Understanding the Different Types of Dementia: Classification, Differential Diagnosis, and Risk Factors

1. The DementiasWilliam S. Woodfin, M.D.Neurology Specialists of DallasClinical Assoc. Prof. of NeurologyUT Southwestern Medical School

2. Definition • Dementia:The development of multiple cognitive deficits suffficiently severe to cause impairment in occupational or social functioning • Mild Cognitive Impairment: usually refers to a single cognitive domain

3. Classification • Alzheimer’s Disease: Sporadic v. Familial • Parkinson Syndromes • Fronto-Temporal Lobar • Vascular • Infectious • Metabolic • Pseudodementia • Others

4. Differential Diagnosis of Dementia

5. DEMENTIA SYNDROMES Normopressure Hydrocephalus Vascular Parkinsonism Multiple System Atrophy FXTAS Alzheimer’s Disease Lewy Body Parkinson’s Disease Supranuclear Palsy Diffuse Lewy Body Disease Corticobasalganglionic Degeneration Fronto-temporal Dementia Amyloid and Tau α-SYNUCLEINOPATHIES TAUOPATHIES

6. Alzheimer’s • History: Alois Alzheimer 1906 • Epidemiology: * 4 million pts. • * A disease of advancing age but not normal aging. Loss vs. shringage of neurons • * Age 60 1% • Age 85 30-50% • * Underdiagnosed • * Women more than men • * Cost $110 billion

7. Development of multiple cognitive deficits manifested by both memory impairment (amnesia) and 1 or more of the following cognitive disturbances: aphasia, apraxia, agnosia, or disturbance in executive functioning (abstractions) Cognitive deficits cause significant impairment in social functioning and represent a significant decline from a previous level of functioning Course is gradual in onset with continuingcognitive decline Deficits are not due to any other CNS disorder, systemic illness, or substance-induced condition Deficits do not occur exclusively during the courseof delirium DSM-IV Definition of Alzheimer’s Disease Source: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:85-86.

8. Alzheimer’s Disease (AD): More Than Just Memory Loss • AD is a progressive, degenerative disease involving: • A Decline in ability to perform activities of daily living • B Changes in personality and behavior • C Loss of memory and other cognitive functions • D Eventual nursing home placement, death $ Increases in resource utilization

9. Progression of Alzheimer's Disease Early Diagnosis Mild-Moderate Severe 30 Cognitive Symptoms 25 20 Loss of ADLs MMSE score 15 Behavioral Problems 10 Nursing Home Placement 5 Death 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 Years Feldman H, Gracon S. In: Clinical Diagnosis and Management of Alzheimer’s Disease. 1996, 239-253.

10. Risk Factors for Alzheimer’s Disease

11. Apolipoprotein E • ε 4 allele: a “susceptibility gene” on chromosome 19 • single copy→ 2-3 x risk, double copy→ 5 x risk • lowers age of onset • may be assoc. c clearing of Aβ- increased plaques, • but no increase in NFTs • ε 2 allele appears protective • “Not necessary or sufficient”- ½ of AD pts. don’t have • the allele, 10-20% of normal older adults carry one or • two

12. Gross Pathology Temporal lobes esp. hippocampus & entorhinal cortex. Olfactory bulbs and tracts Parietal lobes Subcortical nuclei that project to the cortex: Nucleus Basalis of Meynert (AcH) Locus ceruleus (NE) Raphae nuclei (Serotonin)

13. Neuropathologic ChangesCharacteristic of Alzheimer’s Disease Normal AD NORMAL ALZHEIMER’S AP NFT EXTRACELLULAR INTRACELLULAR AP = amyloid plaques. NFT = neurofibrillary tangles. Courtesy of Albert Enz, PhD, Novartis Pharmaceuticals Corporation. 6

14. βaptists v Tauists

15. Microscopic Pathology • Amyloid (Senile) Plaques: Extraneuronal • Aβ • Dystrophic axons and dendrites • Astrocytes • Microglia • Neurofibrillary Tangles: Intraneuronal- predominantly • axonal, longer axons • Hyperphosphorylated tau protein • Neuronal loss • Vascular change: Cerebral Amyloid Angiopathy • Aβ 40

16. Etiology: Amyloid Hypothesis • Cleavage of transmembranous APP by secretases • Aβ 40 & Aβ 42 • Insoluble oligomers • Insoluble fibrils • Diffuse plaque • Mature plaque- due to inflammatory reaction with astrocytes and microglia • Neuronal and synaptic injury • NFTs and Neuronal death • Loss of neurotransmitters

17. Evidence for the Amyloid Hypothesis • Aβ neurotoxic in vitro • Overexpression of APP in transgenic mice=disease • Mutations in APP = early onset disease • All known mutations= increased Aβ • Downs Syndrome with 3 copies of APP gene • Apolipoprotein E € 4 accelerated Amyloid deposition • Amyloid antibodies in mice and men slows disease

18. Familial Alzheimer’s • Chromosome 14 c presenilin 1 gene • Chromosome 1 c presenilin 2 gene • Both code for a portion of γ-secretase • Chromosome 21 c APP mutations • Onset of sxs. In 40s & 50s

19. PET Imaging of Amyloid

20. Tau Association With Microtubules Hyperphosphorylated tau subunits Tau bound to microtubule Microtubule PHF composed of tau subunits PHF = paired helical filaments.

22. Prevention • Anti-Inflammatories • Hormones • Vitamins and Herbs • Diet and Antioxidants • Alcohol and Smoking • Exercise • Basic Medical Care • Blood Pressure • Lipids • Homocystine • Specific Agents • Cholinesterase Inhibitors • NMDA Receptor Blockers

23. Anti-Inflammatories • Dutch study, NEJM 2001: RR 0.95 < 1 month • 0.83 1-24 months • 0.20 > 2 years • No benefit with trials of: Prednisone • Diclofenac • Rofecoxib • Naproxen

24. Estrogens • Mechanisms: Estrogen receptors associated with NGF receptors • May enhance neurotransmitter function, esp. Ach • May diminish excitatory effect of Aβ • May alter APP resulting in less Aβ • PET shows increased blood flow and glucose metabolism in hippocampus • Early studies mixed: Prior to 1999, 4 impairment, 7 improvement • WHIMS: Estrogen & Progesterone: Mild increase in stroke and dementia • Estrogen alone: stopped this year, risk of dementia about the same • Would earlier institution of estrogens or longer duration of treatment be useful? Cache Co. Utah study

25. Vitamins and Herbs • Vitamin E- No help • Potential toxicity: bleeding, HA,N,V,diarrhea, bone pain, hair loss • Vitamin C- No compelling evidence • Folic Acid- Increasing evidence for protection for AD and VaD • Would use more than 400 mcgm/day • Ginko Biloba- several studies suggest some improvement • St. Johns Wort- caution

26. Diet & Antioxidants • Fats: Diets high in unsaturated, unhydrogenated fats and low in saturated/transunsaturated fats may protect against dementia and coronary disease. • Cholesterol: Mixed findings. Dietary cholesterol has less impact on serum cholesterol than does saturated fat intake. • Dietary Flavinoids: May diminish risk • Caloric Intake: Animal studies show all degenerative diseases associated with aging diminish with reduced caloric intake. • Increased oxidative stress and accumulation of free radicals.

27. Alcohol & Smoking • Red Wine: 250-500 ml/day may protect • May be due to flavanoids, also found in tea,fruit, and vegetables. • Beer: May worsen odds with low intake of thiamine and other B vitamins • Dangers in the elderly: Lean body mass • Trauma • Interactions with medications • Smoking: Accelerates microvascular cerebral disease

28. Exercise • Physical: Decreases glucose and LDL levels, raises HDL • Aerobic vs. anaerobic and frontal lobe function • Mental: Educational attainment • Ongoing cognitive efforts: Nun study- Top 10% were 47% less likely than bottom 10% to become demented. • Sensory support: eyeglasses, hearing aids

29. Basic Medical Care • Control of blood pressure and glucose • Statins: Inhibit activity of β and γ secretase • May limit effects of APO € 4 allele • Endothelial remodeling • Increase e NOS • Decrease endothelin-1 • PROSPER study (Pravastatin) • HPS study (Simvastatin) • Atorvastatin

30. Specific Pharmaceutical Intervention • Cholinesterase Inhibitors: Donepezil (Aricept) • Rivistigmine (Exelon) • Galantamine (Reminyl→Razadyne)) • NMDA Inhibitors: Memantine (Namenda) • Considerations in their use: Cognition • Behavior • Activities of Daily Living • Efficacy, Safety, Side Effects and Cost (~$140/mo.)

31. Parkinson Syndromes • Idiopathic PD: • Up to 40% c dementia; 65% by age 85 • 3rd leading cause overall • Increases c age at dx., early hallucinosis & advanced motor signs, presence of depression

32. Pathological changes are those of Alzheimer’s dis. In addition to the typical pathology of Lewy bodies and neuronal loss in the substantia nigra. • Lewy bodies- intraneuronal, eosinophilic inclusions containing misfolded α-synuclein

33. 2) Diffuse Lewy Body Disease • Motor sxs, dementia c often striking fluctuation and prominent haullucinosis • Lewy bodies are diffusely distributede in the cerebral cortex

34. Fronto-Temporal Lobar • Fronto-Temporal Dementia: Characterized by behavioral & executive function changes. 40-50% is familial. 10-20% of all dementias. Earlier age of onset. Atrophy of frontal & temporal poles. Pick bodies- argyrophilic round intraneuronal inclusions composed mainly of abnormal tau proteins. Unresponsive to AChI- tret c SSRIs & ? Memantine.

35. 2) Primary Progressive Aphasia • Predominantly expressive • Other cognitive domains essentially intact • Focal atrophy seen on imaging • Eventual dementia

36. 3) Semantic Aphasia • Predominantly a receptive aphasia • Atrophy seen more in parietal and posterior temporal regions

37. 4) Other Tauopathies • Progressive Supranuclear Palsy (Steele-Richardson-Olsewski Syn.) • Corticobasal ganglionic degeneration

39. Vascular • 2nd leading cause of dementia • Subtypes: Cortical- large vessel & embolic stroke. Stepwise progression. More severe aphasia. Sensoro-motor abnormalities. • Subcortical- small vessel. Pseudobulbar palsy, gait impairment ( marche à petit pas), urinary incontinence

40. Treatment of Vascular Dementia • Attempt to limit progression: Hypertension, diabetes, homocysteine, lipids, cardiac • Cognitive: possibly AChIs & memantine • Behavioral: above + SSRIs

41. Typical Differential Points of Common Dementias at Initial Presentation MemoryLoss ImpairedLanguage VisuospatialImpairment Motor Signs Abnormal Behavior Vascular Event _ _ _ Alzheimer’sDisease FTD Dementia withLewy Bodies Ischemicvasculardementia NPH + + + + + ++ ± – ± – + – – ± – _ _ + + _ ++ + + ++ _ + _

43. Infectious • Cruetzfeldt-Jacob Disease • Familial • Sporadic • New Variant • Fatal familial insomnia • Gerstmann-Sträussler-Scheinker

44. Other Infectious • HIV • GPI • Lyme disease • Fungal • Tuberculous • PML

45. Metabolic • Thyroid • B 12 • Folate • Thiamine • Hepatic

46. Other • Huntington’s disease: irritability, apathy, impulsive behavior, poor personal hygeine, psychosis. Etiol. unclear until chorea appears esp. c spontaneous mutation. • HD gene on chrom. 4 contains trinucleotide repeats,CAG, encoding for glutamine preventing normal turnover of protein, huntingtin, in cytoplasm and nuclei. Abn. aggregation of this protein may→ pathology, cortical 7 subcortical

47. Other continued • Tumor • Subdural hematoma • Hydrocephalus • Demyelinating

48. Pseudodementia • Probably the most common etiology in the 30-60 patient population • Stress • Depressive disorders • Anxiety disorders

49. Clinical Evaluation • History • Neurological Exam • N-P testing • Blood work • Imaging & EEG

50. Counseling for Patients & Families Prognosis re. rate of decline & life expectancy Patient & family goals for treatment Review of finances & power of attorney Medical advance directives Driving Home safety Wandering (www.alz.org/Services/SafeReturn.asp) Long term care Resources for family and caregiver includ. Alz. Assoc. & ABA Commission on Legal problems for the Elderly