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Dementia

Dementia. Michael A Hill, MD Professor Of Psychiatry. Dementia An acquired syndrome characterized by:. Short-term memory impairment (i.e. learning) AND At least one of the following: Aphasia - language memory impairments Apraxia - motor memory impairments

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Dementia

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  1. Dementia Michael A Hill, MD Professor Of Psychiatry

  2. DementiaAn acquired syndrome characterized by: • Short-term memory impairment (i.e. learning) AND • At least one of the following: • Aphasia - language memory impairments • Apraxia - motor memory impairments • Agnosia - sensory memory impairments • Abstract thinking / Exec. function impairments • Impairment in social and/or occupational fn • Sxs not explainable by another disorder

  3. Etiology & Pathogenesis • Dementia results from impaired functioning of multiple brain systems in both cortical and sub-cortical areas that are associated with short-term memory (i.e. learning) and other higher cognitive functions. Generally this is due to structural brain damage that is often progressive and relatively irreversible

  4. Clinical Presentation of Dementia • Always associated with cognitive disturbances and functional impairments • Visuospatial impairments and behavioral disturbances are usually seen as well • Specific symptoms will vary by type of dementia (Frontal lobe dementias present with personality change and executive dysfunction to a much greater degree than memory impairment)

  5. Memory Impairments • Difficulty learning or retaining new information (repeated conversations) • Information retrieval deficits (can’t recall names, list generation deficits) • Personal episodic memory impairment (misplacing items) • Declarative (semantic) memory (WHAT) > procedural memory (HOW)

  6. Language Deficits • List-generation deficits – verbal fluency (esp. in AD) • Word-finding difficulties (naming problems) • Less complex sentence structure • Relatively preserved auditory comprehension (can understand directions)

  7. Visuospatial impairments • Visual recognition impairments (trouble recognizing familiar faces - CAPGRAS syndrome possible) • Spatial deficits (getting lost in familiar surroundings, 3-D drawing deficits, constructional apraxia)

  8. Functional Impairments • Deficits appear first in IADLs (managing finances, driving, shopping, working, taking medications, keeping appointments) • Eventually problems with ADLs (feeding, grooming, dressing, eating, toileting) • Rate and specific pattern of loss will vary by individual and somewhat by diagnosis • NB: Functional impairment and performance on cognitive testing may not correlate strongly early in the course of dementia

  9. Behavioral Symptoms • Nearly universal and often the main focus of treatment. Inability to manage these symptoms is highly correlated with institutional placement. • PERSONALITY CHANGE: Occurs early • passivity (apathy, social withdrawal) • disinhibition (inappropriate sexual behavior or language, loss of social graces, aggression) • self-centered behaviors (childishness, loss of generosity)

  10. Epidemiology: Prevalence increases with age *Lower numbers represent moderate to severe dementia

  11. Incidence Of Alzheimer’s Disease by Age

  12. Diagnostic ApproachEarly Detection & Screening • Careful history from patient and reliable informant • PE with focus on neurological exam and cognitive testing • Cognitive testing tools such as MMSE are helpful. Score below 24-27 often concerning depending on premorbid abilities • Functional Assessment tools such as the Functional Activities Questionnaire

  13. Primary Care Screening Tools • MMSE (‘normal’ varies somewhat by age and educational level – an 80 y/o with only 4 years of education would be expected to only get a 19/30) • Clock Test – easy to do, quick. Draw a clock, put numbers in correct locations, set hands to ‘10 til 2’. • List generation – number of animals that can be named in 60 seconds. <12 is definitely abnormal, 12-18 is marginal. Can also do words beginning with letter ‘F’. 10+ in one minute is normal. Often very impaired in Alzheimer’s and some types of FTDs. • Trails B testing is useful if frontal lobe deficits suspected (e.g. fronto-temporal dementias, AIDS dementia) • ‘Go No-Go’ Testing (inability to inhibit responses)

  14. Cognitive Testing • Serial 7’s (5 answers) - If you can do it, that’s good, but as many as 50% of normal elderly can’t(WORLD backwards is not much better as only 62% of elderly can do it with no errors) • Orientation:If you are disoriented that’s bad, especially to month or year, however many early dementia patients are fully oriented (40%) • 3-item recall: Not being able to recall 2/3 is bad as only 19% of dementia patients can do this, but 74% or normal elderly can • MMSE: Sensitivity: 87%, Specificity: 82%

  15. MMSE ‘norms’ by Age and Educational Level Educational level

  16. Diagnostic Work-Up • This is done to • (1) rule out disorders besides dementia (e.g. delirium) • (2) to identify reversible/treatable dementias (13+%) • (3) to clarify the specific dementia syndrome • Routine Assessment: CBC with diff, serum electrolytes, Ca++, glucose, BUN/CR, LFTs, TFTs, B12 & folate, U/A, RPR, head imaging • When indicated: Sed. rate, HIV, CXR, heavy metals, LP, EEG, functional imaging, Lyme titers, endocrine studies, rheumatologic studies, Neuropsychological Testing

  17. Guidelines For Use of Specialized Testing • LP: Suspicion of metastatic CA, CNS infections, neuropsyphilis, hydrocephalus, vasculitis. Also for dementia <55 and rapidly progressive dementias • Neuroimaging - consider in all new cases. However without focal symptoms or signs, seizures or gait disturbances in an individual over age 70 - consider this optional • Functional Imaging (SPECT, PET, MRS, fMRI): to clarify type of dementia when necessary (and in the future to track course of illness and response to tx) • EEG - can help distinguish delirium from dementia, can help with seizure disorder and JCD • Neuropsychological testing – language barriers, MR, legal proceedings

  18. Mild Cognitive Impairment • Some cognitive deficits apparent on testing but not to dementia level (MMSE 24-29) range • Minimal, if any, functional impairments • 13-15% per year progress to dementia (A.D.) but not all progress and some improve (especially amnestic type – aMCI) • Predictors of progression: ApoE4 alleles, poor performance on cued recall (amnestic type) and hippocampal atrophy by MRI

  19. Pseudodementia • More appropriately called ‘reversible dementia’ • The classic case is ‘depressive pseudodementia’ with ‘overstated’ cognitive impairments due to decreased concentration and poor effort • However, depression may be a risk factor for dementia • 50% of elderly patients with depressive pseduodementia have Alzheimer’s at 5 year follow-up

  20. Late-Life Depression • Def’n: First Major Depressive Episode occurs after age 65 • High correlation with dementia (50% go on to develop dementia within 3 years!) • Many of these depression may be vascular or post-stroke depressions

  21. Most Common Dementias • Alzheimer’s Disease (AD) (50-75%) • Lewy Body Dementias (DLB) (10-30%) • Vascular Dementias (VaD) (15-20%) • Alcohol-related dementias (including Korsakoff’s (infrequent) and etoh-induced)) • HIV dementia - most common dementia in those under age 55

  22. Classification of Dementias • Primary versus secondarybased on the pathophysiology leading to damaged brain tissue • Cortical versus sub-corticaldepending on the cerebral location of the primary deficits • Reversible versus irreversibledepending on optimal treatment expectations • Early (before age 65) versus late onset

  23. ALZHEIMER’S Pathophysiology • Neuritic plaques -extracellular - abnormal insoluble amyloid (beta) protein fragments • Neurofibrillary tangles - intracellular - disturbed tau-microtubule complexes (hyperphosphorylated tau) • Cholinergic system degeneration with significant loss of neurons in certain areas (such as Nucleus Basalis of Meynert) • Degeneration often begins in enterorhinal cortex and progresses to other limbic structures

  24. Lewy Body Pathology • Concentric spheres found within vacuoles (eosinophilic cytoplasmic inclusions) • Seen in cortex, midbrain and brainstem neurons in patients with idiopathic parkinsonism, Alzheimer's disease and especially Lewy Body dementias • The main structural component is alpha-synuclein. Ubiquitin is sometimes seen also.

  25. Risk Factors for AD • Age • Family history / genetics • Down’s syndrome (trisomy 21) • Head Trauma (esp. late in life) [TBI may double risk] • Female gender (mixed results: age bias and possible higher ‘clinical’ expression in women) • Ethnicity (Caucasians have the lowest risk) • Late-onset depression (after age 65) • Mild Cognitive Impairment (MCI)

  26. Additional Risk Factors for Dementia • Cerebrovascular disease (and the risk factors for CV disease – including smoking, diabetes, hyperlipidemia, hypertension) is associated with vascular dementia risk • Recurrent MDD may be associated with risk of dementia in general.(Kessing and Anderson found risk of dementia to be 6 times higher in patients with 5 or more prior episodes.)1 • Subclinical Hyperthyroidism (especially when antithyroid antibodies are present.2 1Kessing LF, Anderson PK. J Neurol Neurosurg Psychiatry. 2004;75:1662-1666 2Kalmijn S, Mehta KM, Pols HA, et al. Clin Endocrinology (Oxf) 2000;53:733-737

  27. Genetic risk factors • Chromosome 19 - autosomal recessive - Apolipoprotein E-4 allele - associated with late-onset disease (not relevant for non-caucasians) • TOMM40 – newly identified – affects age of onset • Chromosome 1, 14, 21 - autosomal dominant mutations - associated with early-onset/familial cases (5%). Amyloid processing genes. • CLU – clusterin and PICALM (phosphatidylinositol-binding clathin assembly protein) • Chromosome 9 – ‘ubiquilin 1’ polymorphisms – needs replication • BDNF – val/val variant might be protective

  28. Protective Factors in AD • Education • Anti-inflammatory agents (those that decrease amyloid production) • Estrogen replacement therapy (+/-) • Smoking (+)[?nicotine/past use](-) [CVD/current use] • APO E-3, CETP VV (longevity gene) • Vitamin E & other antioxidants? • Homocysteine reduction • Statin use (protects against PD, AD?)

  29. Vascular dementia • Includes Binswanger’s disease, MID, anoxic damage, post-CABG, inflammatory diseases • RISK FACTORS: age, hypertension, diabetes and hyperlipidemia • 2nd most common dementia but incidence drops after the age of 75 (unlike Alzheimer’s disease) • In one study, 87% of ‘vascular dementias’ at autopsy had AD pathology1 1Nolan KA, Lino MM, et al. J Am Geriatr Soc, 1998;46:597-604

  30. Other less common dementias • Primary degenerative dementias • Diffuse Lewy Body dementias (7-26% of dementias) • Frontotemporal dementias (Pick’s, ALS, Huntington’s) • Neurological disordersassociated with dementia • PSP, Parkinson’s dementia, NPH, neoplasms, head trauma, subdurals, demyelinating diseases

  31. Less common dementias (cont.) • Infectious causes • neurosyphilis, Lyme disease • post-encephalitic dementias (esp. herpes) • viral, parasitic, bacterial and fungal meningitidies • opportunistic infections or brain abscess • Human prion disease (transmissible spongiform encephalopathies) - sCJD, ‘Mad-cow disease’(vCJD), Kuru, fatal familial insomnia

  32. General medical causes of dementia • Thyroid and adrenal diseases • Vitamin deficiency states (thiamin, niacin, B12) • Metabolic derangements (hepatic encephalopathy, dialysis dementia, etc.) • Medications(sedatives, antihypertensives, narcotics, anticholinergics) • Whipple’s Disease, sarcoidosis, Wilson’s disease • Toxins (heavy metals, organic poisons)

  33. Rapidly Progressive Dementias • Hashimoto’s Encephalitis (treatable with steroids) • Cerebellar degeneration syndromes • Transmissible spongiform encephalopathies (prion diseases) • Paraneoplastic syndromes • Postviral encephalitis • Rare cases of AD, DLB, FTD

  34. Economic Burden • $80 to $100 billion per year in total treatment costs • Alzheimer’s disease is the third most expensive disease to treat in the United States, following cancer and heart disease • Currently 4 million people have Alzheimer’s disease in the U.S. • More than $213,000 per family for the remainder of the patient’s life, including direct and indirect treatments costs ($47,000 per patient per year)

  35. General Treatment Principles • Treatment Of Underlying Disease Process (Primary Treatment) • Management Of Behaviors and Symptoms (Secondary Treatment) • Caregiver Support and Education

  36. Reversible Dementias • May become irreversible if not treated soon enough • Many dementias may be arrestible if not fully reversible • Rule out ‘depressive pseduodementia’ and delirium which can mimic dementia • Some reversible dementias include: hypoT4, B12 def., some infections and tumors, drug-induced syndromes, etc.

  37. Primary Treatment Strategies • 1. Prevention • Identify risks and mitigate • Develop neuroprotective strategies for those at risk • 2. Slow or halt progression of illness • Understanding pathophysiology leads to treatment ideas • 5 year delay in onset ---> 1/3 decrease in prevalence • Delaying institutionalization by 1 month saves $1.2 billion/yr • 3. Reverse symptoms • Compensate through augmentation of remaining neurons or other systems • Reversal of destructive processes & regeneration of tissue

  38. Delayed Onset Incidence

  39. ALZHEIMER’S Pathophysiology • Neuritic plaques -extracellular - abnormal insoluble amyloid protein fragments • Neurofibrillary tangles - intracellular - disturbed tau-microtubule complexes (hyperphosphorylated tau) • Cholinergic system degeneration with significant loss of neurons in certain areas (such as Nucleus Basalis of Meynert) • Degeneration often begins in enterorhinal cortex and progresses to other limbic structures

  40. CHOLINERGIC SYSTEM STRATEGIES • Reduce Serum anticholinergic load • Precursor strategies (e.g. lecithin and choline) • Receptor/synaptic strategies • Metabolic strategies (anticholinesterases)

  41. Serum Anticholinergic Load & Cognitive Impairment • 90% of community elderly sample had detectable SA levels • An SA level >2.8 pmol/Ml was 13X more likely to be associated with an MMSE of 24 or less in the general elderly population than in those with undetectable SA levels Univ Of Pittsburgh, AAGP 5th Annual Meeting, 2002

  42. Commonly Prescribed Non-Psychiatric Drugs with Significant Anticholinergic Activity • cimetidine & ranitidine • prednisolone • theophylline • digoxin/Lanoxin • furosemide • nifedipine • diphenhydramine (OTC) • To a lesser extent: codeine, warfarin, dipyradimole, isosorbide dinitrate

  43. Current AChE Inhibitors *promotes binding of acetylcholine and stimulates pre-synaptic release of ACh

  44. Anticholinesterase Side Effects(i.e. procholinergic) • GI – nausea, vomiting, diarrhea, increased gastric acid secretion* • Muscle cramps • Fatigue • Insomnia • Syncope (2% vs 1% for placebo) (?bradycardia) *most common with rivastigmine

  45. STRATEGIES TO SLOW OR HALT PROGESSION • Calcium channel modulation and excitatotoxic systems attenuation (such as memantine) • Anti-inflammatory/immunosuppressive strategies(e.g. NSAIDs) • Gene therapyfor defective protein regulation • Toxin removal (Desferroxamine, clioquinol) / Ventriculoperitoneal shunting (COGNIShunt) • Amyloid Protein strategies • Other Neuroprotective strategies

  46. Neuroprotective Strategies • Nerve Growth Factor • Acetyl-l(levo) carnitine (ALCAR) • Estrogen • Homocysteine reduction( folate, B6, B12) • Antioxidants(Vit E, Gingko, deprenyl) • ‘Statins’ (Lipitor, Pravachol) (may lower abnormal amyloid levels) • B-blockers in AD • Rosiglitazone (Avandia) -anti-inflammatory, amyloid processing modulation activities • Levetiracetam(Keppra) for aMCI – reduces hippocampal hyperactivity

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