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Alzheimer’s Disease and Dementia
2012
Diagnosis and Treatment
Richard J. Caselli, MD
Mayo Clinic Arizona
Arizona Alzheimer’s Disease Research Consortium
Definitions
1.
2.
Dementia is the disabling impairment of
multiple cognitive functions. It is not
memory loss alone.
Mild Cognitive Impairment
1.
Single domain
1.
2.
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3.
Amnestic
Non-amnestic (Language, executive, Spatial)
Multiple domain
Alzheimer’s disease and related
disorders
The Genetic Basis of Alzheimer’s Disease
Causative
• Chromosome 21: (APP)
• Chromosome 14:
Presenilin 1
• Chromosome 1:
Presenilin 2
Susceptibility
• Chromosome 19:
Apolipoprotein E
• TOMM40
Milder Risk Factors
CYP46
GAB2
SORL1
Other
Evaluation of the Patient with Dementia
A. Establish Diagnosis
1. Clinical
2. Neuropsychological
3. Laboratory
4. Radiological
And then…
B. Define Symptom Categories
Clinical
• History
-gradual onset, cognitive, behavioral, sleep,
functional (driving)
-PMH: potential contributory factors (vascular,
cancer, metabolic, medications)
• Mental Status Testing
– Orientation, learning/memory, construction,
language, (other)
• Physical exam
– Normal vs parkinsonism, asymmetry, visual,
aphasia
Neuropsychology
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Memory impaired (AVLT, WMS-III)
Language (naming, comprehension)
Spatial (e.g., draw a clock)
Relative preservation mental speed
(COWA)
• Personality changes?
Laboratory
• Blood Tests
– General: CBC, BMP
– “Reversible causes”
• Metabolic: sTSH, B12
• Other (inflammatory, neoplastic, etc)
• Other
– EEG
– Spinal Tap
Differential Diagnosis
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Vascular: Vascular dementia, etc
Inflammatory: CNS vasculitis, NAIM (Hashimoto)
Toxic: meds, especially psychoactive and endocrine
Metabolic: hypothyroid, DM, hypercalcemia
Infectious: fungal, TB meningitis
Nutritional: B12 deficiency
Degenerative: FTD, CJD, etc.
Epileptic: nonconvulsive complex partial status
Trauma: dementia pugilistica
Psychiatric: conversion disorder
Neoplastic: meningeal carcinomatosis, paraneoplastic, etc
Normal Pressure Hydrocephalus
3 Cases
• Rapidly Progressive Dementia
• Parkinsonism and Dementia
• Frontotemporal degeneration
Case 1
• Rapidly Progressive Dementia
Rapidly Progressive “Dementia”
• A 46 year old woman had a 5 month history
of severe personality change that included 1)
increased libido, 2) increased alcohol intake
(1-2 bottles of wine daily), 3) chain smoking
cigarettes, 4) poor judgment (standing
outdoors in snow in her bare feet; opening
the door of a moving car to get out; driving
surreptitiously when told not to [she rented a
car without telling anyone]), and 5)
reduced/erratic sleep patterns.
Rapidly Progressive “Dementia”
• During this time she also appeared to have
impaired memory. For example, going out
with her husband to meet some friends for
dinner she asked where they were going. On
5 occasions she had a seizure-like episode (3
times this occurred while eating) in which her
head and eyes would tip back, and her
breathing would become very labored lasting
up to 30 seconds. A week before presenting
she developed a fixation on candy mints and
started eating ravenously.
Rapidly Progressive “Dementia”
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Orientation
Attention (Digit Span)
Learning (4 words)
Calculations
Information
Abstractions
Constructions
Recall
TOTAL
7/8 (-25 on Benton Orientation)
4/7
4/4
0/4
4/4
2/3 (proverb bizarre)
2/4
3/4 (1/1 with categorical cue)
26/38
Rapidly Progressive “Dementia”
• MRI normal
• EEG normal
• CBC, electrolytes, liver
chemistries, glucose,
BUN, creatinine, sTSH,
B12, RPR, Lyme, RF,
ENA, thyroperoxidase
antibodies, ANA, cANCA, paraneoplastic
antibodies normal
• p-ANCA elevated
Rapidly Progressive “Dementia”
CSF exam
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Protein 54 (normal 14-48)
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Glucose 59 (concurrent serum 87)
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RBC 81.1
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WBC 17.8 (92% lymphocytes)
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Cytology negative
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14-3-3 negative
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Fungal serologies negative (including cocci)
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VDRL negative
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IgG index 1.16 (normal 0-0.85)
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Oligoclonal bands 11
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IgG synthesis rate 28.59 (n0rmal 0-12)
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Other microbiological studies negative
Rapidly Progressive “Dementia”
»
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Orientation
Attention (Digit Sp)
Learning (4 words)
Calculations
Information
Abstractions
Constructions
Recall
TOTAL
Baseline 2 months
19 months
7/8
4/7
4/4
0/4
4/4
2/3
2/4
3/4
26/38
8/8
7/7
4/4
4/4
4/4
3/3
4/4
4/4
38/38
8/8
6/7
4/4
2/4
4/4
3/3
1/4
3/4
30/38
Rapidly Progressive “Dementia”
Rx: High dose Prednisone 120 mg daily and
Cyclophosphamide 100 mg bid with slow taper
Dx: Autoimmune Encephalopathy (aka “Hashimoto’s
Encephalopathy”)
Autoimmune associations:
a. Nonspecific: thyroid, ENA, ANCA, ANA,
hypereosinophilic syndrome, anticardiolipin Ab
b. Specific: paraneoplastic, NMDA-R
Consider in young, rapidly progressive, associated
autoimmunity, unusual clinical profile. Often EEG is very
slow, may be highly steroid responsive, and CSF pleocytosis
may be lacking.
Case 2
• Parkinsonism and Dementia
Parkinsonism and Dementia
• A 58 year old woman developed dream
enactment behavior, occasional
nocturnal hallucinations, and modest
memory loss). MMSE was 27.
Neuropsychological testing showed
reduced learning efficiency and delayed
recall (50%). UPDRS score was zero,
although she had equivocal hypomimia
per her husband.
Parkinsonism and Dementia
• Parkinson’s disease
• Dementia with Lewy Bodies
Overlap with Tauopathies
• Progressive Supranuclear Palsy
• Corticobasal Ganglionic Degeneration
• Tauopathy related FTD-PD
Genetics of Familial Parkinson’s Disease
Gene
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Alpha-Synuclein
Parkin
UCH-L1
PARK3
PARK4
PARK6
PARK7
SCA 2
SCA 3
Chromosome
4
6
4
2
4
1
1
14
12
*Identical twins concordance rate +/- 5%
Inheritance
Auto Dominant
Auto Recessive
Auto Dominant
Auto Dominant
Auto Dominant
Auto Recessive
Auto Recessive
Auto Dominant
Auto Dominant
Frequency of Dementia in Patients with
Parkinson’sDisease
• Prevalence estimates from clinical series
range from 2% to over 77% (median 20-30%)
• Annual incidence ranges from 2.6% to 9.5%
among PD patients initially nondemented,
and increases with age
• Neuropath studies of PD brains show 32%
neocortical LB’s on H&E, but 76% with
ubiquitin stains
• Concomitant AD changes in 50% of PDdementia patients
Dementia With Lewy Bodies:
Five Cardinal Clinical Features
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Dementia
Parkinsonism (levodopa responsive)
Visual Hallucinations
Fluctuations
REM Behavior Disorder
3 Cases
• Frontotemporal degeneration
– Tau
– Progranulin
– TDP 43 (semantic dementia; ALSdementia)
Frontotemporal degeneration
• 78 year old retired Navy Admiral had a
one year history of driving and walking
more slowly, talking less, becoming
more socially withdrawn and passive.
He spent over $100,000 on magazine
subscriptions and other “junk” that he
horded in his garage. At times he
seemed to not recognize people familiar
to him when he first saw them.
Frontotemporal degeneration
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WAIS III
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VC 110
PO 114
WMI 119
PSI 111
AVLT
– 6-6-9-11-9
– STM 89%
– LTM 89%
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BNT 56/60; Token 41/44
WCST
– 6 Categories; 12 Perseverative Errors
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Judgment of Line Orientation 13/30
Facial Recognition Test 36
Famous Faces 2/20
Tauopathies, Progranulinopathies,
and Asymmetric Cortical Degeneration
Syndromes
• Frontotemporal Lobar Degeneration
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With and without ALS
Primary Progressive Nonfluent Aphasia
Semantic Dementia
Frontotemporal dementia (behavioral variant)
• Corticobasal Ganglionic Degeneration
• Progressive Supranuclear Palsy
Frontotemporal Dementia
FTD-like Tauopathy
Bifrontal atrophy in PSP
Corticobasal Ganglionic Degeneration
Treating Dementia
• Medications
• Lifestyle Changes
– Driving
– Assisted Living
– Power of Attorney, etc.
Treatment of the Patient with Dementia by
Symptom Category
1.
2.
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6.
Prevention
Intellectual Decline
Behavioral Disturbances
Sleep Disorders
Associated Problems
Abrupt Decline
Treatment of the Patient with
Dementia: Prevention
1.
2.
3.
4.
Positive clinical trials (?):
Antioxidants (Vitamin E, CoQ10, statins)
Negative clinical trials: vitamin E, B
complex, prednisone, NSAIDs, estrogen,
hydergine, gingko, statins
Ongoing clinical trials: Statins, secretase
inhibitors, anti-aggregants,
immunotherapy
Epidemiologic: Mediterranean diet,
green tea?, red grapes/wine?
Added Impact of CV Risk Factors on e4 Homozygotes
P = NS
P < .001
Caselli RJ et al, Neurology 2011
Treatment of the Patient with
Dementia: Intellectual Decline
1. Mild-moderate Alzheimer’s disease:
Cholinesterase inhibitors
2. Moderate-Severe Alzheimer’s disease:
Memantine (Namenda)
Treatment of the Patient with
Dementia: Behavioral
Disturbances
1. Psychosis and Agitation
a. Atypical Antipsychotic Agents
b. Typical Antipsychotic Agents
c. Environmental Adjustments
2. Depression
3. Anxiety
FDA Public Health Advisory
• April 11,2005
• FDA issued statement saying off label use of
atypical antipsychotics for behavioral
problems in elderly patients with dementia
was associated with a 1.6-1.7 increased risk
of mortality (unpublished data)
• Asked pharmaceutical companies to add a
boxed warning reporting risk and noting that
these medications were not approved for this
indication
• http://www.fda.gov/cder/drug/advisory/antipsychotics.htm
Case 3: Agitation and Caregiver Risk
Treatment of the Patient with
Dementia: Sleep Disorders
1.
2.
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5.
Insomnia
REM Behavior Disorder
Restless Legs Syndrome
Hypersomnolence
Nocturia
Treatment of the Patient with
Dementia: Associated
Problems
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3.
4.
Parkinsonism
Incontinence
Dysphagia
Other Somatic Disorder
Treatment of the Patient with
Dementia: Abrupt Decline
1. Infections (UTI #1)
2. Medications
3. Pain
4. Other SystemicProcess
5. Neurologic Process
6. Post-op
Subdural hematoma in an 83 year old man with
Alzheimer’s disease causing subacute decline in
gait and cognition.
Treating Dementia
• Pharmacotherapy
• Lifestyle Changes
– Driving
– Weapons (remove from the home)
– Assisted Living
– Power of Attorney, etc.
AAN Practice Parameter:
Risk of Driving and Alzheimer’s Disease
Dubinsky, RM, Stein AC, Lyons K, Neurology 2000; 2205-11
(recently updated)
• CDR 0.5 (very mild AD): impairment similar to that
tolerated in teenage drivers and legally intoxicated
(BAC<0.08%) drivers. Consider driving test. Do
reassess every 6 months for progression to CDR
1.0.
• CDR 1.0 (mild AD): “significant traffic safety problem
both from crashes and from driving performance
measurements”. Should not drive.
Revised AAN Practice Parameter: Evaluation
and Management of Driving Risk in Dementia
Iverson DJ, et al. Neurology 2010; 74: 1316-1324
• Level A: CDR (0.5-1.0 consider risk factors)
• Level B: Caregiver’s opinion
• Level C:
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Past driving infractions
Reduced driving mileage or self-reported avoidance
Aggressive/impulsive personality
MMSE<24
• Level U (insufficient evidence)
– Neuropsychological testing
– Driving school interventions
www.alz.org
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Support groups
Respite care
Safe return
Crisis hotline
Research