Alzheimer’s Disease and Dementia Alzheimer’s Disease and Dementia 2012 2012

Diagnosis and TreatmentDiagnosis and Treatment

Richard J. Caselli, MDRichard J. Caselli, MD

Mayo Clinic ArizonaMayo Clinic Arizona

Arizona Alzheimer’s Disease Research ConsortiumArizona Alzheimer’s Disease Research Consortium

DefinitionsDefinitions

1.1. Dementia is the disabling impairment of Dementia is the disabling impairment of multiple cognitive functions. It is not multiple cognitive functions. It is not memory loss alone.memory loss alone.

2.2. Mild Cognitive ImpairmentMild Cognitive Impairment1.1. Single domainSingle domain

1.1. AmnesticAmnestic

2.2. Non-amnestic (Language, executive, Spatial)Non-amnestic (Language, executive, Spatial)

2.2. Multiple domainMultiple domain

3.3. Alzheimer’s disease and related Alzheimer’s disease and related disordersdisorders

The Genetic Basis of Alzheimer’s DiseaseThe Genetic Basis of Alzheimer’s Disease

CausativeCausative• Chromosome 21: (APP)Chromosome 21: (APP)• Chromosome 14: Chromosome 14:

Presenilin 1Presenilin 1• Chromosome 1: Chromosome 1:

Presenilin 2Presenilin 2

SusceptibilitySusceptibility• Chromosome 19: Chromosome 19:

Apolipoprotein EApolipoprotein E• TOMM40TOMM40

Milder Risk FactorsMilder Risk FactorsCYP46CYP46GAB2GAB2SORL1SORL1OtherOther

Evaluation of the Patient with DementiaEvaluation of the Patient with Dementia

A. Establish DiagnosisA. Establish Diagnosis

1. Clinical1. Clinical

2. Neuropsychological2. Neuropsychological

3. Laboratory3. Laboratory

4. Radiological4. Radiological

And then…And then…

B. Define Symptom CategoriesB. Define Symptom Categories

ClinicalClinical

• HistoryHistory-gradual onset, cognitive, behavioral, sleep, -gradual onset, cognitive, behavioral, sleep,

functional (driving)functional (driving)-PMH: potential contributory factors (vascular, -PMH: potential contributory factors (vascular,

cancer, metabolic, medications)cancer, metabolic, medications)• Mental Status TestingMental Status Testing

– Orientation, learning/memory, construction, Orientation, learning/memory, construction, language, (other)language, (other)

• Physical examPhysical exam– Normal vs parkinsonism, asymmetry, visual, Normal vs parkinsonism, asymmetry, visual,

aphasiaaphasia

NeuropsychologyNeuropsychology

• Memory impaired (AVLT, WMS-III)Memory impaired (AVLT, WMS-III)

• Language (naming, comprehension)Language (naming, comprehension)

• Spatial (e.g., draw a clock)Spatial (e.g., draw a clock)

• Relative preservation mental speed Relative preservation mental speed (COWA)(COWA)

• Personality changes?Personality changes?

LaboratoryLaboratory

• Blood TestsBlood Tests– General: CBC, BMPGeneral: CBC, BMP– ““Reversible causes”Reversible causes”

• Metabolic: sTSH, B12Metabolic: sTSH, B12• Other (inflammatory, neoplastic, etc)Other (inflammatory, neoplastic, etc)

• OtherOther– EEGEEG– Spinal TapSpinal Tap

Differential DiagnosisDifferential Diagnosis

• Vascular: Vascular dementia, etcVascular: Vascular dementia, etc• Inflammatory: CNS vasculitis, NAIM (Hashimoto)Inflammatory: CNS vasculitis, NAIM (Hashimoto)• Toxic: meds, especially psychoactive and endocrineToxic: meds, especially psychoactive and endocrine• Metabolic: hypothyroid, DM, hypercalcemiaMetabolic: hypothyroid, DM, hypercalcemia• Infectious: fungal, TB meningitisInfectious: fungal, TB meningitis• Nutritional: B12 deficiencyNutritional: B12 deficiency• Degenerative: FTD, CJD, etc.Degenerative: FTD, CJD, etc.• Epileptic: nonconvulsive complex partial statusEpileptic: nonconvulsive complex partial status• Trauma: dementia pugilisticaTrauma: dementia pugilistica• Psychiatric: conversion disorderPsychiatric: conversion disorder• Neoplastic: meningeal carcinomatosis, paraneoplastic, etcNeoplastic: meningeal carcinomatosis, paraneoplastic, etc• Normal Pressure HydrocephalusNormal Pressure Hydrocephalus

3 Cases3 Cases

• Rapidly Progressive DementiaRapidly Progressive Dementia

• Parkinsonism and DementiaParkinsonism and Dementia

• Frontotemporal degenerationFrontotemporal degeneration

Case 1Case 1

• Rapidly Progressive DementiaRapidly Progressive Dementia

Rapidly Progressive “Dementia”Rapidly Progressive “Dementia”

• A A 4646 year old woman had a year old woman had a 5 month5 month history history of severe personality change that included 1) of severe personality change that included 1) increased libido, 2) increased alcohol intake increased libido, 2) increased alcohol intake (1-2 bottles of wine daily), 3) chain smoking (1-2 bottles of wine daily), 3) chain smoking cigarettes, 4) poor judgment (standing cigarettes, 4) poor judgment (standing outdoors in snow in her bare feet; opening outdoors in snow in her bare feet; opening the door of a moving car to get out; driving the door of a moving car to get out; driving surreptitiously when told not to [she rented a surreptitiously when told not to [she rented a car without telling anyone]), and 5) car without telling anyone]), and 5) reduced/erratic sleep patterns. reduced/erratic sleep patterns.

Rapidly Progressive “Dementia”Rapidly Progressive “Dementia”

• During this time she also appeared to have During this time she also appeared to have impaired memory. For example, going out impaired memory. For example, going out with her husband to meet some friends for with her husband to meet some friends for dinner she asked where they were going. On dinner she asked where they were going. On 5 occasions she had a seizure-like episode (3 5 occasions she had a seizure-like episode (3 times this occurred while eating) in which her times this occurred while eating) in which her head and eyes would tip back, and her head and eyes would tip back, and her breathing would become very labored lasting breathing would become very labored lasting up to 30 seconds. A week before presenting up to 30 seconds. A week before presenting she developed a fixation on candy mints and she developed a fixation on candy mints and started eating ravenously.started eating ravenously.

Rapidly Progressive “Dementia”Rapidly Progressive “Dementia”

Orientation Orientation 7/8 (-25 on Benton 7/8 (-25 on Benton Orientation)Orientation)

• Attention (Digit Span) Attention (Digit Span) 4/74/7• Learning (4 words)Learning (4 words) 4/44/4• CalculationsCalculations 0/40/4• InformationInformation 4/44/4• AbstractionsAbstractions 2/3 (proverb bizarre)2/3 (proverb bizarre)• ConstructionsConstructions 2/42/4• RecallRecall 3/43/4 (1/1 with categorical cue) (1/1 with categorical cue)• TOTALTOTAL 26/3826/38

Rapidly Progressive “Dementia”Rapidly Progressive “Dementia”

• MRI normalMRI normal• EEG normalEEG normal• CBC, electrolytes, liver CBC, electrolytes, liver

chemistries, glucose, chemistries, glucose, BUN, creatinine, sTSH, BUN, creatinine, sTSH, B12, RPR, Lyme, RF, B12, RPR, Lyme, RF, ENA, thyroperoxidase ENA, thyroperoxidase antibodies, ANA, c-antibodies, ANA, c-ANCA, paraneoplastic ANCA, paraneoplastic antibodies normalantibodies normal

• p-ANCA elevatedp-ANCA elevated

Rapidly Progressive “Dementia”Rapidly Progressive “Dementia”

CSF examCSF exam• Protein 54 (normal 14-48)Protein 54 (normal 14-48)• Glucose 59 (concurrent serum 87)Glucose 59 (concurrent serum 87)• RBC 81.1RBC 81.1• WBC 17.8 (92% lymphocytes)WBC 17.8 (92% lymphocytes)• Cytology negativeCytology negative• 14-3-3 negative14-3-3 negative• Fungal serologies negative (including cocci)Fungal serologies negative (including cocci)• VDRL negativeVDRL negative• IgG index 1.16 (normal 0-0.85)IgG index 1.16 (normal 0-0.85)• Oligoclonal bands 11Oligoclonal bands 11• IgG synthesis rate 28.59 (n0rmal 0-12)IgG synthesis rate 28.59 (n0rmal 0-12)• Other microbiological studies negativeOther microbiological studies negative

Rapidly Progressive “Dementia”Rapidly Progressive “Dementia”

» BaselineBaseline 2 months2 months19 months19 months

• Orientation Orientation 7/8 7/8 8/88/8 8/88/8• Attention (Digit Sp) Attention (Digit Sp) 4/74/7 6/76/7 7/77/7• Learning (4 words)Learning (4 words) 4/44/4 4/44/4 4/44/4• CalculationsCalculations 0/40/4 2/42/4 4/44/4• InformationInformation 4/44/4 4/44/4 4/44/4• AbstractionsAbstractions 2/3 2/3 3/33/3 3/33/3• ConstructionsConstructions 2/42/4 1/41/4 4/44/4• RecallRecall 3/43/4 3/43/4 4/44/4• TOTALTOTAL 26/3826/38 30/3830/38 38/3838/38

Rapidly Progressive “Dementia”Rapidly Progressive “Dementia”

Rx: High dose Prednisone 120 mg daily and Cyclophosphamide Rx: High dose Prednisone 120 mg daily and Cyclophosphamide 100 mg bid with slow taper100 mg bid with slow taper

Dx: Dx: Autoimmune EncephalopathyAutoimmune Encephalopathy (aka “Hashimoto’s (aka “Hashimoto’s Encephalopathy”)Encephalopathy”)

Autoimmune associations: Autoimmune associations: a. Nonspecific: thyroid, ENA, ANCA, ANA, hypereosinophilic a. Nonspecific: thyroid, ENA, ANCA, ANA, hypereosinophilic syndrome, anticardiolipin Absyndrome, anticardiolipin Abb. Specific: paraneoplastic, NMDA-Rb. Specific: paraneoplastic, NMDA-R

Consider in young, rapidly progressive, associated autoimmunity, Consider in young, rapidly progressive, associated autoimmunity, unusual clinical profile. Often EEG is very slow, may be highly unusual clinical profile. Often EEG is very slow, may be highly steroid responsive, and CSF pleocytosis may be lacking. steroid responsive, and CSF pleocytosis may be lacking.

Case 2Case 2

• Parkinsonism and DementiaParkinsonism and Dementia

Parkinsonism and DementiaParkinsonism and Dementia

• A 58 year old woman developed dream A 58 year old woman developed dream enactment behavior, occasional enactment behavior, occasional nocturnal hallucinations, and modest nocturnal hallucinations, and modest memory loss). MMSE was 27. memory loss). MMSE was 27. Neuropsychological testing showed Neuropsychological testing showed reduced learning efficiency and delayed reduced learning efficiency and delayed recall (50%). UPDRS score was zero, recall (50%). UPDRS score was zero, although she had equivocal hypomimia although she had equivocal hypomimia per her husband.per her husband.

Parkinsonism and DementiaParkinsonism and Dementia

• Parkinson’s diseaseParkinson’s disease• Dementia with Lewy BodiesDementia with Lewy Bodies

Overlap with TauopathiesOverlap with Tauopathies

• Progressive Supranuclear PalsyProgressive Supranuclear Palsy• Corticobasal Ganglionic DegenerationCorticobasal Ganglionic Degeneration• Tauopathy related FTD-PDTauopathy related FTD-PD

Genetics of Familial Parkinson’s DiseaseGenetics of Familial Parkinson’s Disease

GeneGene ChromosomeChromosome InheritanceInheritance

• Alpha-SynucleinAlpha-Synuclein 44 Auto DominantAuto Dominant• ParkinParkin 66 Auto RecessiveAuto Recessive• UCH-L1UCH-L1 44 Auto DominantAuto Dominant• PARK3PARK3 22 Auto DominantAuto Dominant• PARK4PARK4 44 Auto DominantAuto Dominant• PARK6PARK6 11 Auto RecessiveAuto Recessive• PARK7PARK7 11 Auto RecessiveAuto Recessive• SCA 2SCA 2 1414 Auto DominantAuto Dominant• SCA 3SCA 3 1212 Auto DominantAuto Dominant

*Identical twins concordance rate +/- 5%*Identical twins concordance rate +/- 5%

Frequency of Dementia in Patients with Frequency of Dementia in Patients with Parkinson’sDiseaseParkinson’sDisease

• Prevalence estimates from clinical series Prevalence estimates from clinical series range from 2% to over 77% (median 20-30%)range from 2% to over 77% (median 20-30%)

• Annual incidence ranges from 2.6% to 9.5% Annual incidence ranges from 2.6% to 9.5% among PD patients initially nondemented, among PD patients initially nondemented, and increases with ageand increases with age

• Neuropath studies of PD brains show 32% Neuropath studies of PD brains show 32% neocortical LB’s on H&E, but 76% with neocortical LB’s on H&E, but 76% with ubiquitin stainsubiquitin stains

• Concomitant AD changes in 50% of PD-Concomitant AD changes in 50% of PD-dementia patientsdementia patients

Dementia With Lewy Bodies:Dementia With Lewy Bodies:Five Cardinal Clinical FeaturesFive Cardinal Clinical Features

• DementiaDementia

• Parkinsonism (levodopa responsive)Parkinsonism (levodopa responsive)

• Visual HallucinationsVisual Hallucinations

• FluctuationsFluctuations

• REM Behavior DisorderREM Behavior Disorder

3 Cases3 Cases

• Frontotemporal degenerationFrontotemporal degeneration– TauTau– ProgranulinProgranulin– TDP 43 (semantic dementia; ALS-TDP 43 (semantic dementia; ALS-

dementia)dementia)

Frontotemporal degenerationFrontotemporal degeneration

• 78 year old retired Navy Admiral had a 78 year old retired Navy Admiral had a one year history of driving and walking one year history of driving and walking more slowly, talking less, becoming more slowly, talking less, becoming more socially withdrawn and passive. more socially withdrawn and passive. He spent over $100,000 on magazine He spent over $100,000 on magazine subscriptions and other “junk” that he subscriptions and other “junk” that he horded in his garage. At times he horded in his garage. At times he seemed to not recognize people familiar seemed to not recognize people familiar to him when he first saw them.to him when he first saw them.

Frontotemporal degenerationFrontotemporal degeneration

• WAIS IIIWAIS III– VC 110VC 110– PO 114PO 114– WMI 119WMI 119– PSI 111PSI 111

• AVLTAVLT– 6-6-9-11-96-6-9-11-9– STM 89%STM 89%– LTM 89%LTM 89%

• BNT 56/60; Token 41/44BNT 56/60; Token 41/44• WCSTWCST

– 6 Categories; 12 Perseverative Errors6 Categories; 12 Perseverative Errors

• Judgment of Line Orientation 13/30Judgment of Line Orientation 13/30• Facial Recognition Test 36Facial Recognition Test 36• Famous Faces 2/20Famous Faces 2/20

Tauopathies, Progranulinopathies, Tauopathies, Progranulinopathies,

andand Asymmetric Cortical Degeneration Asymmetric Cortical Degeneration SyndromesSyndromes

• Frontotemporal Lobar DegenerationFrontotemporal Lobar Degeneration– With and without ALSWith and without ALS– Primary Progressive Nonfluent AphasiaPrimary Progressive Nonfluent Aphasia– Semantic DementiaSemantic Dementia– Frontotemporal dementia (behavioral variant)Frontotemporal dementia (behavioral variant)

• Corticobasal Ganglionic DegenerationCorticobasal Ganglionic Degeneration• Progressive Supranuclear PalsyProgressive Supranuclear Palsy

Frontotemporal DementiaFrontotemporal Dementia

FTD-like Tauopathy FTD-like Tauopathy Bifrontal atrophy in PSPBifrontal atrophy in PSP

Corticobasal Ganglionic DegenerationCorticobasal Ganglionic Degeneration

Treating DementiaTreating Dementia

• MedicationsMedications

• Lifestyle ChangesLifestyle Changes– DrivingDriving– Assisted LivingAssisted Living– Power of Attorney, etc.Power of Attorney, etc.

Treatment of the Patient with Dementia by Treatment of the Patient with Dementia by Symptom CategorySymptom Category

1. Prevention1. Prevention

2. Intellectual Decline2. Intellectual Decline

3. Behavioral Disturbances3. Behavioral Disturbances

4. Sleep Disorders4. Sleep Disorders

5. Associated Problems5. Associated Problems

6. Abrupt Decline6. Abrupt Decline

Treatment of the Patient with Treatment of the Patient with Dementia: PreventionDementia: Prevention

1.1. Positive clinical trials (?):Positive clinical trials (?):

Antioxidants (Vitamin E, CoQ10, statins)Antioxidants (Vitamin E, CoQ10, statins)

2. Negative clinical trials: vitamin E, B 2. Negative clinical trials: vitamin E, B complex, prednisone, NSAIDs, estrogen, complex, prednisone, NSAIDs, estrogen, hydergine, gingko, statinshydergine, gingko, statins

3.3. Ongoing clinical trials: Statins, secretase Ongoing clinical trials: Statins, secretase inhibitors, anti-aggregants, inhibitors, anti-aggregants, immunotherapyimmunotherapy

4.4. Epidemiologic: Mediterranean diet, Epidemiologic: Mediterranean diet, green tea?, red grapes/wine?green tea?, red grapes/wine?

Added Impact of CV Risk Factors on e4 Homozygotes

P < .001P = NS

Caselli RJ et al, Neurology 2011

Treatment of the Patient with Treatment of the Patient with Dementia: Intellectual DeclineDementia: Intellectual Decline

1. 1. Mild-moderate Alzheimer’s disease: Mild-moderate Alzheimer’s disease: Cholinesterase inhibitorsCholinesterase inhibitors

2. Moderate-Severe Alzheimer’s disease: 2. Moderate-Severe Alzheimer’s disease: Memantine (Namenda)Memantine (Namenda)

Treatment of the Patient with Treatment of the Patient with Dementia: Behavioral Dementia: Behavioral

DisturbancesDisturbances

1. Psychosis and Agitation1. Psychosis and Agitationa. Atypical Antipsychotic Agentsa. Atypical Antipsychotic Agents

b. Typical Antipsychotic Agentsb. Typical Antipsychotic Agents

c. Environmental Adjustmentsc. Environmental Adjustments

2. Depression2. Depression

3. Anxiety3. Anxiety

FDA Public Health AdvisoryFDA 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 RiskCase 3: Agitation and Caregiver Risk

Treatment of the Patient with Treatment of the Patient with Dementia: Sleep DisordersDementia: Sleep Disorders

1. Insomnia1. Insomnia

2. REM Behavior Disorder2. REM Behavior Disorder

3. Restless Legs Syndrome3. Restless Legs Syndrome

4. Hypersomnolence4. Hypersomnolence

5. Nocturia5. Nocturia

Treatment of the Patient with Treatment of the Patient with Dementia: Associated Dementia: Associated

ProblemsProblems

1. Parkinsonism1. Parkinsonism

2. Incontinence2. Incontinence

3. Dysphagia3. Dysphagia

4. Other Somatic Disorder 4. Other Somatic Disorder

Treatment of the Patient with Treatment of the Patient with Dementia: Abrupt DeclineDementia: Abrupt Decline

1. Infections (UTI #1)1. Infections (UTI #1)

2. Medications2. Medications

3. Pain 3. Pain

4. Other SystemicProcess4. Other SystemicProcess

5. Neurologic Process5. Neurologic Process

6. Post-op6. Post-op

Subdural hematoma in an 83 year old man with Subdural hematoma in an 83 year old man with Alzheimer’s disease causing subacute decline in Alzheimer’s disease causing subacute decline in

gait and cognition.gait and cognition.

Treating DementiaTreating Dementia

• PharmacotherapyPharmacotherapy

• Lifestyle ChangesLifestyle Changes– DrivingDriving– Weapons (remove from the home)Weapons (remove from the home)– Assisted LivingAssisted Living– Power of Attorney, etc.Power of Attorney, etc.

AAN Practice Parameter: AAN Practice Parameter: Risk of Driving and Alzheimer’s DiseaseRisk of Driving and Alzheimer’s Disease

Dubinsky, RM, Stein AC, Lyons K, Neurology 2000; 2205-11Dubinsky, RM, Stein AC, Lyons K, Neurology 2000; 2205-11

(recently updated)(recently updated)

• CDR 0.5CDR 0.5 ( (very mild ADvery mild AD): impairment similar to that ): impairment similar to that tolerated in teenage drivers and legally intoxicated tolerated in teenage drivers and legally intoxicated (BAC<0.08%) drivers. (BAC<0.08%) drivers. Consider driving testConsider driving test. . Do Do reassess every 6 months for progression to CDR reassess every 6 months for progression to CDR 1.01.0..

• CDR 1.0CDR 1.0 ( (mild ADmild AD): “significant traffic safety problem ): “significant traffic safety problem both from crashes and from driving performance both from crashes and from driving performance measurements”. measurements”. Should not driveShould not drive..

Revised AAN Practice Parameter: Evaluation Revised AAN Practice Parameter: Evaluation and Management of Driving Risk in Dementiaand Management of Driving Risk in Dementia

Iverson DJ, et al. Neurology Iverson DJ, et al. Neurology 20102010; 74: 1316-1324; 74: 1316-1324

• Level A: CDR (0.5-1.0 consider risk factors)Level A: CDR (0.5-1.0 consider risk factors)• Level B: Caregiver’s opinionLevel B: Caregiver’s opinion• Level C:Level C:

– Past driving infractionsPast driving infractions– Reduced driving mileage or self-reported avoidanceReduced driving mileage or self-reported avoidance– Aggressive/impulsive personalityAggressive/impulsive personality– MMSEMMSE<<2424

• Level U (insufficient evidence)Level U (insufficient evidence)– Neuropsychological testingNeuropsychological testing– Driving school interventionsDriving school interventions

www.alz.orgwww.alz.org

• Support groupsSupport groups

• Respite careRespite care

• Safe returnSafe return

• Crisis hotlineCrisis hotline

• ResearchResearch