Dementia: Diagnosis and Treatment

Case Mr. Jones is a 72 y/o gentleman brought to you by his daughter for progressive memory loss. He denies any problems. She reports that he was an accountant, and is now unable to keep his own check book straight. He has also had difficulty with getting lost while driving to the store. His wife died 2 years ago, and he was diagnosed with depression at that time. In addition, he has HTN and DM. His father was diagnosed with alzheimers disease at the age of 85. On exam, his BP is 170/90; he is oriented, scores 26/30 on the MMSE (0/3 recall and difficulty with the intersecting pentagon); he is unable to do the clockface.A few months later, his MMSE is 24/30; on exam he has some mild cogwheel rigidity and a slight shuffling gate, but no tremor. His daughter reports that he has been having vivid visual hallucinations and paranoid thought

Questions1. What are some limitations to the MMSE?2. Is there any association between HTN and dementia in the elderly?3. What are the risk factors for dementia?4. Would apo E testing be of benefit in this case?5. What type of dementia might Mr. Jones have?6. What medications should be avoided with this type of dementia?

Outline1. Risk factors and definition of dementia2. Types of Dementias3. MMSE and testing4. Treatment options

Risk factors for dementiaAge (risk of AD 1% age 70-74, 2% age 75-79, 8.4% over age 85)Family hx of AD or Parkinsons (10-30% risk of AD in patients with first degree relative)Head traumaDepression (?early marker for dementia)Low educational attainment??hyperlipidemia?diabetesHTN !!!

Risk factors for ADGender (confounding in literature women more likely to live longer, be older.)Downs syndrome?estrogen (probably not)?NSAIDS (probably not)

Cognitive decline with agingMild changes in memory and rate of information processingNot progressiveDoes not interfere with daily function

DSM Criteria1. Memory impairment2. At least one of the following:AphasiaApraxiaAgnosiaDisturbance in executive functioning3. Disturbance in 1 and 2 interferes with daily function4. Does not occur exclusively during delirium

Activities of Daily LivingADLs: bathing, toileting, transfer, dressing, eatingIADLs (executive functioning):Maintaining householdShoppingTransportationFinances

Diagnosis of DementiaDelirium: acute, clouding of sensorium, fluctuations in level of consciousness, difficulty with attention and concentrationDepression: patient complains of memory lossDelirium and depression: markers of dementia?

5% people over age 65 and 35-50 % over 85 have dementia, therefore pretest probability of dementia in older person with memory loss at least 60%

Alzheimers Disease60-80% of cases of dementia in older patientsMemory loss, personality changes, global cognitive dysfunction and functional impairmentsVisual spatial disturbances (early finding)ApraxiaLanguage disturbancesPersonality changesDelusions/hallucinations (usually later in course)

Alzheimers DiseaseDepression occurs in 1/3Delusions and hallucinations in 1/3Extracellular deposition of amyloid-beta protein, intracellular neurofibrillary tangles, and loss of neuronsDiagnosis at autopsy

Alzheimers DiseaseOnset usually near age 65; older age, more likely diagnosisAbsence of focal neurological signs (but significant overlap in the elderly with hx of CVAs)Aphasia, apraxia, agnosiaFamily hxNormal/nonspecific EEG Personality changes

Vascular dementiaOnset of cognitive deficits associated with a stroke (but often no clear hx of CVA, more multiple small, undiagnosed CVAs)

Abrupt onset of sxs with stepwise deterioration

Findings on neurological examination

Infarcts on cerebral imaging (but ct/mri findings often have no clear relationship)

OverlapMost patients previously categorized as either Alzheimer type or vascular type dementias probably have BOTHLikelihood of AD and vascular disease significantly increases with age, therefore likelihood of both does as wellVascular risk factors predispose to AD -- ?does it allow the symptoms of AD to be unmasked earlier??

Dementia with Parkinsons 30% with PD may develop dementia; Risk Factors:Age over 70DepressionConfusion/psychosis on levodopaFacial masking upon presentationHallucinations and delusionsMay be exacerbated by treatment

Dementia with Lewy BodiesCortical Lewy Bodies on pathOverlap with AD and PDFluctuations in mental status (may appear delirious)Early delusions and hallucinationsMild extrapyramidal signsNeuroleptic hypersensitivity!!!Unexplained falls or transient changes in consciousness

Progressive Supranuclear PalsyUncommonVertical supranuclear palsy with downward gaze abnormalitiesPostural instabilityFalls (especially with stairs)surprised look Difficulty with spilling food/drink

Frontal Lobe DementiaImpairment of executive functionInitiationGoal settingplanningDisinhibited behaviorCognitive testing may be normal/minimally abnormal; memory loss not prominent early feature5-10% cases of dementiaOnset usually 45-65

Frontal Lobe DementiaFocal atrophy of frontal and/or anterior temporal lobesFrontal lobe degeneration of the non-AD type (lack of distinctive histopath findings seen with AD or Picks)May be autosomal dominant (inherited form known as frontotemporal dementia)

Picks DiseaseSubtype of frontal lobe dementiaPick bodies (silver staining intracytoplasmic inclusions in neocortex and hippocampus)Language abnormalitiesLogorrhea (abundant unfocused speech)Echolalia (spontaneous repetition of words/phrases)Palilalia (compulsive repetition of phrases)

Primary Progressive AphasiaPatients slowly develop nonfluent, anomic aphasia with hesitant, effortful speechRepetition, reading, writing also impaired; comprehension initially preservedSlow progression, initially memory preserved but 75% eventually develop nonlanguage deficits; most patients eventually become muteAverage age of onset 60

Reversible Causes of Dementia

?10% of all patients with dementia; in reality, only 2-3% at most will truly have a reversible cause of dementia

Modifiable Causes of DementiaMedicationsAlcoholMetabolic (b12, thyroid, hyponatremia, hypercalcemia, hepatic and renal dysfunction)Depression? (likely marker though)CNS neoplasms, chronic subduralNPH

Normal Pressure HydrocephalusTriad:Gait disturbanceUrinary incontinenceCognitive dysfunction

NPHDiagnosis: initially on neuroimagingMiller Fisher test: objective gait assessment before and after removal of 30 cc CSFRadioisotope diffusion studies of CSF

Creutzfeldt-Jacob DiseaseRapid onset and deteriorationMotor deficitsSeizuresSlowing and periodic complexes on EEGMyotonic activity

Other infections and dementiaSyphilisHIV

MMSE24/30 suggestive of dementia (sens 87%, spec 82%)Not sensitive for MCISpuriously low in people with low educational level, low SES, poor language skills, illiteracy, impaired visionNot sensitive in people with higher educational background

Additional evaluationClockfaceShort assessments with good validity: 3 item recall and clockfaceNeurological exam (focality, frontal release signs such as grasp, jawjerk; apraxia, cogwheeling, eye movements)Lab testing and neuroimagingApolipoprotein E epsilon 4 allele: probably not

PrognosisPrevious estimate of median survival after onset of dementia have ranged from 5-10 yearsLength bias: failing to consider people with rapidly progressive illness who died before they could be included in the study

PrognosisNEJM, april 2001Data from Canadian Study of Health and Aging, estimate adjusted for length bias, with random sample of 10,263 people over age 65 screened for cognitive impairment; for those with dementia, ascertained date of onset and conducted followup for 5 years

Prognosis821 subjects (396 with probably AD)Unadjusted median survival 3.3 yearsMedian survival 3.1 years for those with probably AD

Treatment of AD

TacrineCholinesterase inhibitor1 systematic review with 5 RCTs, 1434 people, 1-39 weeksNo difference in overall clinical improvementSome clinically insignificant improvement in cognitionSignificant risk of LFT abnormalities: NO ON USE

DonepezilAriceptCholinesterse inhibitorEasy titration (start 5/day, then 10)Side effects: GI (nausea, diarrhea)Associated with improved cognitive function; main effect seems to be lessening of rate of decline, delayed time to needing nursing home/more intensive care

Other agentsRivastigmineGalantamineCholinesterase inhibitors?more side effects, more titration requiredFuture directions:Prevention of delirium in at risk patients (cholinergic theory of delirium)Behavioral effects in those with severe dementiaTreatment of Lewy Body dementiaTreatment of mixed Vascular/AD dementia

Comments about cholinesterase inhibitor studiesHighly selected patients (mild-mod dementia)?QOL improvementsNot known: severe dementia and mild CI

MemantineNEJM april 2003Moderate to severe AD (MMSE 3-14)N-methyl D aspartate (NMDA) receptor antagonist; theory that overstimulation of NMDA receptor be glutamate leads to progressive damage in neurodegenerative diseases28 week, double blinded, placebo controlled study; 126 in each group; 67% female, mean age 76, mean MMSE 7.9

MemantineFound less decline in ADL scores, less decline in MMSE (-.5 instead of 1.2)Problem: significant drop outs (overall 28% dropout rate) in both groups; data analyzed did not account for drop outs, followed those at risk

SelegilineUnclear benefitLess than 10mg day, selective MAO B inhibitorSmall studies, not very conclusive

Vitamin E (alpha tocopherol)NEJM 1997: selegiline, vit E, both , placebo for tx of ADDouble blind, placebo controlled, RCT with mod AD; 341 patientsPrimary outcome: time to death, institutionalization, loss of ADLS, severe dementiaBaseline MMSE higher in placebo groupNo difference in outcomes; adjusted for MMSE differences at baseline and found delay in time to NH from 670 days with vit E to 440 days with placebo)

Ginkgo Biloba1 systematic review of 9 double blind RCTs with AD, vascular, or mixed dementiaHeterogeneity, short durationsHigh withdrawal rates; best studies have shown no sig change in clinicians global impression scores

Other treatmentsNO good evidence to support estrogens or NSAIDS

Other treatmentsBehavioral/agitation:Nonpharmacologic strategiesReasons for NH placement:AgitationIncontinenceFallsCaregiver stress

AntipsychoticsCommonly prescribed in older patients with dementia and behavioral problems (agitation, sundowning, aggression)Choices:Haloperidol (0.5mg-1mg)Atypical agents:RisperidoneOlanzapineQuetiapine

Antipsychotics: Big PictureConcern with haloperidol for significant risk of EPS and TD with prolonged use in elderlyAll of risk of sedation, orthostasis and varying amounts of anticholinergic effectsStudies show slight efficacy for behavioral problems in dementiaBUT NOT FDA approved for thisAND INCREASED RISK OF DEATH AND CVA with use of atypical agents

RisperidonePlacebo controlled trials of elderly nursing home residents with dementiaDoses .5 mg to 1 mg up to bidDecrease in aggression and improved behavior scores (moderate effect)EPS: 13-23% on risperidone compared to 7-16% with placebo

RisperidoneCVA: 7.8 % - 9% vs 1.8% on placeboMortality: 3.6% - 5.4% vs 2.4% - 3.1%

Olanzapine5-10 mg day max (studies show NO added benefit to increasing more than 10/day)Moderate improvement in aggression and behavior scores compared to placeboNO difference with EPS rates compared to placeboCVA: 0.6-0.8% vs 0% placeboMortality: 2.9% vs 1.6% for placebo

FDA warningAnalysis of multiple placebo controlled trials of elderly patients with dementia of the atypical agents demonstrated significant increase in mortality, sudden death and CVAs in pooled data (nearly double mortality! Likely class actionMay also apply to older agents such as haloperidolBottom line: caution needed, weigh benefits and risks!

MMSE tipsNo on serial sevens (months backwards, name backwards assessment of attention)Assess literacy priorAssess for dominant hand prior to handing paper overDo not over lead3 item repetition, repeat all 3 then have patients repeat; 3 stage command, repeat all 3 parts of command and then have patient do

Back to the questions1. What are some limitations to the MMSE?2. Is there any association between HTN and dementia in the elderly?3. What are the risk factors for dementia?4. Would apo E testing be of benefit in this case?5. What type of dementia might Mr. Jones have?6. What medications should be avoided with this type of dementia?