SpR/ST Teaching 23/10/07 Dr Maria Corretge Alzheimer’s Dementia SpR/ST Teaching 23/10/07 Dr Maria Corretge

Medical School Essentials AD accounts for 60% of all dementias. Affects 15 million people worldwide. Affects 5% of people over 65 years of age Affects 10 to 20% of people over 80 years of age 400.000 people in the U.K (prevalence) 1Billion per year in cost to the NHS#

Diagnosis Diagnosis (DSMMD): 1 Memory impairment Plus one of the following: Aphasia, apraxia, agnosia, disturbance in executive functioning. Of gradual and progressive decline, with significant decline from previous level of functioning, not due to cerebrovascular disease, PD, Hungtington’s chorea, SDH, NPH, tumour, hypothyroidism, vitamin deficiencies, hypercalcemia, syphilis, HIV, drugs, delirium or depression Overlap with Vascular dementia. No DSMMD criteria for mixed dementia.

Diagnosis II Gold standard is presence of neurofibrillary tangles and plaques in brain tissue (post mortem) BUT: Only 50 to 60% of individuals fulfilling the neuropathologic diagnosis of AD have dementia. Good correlation between neuropathological findings and clinical presentation in familial disease, poor in sporadic disease. Therefore only 60% of patientes with AD are estimated to be correctly diagnosed (throughout all of the disease stages)

Neuroimagining in AD Routine assessment recommended with CT and MRI, to discard other sources of dementia and because of the overlap with cerebrovascular disease. PET could help differenciate AD from LBD MRI and PET are used on research projects to provide measures of preclinical disease and the rate of change, but not used in clinical practice as yet.?useful to predict cases of MCI that would develop into AD

Other diagnostic tools Genotiping :APOE 4 not used (low specificity and sensitivity) CSF measurements of Aβ protein levels, and phosphorylated tau protein levels not recommended yet, under study/review.

Pathophysiology Amyloid deposition disease, with neurofibrillary tangles (tau protein) and plaques (beta amyloid). Mainly in neocortex and hippocampus. Loss of neurones Loss of cholinergic transmission (1982) Vascular risk factors lead to worse cognitive outcomes: Synergistic interaction between artherosclerosis disease and ApoE 4? Or formation of neurofibrillary tangles and amyloid could lead to oxidative stress?

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Genetics Familial form: APP gene in crm 21, presenilin 1 and 2 (PSEN1 PSEN2) Sporadic form: APOE (allele ε 4) (but sporadic form is also hereditary) Presence of the allele ε4 increases risk of dementia by 3 X in heterozygotes and by 15 in homozygotes.

What do these genes code for What do these genes code for? How do pathophysiology and genetics relate? Aβ protein results from the coding of APP gene in familial disease. It is usually produced during normal brain metabolism with the action of secretases (presenilines) under normal circumstances, it is degraded by neprilysin and endothelin-converting enzymes. Downregulation of MEOX2 would lead to loss of cerebral microvessels VEGF polymorphism (vascular endothelial growth factor) associated with sporadic disease.

AD Theories The amyloid cascade hypothesis: There is an imbalance b etween A β production and clearance. The neurovascular hypothesis: Dysfunctional vessels could contribute to cognitive dysfunction by impairing delivery of nutrients to neurons and reducing Aβ clearance from the brain

Prevention Vaccination with anti amyloid antibodies (AN1792, preaggregated Aβ inmunoconjugates) Post mortems have shown vaccinated patients have amyloid in the brain, but in a lesser quantity than A.D patients Vaccinated patients have less cognitive decline 6% of patients developed encephalitis. Active vaccination was stopped but there are new forms on its way.

Prevention II Tackling the cardiovascular added risks: Most evidence is population based, after epidemiological studies. NSAIDS STATINS Oestrogens Vitamin E, other antioxidants

To consider in prevention Identifying cognitive impairement not dementia (CIND). It refers to the state of cognition and functional ability between normal ageing and very mild A.D Vascular risk factors. 50% progress into dementia. 25% revert to normal. 25% stabilise as some form of cognitive impairment. Research needed in wether tackling these risk factors would prevent CIND patients from developing dementia.

Risk Factors for CIND Increasing Age Apo E genotype Lower education Lower functional abilities Hypoccampal/ medial temporal lobe atrophy. Vascular risk factors

Approaches to management Counselling Advocacy Drugs Memory aids Benefits advice Driving advice/assessment Community services Advance directives

Treatments Acetylcholinesterase inhibitors: 30 randomised double blind controlled trials: Cocharane review concluded that they are efficacious in mild to moderate AD. Memantine: Non compettitive NMDA receptor antagonist (glutamate and its receptor NMDA).Randomised control trials: Miodest effects in cognitive and behavioural outcomes in AD at 6 months.

Treatment II-Behavioural signs Olanzapine and risperidone reduce rate of aggression, agitation and psychosis. Divalproate and carbamazepine (no evidence) Lorazepam and oxazepam. Antidepressants if concomitant depression (diagnosis very difficult)

Treatment III: On the pipeline… After the amyloid cascade theory: Trying to reduce the production of APP: β-secretase inhibitors are being tried in AD animal models (mice) Also trying to stimulate alpha secretase (deviating the APP metabolism to itls non-amyloidogenic pathway): Bryostatin (protein kinase C activator) on trial. Many others, but less promising…(anti tau phosphorilation drugs, Aβ fibrillisation inhibitors…)

Own conclusions… Psychological burden and impact in society:“if I ever get like that, shoot me” Epidemiological time bomb Lines of research: And dementia research is underfunded, attracting a mere £11 a patient per year compared with £289 for cancer, not in any of the “high priority research “lines recommended by NICE

NICE Ammendments Donepezil, galantamine and rivastigmine are recommended as options for the treatment of moderate Alzheimer’s disease only. Memantine is not recommended as an option for people with moderately severe to severe Alzheimer’s disease unless it is being used as part of a clinical trial (research). When using the Mini Mental State Examination (MMSE) to assess the severity of Alzheimer’s disease, healthcare professionals should make sure that people from different ethnic or cultural backgrounds and people with disabilities have equal access to treatment. In some cases, healthcare professionals should not rely on the MMSE test – or not rely on it alone – to assess whether someone has moderate Alzheimer’s disease. This may be the case when assessing people who: have learning disabilities or other disabilities such as deafness or blindness, or have difficulty speaking (for example, after a stroke) or other difficulties with communicating, or are not fluent enough in a language in which the MMSE test can be given if this means that the MMSE test will not fairly reflect the severity of the disease. For these people, healthcare professionals should use a different method to judge whether the person has moderate Alzheimer’s disease when deciding about starting or stopping treatment