Fotuhi _ JHH GR _ 21 Jan 2010 Final_ ppt
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Majid Fotuhi, MD, PhDDirector, Center for Memory and Brain Health,
The Sandra and Malcolm Brain & Spine Institute
Assistant Professor of Neurology, Johns Hopkins University School of Medicine
Memory, Aging, and Question of Alzheimer Diagnosis
Disclosures
I have no conflicts of interest to disclose.
Objectives
• To explain the history of the diagnosis of Alzheimer disease
• To describe the limitations of current diagnostic criteria for oldest old
• To define factors that contribute to late-life dementia
• To review strategies for prevention
Berchtold and Cotman, Neurobiol Aging 19(3):173–89, 1998
Changing Perceptions
Plaques and Tangles
Role of Amyloid Plaques in Late-life Dementia
“Plaques are not the cause of senile dementia, but only an accompanying feature of senile involution of the central nervous system.”
Alois Alzheimer (1911)
Science 297(5580):353–6, 2002
http://www.cbsnews.com/blogs/2010/01/12/politics/politicalhotsheet/entry6088901.shtml
Limitation of AD Diagnostic Criteria among Oldest Old
• Plaques and tangles don’t differentiate dementia from no-dementia.
• With each decade of life, relevance of plaques and tangles diminishes.
AD Pathology Cannot Distinguish Dementia from No Dementia
Dementia
No Dementia
Schneider et al., Neurology 69:2197–204, 2007
More Neuropathology, More Dementia
Schneider et al., Ann Neurol 66:200–8, 2009
Relevance of AD Pathology Diminishes with Old Age
Savva et al., NEJM 360:2302–9, 2009
Abbott, Nature 456, Nov 2008
“The amyloid theory is not proven, and we have to be open to the fact that it could be wrong.”
Paul Aisen
50s 60s 70s 80s 90s
“Pure AD” “Mixed Pathology”50%
100%
AD Pathology Often not the Main Culprit among Oldest Old
Hippocampal Atrophy is the Most Robust Marker for Dementia
Duara et al., Neurology 71:1986–92, 2008
Factors that Contribute to Late-life Dementia
and Atrophy in Cortex and Hippocampus:
Beyond Plaques and Tangles
Role of Vascular Lesions
Brain is a Highly Vascular Organ
Zlokovic et al. Neurosurgery 43(4), 877–78, 1998
The Nun Study
• AD pathology causes atrophy in the hippocampus and cortical areas
• Small or large strokes cause atrophy in cortical and subcortical areas
• Worse outcome with both AD and strokes
Higher Risk of AD for Those with Midlife Hypertension plus High Cholesterol
• Longitudinal Study (1972, 1977, 1982, 1998)
• 1449 participants• 57 cases of dementia,
48 with AD• Mild hypertension: <140• Severe hypertension: >160• High cholesterol: >250
BMJ 2001; 322:1447–51
Faster Cognitive Decline in Patients with White Matter Lesions
Ann Neurol 52:335–41, 2002
Obstructive Sleep Apnea • OSA patients have far more cases of
– Myocardial infarction– Stroke– CHF– Pulmonary HTN
• May be due to a combination of – Hypercoagulopathy– Chronic hypoxia– Inflammation and endothelial injury– Hyperactive sympathetic response
Less Grey Matter Brain Volume in Patients with OSA
Am J Respir Crit Care Med 2002; 166:1382–7
Abdominal Obesity Increases Risk of Dementia
Whitmer et al., Neurology 71:1057–62, 2008
Vascular Factors Contribute to Late-life Dementia
Hypertension
Obesity – OSA
WMD
Stroke AD
Diabetes orMetabolic Syndrome
Other Factors that Contribute to Late-Life Dementia
• Apoliporotein E• Inflammation• High homocysteine• Head trauma• Depression/PTSD• Kidney failure• Congestive heart failure
High Homocysteine and Hippocampal Atrophy
Den Heijer et al., Brain 126:170–5, 2003
Hippocampus Atrophy in Cardiovascular Disease
HC Size in CVD
Hippocampus Atrophy in PTSD and Depression
Hippocampus Atrophy in Head Trauma
HC Size in TBI
Why is Hippocampus so Vulnerable?
Differential expression of the different subtypes of metabotropic glutamate receptors may account for the selective vulnerability of CA1 neurons in the hippocampus.
Fotuhi et al., Mol Brain Res 21:283–92, 1994
Nature Reviews Neurology 5(12):649–58, 2009
Brain Atrophy
and Dementia
with Aging
Fotuhi et al., Nature Reviews Neurology 5(12):649–58, 2009
Fotuhi et al., Nature Reviews Neurology 5(12):649–58, 2009
Dynamic Polygon Hypothesis
Prevention Strategies
Preventing Cognitive Decline
The Cache County Study
Cache County Study Design
Wave 23,314
Wave 14,580
5,677 Eligible
Elderly in Cache Co.,
Utah
Wave 32,246
Drug inventory– Current OTC and Rx medicines
(Validated by medicine chest review)
– Prior OTC and Rx medicines
1995–1996 1998–2000 2003–2004
80.0
82.0
84.0
86.0
88.0
90.0
92.0
94.0
BL W2 W3
Followup
3MS
Scor
e
NSAID
VE + VC
Super user
Other user
Non User
Synergistic Role of Antioxidant Supplements and NSAIDs on Cognition
Omega-3 Fatty Acids: DHA
Fotuhi et al., Nature Clinical Practice Neurol 5(3):140–52, 2009
Fotuhi et al., Nature Clinical Practice Neurol 5(3):140–52, 2009
Cognitive Stimulation
Draganski et al. J Neurosci 2006; 26:6314–7
Diet and Exercise
Scarmeas et al., JAMA 302 (6):627–37, 2009
Protective Factors
• Diet high in antioxidants• Fish 2–3 times a week• 1–2 glasses of wine with dinner• Exercise• Leisure activities• Education, cognitive stimulation• Smile more often
Thanks• Peter Zandi, Kathleen Hayden,
Kostas Lyketsos, and all members of the Cache County Study (NIA, NIH, NIMH)
• Payam Mohassel• David Do• Marilyn Albert, Jason Brant,
Barbara Crain, Argye Hillis, Carlos Pardo, Richard O’Brien, Donald Price, Peter Rabins, Ola Selnes, Sol Snyder, andMichael Williams
• Tzipora Sofare
• Vladimir Hachinski(University of Western
Ontario)• Miia Kivipelto
(Karolinska Institute)• Peter Whitehouse
(Case Western University)• Kristine Yaffe
(UCSF)• Anne Young
(Harvard Med School,Mass General Hospital)
Blood Pressure Treatment and Reduced Risk of Dementia
Li et al., BMJ 340:b5465, 2010
More Fitness, Less Brain Atrophy
Burns et al., Neurology 71:210–6, 2008
With Age, AD Pathology Is Less Relevant
Neurology 66:49–55, 2006
Biomarkers, Imaging, and AD
Jagust et al., Neurology 73: 1193–9, 2009
Mitochondria and AD
Starkov et al., Nat Med 14(10): 1020–21, 2008
Alzheimer Overdiagnosis
Carrillo et al., Alzheimer’s & Dementia 5: 182–96, 2009
Role of Stress, Cortisol, and Depression
Cortisol Levels, Memory, and Hippocampal Atrophy
Lupien et al., Nature Neurosci 1(1):69–84, 1991
Role of Inflammation
Hippocampal Atrophy in MS
Sicotte et al., Brain 131:1134–41, 2008
Treating Vascular Risk Factors Slows Decline in Dementia
Deschaintre et al., Neurology 73:674–80, 2009
Exercise Expands Hippocampus
Erickson et al., Hippocampus 19:1030–9, 2009
Multiple Vascular Risk Factors
Risk Factor Score Age >53 4 Education <6 yrs 3 Male sex 1 High blood pressure 2 BMI >30 2 High total cholesterol
2
Physical inactivity 1
Objectives
Age
Cog
nitiv
e R
eser
ve
Latent
MCI
Dementia
1º Prevention
Anatomy of Memory
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