Alzheimer disease and Other Dementias. Epidemiology of Dementia. DSM Definition of Dementia. Common Causes of Dementia

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1 The Brigham Department of Neurology Martin A. Samuels, M.D., Chairman Alzheimer disease and Other Dementias Martin A. Samuels, M.D. Brigham & Women s Hospital, Boston, Massachusetts DSM Definition of Dementia The development of multiple cognitive deficits manifested by both: Memory Impairment One (or more) of the following cognitive disturbances: Aphasia Apraxia Agnosia Disturbance of executive functioning Decline from a previous level of functioning and cause significant impairment in social or occupational functioning. The deficits do not occur exclusively during the course of a delirium. Epidemiology of Dementia 10% of people over the age of 65 4 million cases in the United States 14 million expected by th leading cause of death 110 billion/year caring for patients with dementia Age is a major risk factor y.o. 2% y.o. 4% y.o. 8% y.o. 16% over 85 y.o. 40% Common Causes of Dementia Alzheimer s Disease 50-80% Lewy Body Dementia 20% AD and Vascular Dementia 10% Vascular Dementia 5% Dementia due to alcohol - < 5% Hydrocephalus - < 5% Frontotemporal Dementia - 1% Pathology of Alzheimer Disease Amyloid Plaques Extracellular accumulation of Aβ (fragment of the amyloid precursor protein) Neuritic plaques are amyloid plaques surrounded by dystrophic neuritic processes May be neurotoxic Abnormal processing of APP may be critical to pathophysiology of Alzheimer s disease 1

2 Pathology of Alzheimer Disease Neurofibrillary Tangles Intracellular, paired helical structures composed of hyperphosphorylated tau. Correlate well with disease severity and neuronal death. Pathology of Alzheimer Disease Amyloid angiopathy Infiltration of vessels with Aβ amyloid Pial vessels are most involved May cause hemorrhage Common cause of lobar ICH in the elderly May exist with or without AD Diagnosed by gradient echo MRI (microhemorrhages) 2

3 Impact of AD on Neurotransmitter Systems Significant early involvement of the nucleus basalis of Meynert Major source of cholinergic projections to hippocampus and cortical structures Low acetylcholine levels associated with poor memory Scopolamine produces amnesia in healthy young subjects Levels correlate with impairment in AD Rationale behind use of cholinesterase inhibitors Multiple other neurotransmitter systems involved Genetics of Alzheimer s Disease Genetics of Alzheimer s Disease 95% of cases are NOW considered sporadic 2 to 5% of cases are autosomal dominant Risk Factors 1st degree relative with AD history of stroke history of head injury female sex lack of education ε4 allele of the apolipoprotein E gene (chromosome 19) Cholesterol-transporting protein Increases risk and decreases age of onset ε2 may be protective Mutations of the amyloid precursor protein on chromosome 21 Presenilin 1 protein on chromosome 14 Presenilin 2 protein on chromosome 1 These proteins are likely involved in the cleavage of APP Onset usually before 60 and often significantly earlier 3

4 Clinical Presentation of AD Loss of episodic memory Usually presenting complaint Particularly for more recent events Forgetful of conversations, appointments, where things were placed More remote memories are usually spared early in the course Contributes to difficulty with orientation to time and place Memory impaired at the level of storage, not at encoding and retrieval Deficits in attention and executive function Complex attention impaired early (counting from 20-1, months backwards Abstraction, reasoning, problem solving Subtle early; more prominent later Simple attention impaired late (counting 1-20) Language Naming and mild semantic deficits early Deficits in comprehension, repetition, fluency later Visuo-spatial deficits More prominent in more moderate to severe patients Impaired construction (copying figures) Poor topographic knowledge, getting lost May develop visual agnosia Praxis Difficulty using tools or appliances Difficulty dressing Not usually an early finding Psychiatric and Behavioral Symptoms Depression in 50% of patients Often early in the course New onset depression in elderly may predict develop of AD Apathy, agitation, delusions, and psychosis are common as disease progresses These symptoms may produce the greatest degree of caregiver burden and are more likely to lead to nursing home placement than cognitive symptoms Impaired ADL s and continence also often leads to nursing home placement Evaluation 4

5 History If possible, meet with caregiver and patient separately Mostly from caregiver s perspective Important questions First Symptom? When first detected? Course? Insidious versus rapid versus step-wise Other cognitive domains involved? Functional changes? What things can the patient no longer do? Behavioral/Psychiatric symptoms? Sleep difficulty? General medical complaints are common Past Medical History Risk factors Stroke Cerebrovascular risk factors Head trauma (controversy exists about severity) Diabetes Developmental history Medications Medications that can impact cognition Anti-cholinergics may be particularly detrimental Benzodiazepines Barbiturates Sedating antidepressants, antipsychotics, etc. Major Categories of Medical Disease That Can Cause Dementia/Encephalopathy Immune Mediated Disorders Endocrine Disorders Neoplastic Disorders Vitamin Deficiencies Intoxications Renal and Electrolyte Disorders Hematologic Disorders Hepatic Diseases Gastrointestinal Disorders Infectious Diseases Cardiovascular Disorders Ob/Gyn disorders Pulmonary Diseases Hydrocephalus Psychiatric illnesses Thermal control disorders Evaluation of Dementia to Exclude Medical Causes Careful history for potential drugs and toxins General physical examination CBC, Differential, RBC Indices HIV ESR, CRP, ANA, RF, SSA, SSB SPEP and Immunofixation TSH, FBS, Hemoblobin 1c LFT s, RFT s, Electrolytes, Calcium MRI brain EEG CSF for cells, protein, oligoclonal bands Toxic Screen (add lead, mercury if suspected) Cobalamin level Family and Social History Family history of Alzheimer s disease 25-40% with one afflicted first degree relative Age of onset of family members with AD Is there a family history of any other form of dementia? Level of education Use of alcohol and other drugs Exposure to toxins (e.g. mercury) Supports at home 5

6 Physical Examination General Exam Look for other signs of systemic disease Neurological Exam Normal exam is expected early in the course Evidence against AD Focal signs (stroke or vascular dementia, mass lesions, etc.) Increased tone, rigidity (Parkinson s disease, Lewy Body Dementia, corticobasal degeneration) Decreased vertical eye movements (Progressive supranuclear palsy) Magnetic gait (Normal Pressure Hydrocephalus) Late in the course Brisk reflexes Extensor Plantar responses Frontal release signs (palmomental, grasp, snout, etc) myoclonus Cognitive Exam Use of a standardized scale useful at initial evaluation MMSE or Blessed Dementia Scale (BDS) MMSE and BDS less sensitive to non-alzheimer s dementia Relatively normal score in patients with significant cognitive, functional, and behavioral complaints suggest alternative dementia Pattern of deficits critical in making diagnosis Both scales test a variety of cognitive domains Use of scales allows for evaluation of drug effects 3-4 point improvement on the BDS or 2-3 points on the MMSE with cholinesterase inhibitors Annual comparisons 3-4 point decline on the BDS or 2-3 points on the MMSE per year BDS has a functional scale for the caregiver (left side) EARLY Middle Early Late 6

7 Middle Late Alzheimer s Disease Impairs Episodic Memory Episodic memory relies on encoding, storage, and retrieval Other types of memory may be initially spared Semantic Working Procedural Drill words so that they are encoded If need multiple trials, then encoding deficit For words missed on free recall, test recognition with multiple choice AD marked by memory storage deficit; do poorly with recognition Discrepancy between free recall and recognition may suggest retrieval deficit Encoding and retrieval impairment often seen with frontal lobe injury Storage deficits with medial temporal injury Imaging Everyone deserves at least one image in the course of their disease. Rule out structural lesions (e.g. tumor, hydrocephalus) Assess for cerebrovascular disease MR better for atrophy, small vessel disease and hydrocephalus. CT is reserved for those who cannot undergo MR Healthy Older Adult Alzheimer s Disease Healthy Older Adult Alzheimer s Disease 7

8 Healthy Older Adult Alzheimer s Disease Additional Work-up Behavioral Neurology Evaluation For complicated patients or second opinion Interest in clinical trials Neuropsychology Evaluation To help determine the contributions of depression to a memory disorder Assess decline in high functioning elders (bedside testing may be less sensitive) Brain SPECT Posterior temporal and parietal hypoperfusion In probable AD, increases diagnostic sensitivity from 84% to 92% In possible AD, increases diagnostic sensitivity from 67% to 84% Atypical dementia (ie FTD vesus AD) CSF tau (elevated) and Aß (depressed) are collateral evidence ApoE genotyping (risk factor; not a cause) MRI and SPECT in AD Treatment Function Treatment Outcomes Treatment Time Disease arrest Slowed progression Symptomatic benefit No effect Symptomatic Benefit Cholinesterase Inhibitors: donepezil (Aricept) rivastigmine (Exelon) Butylcholinesterase inhibition galantamine (Reminyl) Allosteric binding to nicotine receptors 8

9 Cholinesterase Inhibitors Efficacy at all stages of disease Improve cognition Enhances global functioning and ADL s Decreased neuropsychiatric symptoms Delays time to nursing home placement Perhaps up to two years Cost-effective Treatment side-effects Gastrointestinal effects anorexia nausea/vomiting diarrhea Vivid dreams take in AM or earlier PM dose Leg cramps Other cholinergic symptoms rarely slows heart rate Treatment expectations Small but noticeable improvements: Less time spent looking for keys, glasses, etc. Repeats self less often Dwells in past less Easier time keeping track of conversation More engaged, outgoing Memantine for Alzheimer s Disease Memantine A moderate affinity, uncompetitive NMDA receptor antagonist May improve signal to noise of glutamatergic neurotransmitter system Theoretical disease modifying effect May reduce glutamate mediated exicitoxic cell death Efficacy in moderate and severe Alzheimer s Disease 28 week trial demonstrating improved ratings of global functioning and performance of ADL s compared to placebo (Reisberg et al., 2003) Well-tolerated Most common side effects include dizziness, somnolence, confusion, and headache May increase some renally excreted drug levels Memantine + Donepezil Tolerability of memantine not affected when combined with cholinesterase inhibitors Memantine + Donepezil (Tariot et al., 2004) 24 week trial in moderate to severe Alzheimer s Disease Patients already on stable dose of Aricept Superior performance on scales measuring cognition, functioning, and behavior compared to Aricept alone Well-tolerated Greater drop-out in placebo group Only headache and confusion greater than placebo Other Treatments Symptomatic Gingko Biloba Demonstrated efficacy of extract (EGb 761) in patients with AD (LeBars et al., 1997; Kanowski and Hoerr, 2003) However, no benefit noted in elderly adults (JAMA, 2002) May have disease modifying effect Huperzine A Possible Disease Modifiers: Vitamin E 2000 IU/day. Side-effect: bleeding. Vitamin C 500 IU/day? Lower homocysteine levels: Folate, B6, B12 Statins? NSAIDSs? On-going clinical trials 9

10 Neurobehavioral Symptoms Treatment should be actively pursued May be most important for reducing caregiver burden and improving quality of life Symptoms may exacerbate cognitive impairment Depression SSRI s first line; avoid antidepressants with strong anticholinergic effect Agitation and Psychosis Atypical neuroleptics Anxiety SSRI s and low dose tricyclic antidepressants Ancillary Services Social Work referral helping patients & families deal with diagnosis Day programs for caregiver respite Support groups Education about what to expect; how best to handle cognitive and behavioral problems Issues of safety Financial planning End-of-life issues (ie living wills, durable powers of attorney) Cogntive Occupational Therapy Can be helpful to provide alternative strategies early on Treatment (continued) The Future Passive and active immunization with Aß Inhibition of γ- and ß-secretases Neurotrophic factors Novel cholinergic agents 10