"Prevention of Cognitive Impairment: Promising Directions in 2007"
Transcript of "Prevention of Cognitive Impairment: Promising Directions in 2007"
Prevention of Cognitive Impairment: What looks Promising in 2007?
Kristine Yaffe, MD
University of California, San Francisco
San Francisco VA Medical Center
Projected Prevalence of Alzheimer Disease in the U.S.
1997 2007 2017 2027 2037 20470
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4
6
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YearYear
U.S
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vale
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AD
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.S. P
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(mill
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s)(m
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ns)
Brookmeyer et al. Brookmeyer et al. American Journal of Public Health. American Journal of Public Health. 1998; 88:1337-1342.1998; 88:1337-1342.
Possible strategies for dementia prevention based on risk factor
modification• Cardiovascular disease (CVD) risk• Obesity/metabolic dysregulation• Physical activity• Intellectual activity• Depression
(While we wait for disease modifying new pharmacological strategies)
Cardiovascular Risk Factors and Dementia
• Increasing evidence that AD has a vascular component
• Increasing evidence that dementia is often “mixed” with AD and vascular pathology
• CVD risk factors may be “modifiable”
• Control of CVD would be beneficial in multiple organ systems
Hypertension and Risk of Dementia: Mid-Life Studies
• Fairly consistent finding between mid-life HTN and late-life dementia
• Findings strongest in those without treatment of HTN
• Supported by neuropath studies with greater plaques and tangles in those with mid-life HTN
Hypertension and Risk of Dementia: Late-Life Studies
• Prospective studies with conflicting findings
• Some suggest increased risk, others no effect and many suggest an inverse association
• Several studies suggest antihypertensive medications reduce risk of AD
• Several RCTs of various agents found mixed results on risk of dementia
Underlying Mechanisms
Macrovasculardisease
• brain infarcts
Microvasculardisease
• insidious ischemia• microinfarcts
Glucose toxicity
• advanced protein glycation• oxidative stress
Insulin
↑ secretion↓ breakdown of β amyloid
Brain pathology
Accelerated aging Alzheimer diseaseVascular dementia
Diabetes
• co-morbidity• medication
• geneticpredisposition
Diabetes and Incident Dementia
Dementia
Dementia
MCI
Dementia
Dementia
Ott, 1996
Leibson, 1997
Yaffe, 2004
Whitmer, 2005
.01 1.0 10.05.0
Risk (Odds) Ratio and 95% Confidence Interval
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Diabetes and risk of AD vs VAD
Curb, 1999
Luchsinger, 2000
Hassing, 2002
Macknight, 2002
Xu, 2004
VaD
AD
VaD
AD
AD
VaD
AD
VaD
AD
VaD
.01 1.0 10.0
.05 5.0Risk (Odds) Ratio and 95% Confidence Interval
.05 5.0
Markers of Glucose Control and Cognitive Impairment
• An association between measures of glucose control and incident cognitive impairment would support the causal argument between DM and dementia
• May suggest pathways for intervention• May suggest those at risk (eg secondary
prevention)• We studied Impaired Fasting Glucose (IFG) and
glycosylated hemoglobin (HbA1C)
Glucose Group Women with outcome (%)
MCI & dementia
OR (95% CI)
Normal 273 (5.9)
Impaired Fasting Glucose (>110mg/dL)
22 (10.1) 1.64 (1.03-2.61)
Diabetes 24 (12.1) 1.79 (1.14-2.81)
Trend 1.40 (1.14-1.72)
Diabetes, impaired fasting glucose, & cognitive impairment in 7027 women
Yaffe et al, Neurology 2004
HbA1C at baseline, per 1% increase
Unadjusted (N=1983)
Age-Adjusted (N=1983)
Multivariate Adjusted* (N=1921)
Mild Cognitive Impairment (MCI)
1.56 (1.21, 2.02)
1.50 (1.14, 1.97)
1.37 (1.00, 1.88)
Any cognitive problem (MCI, dementia, low cognitive score)
1.48 (1.16, 1.90)
1.40 (1.08, 1.83)
1.27 (0.94, 1.73)
*Adjusted for age, education, race, depression, smoking, alcohol, body mass index, history of MI, and raloxifene.
Association of HbA1C and Risk of Developing Cognitive Impairment
Yaffe et al. J Nutr Health Aging 2006
Diabetes and Dementia: Summary
• Most studies suggest an association between diabetes and dementia
• Stronger association with VaD than AD• Markers of glucose control also support
the association• Need trials aimed at treating diabetes or
those at risk and including cognitive outcomes and trials of diabetic agents in MCI and dementia
Pilot Trial of Rosiglitizone for MCI
Watson et al. Am J Geriatr Psychiatry 2005.
Composite CV Risk Factors & Dementia Risk
• May be greater than individual components
• Often occur together (e.g. metabolic syndrome)
• May have interactions with genetics eg ApoE e4 (Haan M et al Jama 2000)
• Offer strategies to modify as a group
The ‘Metabolic Syndrome’
GlucoseIntolerance,
Diabetes
VisceralObesity
Hypertension
Dyslipidemia
Also known as:
– Syndrome X
– Insulin Resistance Syndrome
– The Deadly Quartet
– The Dysmetabolic Syndrome
Metabolic Syndrome Prevalence
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20 30 40 50 60 70 80
Black White Mex. Am
Park, Arch Int Med, 2003
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Men Women
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Metabolic Syndrome and Inflammation: Background
• Negative outcomes of the metabolic syndrome may be linked to increased inflammation.
• Inflammation is associated with AD and cognitive decline as well.
• Thus, we determined if the metabolic syndrome was associated with cognitive decline and if this was mediated by inflammation.
Odds of Cognitive Decline comparing Participants with High vs Low Level of Inflammatory Marker
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IL-6 CRP TNF-α
Inflammatory Marker
OR
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Yaffe et al, Neurology 2003
Metabolic Syndrome and Cognitive Impairment: Health ABC Study
• 2949 participants in Health ABC; 43% African-American; followed for 4 years
• Metabolic syndrome definition 3 criteria (NCEP guidelines):
– Waist: > 102 cm ♂, > 88 cm ♀
– HDL: < 40 for men,< 50 for women
– Triglycerides: ≥ 150 mg/dL
– BP: ≥ 130/ ≥ 85 (or med use)
– Fasting glucose: ≥ 110 mg/dL (or med use)
Likelihood of Cognitive Decline & Metabolic Syndrome
No Metabolic Syndrome N=1534
1.0 1.0
Metabolic Syndrome N=964
1.94 (1.25-3.00) 1.13 (0.87-1.47)
P for interaction = 0.04
High High InflammationInflammationN=618N=618
Low Low InflammatioInflammationnN=1880N=1880
Yaffe et al JAMA 2004
Conclusions: Metabolic Syndrome and Cognition• Metabolic syndrome is associated
with cognitive decline• Especially for those with high
inflammation• Need to determine if reducing
metabolic syndrome or inflammation could prevent cognitive decline
• Need imaging studies to help determine mechanisms
Obesity and Dementia: Why is Fat Bad?
AdiposeTissue
Complement Factors•Adipsin•C3
Growth Factors•TGF-ß•IGF-1•VEGF
Cytokines•TNF•IL-6
Peptides•Adiponectin•PAI-1•Angiotensinogen•Resistin•Visfatin
Hormones•Leptin•Cortisol•Estradiol
Lipoproteins•LPL•CETP•Apo E•PLTP
Proposed Mechanisms Linking Obesity to Dementia
VisceralAdiposetissue
IL-6 & TNF-α
FFAPAI-1
Resistin & Adiponectin
Vascular Inflammation
Dyslipidemia
Hypertension
Insulin Resistance
ReducedThrombolysis
Rosenson, 2005
Dementia
Association between Obesity & Dementia among Kaiser Patients
22,612 Kaiser Permanente Subscribers had MHC exam between 1964-73 and were between ages of 40-45
-11,262 who were not members or alive in January 1994
-9 members with incomplete demographic data
10,456 No Dementia
713 Diagnosed
with Dementia
Obesity and Risk of Dementia
Adjusted for age at midlife exam and education
Adjusted for age at midlife exam, age at case ascertainment, education, race, marital status & sex
Adjusted for all + midlife & late life co morbidity*
Body Mass Index-All**
Hazards Ratio (95 % Confidence Interval)
Hazards Ratio (95% Confidence Interval)
Hazards Ratio (95% Confidence Interval)
Obese 1.38(1.10 to 1.72) 1.56(1.24 to 1.96) 1.74(1.34 to 2.26)
Overweight 1.16(1.01 to 1.34) 1.22(1.04 to 1.42) 1.35(1.14 to 1.60)
Underweight 1.41(0.82 to 2.39) 1.46(0.84 to 2.54) 1.24(0.70 to 2.21)
Whitmer R, …Yaffe K; BMJ, 2005.
Quintiles of Sagittal Abdominal Diameter and Thigh Circumference and Risk of Dementia
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Quintiles of SAD and Thigh Circumfrence
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SAD FullyAdjusted
SAD FullyAdjusted + BMI
Thigh FullyAdjusted
Thigh FulyAjdusted + BMI
Whitmer R….Yaffe K: Under Review
Use it or Lose it???
• Physical activity
• Intellectual activity
Intellectual Activity & Cognition: Potential Mechanism
• Hippocampal neurogenesis in mice by long-term environmental enrichment and improved learning
Kempermann, et al 2002
P=.002
**P<0.01
ACTIVE: Advanced Cognitive Training for Independent and Vital Elderly
• 2802 non-demented elderly (mean age 74) randomized to cognitive training (memory, reasoning or processing speed) or to unspecified control for 10 week classes
• Participants received booster training after 11 months• Each intervention improved the targeted cognitive
ability compared with baseline over 2 yrs. f/up. (p<0.001)
Ball et.al, 2002
Effect of Training After 1 Year
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Training Group
Summary of 5-Year Results
• Effects of training maintained over 5 years– Enhanced by ‘booster’ at 3 years – Less self-reported difficulty with daily activities
in training groups after 5 years
Willis S et al Jama 2006
Physical Activity & Cognition:Potential Mechanisms
• associated with mortality, CAD lipids, HTN and fitness cerebral blood flow neuronal growth in rodents (Gage lab) inflammatory markers• BDNF
Decline in age-adjusted mMMSE over 6-8 years as a
function of physical activity
00.5
11.5
22.5
33.5
44.5
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Low Second Third High
Quartile of Blocks Walked
% D
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mo d
MM
SE
P<0.001 overall
Yaffe et al, Arch Intern Med 2001
Women with more daytime movement (actigraphy) have better cognitive
performance
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Lowest Third
Daytime Movement Quartile
Unadjusted
Adjusted
Barnes….Yaffe : Under Review
Physical & Intellectual Activity: Conclusions
• Both may prevent cognitive decline• Possibly confounded by healthy lifestyle• Need for long-term trials to evaluate if physical and
intellectual activity prevents cognitive decline or improves MCI or dementia
Depressive Symptoms and Dementia Incidence
• Growing evidence that depressive symptoms may be a risk factor for dementia
• Prospective studies
– Depressive symptoms associated with increased risk of cognitive decline and dementia
• Meta-analysis
– Risk of dementia doubled in older adults with depressive symptoms
Prospective Studies of Depression and Risk of Dementia
Buntix, 1996
Devanand, 1996
Henderson, 1997
Chen, 1999
Palsson, 1999
Geerlings, 2000
Summary estimate
Dementia
AD
Dementia
AD
Dementia
AD
.01 1.0 10.0
.05 5.0Jorm, 2001 Risk (Odds) Ratio and 95% Confidence Interval
.5 5.0
Prospective Study of Depressive Symptoms and Risk of Cognitive Decline in Older Women
Adjusted* OR (95% CI)
Cognitive Decline
Number of Depressive Symptoms
No. 0-2 3-5 6
3 MMSE point drop
653 1.00 1.6 (1.2-2.1) 2.1 (1.4-3.1)
Dementia 89 1.00 1.7 (0.9-3.5) 2.3 (0.9-5.9)
*Adjusted for age, education, health status, exercise, alcohol, functional status. Adapted from Yaffe et al., Arch Gen Psychiatry, 1999.
Potential Mechanisms for Depression and Dementia
• Depressive symptoms may reflect:
– Etiologic risk factor for dementia– Early symptom of neurodegeneration– Reaction to early cognitive deficits
• Potential mechanisms for etiology:– Vascular (especially frontal-subcortical)– Alterations in cortisol regulation– Others?
Association between Depressive Symptoms & MCI is Not Attributable to Vascular Factors
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Low
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Depressive Symptoms
Barnes D…Yaffe K. Archives of General Psychiatry 2006
Implications
• If association reflects risk factor or early symptom of neurodegeneration:
– Suggests older adults should be monitored more aggressively for onset of new depressive symptoms.
– Future studies should determine whether treatment of depressive symptoms reduces risk of dementia.
Current Preventative Strategies
• Both depression and CV risk factors offer potential avenues for prevention of AD and other dementias
• Intellectual and physical activity seem promising and low risk!
• May offer insight into etiology and treatment of AD
• Need large RCTs!• Implications for early and mid-life interventions
Recent Studies have Questioned the Following for Prevention:
• Statins
• Vitamin E
• Estrogen
• NSAIDS
"Alice: It would be so nice if something made sense for a change."(Alice’s Adventures in Wonderland; July4, 1865- Charles
L.Dodgson)
Thanks….
NIA
NIDDK
NIH “Healthy
Brain Initiative”
NARSAD