Stroke, type 2 diabetes, creactive protein and homocysteine predict 4 year decline in cognitive func

1
Dementia in Mexican Americans Biomarkers and
Cultural factors in the Sacramento Area Latino
Study on Aging
MN Haan, Professor, Epidemiology University of
Michigan
Funding NIA AG 12975,DK 60753, AG10129, AG10220
USDA 00-35200-9073 Robert Wood Johnson Scholars
(045823), Claude Pepper Center (F014308)
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Acknowledgements

• University of Michigan,
• Allison E Aiello
• Sharon Kardia
• Rod Little
• Lewis Morgenstern
• Caroline Blaum
• Laila Poisson
• SALSA staff
• University of California, Davis
• Dan Mungas
• Ladson Hinton
• SALSA staff
• Josh W Miller
• Ralph Green
• Marisa Ramos
• Lindsay Allen

• University of California, Berkeley
• William Jagust
• University of California, San Francisco
• Kristine Yaffe
• Kala Mehta
• Kaiser Permanente Division of Research
• Rachel A Whitmer
• University of Washington
• Paul Crane
• Suzanne Craft
• Wayne State University, IOG
• Hector Gonzalez

3
Why is ethnicity important in understanding
dementia?Elements of understanding ethnic and
ancestral differences

• International or Regional differences
• -Culture, economics and ancestry in different
  locations
• Cross-cultural differences
• -Culture, economics and ancestry of different
  groups living within the same/proximal geography
• Changing places or changing culture
• Immigration (change in geography)
• Cultural change in place (cultural orientation)

4
Cognitive anthropology defining culture in
relation to cognition

• Tomasello (1999)
• Culture is a fundamental feature of human
  existence based on an innate predisposition in
  humans
• Cultural evolution (change) is a more potent
  force than genetic evolution in changing human
  lives
• Nisbett (2002)
• Cultural practices engender and sustain specific
  cognitive processes which in turn perpetuate
  specific cultural practices

5
Are there studies of culture as an explanatory
factor in representative cohort studies of
dementia risk?

• Only two representative population-based cohort
  studies of dementia risk have included explicit
  measures of culture
• Sacramento Area Latino Study on Aging
• KAME (Japanese in Seattle)
• Measures migration, language, time in country,
  diet, social patterns of friendship, generations
  since immigration, bicultural flexibility,
  socioeconomic consequences of migration
• Issues appropriateness of cognitive assessment
  is not only an issue of language, best techniques
  for translation?

6
Existing evidence for differences in dementia
risk by ancestry, culture, race or ethnicity
North American cohort studies

• Mexicans
• Sacramento Area Latino Study on Aging
• CUPA project (Mexico City)
• African Americans
• Indianapolis
• Chicago
• Various ancestries
• European Americans, Caribbean Hispanics and
  African Americans in North Manhattan
• Asian
• Hawaiian Japanese
• KAME study
• Studies of European ancestry populations
• Cardiovascular Health Study
• Pennsylvania
• Chicago
• Seattle
• Utah

7
Differences in dementia incidence rates within
North Americaby ancestry or ethnicity

Severe cognitive impairment
8
North American variability in dementia risk

• Within European ancestry populations there is
  important variability in dementia risk related to
  place and methodological differences
• The more limited studies of other ancestry/ethnic
  groups suggest variability within and between
  ethnic groups
• Whats missing?
• Population based research on Native Americans,
  South/east Asians, other ancestral/cultural
  groups
• Effects of immigration on risk

9
Mexican ancestry and dementia risk
10
Migration to North America and Hispanic Genetic
Admixture
11
Some issues in measuring ancestry

• Population stratification within an
  ancestral/ethnic group
• Is admixture a measure of ethnicity?
• Health effects may reflect consequences of
  societal reaction to phenotype rather than as
  marker of underlying genetic factors
• Genetic predisposition to disease ? admixture
• Interactions between genetic factors and cultural
  factors
• Changes in culture related to migration
  adaptation that modify disease risk within a
  group thought to be homogeneous genetically

12
Example of population stratification Admixture
among US Hispanics by Region (based on 6 loci)
(Bertoni 2003)
Eastern Region
Western Region
13
Differences in ApoE distribution by Mexican or
European ancestry and country of residence
E4 explains Anye4 14.2 13.4
Anye4 25.9 28.4
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Does ApoE4 influence dementia risk equally in all
population groups?

• What may modify effects of APOE4 on dementia risk
  across diverse populations?
• Socioeconomic and cultural factors
• Early life factors such as immigration, poverty,
  nutrition
• Vascular processes (atherosclerosis, lipids,
  metabolic, inflammatory and immune response)
• Other genetics factors such as PPARa

15
Epidemiologic evidence of an association between
type 2 diabetes and incidence of AD (pro
left) (con- right)
16
Summary of population based cohort studies of
type 2 diabetes or insulin and Alzheimers disease
Haan 2006 Nature Neurology, Clinical Practice
17
Public health importance of the joint occurrence
of diabetes dementia

• Global Increases in prevalence
• Obesity
• 320 million obese adults (IDF) (BMI30)
• Type 2 diabetes
• 80 increase in diabetes-related deaths 2006-2015
• Increases in older population as percent of total
• Increases in dementias with population aging
• Potential effects of these on population burdens
  of cognitive impairment, dementia and Alzheimers

18
Model of links between type 2 diabetes and
dementias
19

• Pathways by which type 2 diabetes may influence
  risk of dementia
• Metabolic Insulin, Insulin resistance
• Nutritional Obesity, homocysteine,
  B-vitamins
• Inflammation C-reactive protein, IL6,
  TNF-?
• Cerebrovascular Stroke, Blood pressure
• White matter changes, blood flow
• Genetic? PPAR, Calpains

20
Suggested model linking diabetes to dementia
Biessels 2005
21
Metabolic syndrome and cognitive decline
association between MS and 4 year decline on
global measure of cognition CRP modifies effect
of metabolic syndrome on cognition in Health ABC
study
P0.47
P0.04)
22
Risk of Alzheimers disease in elderly men and
women with and without Metabolic Syndrome
MS
No MS
Vanhanen, M. et al. Neurology 200667843-847
23
Metabolic syndrome critique

• Clinical view (Kahn 2005)
• Criteria are ambiguous and thresholds rationale
  are ill defined
• Inclusion of diabetes in definition is
  questionable
• Insulin resistance as unifying etiology is
  uncertain
• Basis for inclusion of CVD risk factors is
  unclear
• CVD risk syndrome is ? sum of parts
• Treatment of the syndrome is the same as
  treatment for the parts
• Medical value of diagnosing syndrome is unclear
  
• Epidemiologic view (Haan 2007)
• Does not distinguish modifiable pathways by which
  MS may influence dementia risk

24
Sacramento Area Latino Study on Aging Cohort
Study

• 1,789 Latinos aged 60, primarily Mexican
  American (85) in Sacramento, California
• 60
• Baseline 1998-99, Follow-up planned through 2008
• APOe (any 4) 6.1 (low genetic risk)
• In home clinical evaluations and interviews
• Funding NIA AG 12975 1997-2008
• DK 60753, AG10129, AG10220 USDA 00-35200-9073

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SALSA Measurements of diabetes, stroke, brain
pathology

• Type 2 diabetes
• Baseline prevalence 33
• TX at baseline 57 of identified diabetics
  receiving medication
• BMI 25 40
• Type 2 DM diagnosis fasting glucose 125, use of
  DM medication, Self report of MD diagnosis.
• 85 included at least 2 of these criteria
• Stroke
• Self report of MD diagnosis, hospitalization
• Baseline prevalence 16.5
• MRI (volumetric)
• All dementia cases
• Subsample of diabetes cases
• Random subsample of normals

26
Diagnosis of dementia or CIND in SALSA

• Screening test with 3MSE or Word List
• Referral to extended neuropsychological battery
  for those
  test from baseline
• Clinical Examination
• Expert case adjudication demented or Cognitively
  impaired Not Demented (CIND)
• MR Imaging CIND, demented, Normal, Diabetic
• (Haan et al 2003)

27
Type 2 diabetes and rates of dementia and
dementia/CIND in the SALSA study from a
proportional hazards model including age, gender,
waist to hip ratio, fasting insulin and
c-reactive protein
0.002
Note metabolic syndrome is not associated with
dementia incidence
28
Biomarkers Obesity and central body fat

• Studies using BMI
• BMI a poor measure of metabolic mechanism
• Central body adiposity
• Increased concentration of fat in viscera with
  aging
• Proximal weight loss related to dementia lowers
  value of BMI as a predictor

29
Body mass index as a predictor of dementia
Gustafson 2003
Whitmer 2005
30
Central body fat (waist circumference) vs. BMI
dementia 5-year incidence in SALSA

• Opposite effects of central body adiposity
  (waist) vs. Body Mass Index in relation to
  dementia/CIND incidence
• Adjusted for age, education, height

West, Haan et al 2006
31
Does central obesity affect the brain?waist
circumference and the aging brain in SALSA (MR
substudy)
P0.02
P0.02)
32
Biomarkers Insulin
33
Insulin and dementia

• Summary of studies suggests increased risk of
  dementia associated with peripheral
  hyperinsulinemia (Qiu 2006)
• Insulin is degraded by insulin degrading enzyme
  (IDE)
• IDE degrades ß amyloid

34
Qiu 2006
35
Insulin, body fat and Aß42

• Craft et al
• Aß in AD vs. controls
• High insulin provokes Aß and inflammation
• Balakrishnan et al
• BMIAß42 (r) 0.60
• Fat Mass Aß42(r) 0.55
• Insulin Aß r0.42

JAD 2005
36
Effects of insulin on rates of dementia/CIND by
diabetes status in SALSA by age at dementia/CIND
West, Haan et al 2006.
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Aging and insulin a complication

• Interaction between body fat and insulin
• Lean elderly type 2 diabetics have impaired
  glucose-induced insulin release but low insulin
  resistance
• Obese elderly type 2 diabetics have normal
  circulating insulin and high insulin resistance
• Body fat as percent of total mass increases with
  age and concentrates in viscera
• Effects of insulin may be modified by aging
  processes related to changes in body composition

Scheen 2005
38
Biomarkers Inflammation
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Inflammation C-reactive protein

• Associated with vascular outcomes in a large
  number of observational studies
• Elevated in metabolic syndrome, type 2 diabetes
• Elevated CRP (3.0 mg/l) increased risk of
  vascular outcomes RR than that associated with
  other CV risk factors such as LDL, IL6,
  Homocysteine.
• Clinical guidelines for CRP screening
• Few studies of dementia and CRP
• Rotterdam Study found HR 1.12 (0.99-1.25)
• Judson (2004) study found interaction between E4
  and CRP so that crp in those E4

40
Hazard ratios for combined dementia/CIND
incidence in relation to c-reactive protein (log)
from two proportional hazards regression models
in SALSA
Haan et al in press 2007
41
Apolipoprotein E4 and high sensitivity c-reactive
protein (log) means from a general linear model
(SALSA)
Adjusted Mean difference for AnyE4 vs No E4
0.37, p.002
Haan et al in press 2007
42
Association between c-reactive protein and
incidence of dementia/CIND by E4 status from a
proportional hazards modelincluding E4, hs-CRP,
age, LDL and interaction term for E4 and hs-CRP
P interaction0.03
Haan et al in press 2007
43
Hs-CRP and E4

• E4 modifies the association between hs-crp and
  outcome such that
• E4 hs-crp is inversely associated with
  dementia/CIND incidence and
• E4- hs-crp is not associated with dementia
• No other studies examining E4crp modification in
  relation to dementia outcomes with which to
  compare.
• Potential explanations impaired immune function
  in demented cases

44
Genetics of type 2 diabetes and
dementia?PPAR-Regulated Inflammatory Markers

• PPARa
• C-reactive protein
• Endothelin-1
• Fibrinogen
• IL-6
• PPAR?
• C-reactive protein
• Matrix metalloproteinase-9
• Plasminogen activator inhibitor-1
• TNF-a

45
Risk of dementia/CIND in relation to PPAR-gamma
by type 2 diabetic status (West Haan, 2007)

• PPAR- gamma Pro 12Ala
• influences
• Diabetes
• Obesity
• Metabolic function
• Coded as
• CC (1) vs. CGGG (0)

From a logistic regression model including PPAR,
age, gender and fasting glucose
46
Biomarkers of diet homocysteine and B vitamins
47
Homocysteine and dementia

• Folate supplementation in 1998 (national)
• Modifiable by B vitamin supplementation
• Total HCY (log) associated with increased risk of
  dementia in Framingham (Seshadri 2002)
• RR for AD 1.8 (1.3-2.5)

48
SALSA StudyHazard ratios for combined incident
dementia and CIND in relation to total
homocysteine (log) from a series of proportional
hazards models
Models 2 biomarkers b12, folate, GFR 3 2
stroke, age, education, gender, nativity 4
3excluding stroke cases
Haan 2007
49
Association between homocysteine and dementia or
CIND by plasma B12 tertile (Low high (498 pg/mL) compared to middle tertile
from two proportional hazards models - 1
including only B12 and 2 adding adjustment for
education. P value are for the interaction terms
between plasma B12 indicator variables and HCY.
Haan 2007
50
Neuroimaging studies diabetes and dementia
51
Imaging studies effects of type 2 diabetes on
brain structure white matter and hippocampal
atrophy
52
Type 2 diabetes and atrophy of hippocampus and
amygdala
2003
53
Association between glycated hemoglobin A (HbA1c)
by quartile and rate of brain atrophy

• Box plots demonstrate
• significant differences in
• brain atrophy rates by
• quartiles of HbA1c levels
• (p 0.0001).
• HbA1c chronicity of
• hyperglycemia, marker of
• glucose control

Enzinger, C. et al. Neurology 2005641704-1711
54
Effects of diabetes and stroke on brain structure
in SALSA

• MRI using standard methods (n146)
• (Jagust et al 2002)
• Measures
• White matter hyperintensities (semi
  quantitative)
• Hippocampal volume by location (anterior,
  posterior, right left)
• Analyses Compare by group (a) posterior vs
  anterior volume (b) White matter

55
White matter hyperintensities (log) by demented
status and presence of stroke or diabetes
p.006, p.05
56
Anterior and posterior hippocampal volume
(mean) by presence of combined dementia or CIND
incidence and baseline diabetes
p0.008, p 57
Summary Volumetric MRI findings

• Hippocampal volume is smaller in those with
  dementia
• Greater difference between posterior atrophy and
  anterior atrophy in demented cases vs non
  demented cases
• This locational difference is greater in diabetes
  vs. non diabetics
• Posterior anterior hippocampal difference is
  consistent with Wolf et al (2001) findings for
  overall dementia
• London Taxi driver study Greater volume in
  posterior Hipp.
• White matter hyperintensities are increased by
  presence of diabetes and stroke in those with
  dementia more than those with only vascular or
  dementia conditions

58
Interventions and Treatments Are we there yet?
59
Cochrane Reviews

• Cognitive function has not been included as
  an outcome in large scale RCTs of type 2
  diabetes.
• There is sufficient evidence to support the
  view that there is an up to twofold increase in
  risk of cognitive impairment or dementia in
  people with diabetes

Sastre Evans 2006
60
Could diabetes behavioral interventions reduce
dementia risks? Examples of exercise and weight
reduction

• Weight reduction
• No RZ trials
• Timing of change
• Proximal pathology
• Younger or middle age definite effect on
  diabetes risk
• Weight reduction on dementia in elderly
  participants

Observational study of exercise
Larsen, 2006
61
Randomized Trials of drug treatments for
ADTrial of Rosaglitazone treatment in AD
patients (preliminary)

• Risner et al (2006) preliminary results of
  Rosaglitazone treatment in 511 AD patients
• No significant effect overall
• Post-hoc Modification by APOE (n322 subset)
• Effect of TX in E4- but not in E4

Affects insulin resistance
62
Randomized trials of type 2 diabetics and
cognitive outcomes

• ACCORD trial (CVD risk) cognitive substudy
• In progress PHASE III trial, age 55, n2800
• Randomized to treatment with standard DM TX vs.
  intensive management (DM, HTN, lipids)
• Outcomes memory, exec function, MRI (volumetric)
• UK PDS study (10 years ago)
• Found better cognitive outcomes in those treated
  intensively (limited measures of cognition and no
  MR)

NHLBI funded
63
Conclusions

• Population based studies link dementia with type
  2 diabetes and its cofactors
• Hippocampal atrophy in type 2 diabetes
• IDE-Aß possible pathway affected by peripheral
  and CNS insulin
• Pending trials of (1) insulin sensitizer in MCI
  patients and (2) intensive DM treatment in
  relation to cognitive and brain outcomes

64
Conclusions

• Type 2 diabetes increases the incidence rates of
  dementia and CIND
• Homocysteine is associated with an increased risk
  of combined outcome
• C-reactive protein is associated with an
  increased risk of combined outcome in the absence
  of E4
• Insulin may serve as a pathway for the
  association between type 2 diabetes and
  dementia/CIND
• MR sub analyses suggest atrophy in posterior
  hippocampus and elevated WM underlying brain
  changes related to type 2 diabetes and stroke
• Possible behavioral interventions or treatment?

65
B-vitamins/Homocysteine
Diet
Lipids
Inflammation
Dementia/AD
Central body obesity
Environmental social factors
Brain Changes
Diabetes
Insulin
Physical activity
Muscle mass
Genetics
Hypertension/Stroke
Conceptual map of sequence of changes in type 2
diabetes association With dementia
Early factors
Late
Aging
66
Questions?