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