Dementia: Diagnosis and TreatmentDebra L. Bynum, MDDivision of Geriatric MedicineUniversity of North Carolina at Chapel Hill

Case Mr. Jones is a 72-year-old gentleman brought to you by his daughter for progressive memory loss. He denies any problems. Previously an accountant, he is now unable to balance his check book. He has had difficulty with getting lost while driving to the store. He was diagnosed with depression two years ago after his wife died. 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.

Questions:What are some limitations to the MMSE?Is there any association between HTN and dementia in the elderly?What are the risk factors for dementia?What type of dementia might Mr. Jones have?

OutlineRisk factors and definition of dementiaTypes of dementiasMMSE and testingTreatment options

Question:What are some risk factors for the development of dementia?

Risk Factors for DementiaAge 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)

Question:What is the definition of a dementia? What is the line between normal memory loss with age and dementia

Cognitive Decline with AgingMild changes in memory and rate of information processingNot progressiveDoes not interfere with daily function or independence

Mild Cognitive Impairment12% of people over age 70Usually memory affectedDoes not significantly interfere with daily function3 times increased risk of developing AD1015% /year will develop dementia

DSM Criteria1. Memory impairment2. At least one of the following:AphasiaApraxiaAgnosiaDisturbance in executive functioning3. Disturbance in 1 and 2 interferes with daily function or independence4. 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 3550 % over 85 have dementia, therefore pretest probability of dementia in older person with memory loss at least 60%

Question:What are some classic features of an Alzheimers type dementia?

Alzheimers DiseaseRole of the HippocampusPatient HM with surgery for seizures to remove bilateral medial temporal lobes resulting in severe anterograde amnesiaFormation of new memoriesSpatial navigationEarly evidence for damage in this area

Alzheimers Disease6080% of cases of dementia in older patientsEarly personality changesLoss of short term memoryFunctional impairmentVisual spatial disturbances (early finding)ApraxiaLanguage disturbancesDelusions/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 neurons at autopsyClinical diagnosis: 87% of diagnosed AD confirmed pathologically (but high pretest probability increases predictive value of clinical diagnosis!!!)

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 hx (especially for early types)Normal/nonspecific EEG MRI: bilateral hippocampal atrophy (suggestive)

Question:What features would make you think more about a vascular etiology to a dementia?

Vascular DementiaOnset of cognitive deficits associated with a stroke (but often no clear hx of CVA but multiple small, undiagnosed CVAs)Abrupt onset of sxs with stepwise deteriorationFindings on neurological examinationInfarcts on cerebral imaging (but ct/mri findings often have no clear relationship)

OverlapMost patients previously categorized as either Alzheimers 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??

Question:What is the risk of dementia with Parkinsons disease?

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

Some Other Dementias

Dementia with Lewy BodiesCortical Lewy Bodies on path1020% of dementiasCompare to PD: Lewy Bodies in substantia nigraOverlap with AD and PD40% patients with AD have LBs on path

Dementia with Lewy BodiesVisual hallucinations (early)ParkinsonismCognitive fluctuationsDysautonomiaSleep disorders Neuroleptic sensitivityMemory changes later in course

Dementia with Lewy BodiesVisual hallucinations2/3 of patients with DLBRare in ADMay precede other symptoms of DLBPsychosis, paranoia and other psychiatric manifestations early in course

Dementia with Lewy BodiesCognitive Fluctuations6080%EpisodicLoss of consciousness, staring spells, more confused or delirious like behaviorDays of long napsSignificant impact on functional status

Dementia with Lewy BodiesParkinsonism7090%More bilateral and symmetric than with PDTremor less commonBradykinesia, rigidity, gait changes

Dementia with Lewy BodiesSleep disordersREM sleep behavior disorder/parasomniaActing out of dreams: REM dreams without usual muscle atonia85% of patients with DLBMay precede other symptoms by years

DLB: Neuroleptic Hypersensitivity3050% of patientsMay induce Parkinsonian symptoms or cognitive changes that are not reversible, leading to rapid decline in overall statusNOT dose relatedSlightly less likely with newer atypical antipsychotics, but can STILL happen

DLB: TreatmentMore progressive course than AD or Vascular dementiaPossibly better response to cholinergic drugs than AD or vascular dementias?response of psychiatric type symptoms to cholinergic agents/cholinesterase inhibitors

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

Frontotemporal DementiaImpairment of executive functionInitiationGoal settingPlanningDisinhibited/inappropriate behavior (90%)Cognitive testing may be normal; memory loss NOT prominent early feature510% cases of dementiaOnset usually 4565 (rare after age 75)Familial: 2040%

Picks DiseaseSubtype of frontal lobe dementiaPick bodies (silver staining intracytoplasmic inclusions in neocortex and hippocampus)?Serotonergic deficit?Language abnormalities and behavioral disturbancesLogorrhea (abundant unfocused speech)Echolalia (spontaneous repetition of words/phrases)Palilalia (compulsive repetition of phrases)Fluent or non-fluent forms

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

Reversible Causes of Dementia?10% of all patients with dementia; in reality, only 23% 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

Question:An elderly patient with ataxia, incontinence, memory loss and large ventricles scan should raise suspicion for ?

Normal Pressure HydrocephalusTriad:Gait disturbanceUrinary incontinenceCognitive dysfunction

NPH: Clinical FeaturesGaitEarly FeatureMost responsive to shuntingMagnetic/gait apraxia/frontal ataxiaCognitivePsychomotor slowing, apathy, decreased attentionUrinaryUrgency or incontinence

NPHHydrocephalus in absence of papilledema, with normal CSF pressureBegins as transient/intermittent increased CSF pressure, leading to ventricular enlargement; ventricular enlargement leads to normalization of CSF pressureThought to be due to decreased CSF absorption at arachnoid villiCauses: SAH, tumors, CVA

NPHDiagnosis: initially on neuroimagingVentricular enlargement our of proportion to sulcal atrophyMiller Fisher test: objective gait assessment before and after removal of 30 cc CSFRadioisotope diffusion studies of CSFMRI: turbulent flow in posterior third ventricle and within aqueduct of sylviusMRI flow imaging SPECT (Single Photon emission CT): decreased blood flow in frontal and periventricular areas

NPH: ?Shunting?Limited dataGait may be most responsivePredictors of better outcome:Lack of significant dementiaKnown etiology (prior SAH)New (< 6 months) symptomsProminence of gait abnormality

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

Other Infections and DementiaSyphilisHIV

Question:What are some tools available to assess for the presence and severity of cognitive impairment?

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

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

Other Evaluation ToolsTrails B testNumbers 125 and letters scattered across page; patient must connect, 1-A, 2-B, 3-C, etc; normally able to do in

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 neuroimaging

Treatment of AD

TacrineCholinesterase inhibitor1 systematic review with 5 RCTs, 1434 people, 139 weeksNo difference in overall clinical improvementSome clinically insignificant improvement in cognitionSignificant risk of LFT abnormalities: NOT USED

DonepezilAriceptCholinesterse inhibitorEasy titration (start 5/day, then 10)Side effects: GI (nausea, diarrhea)Can be associated with bradycardiaMain 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 dementia?Treatment of Lewy Body dementiaTreatment of mixed Vascular/AD dementia

Comments about Cholinesterase Inhibitor StudiesHighly selected patients (mild moderate dementia)?QOL improvementsNot known: severe dementia and mild CI

MemantineNEJM April 2003Moderate to severe AD (MMSE 314)N-methyl D aspartate (NMDA) receptor antagonist; theory that overstimulation of NMDA receptor by glutamate leads to progressive neurodegenerative damage28-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 Primary 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 significant 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

?Antipsychotics NO data to support any significant benefit for treating behavioral symptoms of dementia with antipsychotic agentsSmall group of patients with active psychoses, disturbing hallucinations, or aggressive behaviors who may have some benefit

AntipsychoticsSide Effects:SedationAnticholinergic effectsProlonged QTEdemaOrthostasisWeight gainConfusionWarnings:FDA black box warning for increased mortality (OR 1.51.7), and increased ?increased stroke risk

AntipsychoticsNO if you suspect DLB

AntipsychoticsRisperidone (0.5 BID)Olanzepine (zyprexa): 2.55 mg/dayQuetiapine (seroquel)Rapid titration, use in PD12.5200 mg/dayClozapineUse in PD (least risk of tremor)Agranulocytosis and limited useZiprasidone (geodon)QT prolongation

Prevention?HTN and DM linked to ALL types dementiaStudies of treating systolic hypertension in the elderly (SHEPS and others): decreased risk of development of cognitive impairment in patients in treatment groupDecreased risk included vascular AND Alzheimer type dementiasCholinesterase inhibitors seem to work as well (or as poorly) for both vascular and Alzheimer type of dementiasWhat is the link? Both common, ?unmasking?

?Link with HyperlipidemiaConflicting dataRetrospective studies suggest decreased risk in those patients who are treated with statinsPROSPER study6000 patients age 7080 with vascular risk factors given pravastatin or placebo3 year: no effect on cognitive function?Long enough follow up?

FutureTreating vascular risk factors to decrease development/unmasking of dementia?Actively seeking to differentiate different types of dementia, while alsoRecognizing significant OVERLAP of dementia etiologies in older patientsMove toward agents other than cholinesterase inhibitors?Move away from broad use of antipsychotic agents