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
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
18. 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).
20. 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
21. 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)
24. 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
25.
26. 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
27. 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
28. 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
29. - Thank you
Paul Francis
Paul.francis@kcl.ac.uk
Brains for Dementia Research
Editor's Notes
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