Dementia And NeuropsychiatryDr. Pichai Roj, Tu R3

HippocampusHippocampal formation - subiculum - hippocampus - dentate gyrus

Thalamic and midline structures involved in memory

1.Primary areaFrontal lobes

Parietal lobes

Temporal lobes

Occipital lobes

Association areas1.Parieto-occipito-temporal association areas

2.Prefrontal association area

3.Limbic association area

Functions of the parieto-occipitotemporal cortex in the nondominant hemisphereInterpreting music

Nonverbal visual experiences

Visuospatial

2.Prefrontal association areaPlanning

Elaboration of thoughts

Received preanalyzed data

Working memories

Frontal Subcortical CircuitsDLPF cortx Lat Orbital cortx Ant Cingulate cortx

caudate(DL) caudate(VM) nuc accumbens

GP(lat DM) GP(med DM) GP(rostrolat)

Thal Thal Thal (VA,MD) (VA,MD) (MD)Arch Neurol 1993;50:873-880.

Frontal lobe syndromesDorsolateral: Executive dysfunctionOrbitofrontal: Disinhition, AnosmiaMedial frontal / anterior cingulate: apathy

Orbitofrontal syndromeDisinhibitionImpulsiveMood changes: Lability, irritability, hypomania, mania

Medial frontal syndromeApathyloss of generative thoughttranscortical motor aphasia( preserved repetition, comprehension)contralateral neglectAkinetic mutism ( unilateral--> transient, bilateral--> permanent)

3.Limbic association areaAnterior pole of the temporal lobe

Ventral portion of the frontal lobe

Cingulate gyrus

Behavior,emotions and motivation

Classification of memory systems( by time )1.Short-term memory - sec to min

2.Intermediate long-term memory - days to weeks and then lost

3.Long-term memory - yrs ,lifetime

Long term memoryDeclarativeProceduralEpisodicSemanticSkillsClassical conditioningOthers

Approach To Dementia

Whom should we suspect?

DSM IV criteria for dementiaMultiple cognitive deficit include memory impairment and at least one Aphasia Apraxia Agnosia Disturbance in executive functionSevere impair occupation or socialExclude course of delirium Etiology may related medical condition ,substance abuse or combination

Approach Dementia

Subcortical dementCortical dementiaseverityMild to moderateMore severe earlySpeed impairSlowNormal Neuropsychology deficitFrontal memory (recall impairment)Dysphasia ,agnosia ,dyspraxianeuropsychiatryApathy depressionDepression less Motor abnormalDysarthria ,EPSGegenhalten ,lesspathologyStriatum ,thalamusCortical area

Cortical vs SubcorticalCorticalADFTD

SubcorticalVaDPD, PSP, Huntingtons disease, Wilsons disease, SCAHydrocephalusWM diseasesEtc.

Approach DementiaAnterior: FTDPosterior: AD

Clinical course:-Progessive-Treatable

Reversible dementiaDDrugsEEmotional disordersMMetabolic and endocrine disordersEEye and ear dysfunctionNNutritional deficienciesTTumors, traumaIInfectionsAAtherosclerosis, Alcohol

Neurodegenerative diseaseAlzheimers diseaseFrontotemporal dementia, CBDParkinsonian dementia ;Parkinsons disease dementia ,DLB ,MSA

DDx cognitive impairmentAging change?MCIDeliriumDepression (pseudodementia)Amnestic syndromeDementia

HistoryDementiaDepressionDefinite onset (can be dated)Duration before consultedRapid progressionPts complaint of cognitive lossPts description of cogitive lossFamily awaren of dysfunction&severityLoss of social skillsHx psychopathologyUnusual

Long

UnusualVariable (minimal)

VagueVariable (usual in later stage)LateuncommonUsual

Short

UsualEmphasized

DetailedUsual

Earlycommon

ExaminationDementiaDepressionRecent:remote memory lossSpecific memory loss (patchy)Attention&concentrationDont know answersNear miss answers

Performance on tasks of similar difficultiesPts emotional reaction to symptomsRecent>remote

Uncommon

Often poorUncommonVariable(common in later stages)Consistent

Variable (unconcerned in later stages)Equal

Common

Often goodCommonUncommon

Variable

Great distress

Examination (2)DementiaDepressionPts affect

Pts efforts in attempting to perform tasksPts efforts to cope with dysfunctionlabile., blunt or depressedGreat

MaximalDepressed

Small

Minimal

FeatureDeliriumDementiaOnsetAcute, often at nightInsidiousCourse over 24 hoursFluctuating with lucid intervals during day, worse at nightGenerally stable over course of dayDurationHours to weeksMonths to yearsConsciousnessReducedClearAttentionGlobally disorderedHypoalert or hyperalert,DistractibleFluctuates over course of dayUsually normal

FeatureDeliriumDementiaOrientationUsually impaired for time, tendency to mistake unfamiliar for familiar place and personsOften impairedThinkingDisorganizedImpoverishedPerceptionIllusions and hallucinations (usually visual)Usually normalPsychomotor activity Often normalSpeechIncoherent, hesitant, slow or rapidDifficulty in finding wordSleep-wake cycleAlways disruptedOften fragmented sleepPhysical illness or drug toxicityEither or both are presentOften absent, esp in AD

INVESTIGATERoutine CBC ,ERS ,Urea or creatinine electrolyte ,Liver function test calcium ,glucose ,Vitamin B12 and folate ,Thyroid funtion test ,syphilisCommon CT or MRI brainOccasional HIV ,CSF ,EEG ,SPECT

Biomarker in ADTau level -elevatedAB 1-42-deceaseNeuropile-thread proteinBiomarker-nonspecific for AD and other -accurate differential AD from normal elderly subjects

Neuropsychiatry Test

MENTAL STATUS EXAMINATIONDrowsyObtundationStuporcoma

DDX StuporousAkinetic mutism : a state of silent , alert appearing immobility. The patients eyes are open and may follow environmental events. There are regular sleep-wake cycles. He may be inert or may have occasional brief movements - Large frontal lobe injuries - Bilateral cingulate gyrus damage - Midbrain

Locked-in syndrome : The patient mute and paralyzed.The patient can communicate by eye movement. Intellectual function is not impairedBilateral pontine lesions

AttentionForward digit span : the numbers are given at a rate of one per second in a monotonous voice. 7 is normal. < 5 is abnormal

Individuals with normal attention perform the test perfectlyToxic or metabolic disorderIncreased ICPFrontal lobe disorder Focal lesion of the posterior R hemisphere

Memory1.Learning

- examiners name,3 words ,3 objects

2.Backward memory

- backward spelling ,serial subtraction

3.Delayed recall - 30 minutes

4.Retrograde memory

- retrieve knowledge from the past

Non-verbal memoryPatients are asked to copy several figures ; a few minutes later the patients must reproduce the drawings from memory

Design fluency test

LanguageSpontaneous speech : aphasiaLanguage comprehensionRepetition : pt with shortened digit span will be able to repeat only brief phrases. Conversely, the digit span is a repetition test, pt with repetition disturbances will have abnormal digit spans.Naming : adequte vision must be ensured before the test. Low and high frequency wordsReading Writing

Word list generationAsking the patient to think of as many members of a specific category ( category fluency ) or as many words beginning with a specific letter ( semantic fluency ) as possible in 1 minuteNormal 12-24 animal names,

Word list generation is sensitive to anomia and word finding disturbances, lexical search abnormalities associated with frontal subcortical systems dysfunction and psychomotor retardation

Visuospatial skillVisuospatial abilitiesSpatial attentionPerceptionConstructionVisuospatial problem solvingVisuospatial memory

Construction tasks are the most widely used screening tests of visuospatial ability.

Clock drawingCopying figures of increasing complexity

Tests of copying

Injury of the posterior aspect of the R hemisphere produces the most severe visuospatial deficits Dysfunction of frontal, occipital or L parietal lobe can affect drawing abilitiesThe R hemisphere mediates the external configurationThe L hemisphere mediates the internal details

Clock Drawing Test

CalculationIn MSE : addition, multiplication, subtraction and divisionOne or 2 digit tasks : 16 + 32, 15 x 3100-7: at least 5 serialIt is determined by pts education and occupational history.Damage to the posterior aspect of the L hemisphere

AbstractionThis skill refer to the patients ability to derive a general principle from a specific example.SimilarityDifferenceSimilariy : identify the class or category of which 2 items are membersDifference : identify the salient distinguishing feature between 2 similar items

Depends on the patients educationThese tests are culturally biasedAbstraction is sensitive to many types of brain dysfunctionTask failure is a nonspecific indicator of cerebral dysfunctionCommon in frontal systems disorders

Judgment and insightTo yield ecologically valid results that meaningfully relate to the individual s everyday decisionsQuestions : insight into their own conditions, their plans for the future and their understanding of their own limitation best demonstrate their insight and judgmentOrbitofrontal damage

Frontal subcortical systems tasksAlternating programs

Copying multiple loop figures

Serial hands sequencethe pt is then asked to say aloud fist, slap, cut

Mild Cognitive Impairment (MCI)

Mild Cognitive ImpairmentMemory complaint by the patient, family or physicianNormal ADLsNormal global cognitive functionObjective memory impairment or impairment in one other area of cognitive function as evidence by score 1.5-2.0 SD below the age appropriate meanClinical Dementia Rating ScaleNot demented

MCIIncrease risk AD 12-15% per yearsNormal risk 1-2 % per yearNon amnestic MCI or MCI with multiple domain impairment risk dementia not completeNeuropathological change ; choline acetyltranferase deficit and loss of cholinergic basal forebrain

Common causes of dementia in practiceAD: 50-60%VAD: ??? DLBFTDOthers: 5-10%

DementiaEarly amnesiaYesNoFluent aphasiaApraxiaAgnosiaParkinsonian featuresVisual hallucinationFluctuationAtherosclerotic Hx Focal neurologic signs, motor signsBehavioral changesNonfluent aphasiaADDLBVaDFTD

ALZHEIMERS DISEASEMost cases are sporadicFamilial autosomal dominant formMEMORY LOSS, APHASIA, APRAXIA AND VISUOSPATIAL ABNORMALITIES = HALLMARKSPRIMARY MOTOR AND SENSORY FUNCTIONS USUALLY NORMAL

Alzheimers disease : more than memory loss-Decline in cognitive -Loss of ADL-Non-cognitive symptoms-Psychiatric symptoms

Cognitive DeficitsDysphasia : anomia ,aphasiaDyspraxiaDisorientation Impaired calculationImpair judgement and problem-solving

NON-COGNITIVE NEURO SIGNS - ODOUR THRESHOLD RECOGNITION - FRONTAL RELEASE SIGN - IMPAIRED STEREOGNOSIS AND GRAPHESTHESIA - SPEED OF GAIT LENGTH OF STEPS

PSYCHIATRIC SYMPTOMSAnxiety ,depression ,blunted affectHallucination ,delusionPhysical and verbal aggressive ,repetitive mannerism ,uncooperativeness

Behaviour problem in dementiaVerbal aggressive54%Physical aggressive/agitation 42%Sleep disturbance38%Restlessness 38%Wandering 30%Apathy /withdrawal27%

Vascular DementiaRelation between dementia and CVD: onset within 3 mo. of stroke, abrupt onset ,stepwise decline Complex interactionVascular etiologies: cerebrovascular disease, and other vascular risk factorsChanges in the brain: infarcts, white matter lesion (WMLs), atrophyCognitive, behavior and other neurological deficit Criteria for VaD : Cerebrovascular disease and its effect on cognitve expandsMixed AD and CVD commonVAD not diagnosis until at least 3 months after stroke

NIND-AIREN Criteria for VADRequire elements 1. dementia with memory def. and >or= 2 in cognitive domains 2. Hx of CVD 3. elements 1+2, relationship stroke and dementia, abrupt onset or stepwise decline in cognitive func., or fluctuating course, and/or brain imaging finding document damaged.

Categories of VADMulti-infarct dementia (MID) which develops gradually mini-strokes or transient ischaemic attacks (TIAs see below) ,MID affects the cerebral cortex, which is the outerSubcortical vascular dementia (Binswangers disease or lacunar) which involves vascular damage to the nerve cell fibres (deep white matter) by affecting the sheath nerve fibres in the brain (demyelination). Strategic VaD : thalamic dementia

NINDS-AIREN criteriaSupportive informations 1. Hx risk factors of CVD 2. Hx falling or gait disturbance 3. Early urinary incontinence wo urological conditions 4. Frontal lobe / extrapyramidal feature 5. Pseudobulbar feature

Diagnostic LabelingPossible VAD; inclusion criteria by clinical evaluation, neurological ex, cognitive impairment, documented MMSE or Capacity Screen Examination, Hx stroke+ neuro defPropable VAD ; above + neuroimaging CT/MRIDefinite VAD; above+ neuroimaging+ neuropathology

Clinical presentationSmall vessel disease Lacunes & white matter infarction = WHITE MATTER DISEASEMotor & Cognitive Executive SlowingForgetfulnesMood ChangesDysarthriaUrinary Symptoms Short- Stepped Gait

type1 Multi infarct , large sized arterytype2Single/multi infarct, basal ganglia, thalamus, angular gyrustype3Multi subcortical lacunar, deep penetrating artery , most commontype4Binswanger s subcortical leukoencephalopathytype5Combine small/ large infarct, subcortical and corticaltype6ICHtype7CADASILtype8Mixed with AD

Subcortical Arteriosclerotic Encephalopathy (SAE)Bingswanger disease -young patients with HT (50-60)-gradual stepwise progression with stroke-gradual cognitive impairment ;memory deficit ,apathy ,and slow thinking-motor abnormalities ;clumsiness ,slow action ,and gait disturbance.Reflex asymmetry ,extensor plantar response ,frontal lobe sign

Cerebral Autosomal Domonate Arteriopathy with Subcortical Infracts and Leukoencephalopathy (CADASIL)Mid- adult life; mean 43.3 yrsClinical manifestations; migrain with aura, seizure, organic psychiatric symp.Negative asso CVD risk factors, arteriosclerosisSubcortical dementia ,momory and frontal deficit

Imaging lesion and Clinical symptomsSize and number of lesion not explain cognitive functionStrategically location cause cognitive disorder-Thalamic lesion :dominant hemisphere -language deficit ,retrograde amnesia if bilateral cause memory loss ,frontal deficit-basal ganglia (globus pallidus,head caudate) -fronatal lobe disease ,apathy ,abulia -disihbition ,aggressive ,psychotic feature

Dementia with Lewy BodiesCortical Lewy bodies (CLB) typically found in Parkinsons disease and dementia with Lewy bodies (DLB)CLBdemonstrated using alpha-synuclein immunohistochemistryLewy body counts were increased nearly 10-fold in the neocortex, limbic cortex, and amygdala

3 core diagnostic features 1. Fluctuating confusion 2. Persistent visual hallucinations 3. Spontaneous Parkinsonism

(Probable = 2/3 Possible = 1/3)

Clinical featureDementia in association with : - fluctuations in cognition (especially attention and alertness) - visual hallucinations (typically well formed) - mild spontaneous Parkinsonism

Supportive features : - repeated or unexplained falls - syncope or transient loss of consciousness - neuroleptic sensitivity syndrome - hallucinations in other modalities - systematised delusions

Galton and Hodges, 1999

Dementia :attention ,frontal-executive ,and visuospatial deficits ,short term memory better than AD ,100%Fluctuating cognition :variable altered level of attention or arousal ,60-80%Visual hallucination :recurrent ,variable degree ,50-75%Parkinsonism :spontaneous ,rigidity ,and bradykinesia ,intention tremor ,80-90%

Cognitive and neuropsychiatric feature appearing within 1 year of motor signDopaminergic provoke psychosisAntipsychotic agents induce motor disabilitiesSensitivity reaction to neuroleptic drugs

Frontotemperal dementiaClinical course during the first 2 years is as follows:Psychiatric abnormalities Patients with orbitofrontal dysfunction become aggressive and socially inappropriate. They may steal or demonstrate obsessive or repetitive stereotyped behaviors. Patients with dorsomedial or dorsolateral frontal dysfunction may demonstrate a lack of concern, apathy, or decreased spontaneity. Patients may be depressed early in the disease. These mood changes can predate amnesia.

Speech and language abnormalities often begin early and progress rapidly. Patients usually have relatively little limb apraxia and/or visuospatial dysfunction, thus distinguishing them from patients with diffuse bihemispheric impairment. Even memory impairment is relatively less severe than speech/language and behavioral changes.Incontinence can occur early. Parkinsonism, with its concomitant history of rigidity and gait impairment, can occur.

General neurologic examination may include some of the following abnormalities:Primitive reflexes such as grasp, suck, and snout (not palmomental reflex, which is often present in healthy individuals; Sjogren, 1997)Akinesia, plastic rigidity, or paratonia on motor examination (Beversdorf, 1998)Resting tremor (uncommon; its presence suggests Parkinson disease or a Parkinson-plus syndrome)

Mental status/neuropsychological examination may reveal the following:Verbal output that is often nonfluent Most patients have difficulty in naming common objects or pictures (anomia). Spontaneous speech can be sparse yet "fluent" in character, with preserved grammar.Perseveration Relatively preserved visuospatial and visual orientation skills

ClinicalVaDADRisk factors

OnsetProgression Neuro signsGait Memory Executive functionType of dementiaHachinski Ischemic ScoreNeuroimaging Transient ischemic attack, strokes, Atherosclerotic risk factors: DM, HTSudden or insidiousSlow or stepwiseNeurologic deficitsEarly abnormalities Slightly impaired early Markedly impaired earlySubcortical> 7

Infarction, white matter lesionsLess

Insidious Gradually progressive NormalNormal Prominent Impaired in later stageCortical< 4

Normal or hippocampal atrophy

Clinical differenceDLBPDDTremorLess More oftenMotor symptomsBilateral Unilateral at onsetAxial involvement : postural instability, masked faceMore oftenLess Parkinsonism signs at dementia diagnosis25-50%All casesResponse to levodopa Poor Good Cognitive impairmentBefore or within 1 yrs of parkinsonismAfter parkinsonism > 1 yrs at least

DLBAD 93.8 31.3ParkinsonismFluctuation 50-75 deliriumVerbal memorysemantic memoryepisodic memoryExecutive functionAttention, visuospatial function, constructional abilitiesVisual hallucination Neuroleptics Extrapyramidal

Clinical differencesFTDADOnsetEarly behavioral symptomsEarly socially inappropriate behaviorsMemory problemsLanguage problems

Visuospatial problemsMotor signsMood

AppetitePsychotic symptomsMost < 75 yrsCommon Common

Initially intactcan occur as an isolated cognitive entity in PPALess More oftenIrritability, anhedonia, withdrawal, alexithymia, euphoria,, no suicidal idea and guiltappetite, weight gain, CHO cravingRarely persecutory delusion, maybe jealous, somatic, religious and often bizarre markedly with ageUnusual Later stage

Presenting symptomAlways associated with memory problemsMore Less Sadness, anhedonia, apathy, insomnia, guilty

InappetiteTypically delusion of misidentification and persecutory (in moderate to severe cases)

NPH6th-7th decade50%: known causes, 50% idiopathicImprovement after shunting 30-50% of idiopathic and 50-70% of secondary NPHTriad: gait difficulty, subcortical cognitive problems, urinary incontinence

NPHExamination: Mild spasticity of lower extremitiesBBK presentStrength leg preservedCognitive impairment: Prominent attention, memory impairment, executive, frontal lobe dysfunctionSubcortical dementia

Diagnostic testsNeuropsychological assessmentNeuroimaging techniques: CT, MRICSF removalCisternographyMeasurement of cerebral blood flow and metabolismPressure monitoring and hydrodynamic tests

Prognostic factor for shuntingGait disturbanceBrief symptom durationLack of dementia at the onsetPositive - Lumbar punture and CSF drainageIncrease adequctal flow on MRICSF dynamic study isotope cistenographyBiomarker E-4 alles of ApoE gene

ManagementNonpharmacologic treatmentPatient, caregiver & healthcare workers educationCaregiver supportPatient psychological treatmentFinancial &legal issuesPharmacologic treatmentCognitive symptomsNon-cognitive symptoms: neuropsychiatric problems

Antiamyloid TherapiesNo antiamyloid therapies are currently available.Immunization reduces pathological signs of AD in transgenic mice that have APP mutation.This clinical trial was interrupted when encephalitis developed in 6 % of the patients.Inhibitors to and secretase are under active study.

Cholinesterase inhibitors

AChEI in ADEfficacy in mild to moderate ADAChEI in moderate to severe ADAChEI in VaDAChEI in DLBAChEI in dementia associated PD

Cholinergic dysfunction and AChI in VaDCholinergic structures are vulnerable to ischemic damage.Localized stroke interrupt cholinergic bundle that extend from nucleus basalis to cerebral cortex and amygdalaLoss of cholinergic neurons in 40% of VaD with reduced acetylcholine activity in cortex, hippocampus, striatum and CSF

Pharmacologic Rx in VaDAspirinPentoxifyllinePosatirelinPropentofyllineNicergolineNimodipineMemantineAChIs

Memantine

N-methyl-D-aspartate antagonist Interfere glutamatergic excitotoxicity improvement on the function on hippocampal neuronsModerate-to-severe AD (alone and combine with AChE inhibitors).

Management of DLBTarget symptom include : - EPS - Cognitive impairment - Neuropsychiatric features (hallucination depression , sleep disorder, behavioral disturbance ) - ANS

Antiparkinsonian drug : lowest dose of levodopa monotherapyNeuroleptic agent : provoke severe EPS 50% in DLB, increase MR 2-3 times low dose atypical antipsychotic drugsCholinesterase inhibitor : significant improved in fluctuating cognitive impairment, visual hallucination, apathy, anxiety, sleep disturbance

Health Maintenance and General Medical TreatmentExerciseControl hypertension and other medical conditionsAnnual immunization against influenzaDental hygieneUse of eye-glasses and hearing aids Nutrition, hydration, and skin care.

Imaging Brain

AD

AD

Diagnosis ;MRI; numerous small deep infarction with diffuse myelin loss and pallor hemispheric WM ,internal capsule and basal ganglia ,and lacunar infractCADASIL IMAGING

Multiple infraction

Multiple subcortical infraction

Strategic infraction

FTD

Hydrocephalus

Hydrocephalus

hydrocephalus

Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy

Creutzfeldt-Jakob diseaseBasal ganglia and cortical-subcortical involvement

Von Economo encephalitis

Progressive Supranuclear palsy

Progressive Supranuclear palsyimaging atrophy of midbrain (substantia nigra) and pontine tegmentum with abnormally enlarged prepontine cistern variable atrophy of globus pallidus some cases show atrophy of fronto-temporal regions with enlarged lateral ventricles and third ventricle some cases show atrophy of motor cortex

MSA(A) Hyperintense rim in the outer margin of putamen (black arrow), putaminal hypointensity and atrophy (white arrow) in a patient with MSA-p.(B) Hyperintensity of the middle cerebellar peduncles (black arrow) and hot-cross bun sign (white arrow) in a patient with MSA-c on a T2-weighted imageof 1.5-T MRI.

Wilsons disease

Hallervordan-Spatz disease

Hallervordan-Spatz disease

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