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Global demographic changes and the challenge of dementia

Global demographic changes and the challenge of dementia. Marc I Combrinck Division of Neurology, Groote Schuur Hospital & Walter & Albertina Sisulu Institute of Ageing, University of Cape Town. Aspects. world demographic trends dementia Alzheimer’s disease

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Global demographic changes and the challenge of dementia

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  1. Global demographic changes and the challenge of dementia Marc I Combrinck Division of Neurology, Groote Schuur Hospital & Walter & Albertina Sisulu Institute of Ageing, University of Cape Town

  2. Aspects • world demographic trends • dementia • Alzheimer’s disease • projected prevalence rates • costs • treatment, prevention • Sub-Saharan Africa & HIV/AIDS dementia

  3. Life Expectancy at Birth

  4. Medical consequences I an increase in age-related diseases • dementia, depression • stroke • chronic musculo-skeletal disorders, arthritis, falls, hip fractures • cardiovascular diseases • cancers (prostate, colon) • macular degeneration

  5. Medical consequences II • multi-morbidity • polypharmacy

  6. Dementia • chronic progressive disorder • deterioration in multiple aspects of cognitive function • associated with behavioural & psychological symptoms • severe impact on quality of life • longest duration of burden on patient, family & society

  7. Causes of dementia • primary neurodegenerative diseases: Alzheimer’s, vascular disease, fronto-temporal dementia, Lewy body dementia • secondary: hypothyroidism, CNS infections, vitamin B-12 deficiency, chronic subdural haematoma, tumour, etc.

  8. Alzheimer-type pathology • Silver stained plaques and tangles • Thick arrow: senile • (neuritic) plaque • Small arrow: diffuse • plaque • Star: tangle

  9. N C Amyloid hypothesis  Secretase  Secretase KPI 670, 671 717 APP Cell proliferation Calcium regulation Membrane  Secretase  Secretase A APPs Aggregated A Reduced Ca++ Neuroprotection Neuroplasticity Increased Ca++ Neurotoxicity Abnormal outgrowth

  10. Pathogenesis of amyloidosis in AD

  11. Brain atrophy in Alzheimer’s disease

  12. control  AD

  13. Risk factors for AD • Age

  14. AD prevalence rates US General Accounting Office (1998) % prevalence rate – all severity levels Age males females 65 0.6 0.8 70 1.3 1.7 75 2.7 3.5 80 5.6 7.1 85 11.1 13.8 90 20.8 25.2 95 35.6 41.5

  15. Ferri CP et al. Lancet 2005; 366: 2112 - 2117

  16. In 2010, 57.7% of people with dementia live in low and middle income countries. By 2050, this will rise to 70.5%.

  17. Established age family history Down’s syndrome apolipoprotein e4 allele autosomal dominant mutations: amyloid precursor protein gene (APP) chr 21, presenilin-1 gene chr 14, presenilin-2 gene chr 1. (<2% cases) AD: risk factors I

  18. AD risk factors II Probable • depression • hypertension • head injury • homocysteine

  19. AD: risk factors III Possible • gender (F>M) • education / neuro-cognitive reserve • diabetes • smoking • cholesterol • herpes simplex virus-I?

  20. Possible protective factors • anti-inflammatory drugs • oestrogen • apolipoprotein e2 allele • high neurocognitive reserve & ­ cognitively stimulating activities • cholesterol lowering drugs (statins) • alcohol

  21. AD & vascular disease

  22. AD: cholinergic hypothesis

  23. drug treatment • centrally acting acetylcholinesterase inhibitors e.g. donepezil, rivastigmine, galantamine • NMDA receptor antagonist: memantine symptomatic treatment in early disease, only 30-40% respond

  24. new drugs? • -secretase inhibitors • ß-secretase inhibitors • ß-amyloid immunisation • anti- ß-amyloid monoclonal antibodies • mitochondrial stabilisers

  25. Alzheimer’s prevention? • treat vascular risk factors - dyslipidaemia, hypertension, diabetes mellitus • lifestyle changes: improve diet, lose weight, exercise more, stop smoking • keep mentally active • vitamin D? anti-oxidants? statins? vitamin B group? non steroidal anti-inflammatory drugs? • no proven interventions in randomised control trials

  26. Alzheimer’s disease in Africa?

  27. Alzheimer’s disease in Africa II • Nigeria: Ibadan vs. African Americans in Indianapolis • no other good studies • few pathological reports • clinical anecdotal evidence

  28. Life expectancy at birth: Sub-Saharan Africa

  29. South Africa • 65+ population: 5% (Japan 23%) but marked socio-economic differences: “whites”: 13% “blacks” 4% • 80+ population: 0.7% (Japan 5%) “whites” 2.4%, “blacks” 0.5%

  30. HIV/AIDS South Africa • estimated 16.6% of population infected • = 8 out of 48 x106 people

  31. HIV-associated dementia/neuro-cognitive disorders • a subcortical dementia • progressive cognitive & behavioural decline memory deficits, psychomotor slowing, apathy • slowed eye & limb movements • hyper-reflexia, hypertonia, frontal lobe release signs

  32. HIV encephalopathy II • macrophage, microglial and astrocyte activation • multi-nucleated giant cells • basal ganglia, deep white matter, brainstem especially affected

  33. HIV encephalopathy CT MRI-FLAIR

  34. HIV dementia / HIVassociated neuro-cognitive disorders III • prevalence? 20-30% Uganda, South Africa • risk factors: high initial viral load, low CD4 counts, age, anaemia, systemic symptoms • APOE ε4 allele • anti-retroviral drug therapy   incidence & often reverses deficits

  35. HIV encephalopathy IV • HAART   HIV dementia but  minor cognitive-motor disorders (MCMD) • CNS sanctuary for latent or slowly replicating virus? • slow neurodegeneration

  36. APOE ε4 & HIV HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy ELIZABETH H. CORDER, KEVIN ROBERTSON, LARS LANNFELT, NENAD BOGDANOVIC, GÖSTA EGGERTSEN, JEAN WILKINS, COLIN HALL Nature Medicine 1998;4(10):1182-4 E4 allele accelerates AIDS progression (Burt, PNAS 2008; 105: 8718)

  37. HIV dementia & Alzheimer’s • common pathological mechanisms? • activation of microglial cells  release of inflammatory cytokines  damage to neurones & their synaptic connectionscognitive impairment • -amyloid found in both • apolipoprotein E e4 a risk factor for both?

  38. Impact of HIV/AIDS on elderly • Care of ill children • Care of AIDS orphaned grand-children

  39. Summary • increased life expectancy in industrialised countries and low to middle income countries of Asia, Latin America • increased dementia prevalence • increased dependent elderly population • increased stress on social welfare systems & economies • no good treatment available yet • no proven preventative strategies • additional problem of HIV dementia, especially in southern Africa

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