An update on diagnostics and management Dementia An update on diagnostics and management Dennis Chan Senior Lecturer in Neurology Brighton and Sussex Medical School

VERY POOR The National Context National Audit Office Report 2007 headline point on national performance? VERY POOR

Summary points (1) Early diagnosis and intervention in dementia is cost-effective Only 33-50% of patients ever receive a formal diagnosis. In terms of the percentage of suitable patients receiving anti-dementia drugs, UK performance is below almost all northern and western European nations. In the UK the average reported time to diagnose the disease is up to twice as long as in other European countries. Surveys revealed a lack of urgency among GPs about diagnosis, due to the perception that management options are limited. Less than a third of GPs agreed that there were satisfactory specialist services to meet need.

Summary points (2) A wide range of screening tests are employed by GPs, psychiatrists and others but specialist knowledge is required to make the best use of them; brain scanning is recommended as a diagnostic investigation by NICE but this is used regularly by only 66% of community mental health teams (CMHTs). The role of CMHTs in diagnosis and early treatment is inconsistent across the UK and focuses mainly on people with severe mental illness. Earlier diagnosis may be cost-effective by enabling more to be done to delay disease progression. Having a clear diagnosis also reduces the number and length of acute hospital episodes and delays need for admission to more expensive long-term care.

Conclusions Dementia presents a significant and urgent challenge to health and social care in terms of cost and numbers of people affected. Until 2005, the Department of Health and local commissioners attached little priority to dementia, partly due to the focus on cancer and heart disease. Services are not currently delivering value for money to taxpayers or people with dementia and their families. Too few people are being diagnosed, or diagnosed early. Early, proven cost-effective, interventions are not being made widely available. The rapid ageing of the population means that costs will rise and services are likely to become increasingly inconsistent and unsustainable without redesign.

Conclusions Dementia presents a significant and urgent challenge to health and social care in terms of cost and numbers of people affected. Until 2005, the Department of Health and local commissioners attached little priority to dementia, partly due to the focus on cancer and heart disease. Services are not currently delivering value for money to taxpayers or people with dementia and their families. Too few people are being diagnosed, or diagnosed early. Early, proven cost-effective, interventions are not being made widely available. The rapid ageing of the population means that costs will rise and services are likely to become increasingly inconsistent and unsustainable without redesign. The opportunity now exists to address these challenges.

The development of multiple cognitive deficits manifested by both: memory impairment one or more of the following: aphasia apraxia agnosia disturbance of executive functioning

The Dementias Degenerative Vascular Alzheimer’s disease Dementia with Lewy bodies/Parkinson’s disease dementia Frontotemporal lobar degeneration Progressive supranuclear palsy Corticobasal degeneration Vascular Vascular dementia Cerebral amyloid angiopathy Post-stroke dementia Mixed degenerative and vascular dementia

Other diseases associated with cognitive impairment Prion diseases Metabolic disorders HIV-related dementia Wernicke encephalopathy Encephalitis Viral Paraneoplastic autoimmune Systemic diseases Vasculitis Space-occupying lesions tumours Depression

Alzheimer’s disease

adapted from Jack et al. Brain 2009

SMI MCI adapted from Jack et al. Brain 2009

Diagnostic criteria for AD (revised 2011) Probable AD Fulfils criteria for dementia insidious onset, progressive decline absence of other explanation for cognitive decline eg vascular dementia, Lewy body dementia Probable AD with biomarker evidence abnormal CSF levels of amyloid/tau abnormal amyloid-PET scanning hippocampal atrophy on MRI Possible AD atypical clinical course aetiologically mixed eg concomitant vascular disease

Lewy body dementia

Dementia with Lewy Bodies Second commonest degenerative dementia 10-15% at autopsy Two defined syndromes Dementia with Lewy bodies (DLB) Parkinson’s disease with dementia (PDD) The “one year rule”

Symptomatology Cognitive impairment Fluctuation in cognition Hallucinations REM sleep behaviour disorder

Frontotemporal dementia

Frontotemporal lobar degeneration Common cause of young onset dementia second commonest degenerative cause after AD Prototypical syndromes Frontotemporal dementia Progressive nonfluent aphasia Semantic dementia

Treatment – an update

Current treatment options Alzheimer’s disease ACHeI inhibitors NMDA antagonist (memantine) Vascular dementia management of risk factors Lewy body dementia rivastigmine Frontotemporal lobar degeneration supportive citalopram

Revised NICE guidelines March 2011 Cholinesterase inhibitors in mild as well as moderate AD Memantine (Ebixa™) in severe AD Combination therapy not recommended

Treatment – the future

Impaired Aβ clearance

NSAIDs α-secretase promoters ß-, γ-secretase inhibitors Impaired Aβ clearance ß-, γ-secretase inhibitors Heavy metal chelators Statins Anti-amyloid immunotherapy NSAIDs Anti-oxidants Tau aggregation inhibitors

>250 compounds currently in testing ~10 in Phase III trials Drugs Potential Launch by 2012 Phase III Agents LY2062430 (Amyloid beta MaB) Dimebon (Mitochondrial function) Bapineuzumab (MaB) Semagacestat (Amyloid beta peptide) Gammagard (Immunoglobulin) Rosiglitazone XR (TZD) Aricept modified release (ACheI) Ebixa modified release (NMDA antagonist) Generics Donepezil Rivastigmine Galantamine Memantine >250 compounds currently in testing ~10 in Phase III trials

>250 compounds currently in testing ~10 in Phase III trials Drugs Potential Launch by 2012 Phase III Agents LY2062430 (Amyloid beta MaB) Dimebon (Mitochondrial function) Bapineuzumab (MaB) Semagacestat (Amyloid beta peptide) Gammagard (Immunoglobulin) Rosiglitazone XR (TZD) Aricept modified release (ACheI) Ebixa modified release (NMDA antagonist) Generics Donepezil Rivastigmine Galantamine Memantine >250 compounds currently in testing ~10 in Phase III trials

Bapineuzumab: monoclonal Ab against N-terminus of Aβ42 Schenk et al. Nature (1999)

In Conclusion Different diseases have different biological signatures these will inform diagnostics and treatment Novel diagnostic techniques will be required Disease-modifying treatments will soon be available Future management of dementia will increasingly focus on treatment of the underlying pathology Alzheimer’s disease as a preventable disorder?

The greatest challenge of all? In Conclusion Disease-modifying treatments will soon be available Earlier diagnosis is an imperative Different diseases have different biological signatures these will inform diagnostics and treatment Novel diagnostic techniques will be required The greatest challenge of all?

CHANGING THE PERCEPTION OF DEMENTIA