The Relationship Between Risk, Cognition and Structural Changes in the Brain

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The Relationship Between Risk, Cognition and
Structural Changes in the Brain
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Investigators and Project Staff

• Regina McGlinchey, Ph.D, Co-leader, Stats/Design
• Christopher Brady, Ph.D, Co-leader, Geropsych
• Farzaneh Sorond, M.D. and Jorge Serrador, Ph.D
• Shannon Downey, Marcie Freeman, M.Ed., Sheila
  Burch, MSW, Subject Recruitment
• Laura Grande, Ph.D, Project
• coordinator/Neuropsychologist
• James Rudolph, M.D., Project Physician
• Margaret Ahlquist,BS, Lab Tech/Research Assistant
• David Schnyer, Ph.D, neuroimaging consultant
• Lew Lipsitz, M.D., hypertension and gait
  consultant
• William Milberg, Ph.D, Humble Project Leader

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Vascular Dementia between 1980s and the 1990s
An Epidemiological Mystery?
Skoog et al (NEJM 1993 826 , 85 y.o.s in
Gothenberg Prevalance of all dementias 29.8
of whom 43.5 Alzheimers Disease 46.5 Vascular
Dementia (MID, Hypoperfusion etc.)
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Vascular Dementia between 1980s and the 1990s
An Epidemiological Mystery?
Knopman et al (Arch Neurol 2003 419 patients
with dementia (Rochester Epi Project), 51
Alzheimers Disease 13 Vascular Dementia 12
Mixed
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So What Happened

• Ante-Mortem versus Post-Mortem Methods
• Cultural Differences Between Minnesota and Sweden
• Vascular Dementia was cured!
• The DSM III versus DSM IV

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DSM-III Definition of Dementia(circa 1980)

• a loss of intellectual abilities of sufficient
  severity to interfere with social or occupational
  functioning.
• the deficit is multifaceted and involves memory,
  judgment, abstract thought, and a variety of
  other higher cortical functions (page 107)

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Diagnostic criteria for Dementia of the
Alzheimers Type The development of multiple
cognitive deficits manifested by both memory
impairment (impaired ability to learn new
information or to recall previously learned
information) one (or more) of the following
cognitive disturbances aphasia (language
disturbance) apraxia (impaired ability to carry
out motor activities despite intact motor
function) agnosia (failure to recognize or
identify objects despite intact sensory
function) disturbance in executive functioning
(i.e., planning, organizing, sequencing,
abstracting) The cognitive deficits in Criteria
A1 and A2 each cause significant impairment in
social or occupational functioning and represent
a significant decline from a previous level of
functioning. The course is characterized by
gradual onset and continuing cognitive
decline. The cognitive deficits in Criteria A1
and A2 are not due to any of the
following other central nervous system
conditions that cause progressive deficits in
memory and cognition (e.g., cerebrovascular
disease, Parkinsons disease, Huntingtons
disease, subdural hematoma, normal-pressure
hydrocephalus, brain tumor) systemic conditions
that are known to cause dementia (e.g.,
hypothyroidism, vitamin B12 or folic acid
deficiency, niacin deficiency, hypercalcemia,
neurosyphilis, HIV infection) substance-induced
conditions The deficits do not occur exclusively
during the course of a delirium. The disturbance
is not better accounted for by another Axis I
disorder (e.g., Major Depressive Disorder,
Schizophrenia).
(DSM-IV-TR p. 157)
(Page 157 DSM-IV 1994, TR in 2000)
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(DSM-IV-TR p. 160)
Diagnostic criteria for 290.4x Vascular
Dementia The development of multiple cognitive
deficits manifested by both memory impairment
(impaired ability to learn new information or to
recall previously learned information) one (or
more) of the following cognitive
disturbances aphasia (language
disturbance) Apraxia (impaired ability to carry
out motor activities despite intact motor
function))agnosia (failure to recognize or
identify objects despite intact sensory
function) disturbance in executive functioning
(i.e., planning, organizing, sequencing,
abstracting) The cognitive deficits in Criteria
A1 and A2 each cause significant impairment in
social or occupational functioning and represent
a significant decline from a previous level of
functioning. Focal neurological signs and
symptoms (e.g., exaggeration of deep tendon
reflexes, extensor plantar response, pseudobulbar
palsy, gait abnormalities, weakness of an
extremity) or laboratory evidence indicative of
cerebrovascular disease (e.g., multiple
infarctions involving cortex and underlying white
matter) that are judged to be etiologically
related to the disturbance. The deficits do not
occur exclusively during the course of a
delirium.
(Page 160 DSM-IV 1994, TR in 2000)
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Most AD Begins in TemporalLimbic Cortex
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Cognitive Disorders Accompany Disease of
theCerebral White Matter
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Sub- Cortical Microvascular Disease May Have its
Greatest Impact on Frontal Association Cortex
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Executive Functions

• Starting
• Stopping
• Sustaining
• Socialization
• Switching
• Sequencing
• Self-Organization
• Source Monitoring
• Scheduling

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CVD risk factors Health Normative Aging Study
(NAS) An ongoing longitudinal research project
started in 1963 at the VA Boston Healthcare
System. The NAS has collected an extensive
database of medical, psychological, and lifestyle
information on a cohort of 2,280
initially-healthy men. 1,461 participants
currently active 1,000 receive triennial
examinations.
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Cerebrovascular Risk Factors

• Note SBP systolic blood pressure
• Hyp Rx under hypertensive therapy
• DM history of diabetes mellitus
• Cigs smokes cigarettes
• CHD history of myocardial infarction,
• angina pectoris, or coronary insufficiency
• AF history of atrial fibrillation
• LVH left ventricular hypertrophy on
  electrocardiogram

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Data collection points from NAS sample Visit
1 Visit 2 Neuropsychological
tests Neuropsychological tests Medical exam
Medical exam Note. There were 3 years between
visits.
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NAS stroke-free sample in Brady et al. (2001) n
256 Age 66.5 (range 50 - 85) Education
14.2 (range 6 - 24) Stroke risk score 8.4
(range 1 - 17)
Neuropsychological exam (started 1993) Verbal
fluency (animal) Digit span backward Word list
learning (10 item) - immediate and delayed
recall Pattern comparison
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Variables predicting 3-year test score decline
Age Education Stroke risk score Question
addressed by this analysis Does CVD risk status
at visit 1 predict cognitive change seen 3 years
later at visit 2?
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Stroke risk was associated only with decline in
verbal fluency
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Summary Results in relatively healthy older
men Increasing age was associated with decline
on all tests. Increasing stroke risk was
associated only with decline in verbal fluency,
an index of executive function. The relation
between stroke risk and executive decline was
nearly (89) as large as the relation between
age and executive decline. These results
suggest that even in relatively healthy older
men, stroke risk exerted specific effects on a
test of executive function but not on memory or
visuospatial functions, and that the magnitude
of these effects rivaled those of age effects.
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The Relationship of CV Risk to Cognitionin
Older African-Americans

• Pugh
• Kiely
• Lipsitz
• Milberg

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Prevalence of Most Risk Factors is Higher in the
African-American than General Population!
-Lynch et al (2001) African-American
Antiplatelet Stroke Prevention Study vs. 23 other
stroke prevention studies Hypertension 84 vs.
c. 47 Diabetes 39.1 vs. 17.1
-Brancati et al (1996) population based
study Diabetes 10.3 vs. 4.6 (double even
controlling for SES!)
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Pugh, KG., Kiely DK, Milberg WP, Lipsitz, (2003)
Selective impairment of frontal-subcortical
cognitve function in african-americans with
cardiovascular risk Factors.
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Pugh, Kiely, Milberg and Lipsitz (JAGS 2003)
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Pugh, Kiely, Milberg and Lipsitz (JAGS 2003)
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A Causal Triangle of Age Related Cognitive
Disorders
Risk
Normal Aging----------Disease
Cognition
Brain
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Risk, MRI Morphometry and Cognition
Data From Harvard Older Americans Independence
Center (AG08812 Lewis Lipsitz, PI) and VA Merit
Review Collaborators E. Leritz, D. Salat, L.
Lipsitz, R. McGlinchey
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(completed sample expected 300-400 by 2008)
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Neuropsych Factor Analysis
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Physio Factor Analysis
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Item v. Source Memory

• Male v. Female Speaker
• Forced Choice Sentence Recognition

The seat on the bus was empty
I will go to the movies on Saturday night.
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NS

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NS

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Three MRI Morphometric Techniques

• Regional Morphometry
• Cortical Thickness Maps
• Diffusion Tensor Imaging

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Morphometry and Factor Analysis
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APOE and hippocampal volume
NS

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Freesurfer Finds Pial Surface and the Grey/White
Matter Junction
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Inflates the Cortical Surface Showing Sulcal and
Gyral Surfaces
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APOE and cortical thickness
Left Hemisphere
Right Hemisphere
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Physio Factor Analysis
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Physio factor 1 Thickness(BP Factor)
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Physio 2 and Thickness(metabolic/cholesterol)
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Physio 3 Thickness(Cholesterol)
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Physio 4 (Glucose)
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Neuropsych Factor Analysis
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NP CVLT Factor
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NP Factor 2 (Executive Function)
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NP Factor 3 (Logical Memory)
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NP Factor 4(retrieval-based factor)
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FA and Blood Pressure

• Top-Anterior callosum FA and BP
• (r-.600, p
• Bottom-Global (whole brain) FA and BP
• (r-.559, p

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DTI and BP factor
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A Causal Triangle of Age Related Cognitive
Disorders
Risk
Normal Aging----------Disease
Cognition
Brain
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The End