Dementia

1. Dementia

2. Dementia • importance • growing medico-social problem worldwide • rising proportion in the elderly. • prevalence < in developing countries based on cross-cultural, transnational studies in people of same genetic stock but living in different environmt

3. Introduction • Alzheimer’s Disease (AD) • commonest most countries • apart from Japan, china and Russia. • molecular basis of the dementias, • AD and some gene loci have been mapped to chromosome 21,1,14,19,17 • lack of association of AD with Apolipoprotein E (located on chromosomes 19) in Nigerians and weaker association in African-Americans cf with Caucasians.

4. Dementia- defn • defned as global impairment of • brain function, which affects the • performances of normal daily • activities • in a conscious and alert state. • It can be described simply as • “brain failure/“loss of the mind”

5. Dementia- defn • Progressive decline of MAJOI • Memory, • Affect, • Judgment, • Orientation and • Intelligence / Insight

6. Dementia • > 1980 • Dx of elderly ( > 65 years) • rapidly growing segment of d populatn due to longer life expectancy. • risk of developing D in the absence of adequate prevention or cure • lead to an epidemic worldwide

7. Dementia • WHO • 80% of the monthly increase of 1 million elderly persons occur in developing countries. • imposes stress on families and care-givers. • cost of care – enormous third leading cause of death among the elderly • malignant condition - carries as much risk of death as cancer in persons > 75 years. • constitutes a medico-social threat.

8. Epidemiology prevalence of dementia increases with age rate doubling every 5 years 1% in 60 -64 year-olds 30-40% in > 85 years prevalence in a Nigerian community was 2.29% and rising figures with progressive aging were observed 9.59% in > 85 years.

9. Epidemiology • No definite sex predilection • No race is immune • VD commoner in blacks; B/C higher stroke risk • AD commoner in whites.

10. Aetiology • interplay of factors involved.

11. Aetiology • definite risk factors: • old age, • Down’s syndrome, • genetic predisposition, • familial aggregation.

12. Aetiology • possible risk factors: • head trauma, • depression, • thyroid disorders, • rural living and • old maternal age at birth

13. Aetiology • contentious ones : • low educational attainment, • aluminum, • occupational exposure to glue(sniffing) or other solvents alcohol • paternal age.

14. Aetiology • inverse association (possibly protective) : • smoking, • use of anti-inflammatory drugs and • estrogen replacement therapy. - promote growth of cholinergic neurons and possibly interact with apolipoprotein E.

15. Aetiology • risk factors for stroke : • hypertension, • diabetes mellitus and • cardiovascular disorders • should be considered for VD

16. Pathogenesis of dementia • Neuronal death and loss of synapses in critical areas of the brain: • the limbic cortex, cholinergic basal forebrain (nucleus of Meynert), necortex and brain stem • due to diverse etiology (vascular, genetic, idiopathic , degenerative, toxic, inflammatory).

17. AAN 2011 Hawaii • Amyloid • Hipocampal sclerosis • Cortical atrophy • Lewy bodies • Lacunar and micro-infarcts • All have cumulative effects in causation

18. Pathogenesis of dementia • Accumulation of abnormal proteins and inclusion in the brain: • amyloid, • tau, • lewy bodies etc • as a result of neuronal death or abnormal protein processing.

19. Pathogenesis of dementia • Depletion of neurotransmitters: • acetyl choline, • noradrenaline, • dopamine, • glutamate, • substance P and • serotonin.

20. CLINICAL ASPECTS AND CLASSIFICATION • clinical syndrome characterized by impairment in multiple domains of cognitive functions in the absence of delirium.

21. CLINICAL ASPECTS AND CLASSIFICATION • essential components :persistent memory impairment far beyond what can be accounted for by age alone. • impaired ability to learn new or recall previously - learned information.

22. CLINICAL ASPECTS AND CLASSIFICATION • other cognitive deficits present in various combinations include: language disturbance (aphasia), impaired ability to carry out motor activities in the absence of paralysis (apraxia), failure to recognize object despite intact sensory system (agnosia), problems with judgment, personality change, calculation and abstraction

23. Clinical Features • The cognitive impairment is accompanied by a decline in occupational and social functioning from a previous level of performance. • pt with memory problem

24. Clinical Features • may forget to turn off the gas after cooking frequently get food burnt wt home disasters Forgetting to close water faucets - flooding. • Problems with calculation - inability to handle finances which affects business, • problems with judgment can manifest as not knowing what to do when a lit kerosene stoves catches fire.

25. Clinical features • early stage: • social skills • personal care preserved.

26. Clinical features • Over time, • b/co messy when eating • problems with dressing and toileting.

27. Clinical features • advanced stage, takes about 10 years • dehumanized – totally dependent, mute, bedridden, incontinent and uncomprehending. • At this end stage, need for constant supervision.

28. classification • The degenerative dementias constitute the commonest type • AD-single most frequently encounterd

29. Degenerative dementia • Alzheimer’s Disease • Cortical Lewy Body diseases/Parkinson’s disease • Pick’s disease/Fronto-temporal degeneration • Huntington’s disease • Progressive supranuclear palsy • Prion disease/Spongiform encephalopathies

30. Degenerative dementia • Vascular dementia • Multi-infarct syndrome • Binswanger’s disease • Strategic infarct (angular gyrus, thalamic) • Mixed (cortical /Subcortical involvement) CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy)

31. Classification Reversible/Treatable causes • Brain infection including HIV, neuro-syphillis • Cerebral tumors • Chronic subdural hematoma • Normal Pressure Hydrocephalus • Cardiopulmonary disorders • Liver/Renal failure

32. Classification • Reversible / treatable • Thiamine and other vitamin deficiencies • Dialysis disequilibrium • Hypothyroidism • Alcohol and/or substance abuse • Depression • Heavy metal poisoning

33. Alzheimer’s Disease (AD) • commonest type • accounts for 50-75% • named after a German neuropathologist. • Alois Alzheimer - 1977 reported the neuropathological findings in a 55 year-old woman who had memory, language and behavioural changes that progressed over a 5 year period before she died. • brain histology showed abnormal deposition of amyloid in the form of neuritic plaques and neurofibrillary tangles with silver stains

34. AD • recent community-based study in Ibadan • AD affects elderly Nigerians, commonest • The prevalence was 1.41% • cf with 6.24% in African-Americans. • Age gradient was also evident • rate rising from • 0.52% -aged between 65 and 74 y to • 5.91% in persons > 85 y.

35. AD - neuropathology • gross finding: severe brain atrophy with thinning of the cortex. • Histology: there is loss of neurons and synapses in many areas of the brain • intra-neuronal accumulation of paired helical and straight filaments (neurofibrilliary tangles) associated with tau, microtubule associated protein and ubiquitin.

36. AD - neuropathology • extra-neuronal deposition of amyloid (neuritic plaques) in the amygdala, hippocampus, neocortex, cholinergic forebrain neucleus (nucleus of Meynert) and around blood vessels (congophilic angiopathy). • other findings: Hirano bodies which are rod-shaped, eosinophilic cytoplasmic inclusions and granulo vacuolar degeneration (intra-cytoplasmic electrondense granules) especially in the pyramidal cell of the hippocampus.

37. Neuropathology • neuronal loss - due to apoptosis, excito-toxic damage or other insults. • Neurotransmitters: serotonin, noradrenaline, dopamine, glutamate and substance P. • changes in neurotransmitters responsible for the behavioural changes encountered

38. Neuropathology • memory impairment due largely to deficiency of Ach. • loss of synapses in the neocortex causes functional disconnection between regions of the brain concerned with cognition most especially the association areas. • This may be associated with deficiency or failure of delivery of essential trophic factors for neuronal functional integrity.

39. amyloid cascade theory • abnormal processing of a trans-membrane protein called amyloid [βA4 precursor protein (APP). • synthesized as a large precursor protein b/t 714 and 770 amino acids. • processed by cleavage involving various secretases (αβү) into a 40-42/43 AA residue which is deposited as amyloid. • The α pathway involves cleavage between 687 and 688 while β occurs b/t 671 and 672 residues.

40. amyloid cascade theory • The y process cleaves at position 712 and appears to be central to the production of long Aβ which is deposited. • The gene is located on chromosome 21. • Five mutations in the gene have been identified that can lead to AD: • Down’s syndrome resulting in more APP production, mutation between 670/671 which potentiates B secretase activity and mutation at either position 716 or 717 which alter the site of y cleavage.

41. amyloid cascade theory • mutation of another set of trans-membrane proteins called the presenilins : also shown to cause subtle alteration in APP processing leading to more AB production. • The two identified are: • presenilin 1 on chromosome 14 and • presenilin 2 on chromosome 1.

42. amyloid cascade theory • significantly less BA4 amyloid deposited in the brains of non-demented elderly Nigerian which may agree with the epidemiological finding of lower AD prevalence. • amyloid cascade theory appears to be the most dominant hypothesis presently, it is not exhaustive • b/c no correlation between the extent of amyloid deposition and clinical staging of the disease • .

43. Terry’s hypothesis • “tangles do not cause of and plaques are not the major cause of synaptic loss. Each of these phenomena might well lie along separate pathogenetic streams flowing in parallel from the underlying, still uncertain source. Their effects are presumably addictive with synaptic loss appearing to be the most powerful ubiquitious proximate factor leading to dementia.

44. Apolipoprotein E (APOE) • Since 1993, APOE has been identified as a susceptibility protein that binds B-amyloid in the cerebrospinal fluid. • It is a 299 amino acid glycoprotein that maps to chromosome 19. • It is a ligand for lipid transport and had high affinity for BA4 amyloid. It exists in three allelic forms: APOE-e2, APOE-e3, APOE-e4.

45. Apolipoprotein E (APOE) • In cultured neurons, • APOE-e3 (most frequent allele) stimulates sprouting • e2 is supposed to be protective and is associated with delayed age on onset of AD. • e4 is inhibitory and causes neuro-degeneration. • Amongst Caucasians, • the e4 allele, especially the homozygous form, increases the risk of developing AD

46. APOE • There appears to be a racial influence and possible gene-environment interaction with regards to APOE and AD because APOE-e4 showed weak association in Nigerians.

47. AD - clinical diagnosis • on the basis of the SSM-IV or the ICD-1OR37 criteria with emphasis on gradual and progressive decline in cognitive function in the absence of the known causes. However, definite diagnosis requires histological confirmation either at autopsy or brain tissue obtained by biopsy.

48. AD - clinical diagnosis • Quantitation of the amount of amyloid plaques and tangles should exceed what is expected with age. • Three levels of diagnostic certainty are provided by the NINCDS-ADRDA criteria.

49. AD - clinical diagnosis • probable:– on the basis of typical clinical features in the absence of histological confirmation • possible: there are atypical features. • Definite :histological confirmation in pts with typical features

50. Other degenerative dementia • Pick’s disease (PD) was first reported in 1892 as dementia associated with fronto-temporal brain atrophy. It usually presents between the ages of 50 and 70 years with mood disturbance, irritability, loss of social awareness. Aberrant behaviours and bulimia. There is language disturbance either in the form of logorrhea or preservation which ends in mutism. The usual alerting feature is social disinhibition.