Global demographic changes and the challenge of dementia Marc I combrinck

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

• projected prevalence rates

• costs

• treatment, prevention

• Sub-Saharan Africa & HIV/AIDS dementia

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

Medical consequences II

• multi-morbidity

• polypharmacy

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

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.

Alzheimer-type pathology

Amyloid hypothesis

Pathogenesis of amyloidosis in AD

Brain atrophy in Alzheimer’s disease

Risk factors for AD

• Age

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

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

AD: risk factors I

• 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 II

• Probable

• depression

• hypertension

• head injury

• homocysteine

AD: risk factors III

• Possible

• gender (F>M)

• education / neuro-cognitive reserve

• diabetes

• smoking

• cholesterol

• herpes simplex virus-I?

Possible protective factors

• anti-inflammatory drugs

• oestrogen

• apolipoprotein e2 allele

• high neurocognitive reserve & ­ cognitively stimulating activities

• cholesterol lowering drugs (statins)

• alcohol

AD & vascular disease

AD: cholinergic hypothesis

drug treatment

• centrally acting acetylcholinesterase inhibitors e.g. donepezil, rivastigmine, galantamine

• NMDA receptor antagonist: memantine

• symptomatic treatment in early disease, only 30-40% respond

new drugs?

• -secretase inhibitors

• ß-secretase inhibitors

• ß-amyloid immunisation

• anti- ß-amyloid monoclonal antibodies

• mitochondrial stabilisers

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

Alzheimer’s disease in Africa?

Alzheimer’s disease in Africa II

• Nigeria: Ibadan vs. African Americans in Indianapolis

• no other good studies

• few pathological reports

• clinical anecdotal evidence

Life expectancy at birth: Sub-Saharan Africa

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%

HIV/AIDS South Africa

• estimated 16.6% of population infected

• = 8 out of 48 x106 people

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

HIV encephalopathy II

• macrophage, microglial and astrocyte activation

• multi-nucleated giant cells

• basal ganglia, deep white matter, brainstem especially affected

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

HIV encephalopathy IV

• HAART   HIV dementia but  minor cognitive-motor disorders (MCMD)

• CNS sanctuary for latent or slowly replicating virus?

• slow neurodegeneration

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)

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?

Impact of HIV/AIDS on elderly

• Care of ill children

• Care of AIDS orphaned grand-children

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