Volunteers, assessments, brains and research: the story of Brains for Dementia Research so far by Paul Francis

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  • Immunisation of Alzheimer’s patients with amyloid-β peptide to clear amyloid plaques from the brain. Eight participants received the immunisation and were then examined neuropathologically. Plaque removal was found to be variable, although immunisation did seem to initiate a long-term process with post-mortem evidence five years after the last immunisation. Biomarkers - For treatment to be most effective it needs to be given at an earlier stage in the disease processGenetic Studies - These may use brain tissue from hundreds to a few thousand individuals, looking for genes associated with dementiaClinico-pathological studies - much to be done before we understand what underlying patterns of cellular and chemical changes are responsible for particular symptoms, such as aggression.  This is only possible when researchers have both the clinical information and brain tissue together
  • Top down – timeline funding, Timeline participant numbers, Timeline CRN involvement
  • This comprises questions and tasks to build a profile of how the brain is functioning over time. For example participants might be asked to name everyday objects, or asked to write a sentence. If applicable, carers may be asked about behaviour and other aspects of daily living. Assessment is carried out in the setting of an informal interview. We aim to minimise inconvenience to participants and appreciate it may not be possible to complete every assessment
  • This comprises questions and tasks to build a profile of how the brain is functioning over time. For example participants might be asked to name everyday objects, or asked to write a sentence. If applicable, carers may be asked about behaviour and other aspects of daily living. Assessment is carried out in the setting of an informal interview. We aim to minimise inconvenience to participants and appreciate it may not be possible to complete every assessment
  • Coroners office may need to be informed if (i) a fall may have contributed to death, (ii) any surgery within last year, (iii) cause of death unknown.
  • Coroners office may need to be informed if (i) a fall may have contributed to death, (ii) any surgery within last year, (iii) cause of death unknown.
  • One of the largest cohort of DLB/PDD cases
  • Still 25% of scores missing, updates needed to be done with some IOP cases

Transcript

  • 1. Volunteers, assessments, brains and research: the story of Brains for Dementia Research so far Paul Francis Brains for Dementia Research
  • 2. Agenda for this talk 1. The need for post-mortem brains for research: Dementia is a human condition, animal & cell models will only ever reflect aspects of the disease process 2. Brains for Dementia Research: what we do and how we do it.
  • 3. Cholinergic Markers in Alzheimer’s Disease % of control ChAT activity 35–50 ACh synthesis 40–50 Choline uptake 60 AChE activity 40–60 Nicotinic binding 60–70 Muscarinic binding 80–100 Bowen et al 1976; Davies and Maloney, 1976; Perry et al 1977; Reviewed: Francis et al, 1993; 1998
  • 4. Donepezil - MMSE Results 1.5 1.2 Change in MMSE 0.9 0.6 Clinical improvement 0.3 0.0 –0.3 Clinical decline –0.6 Placebo Aricept: 5 mg/day 10 –0.9 –1.2 mg/day –1.5 0 6 12 18 Study week Endpoint Aricept trial: Rogers et al. Neurology 1998;50:136–145 30
  • 5. The landscape of AD drugs Drug Hypothesised MoA Phase II Phase III Approved therapies AChEIs Cholinesterase inhibitor   Memantine NMDA antagonist   In development / failed development IVIg Anti-Aβ polyclonal antibodies  x Dimebon (latrepirdine) Enhances mitochondrial function   Bapineuzumab [+ !] Anti-Aβ monoclonal antibodies  – Missed primary endpoint  Solanezumab Anti-Aβ monoclonal antibody Amyloid concentrations affected but not correlated to cognitive improvements Ongoing  – Missed primary endpoint  Semagacestat -secretase inhibitor Lu AE 58054 5-HT6 antagonist  GSK SB 742457 5-HT6 antagonist  PF-04494700 RAGE inhibitor Ongoing ACC-001 Active Aβ vaccination Ongoing Rember Tau aggregation inhibitor Tarenflurbil -secretase modulator  – Missed primary endpoint Ongoing  – Missed primary endpoint  Tramiprosate Direct Aβ binding to prevent Aβ aggregation  – Missed primary endpoint  Rosiglitazone Ppar -agonist  – Missed primary endpoint  Phenserine AChEI and anti-amyloid  – Missed primary endpoint  Sirrocco Nicotinic agonist  – Missed primary endpoint EVP-6124 Souvenaid® 5 7 partial nicotinic agonist Maintenance of synaptic integrity   
  • 6. Examples of new uses of brain banked material for dementia research • Effects of anti-dementia medications: • Large scale genetic studies – Pathological confirmation – Effects on pathological hallmarks • Clinico-pathological studies • Biomarkers Holmes et al. Lancet 2008
  • 7. Brain banks - mismatch By diagnosis AD and other dementia MND Brain bank cases Brain bank tissue requests Control / MCI AD CVD CBD DLB FTLD PD MSA Pick's Control
  • 8. BDR is made up of 6 centres, each with a recruitment field worker and brain bank technician. NEWCASTLE MANCHESTER BDR brain donation is supported by many mortuaries and Anatomical pathology technicians across England and Wales CARDIFF BDR recruitment is supported by DeNDRoN, MHRN & CLRN South-West Lincolnshire Yorkshire East Anglia Thames Valley Kent West Midlands WLMHT OXFORD LONDON BRISTOL
  • 9. BDR Recruitment Timelines May 2008 start, for 5 years, all sites active by November 2008 April 2013 second funding term starts March 2011 midterm review June 2012 BDR2 application submitted Spring 2013 201 brains Autumn 2009 135 Thames Valley DeNDRoN:Oxon, Northants, Bucks , Berks SLaM, Summer 2009 Spring 2010 Spring 2011 Spring 2012 Spring 2013 611 1031 1537 2150 SW DeNDRoN Spring 2011: Lincolnshire Devon, Glos, B PFT Summer ath & Avon 2010 Cornwall, Som Bristol centre erset added Autumn 2010 April 2012 North East, North West, Midlands, East Anglia, Kent & Medway, South Coast, North London, South London all in progress
  • 10. What being a donor involves • Monitoring by a trained nurse or psychologist will take place every year (every 2 to 5 years for those without a diagnosis of memory impairment/dementia). • Participation is entirely voluntary and should potential donors or their carers (where applicable) feel it inappropriate to continue with assessments their wishes will be respected.
  • 11. BDR minimum clinical dataset •Structured baseline history (from informant ) •Demographics, family and drug history •Clinical dementia subtype diagnosis using operational criteria •Functional assessment - Bristol ADL •Cognitive assessment – MMSE, MoCA •Mood assessment - Cornell / Geriatric Depression Scale •Behavioural assessment - NPI •Other assessments include CERAD cognitive battery, ADASCog, Hachinski, TICSm, CFAS RInI •Many participants are in other studies, so may have MR scans, bloods and other assessment data available
  • 12. BDR – the participant’s view ‘…I took my friend to dementia assessments and watched her weeping as she knew the questions were simple but could not answer that’s why I have called you.’ ‘....I have had 10 years on my own, as my wife suffered terribly with dementia. I would like to do something to help.’
  • 13. From each brain donation we have a number of available samples CSF
  • 14. • Contact BDRCC • Informal discussion Submit application Tissue Requests • Request considered • Request approved / amended Tissue Request Committee •Ethical approval given •Material Transfer Agreement between universities Tissue provided
  • 15. BDR – tissue requests – over 50 Research Location Full Title of Project UCLAN Susceptibility of Alzheimer's Disease brains to infection from oral pathogens KCL Gene expression in Down syndrome Centre for life sciences Neurochemistry and biomarkers discovery in vascular dementia KCL An investigation of the association between clusterin (apolipoprotein-J) and amyloid betaprotein in Alzheimer's disease brain tissue Spain Insulin and Alzheimer´s disease: implication in the ethipathogenic mechanisms and therapeutic possibilities Exeter An Investigation of Pyroglutamyl peptidases in Alzheimers Disease IoP KCL Relationship between the behavioural aspects of Alzheimers Dementia and brain processing of the amyloid precursor protein Brunel Novel role of Orexin signalling in the pathophysiology of Alzheimer’s disease IoP KCL A post mortem brain RNA resource from people with Alzhimer's disease and related conditions
  • 16. LEWY BODY DEMENTIAS
  • 17. Lewy body dementias • DLB –Dementia with Lewy bodies (dementia within 1 year of parkinsonism) • PDD – Parkinson disease with dementia • LB dementias – DLB & PDD • LBD – Lewy body disease (PD, PDD & DLB) • DLB -accounts for 15-20% of all dementia in old age but only widely recognised since mid1990’s. • PDD – dementia in PD (48% crosssectional, 78% cumulative).
  • 18. Behavioural and cognitive symptoms in DLB/PDD. • Behaviour (NPI) – – – – – – Apathy Agitation Anxiety, panic disorder (40%) Depression (40%) Sleep-wake cycle disturbance Psychosis (hallucinations, delusions) (15-25%) • Cognition – Confusion, fluctuations – Cognitive deficit (attention, executive, visuospatial, language, memory) (Hanagasi and Emre, 2005 ; Lippa et al, 2007)
  • 19. Pathology of LBD Degeneration of substantia nigra, intracellular inclusions called Lewy bodies (LBs) - the major component is the protein α-synuclein Spillantini et al, Nature 1997 Lewy neurites in SN LB in SN neuron LBs in cingulate cortex Degeneration of cortical areas (atrophy of frontal, temporal, parietal lobes and cingulate gyrus) with appearance of cortical Lewy bodies Watson et al, Dement Geriatr Cogn Disord 2009 A significant number of LBD autopsy cases showed mix pathology with AD features: Plaques and Tangles
  • 20. Cases studied CONTROL Number of cases DLB PDD AD 24 50 33 16 Age of death 80.4 1.4 81.7 1.0 79.8 1.1 88.0 2.0 PMD (hours) 37.1 6.4 42.9 4.1 33.4 2.9 25.4 5.4 Gender M/F (%) Brain pH 58 / 42 6.47 0.07 56 / 44 6.52 0.04 53 / 47 6.47 0.06 31/69 6.30 0.08 • Detailed clinical information available for these cases: - Neuropathology report: Braak stage, CERAD, semi- quantitative scores of LBs, plaques and tangles - Cognitive and psychiatric tests: MMSE (mini-mental state examination) to assess cognitive decline Scoring of neuropsychiatric symptoms (frequency and intensity)
  • 21. Mixed pathology in PDD/DLB PDD DLB Howlett et al, in preparation
  • 22. Chemical synapse Bear, Connors and Paradiso
  • 23. Relationship of ZnT3 to cognition ** *** * ZnT3 (relative units) 2.0 1.5 1.0 0.5 5 4 3 2 1 0 0.0 Classification of cognitive impairment Whitfield et al, 2013 submitted
  • 24. ZnT3 concentration Zinc transporter 3 reduced in depression in dementia The ZnT3 concentration in frontal cortex is significantly different between depression groups 0 and 3. P=0.018 Severity of depression
  • 25. Correlations with clinical features: depression Munc 18 BA9 2 1.5 * Munc 18 BA24 ** * 2 * 1.5 ** 1 1 0.5 0.5 absent 0 0 intermittent mild N= 27 for absent N= 22 for intermittent mild N= 12 for intermittent significant N= 11 for persistent intermittent significant persistant N= 28 for absent N= 23 for intermittent mild N= 12 for intermittent significant N= 11 for persistent • Level of Munc18 protein expression decreased with the severity of Depression Julie Vallortigara
  • 26. Summary • Banked post-mortem brain has made and continues to make important contributions to dementia research. • BDR can contribute through: – Large cohort of highly committed participants – Availability of extensive clinical data – Increasing numbers of brains with linked data
  • 27. - Thank you Paul Francis Paul.francis@kcl.ac.uk Brains for Dementia Research