aging versus dementia due to alzheimer’s disease

7/31/2019 Aging versus Dementia due to Alzheimers Disease

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Aging versus Dementia due toAlzheimer s Disease

R. Scott Turner, MD, PhD

Director, Memory Disorders ProgramProfessor, Department of Neurology

Georgetown UniversityWashington, DC

memory.georgetown.edu

[email protected]


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Case 1

A 64 year old judge was referred by her PCP for evaluation of memory loss. Her husband reports memory loss and

repeating questions for about 18 months.Her colleagues and law clerks haveexpressed concerns due to several smallmistakes. She reports that she has

fallen

a little behind at work

, and is planning toretire in 1 month because she has lost the

trust and confidence

of her colleagues


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Case 1

She has a history of well-controlledhypertension and takes only an anti-hypertensive medication. She has no other medical or psychiatric history. There is nohistory of stroke, TIA, alcohol abuse, gaitdisorder, falls, or head trauma. Her parentsdied in their 60

s of

old age

. She works as a judge and lives with her husband. She statesthat at one time her IQ was

170

.


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Risk factors for AD

Age Family history/genetics

ApoE polymorphism Minority (African-American, Hispanic)

Downs syndrome Traumatic brain injury with loss of consciousness Smoking

Diabetes Stroke Low education, occupational level


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NIH conference April 2010

Factors that may affect risk of both AD & cognitivedecline with aging (ARHQ publication 10-E005; Plassman et al., Annals of Internal Medicine; Archives of Neurology, 2011)

Increase risk ApoE4, diabetes, current smoking, depression

Decrease risk Physical activity, Mediterranean diet/vegetable

intake, cognitive training/cognitively engagingactivities

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Normal aging

Can

t find your keys Search for casual names and words Briefly forget conversation details

Can t find a recipe Forget to enter a check Cancel a date with friends Miss an occasional turn


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Early Alzheimer s disease

Routinely place important items in oddplaces

Forget names of family and common

objects Frequently forget entire conversations Can

t follow recipe directions

Can no longer manage checkbook Withdraw from usual interests Get lost in familiar places


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ADLs

Complex Working, living alone, driving, keeping

appointments, handling finances, dailymedications

Basic Dressing, bathing, grooming, toileting,

walking, transfers, eating


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MMSE is Alzheimer

sdisease-centric


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Case 1

Pleasant, cooperative, and well-appearing elderly woman. Vital signsnormal, as is the general medical

examination. Mental statusexamination reveals good attentionwith deficits in memory, orientation,language, and visuospatial skills. TheMMSE score is 25/30, with points off for orientation and memory,consistent with a mild dementia.


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Case 1

The remainder of the neurologicalexamination reveals normal eyemovements, strength, tone, sensation

and coordination. There are no signs of parkinsonism. Reflexes are 2+ andsymmetric. Gait is normal. There areno asymmetric features.


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Case 1

A CBC, chemistry panel, thyroid function tests, andB12 were all normal. A test for syphilis wasnegative.

A head MRI revealed cortical atrophy and

periventricular white matter changes (

small vesselischemic changes

). No tumor, hemorrhage,subdural hematoma, or large cerebral infarct.

Neuropsychologic evaluation confirmed milddementia, with deficits in memory, language,visuospatial skills, and frontal/executive function,and a lower than expected IQ.


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Case 1

prescribed a cholinesterase inhibitor; effects andside-effects of the drug were discussed. advised to continue treatment for hypertension with

her primary care physician.

discussed prognosis, advance directives, andlimitations concerning complex ADLs, includingdriving, handling finances, taking medications...

recommended ad libitum physical activity, socialactivity, and mental activity.

Qualified and interested, thus offered enrollment ina 12 month clinical trial of drug x (add-on to currentdrug therapy).


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March 2011

US life expectancy hits new record more than 78years old (75.5 for men, 80.5 for women)

19

Social Sec.1935


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October 2011

World populationreaches 7 billion, andgraying rapidly(Washington Post)

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AD Facts and Figures 2011 (Alz. Assoc.)


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Diagnostic criteria

A. Dementia Interferes with ability to function at work or at usual activities A decline from a previous level of functioning Not delirium or psychiatric disorder Diagnosed by history, examination Involves at least 2 cognitive domains:

Memory Reasoning and judgment Visuospatial

Language Personality, behavior, comportment

Alzheimer s and Dementia, April 2011


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Kretzschmar, 2009


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Reagan Pathologic Criteria for AD

Likelihood Low Intermediate HighNeuritic

plaques and

neurofibrillarytangles

A more limited

distribution or severity

Limbic regions Neocortex

CERAD plaquescore infrequent moderate frequent

Braak andBraak staging I/II III/IV V/VI

Neurobiology of Aging 18, S1-S2, 1997


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Amyloid Precursor Protein (APP) catabolism

Ab NH2 COOH

a -secretase

p3

g-secretase (presenilin)

Ab

g-secretase

b-secretase (BACE-1)


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Apolipoprotein E(ApoE)

Strittmatter et al,

Science 1993

Genetics of sporadic AD


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The amyloid cascade

APP----->soluble A b --->insoluble A b -->neuronal-->neuronalamyloid morbidity mortality

diffuse plaque, NP NFT, ghost tanglesloss of synapses, enzymes

loss of neurotransmittersexcitotoxicity

inflammatory responsesapoptosis?

mitochondrial & oxidative injury

Normal cognition--------->memory loss--->dementia-->death(mild, moderate, severe)

Ab immunization?

b - or g-secretaseinhibitors?

Turner, Seminars in Neurology 2006


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The amyloid cascade

APP----->soluble A b--->insoluble A b-->neuronal-->neuronalamyloid morbidity mortality

diffuse plaque, NP NFT, ghost tanglesloss of synapses, enzymes

loss of neurotransmittersinflammatory responses

excitotoxicityapoptosis?

mitochondrial & oxidative injury

Normal cognition--------->memory loss--->dementia-->death(mild, moderate, severe)

cholinesteraseinhibitors

memantine

Turner, Seminars in Neurology 2006


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FDA-approved drugs for dementia due to ADDonepezil (Aricept) tablet, orally-disintegrating tablet

5 mg daily, increase to 10 mg daily after 4-6 weeks; then 23 mg daily after 3 months (optional)

Rivastagmine (Exelon) capsule, transdermal patch, liquid 1.5 mg twice daily, increase to 3, 4.5, and 6 mg twice daily in 2 week

intervals 1 patch daily (4.6 mg daily, increase to 9.5 mg daily after 4 weeks)

Galantamine (Razadyne, Razadyne ER) tablet, ER capsule, liquid 4 mg twice daily, increase to 8 and 12 mg twice daily in 4 week intervals

for ER, 8 mg daily, increase to 16 and 24 mg daily in 4 week intervals

Memantine (Namenda, Ebixa) tablet, liquid

Start 5 mg daily, increasing in 1 week intervals up to 10 mg twice daily


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Donepezil (Aricept)

Rogers et al, Neurology 1998

18F-AV45 Distinguishes Patients with AD


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Confidential

Avid 18 F-PET A - Amyloid Imaging

Healthy74 FMMSE 30

AD77 F

MMSE 24

F-AV45 Distinguishes Patients with ADfrom Cognitively Normal Controls


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CSFbiomarkers

Shaw et al, AnnalsNeurology 2009

A 42

Tau

Normal

AD


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Langbaumet al,Neuroimage

2009

FDG-PET:

AD

MCI
http://w3.uokhsc.edu/pathology/deptlabs/alz-2.jpg


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AD brains revealatrophy --

particularly in regionsmediating higher cognitive functions
http://w3.uokhsc.edu/pathology/deptlabs/alz-2.jpg


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MRI atrophy inMCI & AD

McDonald et al,Neurology 2009


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MCI Progression

Petersen et al, Archives Neurology 2009


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Phase II Bapinezumabwith PIB-PET

Rinee et al, Lancet Neurology,

March 2010


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Summary

We are witnessing a growing epidemic of dementia in the USand the world, most of which is AD

The amyloid hypothesis is alive and well, and does not exclude other important and essential pathologic processes

The genetics of familial AD provides the strongest evidence for the amyloid hypothesis

Despite recent high-profile failures, many active trials target Ab /amyloid generation or clearance

Other AD trials target other essential pathologic processes, withthe probable result of a therapeutic cocktail (as now)


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Summary

Current (FDA-approved) therapies for AD provide consistent yetmodest, temporary, and palliative benefits

We are searching for disease-modifying treatments to haltdementia progression, or prevent dementia onset

We are in need of validated biomarkers for: screening,diagnostic accuracy, evidence of efficacy, reduction of the costof clinical trials (decreased numbers of participants)

Treatments and prevention will increasingly target subjects with

MCI, then healthy high-risk individuals Future treatments will be tailored to ApoE genotype

(pharmacogenomics, personalized medicine)

d


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Aging versus Dementia due to

Alzheimer s Disease

R. Scott Turner, MD, PhD

Director, Memory Disorders ProgramProfessor, Department of Neurology

Georgetown UniversityWashington, DC


aging versus dementia due to alzheimer’s disease

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