive autopsies
• 50 with dementia
• 91 without dementia
• Age at death 88 43 male 14 years education
  mean MMSE 23
• More than 85 had one or more chronic brain
  abnormalities
• 57 met NIA-Reagan criteria for AD
• 37 had cerebral infarctions
• 17 had PD/LBD

Schneider JA, et al. Neurology 2007in press.
Memory and Aging Project
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Alpha-Synuclein in substantia nigra
Alpha-Synuclein in hippocampus
Alpha-Synuclein in neocortex
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Religious Orders Study
Schneider JA, et al. Neurology 2004621148-1155.
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Relation of AD pathology, infarcts, and Lewy
bodies to cognition
Religious Orders Study Memory and Aging Project
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Relation of AD pathology to physical frailty
Memory and Aging Project
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Buchman AS, et al. Neurology 200667194954.
Religious Orders Study
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Relation of infarcts to parkinsonian gait
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Schneider JA, et al. Stroke 200536954-959.
Bennett DA, et al. JNNP 2005761194-1199.
Religious Orders Study
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Religious Orders Study
Arvanitakis Z, et al. Neurology 20066719601965.
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Wilson RS, et al. JNNP 20077830-35.
Memory and Aging Project
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PHFtau tangles and Amyloid in Motor Regions
Memory and Aging Project
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Amyloid and PHFtau tangles in Primary Motor Cortex
Memory and Aging Project
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Schneider JA, et al. Ann Neurol 20065916673.
Religious Orders Study
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Parkinsonian signs Physical Frailty Grip
strength Loss of BMI
Odor Identification
Cognitive Decline
Amyloid Tangles
Apolipoprotein E e4
Infarcts Lewy bodies
Apolipoprotein E e4 Diabetes
Unknown neurobiologic indices
Depressive symptoms
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At this point in Davids talk, Luigi installs a
new brain
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Pathology Accumulates in Old Brains Role of
Inflammation?
pro-inflammatory cytokines IL-6 and IL-1ß
anti-inflammatory cytokine IL-10
Religious Orders Study
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Pathology Accumulates in Old Brains Role of
Inflammation?
Religious Orders Study
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Pathology Accumulates in Old Brains Role of
Inflammation?
Religious Orders Study
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Objectives

• Review the design of two large, longitudinal
  epidemiologic studies of aging that include data
  on cognitive and motor function, mood, and organ
  donation at death
• Examine evidence of common causation of
  age-related decline in cognitive and motor
  function
• Relation of change in cognitive function to
  change in motor function
• Common risk factors for change cognitive and
  motor function
• Common neuropathologic indices for cognitive and
  motor function
• Examine relation of mood to decline in cognitive
  and motor function and neuropathologic indices

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Religious Orders Study
Wilson RS, et al. Neurology 200259364-370.
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Depressive Symptoms and Change in Mobility
Memory and Aging Project
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Wilson RS, et al. Neurology 200361364-370.
Religious Orders Study
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Religious Orders Study
Bennett DA, et al. Am J Geri Psych
200412211-219.
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PHFtau tangles and Amyloid in Regions that
Regulate Affect
Memory and Aging Project
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Locus Coeruleus
Memory and Aging Project
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Dorsal Raphe
Memory and Aging Project
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Parkinsonian signs Physical Frailty Grip
strength Loss of BMI
Odor Identification
Cognitive Decline
Amyloid Tangles
Apolipoprotein E e4
Infarcts Lewy bodies
Apolipoprotein E e4 Diabetes
Unknown neurobiologic indices
Depressive symptoms
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Summary

• Evidence of a common causation of age-related
  decline in cognitive and motor function
• Motor function and decline in motor function
  predict incident AD and cognitive decline
• Common risk factors predict decline in cognitive
  and motor function
• AD pathology, cerebrovascular disease, and Lewy
  bodies are related to both cognitive and motor
  function, and to the risk factors that predict
  cognitive and motor decline
• Mood is related to decline in cognitive and motor
  function, but its neuropathologic basis is poorly
  understood

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Parkinsonian signs Physical Frailty Grip
strength Loss of BMI
Odor Identification
Cognitive Decline
Amyloid Tangles
Apolipoprotein E e4
Infarcts Lewy bodies
Apolipoprotein E e4 Diabetes
Unknown neurobiologic indices
Depressive symptoms
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Precepts of Ptah-Hotep -c2200 BCE (Reign of Pepi
II)
.the progress of age changes into senility.
Decay falls upon man and decline takes the place
of youth... sight fails, the ear becomes deaf
his strength dissolves... speech fails him the
mind decays, remembering not the day before.
Mastaba of the prefect Ptah-Hotep
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Teeth are often used to age mummies.
Adult teeth are visible coming in behind the baby
teeth, indicating that the individual was
probably under ten years old.
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In ancient Egypt, the teeth were rapidly worn
down throughout life by the consumption of a
coarse diet. Eventually, the enamel and dentin
were worn away, exposing the pulp. Painful
chronic infection resulted. Dentists would drain
abscesses through a hollow reed.
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Queen Ankh-nes-meryre II and Her Son King Pepi II

• 5th King of the 6th Dynasty. Reportedly
  ruled Egypt for 92 years (2246-2152 BCE) and
  lived to age 100.

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Top 10 Longest Rulers in History
King Pepi II of Egypt - 92 years King Louis XIV
of France - 72 years Prince John II of
Liechtenstein - 71 years King Franz Josef of
Austria-Hungary - 67 years Ramses the II of
Egypt - 66 years Queen Victoria of England - 64
years King George III of England - 60 years
King Louis XV of France - 59 years Emperor
Pedro II of Brazil - 58 years Queen Wilhelmena
of Netherlands - 58 years
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Bennett DA, et al. Arch Neurol 61378-384
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Bennett DA, et al. Arch Neurol 61378-384
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Memory and Aging Project
Schneider JA, et al. Neurology 2007in press.