廣東科學技術(shù)職業(yè)學院高爾夫設(shè)備采購

1、DementiaMichael A Hill, MDProfessor Of Psychiatry雷達物位計 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 impairmentsAbstract thin

2、king / Exec. function impairmentsImpairment in social and/or occupational fnSxs not explainable by another disorder Etiology & PathogenesisDementia results from impaired functioning of multiple brain systems in both cortical and sub-cortical areas that are associated with short-term memory (i.e. lea

3、rning) and other higher cognitive functions. Generally this is due to structural brain damage that is often progressive and relatively irreversibleClinical Presentation of DementiaAlways associated with cognitive disturbances and functional impairmentsVisuospatial impairments and behavioral disturba

4、nces 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) Memory ImpairmentsDifficulty learning or retaining new information (repeated conversations)I

5、nformation retrieval deficits (cant recall names, list generation deficits)Personal episodic memory impairment (misplacing items)Declarative (semantic) memory (WHAT) procedural memory (HOW) Language DeficitsList-generation deficits verbal fluency (esp. in AD)Word-finding difficulties (naming problem

6、s)Less complex sentence structureRelatively preserved auditory comprehension (can understand directions)Visuospatial impairmentsVisual recognition impairments (trouble recognizing familiar faces - CAPGRAS syndrome possible)Spatial deficits (getting lost in familiar surroundings, 3-D drawing deficits

7、, constructional apraxia)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 specific pattern of loss will vary by individu

8、al and somewhat by diagnosisNB: Functional impairment and performance on cognitive testing may not correlate strongly early in the course of dementiaBehavioral SymptomsNearly universal and often the main focus of treatment. Inability to manage these symptoms is highly correlated with institutional p

9、lacement.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)Epidemiology: Prevalence increases with age*Lower numbers represent mode

10、rate to severe dementiaIncidence Of Alzheimers Disease by AgeDiagnostic ApproachEarly Detection & ScreeningCareful history from patient and reliable informantPE with focus on neurological exam and cognitive testingCognitive testing tools such as MMSE are helpful. Score below 24-27 often concerning d

11、epending on premorbid abilitiesFunctional Assessment tools such as the Functional Activities QuestionnairePrimary Care Screening ToolsMMSE (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.

12、 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. 12yAGE18-242328293035-392327293050-542227293070-742126282980-8419252628Diagnostic Work-UpThis is done to (1) rule out disorders besides dementia (e.g. delirium)(2

13、) 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 indicated: Sed. rate, HIV, CXR, heavy metals, LP, EEG, functional imaging

14、, Lyme titers, endocrine studies, rheumatologic studies, Neuropsychological TestingGuidelines For Use of Specialized TestingLP: Suspicion of metastatic CA, CNS infections, neuropsyphilis, hydrocephalus, vasculitis. Also for dementia 1/3 decrease in prevalenceDelaying institutionalization by 1 month

15、saves $1.2 billion/yr3. Reverse symptomsCompensate through augmentation of remaining neurons or other systemsReversal of destructive processes & regeneration of tissue Delayed Onset IncidenceALZHEIMERS PathophysiologyNeuritic plaques -extracellular - abnormal insoluble amyloid protein fragmentsNeuro

16、fibrillary 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 stru

17、cturesReduce Serum anticholinergic load Precursor strategies (e.g. lecithin and choline)Receptor/synaptic strategiesMetabolic strategies (anticholinesterases)CHOLINERGIC SYSTEM STRATEGIESSerum Anticholinergic Load & Cognitive Impairment90% of community elderly sample had detectable SA levelsAn SA le

18、vel 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, 2002Commonly Prescribed Non-Psychiatric Drugs with Significant Anticholinergic Activitycimetidine &

19、ranitidineprednisolonetheophyllinedigoxin/Lanoxinfurosemidenifedipinediphenhydramine (OTC)To a lesser extent: codeine, warfarin, dipyradimole, isosorbide dinitrateCurrent AChE Inhibitors*promotes binding of acetylcholine and stimulates pre-synaptic release of AChAnticholinesterase Side Effects(i.e.

20、procholinergic)GI nausea, vomiting, diarrhea, increased gastric acid secretion*Muscle crampsFatigueInsomniaSyncope (2% vs 1% for placebo) (?bradycardia)*most common with rivastigmineCalcium channel modulation and excitatotoxic systems attenuation (such as memantine)Anti-inflammatory/immunosuppressiv

21、e strategies(e.g. NSAIDs)Gene therapy for defective protein regulationToxin removal (Desferroxamine, clioquinol) / Ventriculoperitoneal shunting (COGNIShunt)Amyloid Protein strategiesOther Neuroprotective strategiesSTRATEGIES TO SLOW OR HALT PROGESSIONNeuroprotective StrategiesNerve Growth Factor Ac

22、etyl-l(levo) carnitine (ALCAR)EstrogenHomocysteine reduction( folate, B6, B12)Antioxidants (Vit E, Gingko, deprenyl)Statins (Lipitor, Pravachol) (may lower abnormal amyloid levels)B-blockers in ADRosiglitazone (Avandia) -anti-inflammatory, amyloid processing modulation activitiesLevetiracetam(Keppra

23、) for aMCI reduces hippocampal hyperactivityNutraceutical StrategiesVitamin E (antioxidant)Homocysteine Reduction (folate, B6, B12)Beta-carotene Physicians Health Study II found a cognitive protective effect of 50 mg every other day over two decades of useGingko (antioxidant)Resveratrol (a type of p

24、olyphenol found in red grape skins and thus red wine) ?anti-inflammatory, anti-aging, anti-cancerVitamin EPotent antioxidant propertiesHas been shown to slow progression at least as much as Deprenyl in one head-to-head studyRecent study showed no difference from placebo in preventing progression fro

25、m 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 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: u

26、p to 1000 IU bidConsider 400-800 IU per day for preventionMay work better if combined with Vitamin CDaysEstrogenAt this point the summary of many studies suggests that Hormone replacement therapy (HRT) is questionably effective in slowing the onset of AD in some womenThe earlier started, the better.

27、 Limited exposure may be best.Progesterone may be detrimentalTacrine response can be enhanced by EstrogenWHY? neurotrophic effects, incr. ChAT, high serum E2 suppresses Apo EStatinsLovastatin(Mevacor), pravastatin(Pravachol), simvastatin(Zocor), atorvastatin(Lipitor)May prevent aggregation of B-amyl

28、oid* in the brain by preventing cholesterol build up. May activate alpha-secretase.Conflicting evidence recent U of Wash study did not find a benefit, 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 enha

29、nce tissue plaminogen activator (tPA) and thus production of plasmin may be important. Plasmin may activate alpha-secretase and can also increase production of BDNF.*AKA amyloid-beta peptide or ABetaMemantineGlutamate is the principal excitatory neurotransmitter in brain regions associated with cogn

30、ition and memory (i.e. it stimulates cholinergic neurons)Glutamate hypothesis of dementia suggests that overactivation of these neurons leads 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

31、 release of glutamate that is the problem.Memantine is a weak antagonist of glutamate-gated NMDA receptor channels which prevents overactivation during memory formation but allows normal functionMemantineTrade name: NamendaDose range: 5 to 20 mg (bid dosing)Side effects: Constipation, somnolence, co

32、nfusion/psychosisAgitation was significantly less likely in memantine groups than placeboNSAID Use & AD in Elderly Patients2708 patients enrolledExamined NSAID use and prevalence of Alzheimers DiseaseNSAID users had 50% lower risk of being affected by ADAspirin trended this way but was not significa

33、ntTreatment studies have not shown any consistent benefits yet however.Landi, et al, Am J Geriatric Psychiatry, March-April, 2003Abnormal Amyloid Protein StrategiesMost genetic mutations associated with AD affect amyloid processingSenile plaques contain abnormal amyloid B fragments (that precipitate

34、 out of solution easily)Attack enzymatic pathways that lead to production of abnormal type and amount of amyloid ( beta or gamma-secretase inhibitors)Enhance alpha-secretase system to promote normal amyloidPrevent aggregation (NSAIDS may do this!)Alter the abnormal gene expressionGAG mimetics (glyco

35、saminoglycans) Alzhemed interferes with formation of insoluble amyloid protein fragmentsAnti-amyloid TreatmentsGamma and beta secreatase inhibitorsPoor response to gamma inhibitors in Phase III trials so farAggregation inhibitors (e.g. tamiprosate) negative in Phase III trialsImmunotherapyAN-1792 wo

36、rked in mice but high rate of encephalitis in humans less powerful antigen form being developedPassive immunization bapineuzumab monocloncal AB against amyloid-B proteinAutophagy enhancersReversal StrategiesDestroy the current plaques/amyloid Vaccination Strategy: AN-1792 vaccine is in testing. This

37、 is an amyloid B protein fragment which can induce antibodies that bind to plaques and activate microglial destruction processes. Trial halted b/o menigoencephalopathiesPlaque bustersAlzhemed prevents Amyloid B fragments from forming fibrilsClioquinol - A metal-protein-attenuating compound (MPAC) th

38、at inhibits zinc and copper ions from binding to beta-amyloid, thereby helping to dissolve it and prevent it from accumulating. Transthyretin shows promise at interfering with toxic effectsGenerate new tissue -Neuroregeneration strategies (STEM cells)Neurotransplantation strategiesOther Drugs in the

39、 PipelineTau protein modulators (to prevent abnormal phosphorylated tau proteinBeta and gamma-secretase inhibitorsAlpha secretase stimulatorsBryostatin CA drug that stimulates brain protein production. Reduces B-amyloid levels in mice, enhances memory and learning.New generation NSAIDS (flubiprofen)

40、 testing in humans looks promisingImmune enhancers (immunoglobulin)New vaccines and new anticholinesterases (huperzine)Caregiver BurdenAlzheimers caregivers spend an average of 69 to 100 hours per week providing careCaregivers of patients suffering from dementia(compared to control subjects) reporte

41、d:46% more physician visitsOver 70% more prescribed drugsMore likely to be hospitalizedMore than 50% of caregivers are at risk for clinical depressionStaging of DementiasMILD: difficulties with checkbook maintenance, complex meal preparations, complicated medication schedulesMODERATE: difficulties w

42、ith simple food preparation, household or yard work. May need some assistance with self-careSEVERE: Need considerable assistance with feeding, grooming and toiletingPROFOUND: Largely oblivious to surroundings, totally dependentTERMINAL: Bed bound; require constant careCommon Associated Problemsdepre

43、ssion (occurs in 20-40% - esp. AD and VaD)psychosis (occurs in 30- 50%) - usually see paranoid delusions (theft, infidelity)wandering/purposeless activityagitation/threatening behaviorsleep disturbances delirium - minor insults can lead to major decompensationsDELIRIUMDefinition - transient, usually

44、 reversible, dysfunction of global cerebral metabolism or physiology that has an acute or subacute onset manifested by a wide array of neuropsychiatric abnormalities, and often associated with life-threatening medical disordersAKA acute organic brain syndrome, acute encephalopathyDelirium (signs and

45、 sx)Symptoms: Impairments of alertness (arousal) and attention are the core deficits. 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 leadi

46、ng to a host of potential secondary sx such as psychosis, sleep-wake cycle disturbances, 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

47、-binding protein produced and released primarily by astrocytes in the CNS, where it exerts neurotropic and gliotropic actions. Several studies have investigated the potential role of S100B as a peripheral biochemical marker of neural injury.General rules of thumb: Delirium Dementiaacute chronic reve

48、rsible irreversible physiological structural primary attention primary memory deficits deficitsDelirium and dementia can coexist; in fact delirium is very common in demented patientsDelirium vs Dementia(summary)DSM-IV DIAGNOSISCriteriaA. Disturbance of consciousness with decreased attention/focusB.

49、Change in cognition or development of perceptual disturbancesC. Develops rapidly and fluctuates over timeCode as Delirium due to.1. General Medical Condition (specify)2. Substance Intoxication/Withdrawal3. Multiple Etiologies4. NOSEpidemiology of DeliriumVery Common - 10-15% med/surg inpatients (30%

50、+ if elderly); 2/3 of patients admitted from NH have delirium30% of Adult 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

51、 go undetectedAnnual costs exceed $8 billionAll sudden mental status changes in dementia patients should be considered a delirium until proven otherwiseEtiology of deliriummany potential causesoften multifactorial (only 56% have a single probable etiology)infections, metabolic derangements, anoxia,

52、drug intoxications, withdrawals, CNS disease, toxins, fevers, etc.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 deliriumDELIRIUM - Gen

53、eral TreatmentTreatment:Must look for medical cause(s) and treat 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 dopami

54、ne blocking propertiesAvoid anticholinergic, antihistaminic, and sedating drugsSpecific 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 antagon

55、ists have been useful in some cases of hepatic encephalopathyWhat about stimulants?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:agitationdepressi

56、ondelusions/psychosisAdditional behavioral problemsdisinhibition, apathy, personality change, anxiety, wandering, insomniaCauses of Behavioral ProblemsBiological (due to the disease process itself e.g.)Psychological (loss of function and autonomy, attempts to maintain some control, denial of deficit

57、s, etc.)Social (family distress, economic issues, family conflicts over care)Environmental (increased sensitivity to changes, issues of safety, etc.)General Treatment StrategiesDefine symptoms clearlyRule out other psychiatric illness (e.g. MDD)Rule out medical causes for the symptoms (e.g. intercur

58、rent illness, medication reactions, etc.)Identify non-pharmacologic strategiesPharmacotherapyEnvironmental StrategiesIdentify provocations and rectify if possibleAppropriate re-orientation strategies task simplificationOptimize sensory input i.e. correct visual and hearing impairmentsBehavior manage

59、ment strategies that respect the patients need for control and autonomy (announcing intentions, single-step instructions e.g.)Optimize physical activity, social stimulation, reminiscingManagement IssuesAlleviate patients distressReduce care-giver burdenDelay institutionalizationAssure safetyPatients

60、 often become more like themselvesCaregiver information and supportCaregivers should:Encourage independence for the Alzheimers patient without sacrificing securityAssist the patient, but only if necessary (i.e. allow the patient as much control as possible)Learn to compromiseDevelop ways to share ac