1. How To Improve Memory Performance and Keep Your Brain Young Gary W. Small, MD Parlow-Solomon Professor on Aging Professor of Psychiatry & Biobehavioral Sciences David Geffen School of Medicine University of California, Los Angeles Los Angeles, California

2. Keeping Our Brains Young Time Memory Ability No Intervention Early Intervention

3. Alzheimer’s Disease Is the End Result of Brain Aging Small. The Memory Bible. New York, NY: Hyperion; 2002. Mild Cognitive Impairment Alzheimer’s Disease Age-Associated Memory Impairment Time Cognitive Function

4. Risk Factors for Brain Aging  Confirmed  Age  Family history  APOE-4 gene  Possible  Other genes  Head trauma  Lower educational achievement  Chronic stress Small. Br Med J. 2002;324:1502-1505.

5. Protective Factors for Brain Aging  Aerobic exercise  Estrogen  Elevated homocysteine  Antiinflammatory drugs  Antioxidants  Low-fat diet  Wine Small. Br Med J. 2002;324:1502-1505.

6. Time Cognitive Function Cognitive Stress Test Amyloid Imaging Current Initiation of Therapy FDG-PET Genetic Risk Presymptomatic Stages AD Early Detection of Alzheimer’s Disease Onset

7. Cognitive Stress Test With fMRI  Functional brain measures during memory performance may uncover subtle brain dysfunction not observed during mental rest (cf, treadmill ECG for cardiac disease)  Combine neuroimaging and APOE-4 measures of genetic risk in order to identify abnormalities that may predict future cognitive decline Bookheimer et al. N Engl J Med. 2000;343:450-456.

8. Possible Outcomes Using PET as a Surrogate Marker in AAMI Clinical Trials APOE 3/4 and Active Drug APOE 3/4 and Placebo Baseline Follow-up AAMI = age-associated memory impairment. Small. The Memory Bible. New York, NY: Hyperion; 2002. Time Metabolic Function

9. Time Cognitive Function Early Detection and Intervention: Ongoing Placebo-Controlled Trials AD AAMI MCI 1. Celecoxib 2. Donepezil 1. Donepezil vs Vitamin E 2. Donepezil vs Ginkgo 3. Donepezil vs Estrogen 4. Rivastigmine 5. Galantamine 6. Rofecoxib 1° Outcome: clinical exam 1° Outcome: PET + APOE-4 Small. The Memory Bible. New York, NY: Hyperion; 2002.

10. UCLA School of Medicine. 100% 0% Min. Max. 100% 0% Min. Max. MRI FDDNP PET FDG PET AD Patient Control

11. MMSE Scores vs Residence Time (RT) Values Hypothetical Stages V-VI Hypothetical Stages III-IV Hypothetical Stages I-II Residence Time MMSE98765432 10 20 30 15 5 2535Controls AD Shoghi-Jadid et al. Am J Geriatr Psychiatry. 2002;10:24-35.

12. Autoradiography PETMRI Confocal Fluorescence Microscopy Plaques (SP) and tangles (NFT) NFT Plaques and tangles [ 18 F]FDDNP  The Barrio Lab. UCLA School of Medicine. 2001. Min. Activity Max. Activity AD Patient: Comparison of in-vivo and in-vitro Experiments SP striatum

13. Cognitive Reserve fMRI Neuronal Function FDG-PET Plaque/Tangle Load FDDNP-PET Regional Atrophy Structural MRI Genetic Risk Profile NeuropsychologicalProfile DiagnosisTreatment Using Information From Multiple Sources to Improve Early Diagnosis and Treatment

14. Keeping Our Brains Young  Minimize stress  Get regular physical exercise  Eat a healthy brain diet  Choose a lifestyle that protects your brain  Use medicines wisely  Train your brain with mental aerobics

16. ConclusionsConclusions  Brain aging begins early in adult life  Early detection and prevention strategies may be useful in decelerating brain aging  Available symptomatic treatments offer benefit early in the course of dementia and may prove effective for milder cognitive deficits