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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?
Turner, Seminars in Neurology 2006
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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
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)
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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memory.georgetown.edu