Dementia Reforma pregraduální výuky neurologie na 1.LF UK v Praze CZ.2.17/3.1.00/33277

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1 Dementia

2 Problem: medical, social, economic, ethical 10-15% inhabitants of developed countries over 65 years suffer from detectable intelect deterioration and more than 5% are affected so severely they gradually lose their ability to take care of themselves (Wang 1977).

3 % Praha & EU: Investujeme do vaší budoucnosti Problém: medical, social, economic, ethical Estimation of dementia incidence Line 1 Line 2 A

4 ( 10 Definition of dementia (DSM IV., ICD slowly progressing brain disease always with memory disturbance + at least one disruption of cognitive-executive functions (spatial orientation, recognition, learning, thinking, speech, calculation etc) without quantitative disruption of consciousness disease leads to loss of social functions (work, family, self-reliance...)

5 disorders that most frequently mimic dementia Age-dependent memory disturbances, benign senile forgetfulness, MCI transient cognitive disorders accompanying systemic diseases side effects of pharmacotherapy MAJOR DEPRESSION delirium

6 Basic clinical classification of cognitive disorders: ORGANIC EPISODIC DISTURBANCES PERSISTENT DISORDERS delirium normotensive hydrocephalus dementia syndromes brain trauma SDH isolated cognit. impairment epilepsy tumors -sensory intoxication metabolic encephalopathy - symbolic brain hypoperfusion CPM - cognitive brain inflammation intracranial hypertension - mnestic TGA pseudotumor cerebri - dysexecutive PSYCHOGENIC disorders specific by situation

7 Differential diagnosis between dementia and delirium Praha & EU: Investujeme do vaší budoucnosti dementia delirium SLOW, STEALTHY ONSET CHRONIC COURSE PROGRESSION WITHIN MONTHS, YEARS WITHOUT OR WITH MILD FLUCTUATION OF SYMPTOMS VIGILANCE IS NOT AFFECTED WITHOUT DRAMATIC PSYCHOMOTORIC SYMPTOMS, WITHOUT AGITATION, ACUTE DISORIENTATION SUDDEN ONSET ACUTE DISEASE PROGRESSION WITHIN DAYS - WEEKS SUBSTANTIAL FLUCTUATION OF SYMPTOMS FLUCTATION OF VIGILANCE PSYCHOMOTORIC AGITATION FREQUENT HALLUCINATIONS

8 basic examination in a patient with cognitive disorder: MMSE, Clock test, (Addenbrook test?) biochemical screening including blood levels of glucose, B12, T3/4 (TSH) morphological brain imaging techniques (CT, MRI) neurological examination neuropsychological examination

9 MMSE MMSE sensitivity 82% Praha & EU: Investujeme do vaší budoucnosti MMSE specificity 64% In contrast to ACE -R doesn t examine: verbal functions delayed memory retrograde memory memory storage (registration)-recall executive functions neglect Insufficiently: visuospatial functions

10 Addenbrook cognitive test (Mathuranerth et al 2000) ( norm ) score points < 88 points: sensitivity 94%, specificity 89 % < 84 points: specificity 100 % MMSE + clock test are included in the test + substantial increase in sensitivity and specificity + detection of FTLD + outpatient applicability - longer administration - recognition of VD - recognition of LBD

11 Geriatric Depresive Scale Barthel scale Praha & EU: Investujeme do vaší budoucnosti

12 Hachinski Ischaemia Score Hachinski V. C., Iliff L., Du Boulay G. H., McAllister V. L., Marshall J., Ross Russel R. W., Symon L. 1. Abrupt onset 2 2. Stepwise cognitive deterioration 1 3.Fluctuating course 2 4.Nocturnal confusion 1 5.Relative preservation of personality 1 6.Depression 1 7.Somatic complaints 1 8.Emotional incontinence 1 9.History of hypertension or actual hypertension 1 10.History of strokes 2 11.Evidence of associated (extracerebral) atherosclerosis 1 12.Focal neurological symptoms (phatic, motor) 2 13.Focal neurological signs (pathological reflexes, hemianopsia) 2 Assessment 0-4 points: putative Alzheimer s disease 5-6 points: can not differentiate 7 and more points: putative vascular dementia

13 Primary Dementia Praha & EU: Investujeme do vaší budoucnosti - the most common diseases with dementia as an inital or predominant syndrome Alzheimer s disease Vascular dementia transitional forms Lewy body disease Frontotemporal lobar degeneration Dementia with rapid progression (heterogenous ( group

14 Estimated prevalence of particular types of dementia AD-LBD 12% LBD 3% FTD 5% others 5% 2-5% < 65 let VD 5% AD-VD 10% AD 60%

15 TAU PROTEIN Frontotemporal ( Pick ) dementia F Executive dysfunction disinhibition, apathy ALFA SYNUKLEIN ( body (Lewy Parkinson Lewy body brainste m,bg, cortex P,O Visuoconstruction PM retardation, depression, REM, hallucinations BETA AMYLOID Alzheimer s disease T, P Episodic memory aphasia, psychosis Vascular dementia cortex F,T,P,O subcortical Multiple defects Common executive dysfunctions

16 Brain distribution of atrophy in the most common types of dementia

17 Progression of cognitive deterioration Praha & EU: Investujeme do vaší budoucnosti LBD VD AN

18 Secondary dementia Praha & EU: Investujeme do vaší budoucnosti Tumors (up to 52%) Brain trauma and its complications Infection (AIDS complex) Poisoning Disorders of CNS metabolic supply Nutritional deficit Genetic-enzymatic defects Phakomatoses and dysontogenetic disorders Demyelinating diseases Paget s disease Central pontine myelinolysis

19 Alzheimer s disease

20 Epidemiology of AD the most common cause of dementia prevalence % rare presenile form, (40-65 years) with incidence 0,04 %. described rare (0,005 %) early-onset AD form In Czech Republic by estimation affected people, while less then 20% with appropriate treatment.

21

22 Beta-amyloid formation 82 AK beta secretasis presenilin gama secretasis APO E 4

23 Loss of neuronal connectivity Praha & EU: Investujeme do vaší budoucnosti inflammation inflammation inflammation

24 Clinical picture and progression of disease Praha & EU: Investujeme do vaší budoucnosti Mild stage (MMSE 16-25/30) disruption of episodic and short-term memory depression may be present amnestic aphasia (+ other cognitive symptoms) ( 8-16/30 Moderate stage (MMSE complete loss of orientation deterioration of ability to take care of oneself behavioral disorders aimless behavior or apathy ( 8/30 > Advanced (severe) stage (MMSE complete loss of ability to take care of oneself substantially limited communication cognitive medication without effect

25 Diagnostics and therapy of AD Patient affected by cognitive decline? Complaints? Enivronment? Physician? Detailed medical history + objectivizing Screening for cognitive deterioration (MMSE, ACE-R..) Exclusion of depression and other influences (GDS, Zung Scale, NPI..) Exclusion of somatic influences (biochemistry, CBC,T3,4, B12, blood pressure, fever, dyspnoe ) Syndrome: - Isolated cognitive impairment (ICI)? - Mild cognitive impairment (MCI)? - Dementia?

26 LIKELY ALZHEIMER S DISEASE (NINCDS/ADRDA) (National Institute of Neurological and Comunicative Disorders Alzheimer Disease and Related Disorders Association) dementia proven by clinical examination (ACE-R, ADAS, Wechsler-R... ) disruption of two or more cognitive modalities progressive deterioration of memory and other cognitive functions absent disturbance of consciousness onset between years of life, most frequently > 65 years Absence of systemic diseases and other brain diseases that may lead to memory and cognitive decline

27 Diagnostics and therapy of AD In case of suspected Alzheimer s disease Objective neurological examination Brain CT (MRI) A-B-C scaling Biomarkers (?) A: activity of daily living: (Barthel index, PSMS ) B: behavioral changes (neuropsychiatric inventory..) C: cognition (WMS-R, ADAS Cog ) In case of suspected ICI: Objective neurological examination Brain CT (MRI) Targeted psychological examination

28 ? biomarkers, revision 2007 In the proposal of the NINCDS-ADRDA criteria: (Dubois et al.; 2007) disruption of episodic memory +: - positive findings in CSF (tau, phosphotau, APP, presenilin..) - reduced hippocampal volume(voxel b. MRI) - altered perfusion, SPECT or PET - APO E4 (- other genetic markers?)

29 Dementia confirmed? Hachinski: score < 4? ACE R: score > 3,2? Meets the criteria of NINCDS-ADRDA? PUTATIVE AD (ultimate diagnosis can be confirmed only by autopsy if quantitative criteria according to CERAD consensus are met) Does not meet the criteria? Differential diagnosis

30 Therapy of AD Inhibitors of AChE are standard medication for mild and moderate AD ( (MMSE Results of pharmacological studies demonstrate efficacy of early and longterm treatment by AChEI

31 Treatment of AD- Centrally acting inhibitors of acetylcholinesterase Donepezil (Aricept): Initial dose 5 mg, after 4 weeks raised up to 10 mg very good tolerance, few side effects Rivastigmine (Exelon): Initial dose 2x1,5 mg, may be doubled every 14 weeks up to 2x6 mg. Should be taken with food. Nausea 4x and vomiting 6x more common then in donepezil Galantamine (Reminyl): Initial dose 8 mg, raised to 16 mg after 4 weeks, with good tolerance up to 24 mg after other 4 weeks.

32 ( Ebixa ) Memantine akatinol Competitive antagonist of glutamate NMDA receptors Inhibits neuronal apoptosis Modulates information processing in establishing of memory trace ( 16/30 8 Indicated in moderate AD (MMSE In MMSE often favourably combined with IChE Initial dose 5 mg, raised by 5 mg after weeks up to total dose 2x10 mg Minimal side effects

33 Clinical picture and progression of disease Praha & EU: Investujeme do vaší budoucnosti Mild stage (MMSE 16-25/30) disruption of episodic and short-term memory depression may be present amnestic aphasia (+ other cognitive symptoms) ( 8-16/30 Moderate stage (MMSE complete loss of orientation deterioration of ability to take care of oneself behavioral disorders aimless behavior or apathy AChEI memantine ( 8/30 > Advanced (severe) stage (MMSE complete loss of ability to take care of oneself substantially limited communication cognitive medication without effect atyp. neuroleptics (tiapride, olanzapine, quetiapine )

34 regionálníhosníženíkevedean krevníhoprůtokumozkem Praha & EU: Investujeme do vaší budoucnosti INCREASED INCIDENCE OF CVA zejména: TEMPORÁLNÍ a PARIETÁLNÍ kortex Anti-inflammatory medication: anti-inflammatory effect antiplatelet effect Výsledky SPECT vyšetření u zdravé ženy (nahoře) a u pacientky s AN (dole): Acetylsalicylic acid 100mg/1-2x/per day

35 Progressive worsening of symptoms is typical for AD Major symptoms COGNITION MILD FUNCTION. STATE BEHAVIOR Disease stages MILD TO MODERATE MODERATE MMSE moving patient to long-term care facility TAKING CARE OF A CAREGIVER IS A PART OF THE THERAPY!!!

36 Functional capacity of patients scale ADFACS (Alzheimer Disease Functional Assessment and Change Scale) basic ADL using toilet feeding clothing personal hygiene bathing walking instrumental ADL Ability to: use a PHONE take care of HOUSEHOLD use DEVICES in own household take care of own FINANCES do SHOPPING make FOOD ORIENTATE oneself at home, outdoors engage in HOBBIES, leisure activites take care of own CORRESPONDENCE UNDERSTAND situation and EXPLANATIONS

37 Non alzheimer dementias

38 Vascular dementia: NINCDS AIREN kriteria Dementia according to ICD 10 Evidence for cerebrovascular disease Temporal relation of these disorders (tolerance 2 months) Falls + gait disturbances Urinary incontinence Pseudobulbar syndrome Personality changes Focal neurological signs

39 Nonhomogenous group Multiple infarcts of territorial vessels Multi-infarct lesion Infarct in strategically important region Hypoxia-hypoperfusion Combined lesion (most frequently) Critical volume of white matter lesion for dementia 35%

40 Characteristic features of vascular dementia Praha & EU: Investujeme do vaší budoucnosti Hachinski score >6: likely vascular dementia Low sensitivity for mixed (combined) forms (HS 4-6)! Does it meet NINCDS - AIREN criteria? Frequently pronounced disruption of symbolic functions in one domain depending on localization If severe disruption especially in case of global aphasia, dementia not accessible to examination - thus, not diagnosed In case of uncertainty, therapeutic test with acetylcholinesterase inhibitors, objectified by psychological examination in 2-month interval, may be recommended

41 Frontal lobe speech fluency executive dysfunction personality emotional regulation discrimination working memory + recall Temporal + parietal lobe memory tests disruptions of STM, learning, registration sensory-phonemic phatic disorders visuospatial perception disruptions of symbolic functions attention neglect Occipital lobe visual agnosia visuo-constructional abilites Balint s syndrome

42 dysfunction Praha & EU: Investujeme do vaší budoucnosti Promising effect of AChEIs especially in multi-infarct dementia Cognitive rehabilitation speech + other functions depending on individual disablement early initiation! - knowledge of focal symptoms in symbolic and cognitive domain + their correlations with morphologic findings

43 Lewy body disease incidence 12-15% (?) of dementia (common misdiagnosed, as AD) onset: continual or sudden, often misinterpreted as delirium course: shorter than AD CAVE neuroleptic medication!

44 Diagnostic criteria for LBD Major symptoms: Chronic progressive course Short-term fluctuation of attention, cognitive functions, consciousness Hypertonic hypokinetic extrapyramidal syndrome Visual hallucinations Paranoid signs Marked negative effect of neuroleptic medication High incidence of delirium Symptoms that support diagnosis: Frequent falls Vasovagal syncope Common depression Mc Keith et al

45 ( LBD ) Lewy body disease Synucleopathy (cortex + subcortical regions) Beta-amyloid + tubular tangles Continuum LBD - AD Cholinergic and dopamineregic system affected in both cases 1) Diffuse LBD: absence of senile plaques; and Lewy bodies (LB) are distributed in limbic system, brainstem and cortex 2) Senile LBD: numerous senile plaques, except from CERAD LB distributed in a diffuse manner 3) Form of AD with LBD: meets CERAD criteria

46 Treatment of Lewy body disease: Praha & EU: Investujeme do vaší budoucnosti!!!contraindication!!! TYPICAL INCISIVE D2 RECEPTOR-BLOCKING NEUROLEPTIC DRUGS Particularly: Haloperidol Chlorpromazine, Chlorprotixen, Levopromazine, Thioridazine Melperone (Buronil) Prochlorperazine, Perfenazine SOME PROKINETIC DRUGS Cerucal

47 Therapy of Lewy body disease: Acetylcholinesterase inhibitors more cautious titration DONEPEZIL RIVASTIGMIN Antipsychotics only if necessary, in minimal dosage: -QUETIAPINE -RISPERIDONE -OLANZAPINE -ARIPIPRAZOLE -CLOZAPINE Dopaminergic therapy mostly ineffective, some authors recommend: Carbidopa/Levodopa (Sinemet)

48 Frontotemporal lobar degeneration Group of rare diseases affecting frontal lobes Incidence 3-5%, up to 10% in the 7 th decennium onset: slow, most frequently years of age progression: slow clinical picture: early personality changes, disturbances in social and emotional regulation, aphasia, mutism, amimia, stereotypy, delirogenic effects of cognitive drugs OFTEN MISDIAGNOSED AS DEPRESSION!

49 Frontotemporal lobar degeneration (FTLD) Tauopathy: Pick s disease, multiple system atrophy, tauopathy with tau mutation (FTDP-17), corticobasal degeneration progressive supranuclear palsy Pick bodies Non-tauopathies: FTLD in motor neuron disease FTLD with neuronal filamentous inclusions FTLD with ubiquitin inclusions (tauopathy?) FTLD without histological findings (tauopathy?) Microvacuolar degeneration

50 Typical frontal symptomatology NONFLUENT, SEMANTIC APHASIA ECHOPRAXIA repeating of observed movements ECHOLALIA repeating of heard vocalizations loss of DISCRIMINATION, e.g. between pleasant and unpleasant stimuli DELIBERATION of feeding and sexual instincts PUERILISM - childish behavior with inserting objects into mouth loss of SOCIAL SELF-CONTROL emotional incontinence incapability of abstract THINKING incapability of REASONING (interpreting proverbs, understanding relations) EXECUTIVE dysfunction incapability of PLANNING, anticipation deterioration of ATTENTION, short-term and working memory

51 Secondary dementia (from neurological point of view) rare neurodegeneration: parkinson + chorea + heredoataxia toxic metabolic diseases: Wilson s disease Wernicke Korsakov (doesn t fulfill definition of dementia) Disorders of lipid, protein or carbohydrate metabolism inflammatory, immune and systemic diseases AIDS complex SLE spongiform encefalopathy limbic encephalitis

52 Parkinsonism + A group of diseases with common features: parkinsonism without tremor subcortical dementia other characteristic neurological abnormalities overlapping of syndromes insufficient effect of L-dopa ( 20%PD Parkinson s disease with dementia (cca progressive supranuclear palsy multiple system atrophy

53 Chorea + Praha & EU: Investujeme do vaší budoucnosti Huntington s chorea 4-7/ , years (but juvenile forms exist as well) clinical picture: personality changes often as the first symptom. Dementia is preceded by motor dysfunction choreoatethoid dyskinesias; depression, psychotic symptoms. conflicting therapy (neuroleptic medication) AD (mutation - p.4 - CAG triplets) Dif.dg: m. Wilson, SLE, neuroakanthocytosis, Hallervorden- Spatz...

54 Concept of subcortical dementia bradyphrenia perseverations rather deterioration of recall than disruption of memory registration executive dysfunction verbal, visuospatial, functions and personality are relatively preserved motor symptoms of primary disease frequent concomitant depression

55 Fast progressing dementias and subacute confusional states the most common causes Reversible Fatal irreversible With paroxysms of cephalea With gait disorder and incontinence

56 Fast progressing dementias and subacute confusional states reversible: Intoxication: CO, heavy metals, industrial poisons, organophosphates, volatile substances, drugs, ethanol Side effects of medication: sedative drugs, analgesic therapy, cardial medication, onkologic therapy, anticholinergic agents, antiepileptic drugs, antiparkinsonic medication, corticosteroids, cimetidine Ethanol: intoxication, withdrawal syndrome, Wernicke Korsakov Metabolic causes: thyroid dysfunction, deficiency of vit. B12, dysbalance of metabolism of electrolytes, calcium; liver and kidney dysfunctions Cerebral infarct Autoimmune: nonvaskulitic autoimmune inflammatory ME

57 Fast progressing dementias and subacute confusional states With paroxysmal headache: neoplasm: primary or metastatic affliction chronic subdural hematoma craniocerebral trauma chronic meningitis With gait disturbance and incontinence normotensive hydrocephalus multi-infarct dementia

58 Fast progressing dementias and subacute confusional states Fatal irreversible conditions: Creutzfeldt-Jakob spongiform encefalopathy myoclonus extraocular or cerebellar affliction pyramidal/extrapyramidal symptoms akinetic mutism typical elektroencephalogram throughout the course of disease Paraneoplastic limbic encephalitis