The document discusses dementia and Alzheimer's disease. It defines dementia as acquired intellectual impairment affecting social and vocational function. Alzheimer's disease and vascular disease are the most common causes. A clinical diagnosis of Alzheimer's requires cognitive impairment in at least two areas along with progressive worsening of memory and cognition. Pathologically, Alzheimer's is characterized by neuronal loss, neurofibrillary tangles, and senile plaques composed of amyloid beta protein. Treatment focuses on symptom management with acetylcholinesterase inhibitors or NMDA receptor antagonists.

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

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)

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.