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Alzheimer’s Disease and Dementia 2012 Diagnosis and Treatment

Alzheimer’s Disease and Dementia 2012 Diagnosis and Treatment. Richard J. Caselli, MD Mayo Clinic Arizona Arizona Alzheimer’s Disease Research Consortium. Definitions. Dementia is the disabling impairment of multiple cognitive functions. It is not memory loss alone.

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Alzheimer’s Disease and Dementia 2012 Diagnosis and Treatment

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  1. Alzheimer’s Disease and Dementia 2012 Diagnosis and Treatment Richard J. Caselli, MD Mayo Clinic Arizona Arizona Alzheimer’s Disease Research Consortium

  2. Definitions Dementia is the disabling impairment of multiple cognitive functions. It is not memory loss alone. Mild Cognitive Impairment Single domain Amnestic Non-amnestic (Language, executive, Spatial) Multiple domain Alzheimer’s disease and related disorders

  3. 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 The Genetic Basis of Alzheimer’s Disease

  4. Evaluation of the Patient with Dementia A. Establish Diagnosis 1. Clinical 2. Neuropsychological 3. Laboratory 4. Radiological And then… B. Define Symptom Categories

  5. 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

  6. Neuropsychology • Memory impaired (AVLT, WMS-III) • Language (naming, comprehension) • Spatial (e.g., draw a clock) • Relative preservation mental speed (COWA) • Personality changes?

  7. Laboratory • Blood Tests • General: CBC, BMP • “Reversible causes” • Metabolic: sTSH, B12 • Other (inflammatory, neoplastic, etc) • Other • EEG • Spinal Tap

  8. Differential Diagnosis • 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

  9. 3 Cases • Rapidly Progressive Dementia • Parkinsonism and Dementia • Frontotemporal degeneration

  10. Case 1 • Rapidly Progressive Dementia

  11. 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.

  12. 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.

  13. Rapidly Progressive “Dementia” Orientation 7/8 (-25 on Benton Orientation) • Attention (Digit Span) 4/7 • Learning (4 words) 4/4 • Calculations 0/4 • Information 4/4 • Abstractions 2/3 (proverb bizarre) • Constructions 2/4 • Recall 3/4 (1/1 with categorical cue) • TOTAL 26/38

  14. Rapidly Progressive “Dementia” • MRI normal • EEG normal • CBC, electrolytes, liver chemistries, glucose, BUN, creatinine, sTSH, B12, RPR, Lyme, RF, ENA, thyroperoxidase antibodies, ANA, c-ANCA, paraneoplastic antibodies normal • p-ANCA elevated

  15. Rapidly Progressive “Dementia” CSF exam • Protein 54 (normal 14-48) • Glucose 59 (concurrent serum 87) • RBC 81.1 • WBC 17.8 (92% lymphocytes) • Cytology negative • 14-3-3 negative • Fungal serologies negative (including cocci) • VDRL negative • IgG index 1.16 (normal 0-0.85) • Oligoclonal bands 11 • IgG synthesis rate 28.59 (n0rmal 0-12) • Other microbiological studies negative

  16. Rapidly Progressive “Dementia” • Baseline2 months19 months • Orientation 7/8 8/8 8/8 • Attention (Digit Sp) 4/7 6/7 7/7 • Learning (4 words) 4/4 4/4 4/4 • Calculations 0/4 2/4 4/4 • Information 4/4 4/4 4/4 • Abstractions 2/3 3/3 3/3 • Constructions 2/4 1/4 4/4 • Recall 3/43/44/4 • TOTAL 26/38 30/38 38/38

  17. 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.

  18. Case 2 • Parkinsonism and Dementia

  19. 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.

  20. Parkinsonism and Dementia • Parkinson’s disease • Dementia with Lewy Bodies Overlap with Tauopathies • Progressive Supranuclear Palsy • Corticobasal Ganglionic Degeneration • Tauopathy related FTD-PD

  21. Genetics of Familial Parkinson’s DiseaseGeneChromosomeInheritance • Alpha-Synuclein 4 Auto Dominant • Parkin 6 Auto Recessive • UCH-L1 4 Auto Dominant • PARK3 2 Auto Dominant • PARK4 4 Auto Dominant • PARK6 1 Auto Recessive • PARK7 1 Auto Recessive • SCA 2 14 Auto Dominant • SCA 3 12 Auto Dominant *Identical twins concordance rate +/- 5%

  22. 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 PD-dementia patients

  23. Dementia With Lewy Bodies:Five Cardinal Clinical Features • Dementia • Parkinsonism (levodopa responsive) • Visual Hallucinations • Fluctuations • REM Behavior Disorder

  24. 3 Cases • Frontotemporal degeneration • Tau • Progranulin • TDP 43 (semantic dementia; ALS-dementia)

  25. 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.

  26. Frontotemporal degeneration • WAIS III • VC 110 • PO 114 • WMI 119 • PSI 111 • AVLT • 6-6-9-11-9 • STM 89% • LTM 89% • BNT 56/60; Token 41/44 • WCST • 6 Categories; 12 Perseverative Errors • Judgment of Line Orientation 13/30 • Facial Recognition Test 36 • Famous Faces 2/20

  27. Tauopathies, Progranulinopathies, andAsymmetric Cortical Degeneration Syndromes • Frontotemporal Lobar Degeneration • With and without ALS • Primary Progressive Nonfluent Aphasia • Semantic Dementia • Frontotemporal dementia (behavioral variant) • Corticobasal Ganglionic Degeneration • Progressive Supranuclear Palsy

  28. Frontotemporal Dementia

  29. FTD-like Tauopathy Bifrontal atrophy in PSP

  30. Corticobasal Ganglionic Degeneration

  31. Treating Dementia • Medications • Lifestyle Changes • Driving • Assisted Living • Power of Attorney, etc.

  32. Treatment of the Patient with Dementia by Symptom Category 1. Prevention 2. Intellectual Decline 3. Behavioral Disturbances 4. Sleep Disorders 5. Associated Problems 6. Abrupt Decline

  33. Treatment of the Patient with Dementia: Prevention Positive clinical trials (?): Antioxidants (Vitamin E, CoQ10, statins) 2. 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?

  34. Added Impact of CV Risk Factors on e4 Homozygotes P < .001 P = NS Caselli RJ et al, Neurology 2011

  35. Treatment of the Patient with Dementia: Intellectual Decline 1. Mild-moderate Alzheimer’s disease: Cholinesterase inhibitors 2. Moderate-Severe Alzheimer’s disease: Memantine (Namenda)

  36. 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

  37. 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

  38. Case 3: Agitation and Caregiver Risk

  39. Treatment of the Patient with Dementia: Sleep Disorders 1. Insomnia 2. REM Behavior Disorder 3. Restless Legs Syndrome 4. Hypersomnolence 5. Nocturia

  40. Treatment of the Patient with Dementia: Associated Problems 1. Parkinsonism 2. Incontinence 3. Dysphagia 4. Other Somatic Disorder

  41. 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

  42. Subdural hematoma in an 83 year old man with Alzheimer’s disease causing subacute decline in gait and cognition.

  43. Treating Dementia • Pharmacotherapy • Lifestyle Changes • Driving • Weapons (remove from the home) • Assisted Living • Power of Attorney, etc.

  44. AAN Practice Parameter: Risk of Driving and Alzheimer’s DiseaseDubinsky, 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.

  45. Revised AAN Practice Parameter: Evaluation and Management of Driving Risk in DementiaIverson 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: • Past driving infractions • Reduced driving mileage or self-reported avoidance • Aggressive/impulsive personality • MMSE<24 • Level U (insufficient evidence) • Neuropsychological testing • Driving school interventions

  46. www.alz.org • Support groups • Respite care • Safe return • Crisis hotline • Research

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