aging versus dementia due to alzheimer’s disease
TRANSCRIPT
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
1/50
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
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
2/50
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
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
3/50
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
.
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
4/50
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
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
5/50
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
5
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
6/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
7/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
8/50
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
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
9/50
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
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
10/50
ADLs
Complex Working, living alone, driving, keeping
appointments, handling finances, dailymedications
Basic Dressing, bathing, grooming, toileting,
walking, transfers, eating
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
11/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
12/50
MMSE is Alzheimer
sdisease-centric
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
13/50
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.
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
14/50
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.
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
15/50
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.
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
16/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
17/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
18/50
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).
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
19/50
March 2011
US life expectancy hits new record more than 78years old (75.5 for men, 80.5 for women)
19
Social Sec.1935
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
20/50
October 2011
World populationreaches 7 billion, andgraying rapidly(Washington Post)
20
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
21/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
22/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
23/50
AD Facts and Figures 2011 (Alz. Assoc.)
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
24/50
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
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
25/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
26/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
27/50
Kretzschmar, 2009
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
28/50
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
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
29/50
Amyloid Precursor Protein (APP) catabolism
Ab NH2 COOH
a -secretase
p3
g-secretase (presenilin)
Ab
g-secretase
b-secretase (BACE-1)
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
30/50
Apolipoprotein E(ApoE)
Strittmatter et al,
Science 1993
Genetics of sporadic AD
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
31/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
32/50
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
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
33/50
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
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
34/50
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
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
35/50
Donepezil (Aricept)
Rogers et al, Neurology 1998
18F-AV45 Distinguishes Patients with AD
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
36/50
Confidential
Avid 18 F-PET A - Amyloid Imaging
Healthy74 FMMSE 30
AD77 F
MMSE 24
F-AV45 Distinguishes Patients with ADfrom Cognitively Normal Controls
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
37/50
CSFbiomarkers
Shaw et al, AnnalsNeurology 2009
A 42
Tau
Normal
AD
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
38/50
Langbaumet al,Neuroimage
2009
FDG-PET:
AD
MCI
http://w3.uokhsc.edu/pathology/deptlabs/alz-2.jpg -
7/31/2019 Aging versus Dementia due to Alzheimers Disease
39/50
AD brains revealatrophy --
particularly in regionsmediating higher cognitive functions
http://w3.uokhsc.edu/pathology/deptlabs/alz-2.jpg -
7/31/2019 Aging versus Dementia due to Alzheimers Disease
40/50
MRI atrophy inMCI & AD
McDonald et al,Neurology 2009
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
41/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
42/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
43/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
44/50
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
45/50
MCI Progression
Petersen et al, Archives Neurology 2009
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
46/50
Phase II Bapinezumabwith PIB-PET
Rinee et al, Lancet Neurology,
March 2010
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
47/50
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)
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
48/50
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
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
49/50
memory.georgetown.edu
-
7/31/2019 Aging versus Dementia due to Alzheimers Disease
50/50
Aging versus Dementia due to
Alzheimer s Disease
R. Scott Turner, MD, PhD
Director, Memory Disorders ProgramProfessor, Department of Neurology
Georgetown UniversityWashington, DC
memory.georgetown.edu