廣東科學(xué)技術(shù)職業(yè)學(xué)院高爾夫設(shè)備采購

1、DementiaMichael A Hill, MDProfessor Of Psychiatry雷達(dá)(lid)物位計 共九十四頁Dementia An acquired syndrome characterized by:Short-term memory impairment (i.e. learning) ANDAt least one of the following:Aphasia - language memory impairmentsApraxia - motor memory impairmentsAgnosia - sensory memory impairmentsAbs

2、tract thinking / Exec. function impairmentsImpairment in social and/or occupational fnSxs not explainable by another disorder共九十四頁 Etiology & PathogenesisDementia results from impaired functioning of multiple brain systems in both cortical and sub-cortical areas that are associated with short-term m

3、emory (i.e. learning) and other higher cognitive functions. Generally this is due to structural brain damage that is often progressive and relatively irreversible共九十四頁Clinical Presentation of DementiaAlways associated with cognitive disturbances and functional impairmentsVisuospatial impairments and

4、 behavioral disturbances are usually seen as wellSpecific 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)共九十四頁 Memory ImpairmentsDifficulty learning or retaining new information

5、(repeated conversations)Information retrieval deficits (cant recall names, list generation deficits)Personal episodic memory impairment (misplacing items)Declarative (semantic) memory (WHAT) procedural memory (HOW)共九十四頁 Language DeficitsList-generation deficits verbal fluency (esp. in AD)Word-findin

6、g difficulties (naming problems)Less complex sentence structureRelatively preserved auditory comprehension (can understand directions)共九十四頁Visuospatial impairmentsVisual recognition impairments (trouble recognizing familiar faces - CAPGRAS syndrome possible)Spatial deficits (getting lost in familiar

7、 surroundings, 3-D drawing deficits, constructional apraxia)共九十四頁Functional ImpairmentsDeficits appear first in IADLs (managing finances, driving, shopping, working, taking medications, keeping appointments)Eventually problems with ADLs (feeding, grooming, dressing, eating, toileting)Rate and specif

8、ic pattern of loss will vary by individual and somewhat by diagnosisNB: Functional impairment and performance on cognitive testing may not correlate strongly early in the course of dementia共九十四頁Behavioral SymptomsNearly universal and often the main focus of treatment. Inability to manage these sympt

9、oms is highly correlated with institutional placement.PERSONALITY CHANGE: Occurs earlypassivity (apathy, social withdrawal)disinhibition (inappropriate sexual behavior or language, loss of social graces, aggression)self-centered behaviors (childishness, loss of generosity)共九十四頁Epidemiology: Prevalen

10、ce increases with age*Lower numbers represent moderate to severe dementia共九十四頁Incidence Of Alzheimers Disease by Age共九十四頁Diagnostic ApproachEarly Detection & ScreeningCareful history from patient and reliable informantPE with focus on neurological exam and cognitive testingCognitive testing tools su

11、ch as MMSE are helpful. Score below 24-27 often concerning depending on premorbid abilitiesFunctional Assessment tools such as the Functional Activities Questionnaire共九十四頁P(yáng)rimary Care Screening ToolsMMSE (normal varies somewhat by age and educational level an 80 y/o with only 4 years of education wo

12、uld 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. 12yAGE18-242328293035-392327293050-542227293070-742126282980-8419252628共九十四頁Diagnostic Work-UpThi

13、s 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 syndromeRoutine Assessment: CBC with diff, serum electrolytes, Ca+, glucose, BUN/CR, LFTs, TFTs, B12 & folate, U/A, RPR, head imagingWhen ind

14、icated: Sed. rate, HIV, CXR, heavy metals, LP, EEG, functional imaging, Lyme titers, endocrine studies, rheumatologic studies, Neuropsychological Testing共九十四頁Guidelines For Use of Specialized TestingLP: Suspicion of metastatic CA, CNS infections, neuropsyphilis, hydrocephalus, vasculitis. Also for d

15、ementia 1/3 decrease in prevalenceDelaying institutionalization by 1 month saves $1.2 billion/yr3. Reverse symptomsCompensate through augmentation of remaining neurons or other systemsReversal of destructive processes & regeneration of tissue 共九十四頁Delayed Onset Incidence共九十四頁ALZHEIMERS Pathophysiolo

16、gyNeuritic plaques -extracellular - abnormal insoluble amyloid protein fragmentsNeurofibrillary 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

17、)Degeneration often begins in enterorhinal cortex and progresses to other limbic structures共九十四頁Reduce Serum anticholinergic load Precursor strategies (e.g. lecithin and choline)Receptor/synaptic strategiesMetabolic strategies (anticholinesterases)CHOLINERGIC SYSTEM STRATEGIES共九十四頁Serum Anticholiner

18、gic Load & Cognitive Impairment90% of community elderly sample had detectable SA levelsAn 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 levelsUniv Of Pittsburgh, AAGP 5th Annual Meeting, 2002共

19、九十四頁Commonly Prescribed Non-Psychiatric Drugs with Significant Anticholinergic Activitycimetidine & ranitidineprednisolonetheophyllinedigoxin/Lanoxinfurosemidenifedipinediphenhydramine (OTC)To a lesser extent: codeine, warfarin, dipyradimole, isosorbide dinitrate共九十四頁Current AChE Inhibitors*promotes

20、 binding of acetylcholine and stimulates pre-synaptic release of ACh共九十四頁共九十四頁共九十四頁Anticholinesterase Side Effects(i.e. procholinergic)GI nausea, vomiting, diarrhea, increased gastric acid secretion*Muscle crampsFatigueInsomniaSyncope (2% vs 1% for placebo) (?bradycardia)*most common with rivastigmi

21、ne共九十四頁Calcium channel modulation and excitatotoxic systems attenuation (such as memantine)Anti-inflammatory/immunosuppressive strategies(e.g. NSAIDs)Gene therapy for defective protein regulationToxin removal (Desferroxamine, clioquinol) / Ventriculoperitoneal shunting (COGNIShunt)Amyloid Protein st

22、rategiesOther Neuroprotective strategiesSTRATEGIES TO SLOW OR HALT PROGESSION共九十四頁Neuroprotective StrategiesNerve Growth Factor Acetyl-l(levo) carnitine (ALCAR)EstrogenHomocysteine reduction( folate, B6, B12)Antioxidants (Vit E, Gingko, deprenyl)Statins (Lipitor, Pravachol) (may lower abnormal amylo

23、id levels)B-blockers in ADRosiglitazone (Avandia) -anti-inflammatory, amyloid processing modulation activitiesLevetiracetam(Keppra) for aMCI reduces hippocampal hyperactivity共九十四頁Nutraceutical StrategiesVitamin E (antioxidant)Homocysteine Reduction (folate, B6, B12)Beta-carotene Physicians Health St

24、udy II found a cognitive protective effect of 50 mg every other day over two decades of useGingko (antioxidant)Resveratrol (a type of polyphenol found in red grape skins and thus red wine) ?anti-inflammatory, anti-aging, anti-cancer共九十四頁Vitamin EPotent antioxidant propertiesHas been shown to slow pr

25、ogression at least as much as Deprenyl in one head-to-head studyRecent study showed no difference from placebo in preventing progression from MCI to AD over 3 yrs but higher dietary intake over 10 years in non-demented patients resulted in 26% lower incidence of AD (Rotterdam Study)Few side effects

26、even in high doses, though recent studies in Europe suggest a higher death rate in those on hi-dose Vitamin EDoses used in recent studies: up to 1000 IU bidConsider 400-800 IU per day for preventionMay work better if combined with Vitamin C共九十四頁Days共九十四頁EstrogenAt this point the summary of many stud

27、ies suggests that Hormone replacement therapy (HRT) is questionably effective in slowing the onset of AD in some womenThe earlier started, the better. Limited exposure may be best.Progesterone may be detrimentalTacrine response can be enhanced by EstrogenWHY? neurotrophic effects, incr. ChAT, high s

28、erum E2 suppresses Apo E共九十四頁StatinsLovastatin(Mevacor), pravastatin(Pravachol), simvastatin(Zocor), atorvastatin(Lipitor)May prevent aggregation of B-amyloid* in the brain by preventing cholesterol build up. May activate alpha-secretase.Conflicting evidence recent U of Wash study did not find a ben

29、efit, but looked at older individuals on statins only a short while.Earlier studies were more positiveNot sure if all these drugs are equal Ability to enhance tissue plaminogen activator (tPA) and thus production of plasmin may be important. Plasmin may activate alpha-secretase and can also increase

30、 production of BDNF.*AKA amyloid-beta peptide or ABeta共九十四頁MemantineGlutamate is the principal excitatory neurotransmitter in brain regions associated with cognition and memory (i.e. it stimulates cholinergic neurons)Glutamate hypothesis of dementia suggests that overactivation of these neurons lead

31、s to excitatoxic damage to these brain areas (by allowing calcium to continuously leak in to cells). It is post-synaptic receptor sensitivity rather than excess release of glutamate that is the problem.Memantine is a weak antagonist of glutamate-gated NMDA receptor channels which prevents overactiva

32、tion during memory formation but allows normal function共九十四頁MemantineTrade name: NamendaDose range: 5 to 20 mg (bid dosing)Side effects: Constipation, somnolence, confusion/psychosisAgitation was significantly less likely in memantine groups than placebo共九十四頁NSAID Use & AD in Elderly Patients2708 pa

33、tients enrolledExamined NSAID use and prevalence of Alzheimers DiseaseNSAID users had 50% lower risk of being affected by ADAspirin trended this way but was not significantTreatment studies have not shown any consistent benefits yet however.Landi, et al, Am J Geriatric Psychiatry, March-April, 2003共

34、九十四頁Abnormal Amyloid Protein StrategiesMost genetic mutations associated with AD affect amyloid processingSenile plaques contain abnormal amyloid B fragments (that precipitate out of solution easily)Attack enzymatic pathways that lead to production of abnormal type and amount of amyloid ( beta or ga

35、mma-secretase inhibitors)Enhance alpha-secretase system to promote normal amyloidPrevent aggregation (NSAIDS may do this!)Alter the abnormal gene expressionGAG mimetics (glycosaminoglycans) Alzhemed interferes with formation of insoluble amyloid protein fragments共九十四頁Anti-amyloid TreatmentsGamma and

36、 beta secreatase inhibitorsPoor response to gamma inhibitors in Phase III trials so farAggregation inhibitors (e.g. tamiprosate) negative in Phase III trialsImmunotherapyAN-1792 worked in mice but high rate of encephalitis in humans less powerful antigen form being developedPassive immunization bapi

37、neuzumab monocloncal AB against amyloid-B proteinAutophagy enhancers共九十四頁Reversal StrategiesDestroy the current plaques/amyloid Vaccination Strategy: AN-1792 vaccine is in testing. This is an amyloid B protein fragment which can induce antibodies that bind to plaques and activate microglial destruct

38、ion processes. Trial halted b/o menigoencephalopathiesPlaque bustersAlzhemed prevents Amyloid B fragments from forming fibrilsClioquinol - A metal-protein-attenuating compound (MPAC) that inhibits zinc and copper ions from binding to beta-amyloid, thereby helping to dissolve it and prevent it from a

39、ccumulating. Transthyretin shows promise at interfering with toxic effectsGenerate new tissue -Neuroregeneration strategies (STEM cells)Neurotransplantation strategies共九十四頁Other Drugs in the PipelineTau protein modulators (to prevent abnormal phosphorylated tau proteinBeta and gamma-secretase inhibi

40、torsAlpha secretase stimulatorsBryostatin CA drug that stimulates brain protein production. Reduces B-amyloid levels in mice, enhances memory and learning.New generation NSAIDS (flubiprofen) testing in humans looks promisingImmune enhancers (immunoglobulin)New vaccines and new anticholinesterases (h

41、uperzine)共九十四頁Caregiver BurdenAlzheimers caregivers spend an average of 69 to 100 hours per week providing careCaregivers of patients suffering from dementia(compared to control subjects) reported:46% more physician visitsOver 70% more prescribed drugsMore likely to be hospitalizedMore than 50% of c

42、aregivers are at risk for clinical depression共九十四頁Staging of DementiasMILD: difficulties with checkbook maintenance, complex meal preparations, complicated medication schedulesMODERATE: difficulties with simple food preparation, household or yard work. May need some assistance with self-careSEVERE:

43、Need considerable assistance with feeding, grooming and toiletingPROFOUND: Largely oblivious to surroundings, totally dependentTERMINAL: Bed bound; require constant care共九十四頁Common Associated Problemsdepression (occurs in 20-40% - esp. AD and VaD)psychosis (occurs in 30- 50%) - usually see paranoid

44、delusions (theft, infidelity)wandering/purposeless activityagitation/threatening behaviorsleep disturbances delirium - minor insults can lead to major decompensations共九十四頁DELIRIUMDefinition - transient, usually reversible, dysfunction of global cerebral metabolism or physiology that has an acute or

45、subacute onset manifested by a wide array of neuropsychiatric abnormalities, and often associated with life-threatening medical disordersAKA acute organic brain syndrome, acute encephalopathy共九十四頁Delirium (signs and sx)Symptoms: Impairments of alertness (arousal) and attention are the core deficits.

46、 Symptoms will wax and wane as alertness and attention decreases and increases. Functions that depend on attention and alertness including orientation, perception, working memory and awareness will be impaired leading to a host of potential secondary sx such as psychosis, sleep-wake cycle disturbanc

47、es, agitation, anxiety, and neurological abnormalities (dysgraphia, constructional apraxia, tremor, etc.)Signs: EEG slowing, asterixis, sleep/wake cycle changes, S100B* elevations in CSF? *(S100B is a 21-kDa calcium-binding protein produced and released primarily by astrocytes in the CNS, where it e

48、xerts neurotropic and gliotropic actions. Several studies have investigated the potential role of S100B as a peripheral biochemical marker of neural injury.共九十四頁General rules of thumb: Delirium Dementiaacute chronic reversible irreversible physiological structural primary attention primary memory de

49、ficits deficitsDelirium and dementia can coexist; in fact delirium is very common in demented patientsDelirium vs Dementia(summary)共九十四頁DSM-IV DIAGNOSISCriteriaA. Disturbance of consciousness with decreased attention/focusB. Change in cognition or development of perceptual disturbancesC. Develops ra

50、pidly and fluctuates over timeCode as Delirium due to.1. General Medical Condition (specify)2. Substance Intoxication/Withdrawal3. Multiple Etiologies4. NOS共九十四頁Epidemiology of DeliriumVery Common - 10-15% med/surg inpatients (30%+ if elderly); 2/3 of patients admitted from NH have delirium30% of Ad

51、ult Burn Patients80% of delirious patients have pre-existing dementiaMortality rates for elderly hospitalized patients with delirium is as high as 65% in some studies (double the non-delirious rate)As many as two thirds of deliria go undetectedAnnual costs exceed $8 billionAll sudden mental status c

52、hanges in dementia patients should be considered a delirium until proven otherwise共九十四頁Etiology of deliriummany potential causesoften multifactorial (only 56% have a single probable etiology)infections, metabolic derangements, anoxia, drug intoxications, withdrawals, CNS disease, toxins, fevers, etc

53、.susceptibility increased by aging, brain injury (esp. dementia and CV disease), polypharmacy (esp. anticholinergic load), malnutrition and feversuspect UTI, dehydration and/or pneumonia in dementia patients with delirium共九十四頁DELIRIUM - General TreatmentTreatment:Must look for medical cause(s) and t

54、reat as the primary interventionSecondary symptoms can be helped by drugs such as haloperidol or risperidone (unless the cause of the delirium is NMS) and by reorientation strategies. Quetiapine has also become popular due to minimal dopamine blocking propertiesAvoid anticholinergic, antihistaminic,

55、 and sedating drugs共九十四頁Specific TreatmentsAnticholinesterases may be useful if cholinergic systems are impaired (which may be the case in most deliria)Thiamine for W-K, benzodiazepines for etoh/sedative withdrawal deliriumBenzodiazepine antagonists have been useful in some cases of hepatic encephal

56、opathyWhat about stimulants?共九十四頁Behavioral Problems in ADAlmost universally a problem at some point60% of AD at any one time exhibiting significant symptoms (usually delusions and/or agitation)Common problems by order of prevalence:agitationdepressiondelusions/psychosisAdditional behavioral problem

57、sdisinhibition, apathy, personality change, anxiety, wandering, insomnia共九十四頁Causes of Behavioral ProblemsBiological (due to the disease process itself e.g.)Psychological (loss of function and autonomy, attempts to maintain some control, denial of deficits, etc.)Social (family distress, economic iss

58、ues, family conflicts over care)Environmental (increased sensitivity to changes, issues of safety, etc.)共九十四頁General Treatment StrategiesDefine symptoms clearlyRule out other psychiatric illness (e.g. MDD)Rule out medical causes for the symptoms (e.g. intercurrent illness, medication reactions, etc.

59、)Identify non-pharmacologic strategiesPharmacotherapy共九十四頁Environmental StrategiesIdentify provocations and rectify if possibleAppropriate re-orientation strategies task simplificationOptimize sensory input i.e. correct visual and hearing impairmentsBehavior management strategies that respect the pa

60、tients need for control and autonomy (announcing intentions, single-step instructions e.g.)Optimize physical activity, social stimulation, reminiscing共九十四頁Management IssuesAlleviate patients distressReduce care-giver burdenDelay institutionalizationAssure safetyPatients often become more like themse