How To Improve Memory How To Improve Memory Performance and Keep Performance and Keep

Your Brain YoungYour Brain Young

How To Improve Memory How To Improve Memory Performance and Keep Performance and Keep

Your Brain YoungYour Brain Young

Gary W. Small, MDGary W. Small, MDParlow-Solomon Professor on Aging Parlow-Solomon Professor on Aging

Professor of Psychiatry & Professor of Psychiatry & Biobehavioral SciencesBiobehavioral Sciences

David Geffen School of MedicineDavid Geffen School of MedicineUniversity of California, Los AngelesUniversity of California, Los Angeles

Los Angeles, California Los Angeles, California

Keeping Our Brains YoungKeeping Our Brains Young

Time Time

Mem

ory

Ab

ilit

yM

emo

ry A

bil

ity

No InterventionNo Intervention

Early InterventionEarly Intervention

Alzheimer’s Disease Is the End Alzheimer’s Disease Is the End Result of Brain AgingResult of Brain Aging

Alzheimer’s Disease Is the End Alzheimer’s Disease Is the End Result of Brain AgingResult of Brain Aging

Small. Small. The Memory BibleThe Memory Bible. New York, NY: Hyperion; 2002.. New York, NY: Hyperion; 2002.

Mild Mild Cognitive Cognitive

ImpairmentImpairment

Alzheimer’s Alzheimer’s DiseaseDisease

Age-Associated Age-Associated Memory ImpairmentMemory Impairment

Time Time

Cog

nit

ive F

un

cti

on

Cog

nit

ive F

un

cti

on

Risk Factors for Brain AgingRisk Factors for Brain AgingRisk Factors for Brain AgingRisk Factors for Brain Aging

ConfirmedConfirmed AgeAge Family historyFamily history APOE-4 geneAPOE-4 gene

PossiblePossible Other genesOther genes Head traumaHead trauma Lower educational achievementLower educational achievement Chronic stressChronic stress

Small. Small. Br Med JBr Med J. 2002;324:1502-1505.. 2002;324:1502-1505.

Protective Factors for Brain Protective Factors for Brain AgingAging

Protective Factors for Brain Protective Factors for Brain AgingAging

Aerobic exerciseAerobic exerciseEstrogenEstrogenElevated homocysteine Elevated homocysteine Antiinflammatory drugsAntiinflammatory drugsAntioxidantsAntioxidantsLow-fat dietLow-fat dietWineWine

Small. Br Med J. 2002;324:1502-1505.

Time Time

Cog

nit

ive F

un

cti

on

Cog

nit

ive F

un

cti

on Cognitive Stress TestCognitive Stress Test

Amyloid ImagingAmyloid Imaging

Current Initiation Current Initiation of Therapyof Therapy

FDG-PET FDG-PET Genetic Risk Genetic Risk

PresymptomatPresymptomatic Stagesic Stages AA

DD

Early Detection of Early Detection of Alzheimer’s DiseaseAlzheimer’s DiseaseEarly Detection of Early Detection of

Alzheimer’s DiseaseAlzheimer’s Disease

OnsetOnset

Cognitive Stress Test With Cognitive Stress Test With fMRI fMRI

Cognitive Stress Test With Cognitive Stress Test With fMRI fMRI

Functional brain measures during Functional brain measures during memory performance may uncover memory performance may uncover subtle brain dysfunction not subtle brain dysfunction not observed during mental rest (cf, observed during mental rest (cf, treadmill ECG for cardiac disease)treadmill ECG for cardiac disease)

Combine neuroimaging and APOE-Combine neuroimaging and APOE-4 measures of genetic risk in order 4 measures of genetic risk in order to identify abnormalities that may to identify abnormalities that may predict future cognitive declinepredict future cognitive decline

Bookheimer et al. Bookheimer et al. N Engl J MedN Engl J Med. 2000;343:450-456. . 2000;343:450-456.

Possible Outcomes Using PET as a Possible Outcomes Using PET as a Surrogate Marker in AAMI Clinical Surrogate Marker in AAMI Clinical

TrialsTrials

Possible Outcomes Using PET as a Possible Outcomes Using PET as a Surrogate Marker in AAMI Clinical Surrogate Marker in AAMI Clinical

TrialsTrialsAPOE 3/4 and APOE 3/4 and Active DrugActive Drug

APOE 3/4 APOE 3/4 and Placeboand Placebo

BaselineBaseline

Follow-upFollow-up

AAMI = age-associated memory impairment.AAMI = age-associated memory impairment.Small. Small. The Memory BibleThe Memory Bible. New York, NY: Hyperion; 2002.. New York, NY: Hyperion; 2002.

Time Time

Meta

bolic

Meta

bolic

Fu

ncti

on

Fu

ncti

on

Time Time

Cog

nit

ive F

un

cti

on

Cog

nit

ive F

un

cti

on

Early Detection and Early Detection and Intervention: Ongoing Placebo-Intervention: Ongoing Placebo-

Controlled TrialsControlled Trials

Early Detection and Early Detection and Intervention: Ongoing Placebo-Intervention: Ongoing Placebo-

Controlled TrialsControlled Trials

ADAD

AAMIAAMI

MCIMCI

1. Celecoxib1. Celecoxib2. Donepezil2. Donepezil 1. Donepezil vs Vitamin E1. Donepezil vs Vitamin E

2. Donepezil vs Ginkgo2. Donepezil vs Ginkgo3. Donepezil vs Estrogen3. Donepezil vs Estrogen4. Rivastigmine4. Rivastigmine5. Galantamine5. Galantamine6. Rofecoxib6. Rofecoxib

11°° Outcome: clinical exam Outcome: clinical exam11°° Outcome: PET + APOE-4 Outcome: PET + APOE-4

Small. Small. The Memory BibleThe Memory Bible. New York, NY: Hyperion; 2002.. New York, NY: Hyperion; 2002.

UCLA School of UCLA School of Medicine.Medicine.

100%100%

0%0%Min.Min.

Max.Max.100%100%

0%0%Min.Min.

Max.Max.

MRIMRIFDDNP PETFDDNP PET FDG PETFDG PETAD PatientAD Patient

ControlControl

MMSE Scores vs Residence MMSE Scores vs Residence Time (RT) ValuesTime (RT) Values

MMSE Scores vs Residence MMSE Scores vs Residence Time (RT) ValuesTime (RT) Values

HypotheticalHypotheticalStages V-VIStages V-VI

HypotheticalHypotheticalStages III-IVStages III-IV

HypotheticalHypotheticalStages I-IIStages I-II

Residence TimeResidence Time

MM

SE

MM

SE

9988776655443322

1100

2200

3300

1155

55

2255

3355

ControlsControls

ADAD

Shoghi-Jadid et al. Shoghi-Jadid et al. Am J Geriatr Psychiatry. Am J Geriatr Psychiatry. 2002;10:24-35.2002;10:24-35.

AutoradiographyAutoradiographyPETPET MRIMRI

Confocal Fluorescence MicroscopyConfocal Fluorescence Microscopy

Plaques (SP) and tangles (NFT)Plaques (SP) and tangles (NFT)

NFTNFT

Plaques and tanglesPlaques and tangles[[1818F]FDDNPF]FDDNP

The Barrio Lab. UCLA School of Medicine. 2001.The Barrio Lab. UCLA School of Medicine. 2001.

Min. ActivityMin. Activity Max. ActivityMax. Activity

AD Patient: Comparison of AD Patient: Comparison of in-vivoin-vivo and and in-vitroin-vitro Experiments Experiments

AD Patient: Comparison of AD Patient: Comparison of in-vivoin-vivo and and in-vitroin-vitro Experiments Experiments

SPSP

striatumstriatum

Cognitive ReserveCognitive ReservefMRIfMRI

Neuronal FunctionNeuronal FunctionFDG-PETFDG-PET

Plaque/Tangle Load Plaque/Tangle Load FDDNP-PETFDDNP-PET

Regional AtrophyRegional AtrophyStructural MRIStructural MRI

Genetic RiskGenetic RiskProfileProfile

Neuropsychological Neuropsychological ProfileProfile

DiagnosisDiagnosisTreatmentTreatment

Using Information From Multiple Using Information From Multiple Sources to Improve Early Sources to Improve Early Diagnosis and TreatmentDiagnosis and Treatment

Using Information From Multiple Using Information From Multiple Sources to Improve Early Sources to Improve Early Diagnosis and TreatmentDiagnosis and Treatment

Keeping Our Brains YoungKeeping Our Brains YoungKeeping Our Brains YoungKeeping Our Brains Young

Minimize stressMinimize stressGet regular physical exerciseGet regular physical exerciseEat a healthy brain dietEat a healthy brain dietChoose a lifestyle that protects Choose a lifestyle that protects

your brainyour brainUse medicines wiselyUse medicines wiselyTrain your brain with mental Train your brain with mental

aerobics aerobics

ConclusionsConclusionsConclusionsConclusions

Brain aging begins early in adult Brain aging begins early in adult lifelife

Early detection and prevention Early detection and prevention strategies may be useful in strategies may be useful in decelerating brain agingdecelerating brain aging

Available symptomatic treatments Available symptomatic treatments offer benefit early in the course of offer benefit early in the course of dementia and may prove effective dementia and may prove effective for milder cognitive deficitsfor milder cognitive deficits