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The Dementias William S. Woodfin, M.D. Neurology Specialists of Dallas Clinical Assoc. Prof. of Neurology UT Southwestern Medical School 1 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 2 Classification Alzheimer’s Disease: Sporadic v. Familial Parkinson Syndromes Fronto-Temporal Lobar Vascular Infectious Metabolic Pseudodementia Others 3 Differential Diagnosis of Dementia 4 DEMENTIA SYNDROMES Normopressure Hydrocephalus Vascular Parkinsonism Supranuclear Palsy Alzheimer’s Disease Multiple System Atrophy FXTAS Lewy Body Parkinson’s Diffuse Disease Lewy Body Disease Corticobasalganglionic Degeneration Amyloid and Tau Fronto-temporal Dementia TAUOPATHIES 5 α-SYNUCLEINOPATHIES 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 6 DSM-IV Definition of Alzheimer’s Disease 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 continuing cognitive decline Deficits are not due to any other CNS disorder, systemic illness, or substance-induced condition Deficits do not occur exclusively during the course of delirium Source: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:85-86. 7 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 8 Progression of Alzheimer's Disease 30 Early Diagnosis Mild-Moderate Severe Cognitive Symptoms MMSE score 25 20 Loss of ADLs 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. 9 Risk Factors for Alzheimer’s Disease 10 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 11 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) 12 Neuropathologic Changes Characteristic of Alzheimer’s Disease Normal AD ALZHEIMER’S NORMAL AP AP = amyloid plaques. EXTRACELLULAR NFT = neurofibrillary tangles. Courtesy of Albert Enz, PhD, Novartis Pharmaceuticals Corporation. NFT INTRACELLULAR 613 βaptists v Tauists 14 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 15 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 16 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 17 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 18 PET Imaging of Amyloid 19 Tau Association With Microtubules Hyperphosphorylated tau subunits Tau bound to microtubule Microtubule PHF composed of tau subunits PHF = paired helical filaments. 20 21 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 22 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 23 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 24 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 25 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. 26 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 27 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 28 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 29 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.) 30 Parkinson Syndromes 1)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 31 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 αsynuclein 32 2) Diffuse Lewy Body Disease Motor sxs, dementia c often striking fluctuation and prominent haullucinosis Lewy bodies are diffusely distributede in the cerebral cortex 33 Fronto-Temporal Lobar 1)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 bodiesargyrophilic round intraneuronal inclusions composed mainly of abnormal tau proteins. Unresponsive to AChI- tret c SSRIs & ? Memantine. 34 2) Primary Progressive Aphasia Predominantly expressive Other cognitive domains essentially intact Focal atrophy seen on imaging Eventual dementia 35 3) Semantic Aphasia Predominantly a receptive aphasia Atrophy seen more in parietal and posterior temporal regions 36 4) Other Tauopathies Progressive Supranuclear Palsy (Steele-Richardson-Olsewski Syn.) Corticobasal ganglionic degeneration 37 38 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 39 Treatment of Vascular Dementia Attempt to limit progression: Hypertension, diabetes, homocysteine, lipids, cardiac Cognitive: possibly AChIs & memantine Behavioral: above + SSRIs 40 Typical Differential Points of Common Dementias at Initial Presentation Memory Impaired Visuospatial Motor Abnormal Vascular Loss Language Impairment Signs Behavior Event Alzheimer’s Disease + FTD + ± – Dementia with + Lewy Bodies – – ++ + _ _ _ _ _ + ++ + _ Ischemic vascular dementia + ± ± + + ++ NPH + – – + _ _ 41 42 Infectious Cruetzfeldt-Jacob Disease Familial Sporadic New Variant Fatal familial insomnia Gerstmann-Sträussler-Scheinker 43 Other Infectious HIV GPI Lyme disease Fungal Tuberculous PML 44 Metabolic Thyroid B 12 Folate Thiamine Hepatic 45 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 46 Other continued Tumor Subdural hematoma Hydrocephalus Demyelinating 47 Pseudodementia Probably the most common etiology in the 3060 patient population Stress Depressive disorders Anxiety disorders 48 Clinical Evaluation History Neurological Exam N-P testing Blood work Imaging & EEG 49 Patients & Families Counseling for 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 50 51 52