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Clin Neuro Dementia Alz Lec.

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Medical college lectures: neurology 5th year.

Medical college lectures: neurology 5th year.

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  • 1. DEMENTIA& ALZHEIMER’S ! Dr. Mohamad Shaikhani.
  • 2.
    • Dementia:
    • An acquired syndrome of intellectual impairment
    • Interferes with social & vocational function
    • Associated with impairment in at least 3 of the following:
      • Language, visuospatial skills, Memory, Personality & cognition (abstraction mathematics, judgment )
  • 3.
    • Dementia is a clinical syndrome characterised by a loss of previously acquired intellectual function in the absence of impairment of arousal.
    • Alzheimer's disease &diffuse vascular disease are the most common causes.
    • The distinction of senile from pre-senile dementia is unhelpful.
    • Rarer causes should be more actively sought in younger patients &those with short histories
    Dementia:
  • 4. CAUSES OF DEMENTIA Variant CJD Kuru Gerstmann-Sträussler-Scheinker disease Sporadic Creutzfeldt-Jakob disease (CJD) Prion diseases Post-encephalitic Whipple's disease Subacute sclerosing panencephalitis Syphilis HIV Infective Anoxia/carbon monoxide poisoning Heavy metal poisoning Thiamin deficiency B 12 deficiency Alcohol Toxic/nutritional Communicating/non-communicating 'Normal pressure' hydrocephalus Hydrocephalus Punch-drunk syndrome Chronic subdural haematoma Post-head injury Traumatic Sarcoidosis Multiple sclerosis Inflammatory Paraneoplastic syndrome (limbic encephalitis) Primary cerebral tumour Secondary deposits Neoplastic Mitochondrial encephalopathies Leucodystrophies Huntington's disease Wilson's disease Pick's disease Dystrophia myotonica Cortical Lewy body disease Progressive supranuclear palsy Others (e.g. cortico-basal degeneration) Alzheimer's disease Degenerative/inherited Cerebral vasculitis Amyloid angiopathy Multiple emboli Diffuse small-vessel disease Vascular Rare Unusual Common Type
  • 5.  
  • 6.
    • Reversible DEMENTIA:
      • D= Drugs, Delirium
      • E= Emotions (depression)& Endocrine Dis
      • M= Metabolic Disturbances
      • E= Eye & Ear Impairments
      • N= Nutritional Disorders
      • T= Tumors, Toxicity, Trauma to Head
      • I= Infectious Disorders
      • A Alcohol, Arteriosclerosis
      • (Dick-Mulheke- Overview of Alzheimer's Disease)
  • 7.
    • Irreversible DEMENTIA:
      • Alzheimer’s
      • Lewy Body Dementia
      • Pick’s Disease (Frontotemperal Dementia)
      • Parkinson’s
      • Heady Injury
      • Huntington’s Disease
      • Jacob-Cruzefeldt Disease
  • 8.
    • DIAGNOSIS OF DEMENTIA:
    • Behaviorally defined - no lab test provides diagnosis of dementia
    • Dementia is a disease process
    • Not a normal part of aging
  • 9.
    • A natomical substrates of memory in Dementia?
    • A. Medial temporal lobes & hippocampus (also fornix, mamillary bodies of limbic system)
    • B. Medial thalamus - especially dorsal median nucleus
    • C. Nucleus basalis of Meynert
    • D. Need bilateral damage to have memory loss
  • 10.
    • Five most general classifications for Dementia
    • Pure memory loss
    • Cortical dementias
    • Subcortical dementias
    • Mixed Dementias
    • Reversible / Treatable Dementias
  • 11.
    • Pure memory loss: causes
    • Herpes encephalitis sequelae - bilateral medial temporal lobe lesions
    • Korsakoffs amnesia - bilateral dorsal median nuclei & mamillary body damage due to chronic thiamine deficiency
    • Vertebral - basilar infarcts - if result in bilateral temporal lobe lesions
    • Transient global amnesia – TIA/migrainous?
    • Limbic encephalitis - damage to hippocampus/ limbic pathway
  • 12.
    • Two subtypes of Cortical dementias
    • Alzheimer’s disease
    • Pick’s disease
  • 13.
    • Alzheimer’s Disease (AD)
    • Most common neurodegenerative disease of aging.
    • 65% of demented patients
    • Affects 10% > 65
    • Uncommon up to 65 ys , but up to 20% of those >80 ys.
    • Deficits in Memory
    • Forgetfulness, disorientation, speed of performance, problem solving, language, perception & judgment
    • Mental functions become progressively more impaired leading to profound dementia
    • AD Diagnosis:
      • Neurological exam & neuropsychological testing
      • Brain imaging: brain atrophy due to extensive neuronal loss
      • Diagnosis confirmed by histology of post-mortem brain
        • ‘ Plaques’ & ‘tangles’ in hippocampus & cerebral cortex
  • 14.
    • AD/DAT: Epidemiology
    • Prevalence slightly higher in women than men
    • AD subdivided into:
      • Early-onset AD (<65) or late-onset AD (>65)
    • 75% of AD patients have disease onset after 60
    • 60% of AD patients have no family history of disease
    • DAT is Amyloid Protein Aggregation Formation
  • 15.
    • RELATIVE RISK FACTORS
    • Family history of dementia 3.5 (2.6 - 4.6)
    • Family history – Downs 2.7 (1.2 - 5.7)
    • Family history - Parkinson’s 2.4 (1.0 - 5.8)
    • Maternal age > 40 years 1.7 (1.0 - 2.9)
  • 16.
    • DIAGNOSIS OF DAT:
    • A clinical diagnosis&quot;diagnosis by exclusion,&quot;
    • There is no exact clinical test or finding that makes Alzheimer's disease unique.
    • Initial deterioration can be simulate many disorders, so each disorder must be systematically excluded or ruled out before a diagnosis can be made .
  • 17. DIAGNOSTIC CRITERIA FOR DEMENTIA OF THE ALZHEIMER TYPE (DSM-IV, APA, 1994)
    • A. DEVELOPMENT OF MULTIPLE COGNITIVE DEFICITS
    • 1. MEMORY IMPAIRMENT
    • 2, OTHER COGNITIVE IMPAIRMENT
    • B. THESE IMPAIRMENTS CAUSE DYSFUNCTION IN
    • IN SOCIAL OR OCCUPATIONAL ACTIVITIES
    • C. COURSE SHOWS GRADUAL ONSET AND DECLINE
    • D. DEFICITS ARE NOT DUE TO:
    • 1. OTHER CNS CONDITIONS
    • 2. SUBSTANCE INDUCED CONDITIONS
    • F. DO NOT OCCUR EXCLUSIVELY DURING DELIRIUM
    • G. ARE NOT DUE TO OTHER PSYCHIATRIC DISORDER
  • 18.
    • Histopathology of Alzheimer’s Disease
    • Generalized cortical neuronal dropout
    • Neurofibrillary tangles & senile plaques (with amyloid composed of  -A4 protein), granulovacuolar degeneration
    • Neuronal loss in nucleus basalis of Meynert
  • 19. AD: Pathology
    • Abnormalities & loss of neurons in hippocampus, cortex, basal forebrain (ACh)
      • Marked decrease in cortical ChAT & AChE
      • Degree of cholinergic deficit correlates with degree of dementia
  • 20. Senile Plaques
    • Extracellular deposits of amyloid-b peptide forming plaque core surrounded by axons/dendrites & glia
      • Small number of plaques found in normal aging brain
    • Amyloid-b peptide derived from amyloid precursor protein (APP)
      • APP gene is located on chromosome 21
      • Mutations in APP gene give rise to some familial forms of AD
  • 21. Neurofibrillary Tangles
    • Intraneuronal fibers composed of paired helical filaments of tau protein hyperphosphorylated
      • Normally found in axons associated with microtubules
      • In AD: tau protein self-aggregates & is found throughout the neuron
    • Clinical symptoms & severity of AD correlate best with density & distribution of tangles (& not with amyloid-b deposition)
  • 22.  
  • 23.  
  • 24.  
  • 25.  
  • 26.  
  • 27. clinical diagnosis of Alzheimer’s Disease A)Definite Alzheimer’s Disease B) Probable Alzheimer’s Disease C) Possible Alzheimer’s Disease
  • 28.
    • Definite Alzheimer’s Disease
    • Clinical criteria present
    • +
    • Histopathologic evidence from brain biopsy
  • 29.
    • Probable Alzheimer’s Disease
    • Documentation of cognitive impairment with screening mental status examination, confirmed by neuropsychological testing
    • Deficits in two or more areas of cognition
    • Progressive worsening of memory & other cognitive function
    • No disturbance of consciousness
    • Onset between ages 40 - 90, most often after 65
    • Absence of other disorders.
  • 30.
    • Possible Alzheimer’s Disease
    • There are variations in the onset, presentation, or clinical course of a dementing illness that are unusual in DAT but for which there is no alternative explanation
    • There is a second systemic or brain disease capable of producing a dementia syndrome that is not considered to be the cause of the dementia in this case .
    • There is a single gradually progressive deficit
  • 31.
    • staging of Alzheimer’s Disease
    • Mild - although work or social activities are significantly impaired, the capacity for independent living remains, with adequate personal hygiene & relatively intact judgment (~1 -3 yrs)
    • Moderate - Independent living is hazardous& some degree of supervision is necessary (~2-8 yrs)
    • Severe: Activities of daily living are so impaired that continuous supervision is required, e.g., unable to maintain minimal personal hygiene; largely incoherent or mute.
  • 32. MILD COGNITIVE IMPAIRMENT CRITERIA (Amer. Acad. Neurology) (Petersen et al., 2001 – Neurology 56:1133)
    • Memory complaint, preferably corroborated by an informant
    • Objective memory impairment
    • Normal general cognitive function
    • Intact activities of daily living
    • Not demented.
    • Consider age &APOE genotype to differentiate from age-related cognitive dysfunction.
  • 33. MILD COGNITIVE IMPAIRMENT progression: 25 GDS 3 71 NYU 12 Isolated memory loss 74 Seattle 6 CDR 0.5 72 MGH 15 Questionable dementia 66 Columbia 14 Memory Impairment 74 Toronto 12 MCI 81 Mayo Annual conversion rate to AD % Criteria Mean Age Study
  • 34.
    • Pick’s disease
    • An uncommon type of cortical dementia
    • Clinically similar to Alzheimer’s in the late stages
    • Early, extravagant personality changes & stereotyped language output ( repetitive joke telling ) may help differentiate
    • Pathologically there is focal atrophy of the frontal &/or anterior lobes
  • 35.
    • Hallmarks of Subcortical dementias
    • Psychomotor retardation
      • Slowed speech& cognition, motor sequencing problems, abnormal posture & gait
    • Forgetfulness
      • Characterized by difficulty retrieving information- recall often improves if provide a clue
  • 36.
    • Disorders are associated with subcortical dementia
    • a. Parkinson’s disease
    • b. Huntington’s disease
    • c. Progressive supranuclear palsy
    • d. Wilson’s disease
    • e. AIDS dementia
  • 37.
    • Pathology of subcortical dementia
    • Pathologically involves
      • Basal ganglia
      • Thalamus
      • Rostral brainstem
  • 38. “ Distinguishing Features of Cortical & Subcortical Dementia” Psychomotor retardation Forgetfulness Cognitive dilapidation Impaired insight Poor strategy formulation Aphasia- Amnesia Visuospatial disorder Poor abstraction Aculculia Apraxia Agnosia- loss of the power to recognize the import of sensory stimulus. Intellectual Functions Subcortical Cortical
  • 39. “ Distinguishing Features of Cortical & Subcortical Dementia” Depression (rarely, mania) Indifference Personality/Emotions Subcortical Cortical
  • 40. “ Distinguishing Features of Cortical & Subcortical Dementia” Dysarthria Normal (until late) Speech Subcortical Cortical
  • 41. “ Distinguishing Features of Cortical & Subcortical Dementia” Abnormal (parkinsonian, chorea, dystonia, etc.) Normal (until late) Motor Subcortical Cortical
  • 42. “ Distinguishing Features of Cortical & Subcortical Dementia” Thalamus basal ganglia rostral brainstem Neocortical association areas&hippocampus Anatomy Subcortical Cortical
  • 43. Mixed dementias cortical & subcortical structures are involved
  • 44.
    • Causes:
    • 1. Multi-infarct
    • 2. Slow virus
    • 3. General Paresis (Neurosyphilis)
  • 45. Factors involved in Multi-infarct Dementia(vascular dementia)
  • 46.
    • Step-wise progression is hallmark
    • Abrupt onset, focal signs
    • By treating stroke risk factors may prevent progression
  • 47. Factors involved in Slow virus Dementia
  • 48.
    • Ex: Jacob Creutzfeldt Disease
    • Rare, associated with myoclonus
  • 49. Three important facts about Dementia syndrome or pseudodementia:
  • 50.
    • It reverses with antidepressant therapy (“pseudodementia”)
    • It occurs in up to 10% of depressed elderly
    • Many of these (elderly) will later develop irreversible dementia, but benefit from treatment of depression regardless
  • 51. 3 important effects of depression
  • 52.
    • Decreases:
      • concentration
      • response time
      • motivation
  • 53. Differentiate primary depression & primary dementia by History !
  • 54.
    • Depression
      • acute onset
      • family awareness
      • short symptom duration
      • rapid progression
      • history of depression in patient and/or family
      • Dementia
      • slow onset
      • vague family awareness
      • long symptom duration
      • slow progression
  • 55. Differentiate Depression & Dementia by clinical testing
  • 56.
    • depression
      • little effort on tasks
      • “ don’t know” answers
      • absence of dyspraxia, agnosia, language problems
    • dementia –
      • struggles to complete tasks
      • attempts answers but incorrect
      • presence of dyspraxias, agnosias , and language problems
  • 57. 2 facts of Normal Pressure hydrocephalus
  • 58.
    • Clinical triad: ataxia, incontinence, dementia
    • Difficult to identify those who may improve with shunt, high morbidity
  • 59. High risk for Subdural Hematoma
  • 60.
    • Elderly
    • Alcoholics
  • 61. Symptoms of Subdural H
  • 62.
    • Fluctuating symptoms
    • Headaches
    • may have focal signs
  • 63.
    • Workup of the demented patient
    • A. History - important to interview family
    • B. Physical and Neurologic examination
    • C. Mental status
  • 64.
    • Test to examine the mental status
    • Folstein’s mini-mental status examination
    • Widely used at bedside for brief assessment ( not specific or very sensitive )
  • 65.
    • Age-specific norms for the MMSE
    • 60s – 28
    • 70s – 28
    • 80s –26
  • 66.
    • Test that performs a m ore in depth Psychological testing
    • WAIS (Wechsler Adult Intelligence Scale)
      • Discrepancy of 15 points between verbal & performance scores associated with acquired brain dysfunction
  • 67. Available Screening Tests
    • MMSE 10 -- 15 min
        • Too long
    • 7-Minute Screen 7 – 10 min
        • Too complex
    • Clock Drawing Test 2 – 4 min
        • Not sensitive
    • Mini-cog 3 – 5 min
        • Complex scoring, unclear adequacy
    • Memory Impairment Screen 4 min
        • Need for slightly shorter, easier test
    • (a suitably accurate test that takes less than 2 minutes is not available)
  • 68.
    • 13 l ab and other studies used to diagnose demented patients!
    • Electrolytes, BUN, creatinine, CA++
    • CBC
    • Thyroid studies
    • ESR
    • B 12
    • Folate
    • VDRL/FTA-Ab, ANA, Anti DsDNA.
    • EKG
    • CXR
    • CT
    • LP if suspicion of infectious etiology
    • HIV Ab.
    • drug screen if appropriate
    • Brain biopsy.
  • 69.
    • Management of i rreversible dementias
    • Provide structured safe environment
    • Close supervision when indicated
    • Frequent orientation
    • Familiar surroundings provide important cues - deteriorate rapidly when moved (hospitalization)
    • If sudden worsening, evaluate for infection or side effect of new medication
    • Caregiver support
  • 70. AD: Treatment No cure for AD Limited therapy to help symptoms or to slow progression Therapies to improve symptoms: Enhancement of cholinergic system Increase dietary choline: little effect on cognition AChE inhibitors: small cognitive enhancing effect
  • 71. Anticholinesterases, such as donepezil, rivastigmine & galantamine, or NMDA (N-methyl-D-aspartate receptor antagonists (memantine) appear to improve cognitive function to some extent in Alzheimer's disease
  • 72.
    • Tacrine (Cognex)
    • for Alzheimer’s Disease of mild-to-moderate severity
    • Appears to improve or slow the decline in some test scores in a minority of patients (response is dose-related)
    • Associated with an elevation in liver enzyme (SGPT) in nearly 50% of patients (25% 3 x nl); reverses after D/C
  • 73.
    • Areas of investigation
    • Eldepryl (Selegiline) - anti-oxidant therapy
    • NSAIDs
    • ApoE
    • Nerve growth factors
  • 74.
    • Herbal remedies available.
    • Ginkgo biloba.