Toward Treatment and Cure: Latest Research (Dr. R. Scott Turner)

8/6/2019 Toward Treatment and Cure: Latest Research (Dr. R. Scott Turner)

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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 fallena little behind at work, and is planning toretire in 1 month because she has lost thetrust and confidence of her colleagues


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R isk factors for ADAg eFamily history/ g enetics ApoE polymorphism Minority

Downs syndrome Head injury with LOC Smoking Hypertension Diabetes Stroke Low education, occupational level


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NIH conference April 2010

Factors that may affect risk of b oth AD & cognitivedecline with aging (AR HQ 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

5


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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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Case 1

Pleasant, cooperative, and well-appearing elderly woman. Vital signsnormal, as is the general medicalexamination. 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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MMSE is Alzheimersdisease-centric


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Case 1

The remainder of the neurologicalexamination reveals normal eyemovements, strength, tone, sensationand coordination. There are no signs of parkinsonism. R eflexes 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 M R I revealed cortical atrophy andperiventricular 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

has multiple cognitive deficits whichimpair her functional abilities andrepresent a cognitive decline.

There is no evidence for delirium or depression by history, examination, or laboratory evaluation.

Diagnosed with mild dementia due toprobable Alzheimers disease.


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Case 1

prescribed a cholinesterase inhibitor; effects andside-effects of the drug were discussed.

advised to continue treatment for hypertension withher 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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> 65 years old

SS established1935


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21 September 2009

World Alzheimer Day; World Alzheimer R eport releasedwww.actionalz.org/about_wad.asp


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Clinical Criteria for AD

Probable AD (NINCDS-AD R DA) Dementia on clinical examination and

neuropsychologic testing Deficits in two or more areas of cognition Progressive worsening No disturbance of consciousness

Onset 40-90, usually > 65 All else ruled out

McKhann et al, Neurol 1984


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Clinical Criteria for AD

Possible AD Dementia with atypical presentation or course

for AD With a second disorder which may cause

dementia

Definite AD Probable AD diagnosed clinically Brain tissue diagnostic for AD

McKhann et al, Neurol 1984


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Diagnostic criteria

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

MemoryR easoning and judgment

Visuospatial LanguagePersonality, behavior, comportment

Alzheimers and Dementia, April 2011


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Neuropathology of AD

Cruz et al, PNAS 1997


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Kretzschmar, 2009


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R eagan Pathologic Criteria for AD

L ikelihood L ow Intermediate Hi g hNeuritic

plaques andneurofibrillary

tangles

A more limiteddistribution or

severity

Limbic regions Neocortex

CE R AD 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

A FNH2 COOH

E-secretase

p3

K-secretase (presenilin)

A F

K-secretase

F-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 F---> insoluble A F--> neuronal-- > neuronalamyloid morbidity mortality

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

loss of neurotransmittersexcitotoxicity

inflammatory responsesapoptosis?

mitochondrial & oxidative injuryNormal cognition--------- > memory loss-- > dementia-- > death

(mild, moderate, severe)

APP, PS-1,

and PS-2mutations ApoE4

Downs

Age

?

Turner, Seminars in Neurology 2006


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The amyloid cascade

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

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

loss of neurotransmittersexcitotoxicity

inflammatory responsesapoptosis?

mitochondrial & oxidative injuryNormal cognition--------- > memory loss--- > dementia-- > death

(mild, moderate, severe)

A F immunization?

F- or K-

secretaseinhibitors?



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The amyloid cascade

APP----->

soluble A F--->

insoluble A F-->

neuronal-->

neuronalamyloid morbidity mortalitydiffuse plaque, NP NFT, ghost tangles

loss of synapses, enzymesloss of neurotransmittersinflammatory responses

excitotoxicityapoptosis?

mitochondrial & oxidative injury

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

cholinesteraseinhibitors

memantine



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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)

R ivastagmine (Exelon) capsule, transdermal patch, liquid

1.5 mg twice daily, increase to 3, 4.5, and 6 mg twice daily in 2 weekintervals

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

Galantamine ( R azadyne, R azadyne E R ) tablet, E R capsule, liquid

4 mg twice daily, increase to 8 and 12 mg twice daily in 4 week intervals for E R , 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)

R ogers et al, Eur Neuropsychopharmacology 1998


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Confidential

Avid18

F-PET A - Amyloid Imaging

Healthy74 FMMSE 30

AD77 F

MMSE 24

18 F-AV45 Distin g uishes Patients with ADfrom Co g nitively Normal Controls


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CSFbiomarkers

Shaw et al, AnnalsNeurology 2009

A F42

Tau

Normal

AD


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Langbaumet al,Neuroimage

2009

FDG-PET:

AD

MCI


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AD brains revealatrophy --particularly in regionsmediating higher cognitive functions


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MR I atrophy inMCI & AD

McDonald et al,Neurology 2009


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CSF A 42

FDG-PET

MR I hipp

CSF tau

Cog

Fxn


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Prevalence of MCI

Petersen et al, Archives of Neurology 2009


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MCI: R ates of Progression to Dementia

Petersen et al, Archives of Neurology 2009


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MCI Progression

Petersen et al, Archives Neurology 2009


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Goals of AD therapy

Cure

ArrestProgression

SymptomaticTherapy (NOW)

NaturalCourse

Time


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Phase II Bapinezumabwith PIB-PET

R inee 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 A F/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 withMCI, then healthy high-risk individuals

Future treatments will be tailored to ApoE genotype(pharmacogenomics, personalized medicine)


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Toward Treatment and Cure: Latest Research (Dr. R. Scott Turner)