volunteers, assessments, brains and research: the story of brains for dementia research so far by...
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Volunteers, assessments, brains and research: the story of Brains
for Dementia Research so farPaul Francis
Brains for Dementia Research
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.
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
1.5
1.2
0.9
0.6
0.3
0.0
–0.3
–0.6
–0.9
–1.2
–1.50 6 12 18 Endpoint 30
Study week
Chan
ge in
MM
SE
Clinical improvement
Clinical declinePlaceboAricept:5 mg/day10
mg/day
Donepezil - MMSE Results
Aricept trial: Rogers et al. Neurology 1998;50:136–145
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
Semagacestat -secretase inhibitor – Missed primary endpoint
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 – Missed primary endpoint Ongoing
Tarenflurbil -secretase modulator – 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 7 partial nicotinic agonist
Souvenaid® Maintenance of synaptic integrity
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
Brain banks - mismatch
Brain bank cases
By diagnosisAD and other dementiaMND Control / MCI
ADCVDCBDDLBFTLDPDMSAPick'sControl
Brain bank tissue requests
NEWCASTLE
MANCHESTER
OXFORD
LONDON
CARDIFF
BDR is made up of 6 centres, each with a recruitment field worker and brain bank technician.
BRISTOL
BDR recruitment is supported by DeNDRoN, MHRN & CLRNSouth-WestLincolnshireYorkshireEast AngliaThames ValleyKentWest MidlandsWLMHT
BDR brain donation is supported by many mortuaries and Anatomical pathology technicians across England and Wales
BDR Recruitment TimelinesMay 2008 start, for 5
years, all sites active by November 2008
April 2013 second funding term starts
Autumn 2009 135
Spring 2010 611
March 2011 midterm review June 2012 BDR2
application submitted
Spring 2011 1031
Spring 2012 1537
April 2012
Thames Valley DeNDRoN:Oxon,
Northants, Bucks, Berks
Lincolnshire PFT Summer
2010
SLaM, Summer 2009
Bristol centre added
Autumn 2010
SW DeNDRoN Spring 2011: Devon, Glos, Bath & Avon
Cornwall, Somerset
North East, North West, Midlands, East
Anglia, Kent & Medway, South Coast, North London, South London all in progress
Spring 2013 2150
Spring 2013 201 brains
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.
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, ADAS-Cog, Hachinski, TICSm, CFAS RInI•Many participants are in other studies, so may have MR scans, bloods and other assessment data available
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.’
CSF
From each brain donation we have a number of available samples
• Contact BDRCC• Informal
discussion
Submit application
•Ethical approval given•Material Transfer Agreement between universities
Tissue provided
• Request considered• Request approved /
amended
Tissue Request Committee
Tissue Requests
BDR – tissue requests – over 50Research 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 beta-protein 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
IoP KCL The searchable brain bank: A genomic and functional map of brains from people with Alzheimer's disease and related conditions
IoP KCL Depression in Alzheimers Disease - the role of life event, epigenetics and genetics
Miami Association of CR1, CLU, and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals
KCL Biochemical basis of behavioural disturbance in LBD
LEWY BODY DEMENTIAS
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 mid-1990’s.
• PDD – dementia in PD (48% cross-sectional, 78% cumulative).
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)
Pathology of LBD
Degeneration of substantia nigra, intracellular inclusions called Lewy bodies (LBs) - the major component is the protein α-synuclein
Degeneration of cortical areas (atrophy of frontal, temporal, parietal lobes and cingulate gyrus) with appearance of cortical Lewy bodies
LBs in cingulate cortexLB in SN neuronLewy neurites in SN
Spillantini et al, Nature 1997
Watson et al, Dement Geriatr Cogn Disord 2009
A significant number of LBD autopsy cases showed mix pathology with AD features: Plaques and Tangles
Cases studied
CONTROL DLB PDD AD
Number of cases
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 (%)
58 / 42 56 / 44 53 / 47 31/69
Brain pH 6.47 ± 0.07 6.52 ± 0.04 6.47 ± 0.06 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)
Mixed pathology in PDD/DLB
PDD DLB
Howlett et al, in preparation
Chemical synapse
Bear, Connors and Paradiso
Relationship of ZnT3 to cognition
0 1 2 3 4 50.0
0.5
1.0
1.5
2.0
Classification of cognitive impairment
*
***
**Zn
T3
(rel
ativ
e u
nit
s)
Whitfield et al, 2013 submitted
Percentage of individuals according to depression score and diagnosis
absen
tmild
moderate
severe
absen
tmild
moderate
severe
absen
tmild
moderate
severe
absen
tmild
moderate
severe
0
10
20
30
40
50
60
70
80
90
100
PDDDLBADControl
Whitfield et al, 2013 submitted
The ZnT3 concentration in frontal cortex is significantly different between depression groups 0 and 3. P=0.018
ZnT3
con
cent
ratio
n
Severity of depression
Zinc transporter 3 reduced in depression in dementia
Correlations with clinical features: depression
Munc 18 BA9 Munc 18 BA24
• Level of Munc18 protein expression decreased with the severity of Depression
N= 27 for absentN= 22 for intermittent mildN= 12 for intermittent significantN= 11 for persistent
N= 28 for absentN= 23 for intermittent mildN= 12 for intermittent significantN= 11 for persistent
0
0.5
1
1.5
2
absent
intermittent mild
intermittent significant
persistant
* **
***
0
0.5
1
1.5
2
*
Julie Vallortigara
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
