Is Dementia Preventable? Prof Craig Ritchie Professor: Psychiatry of Ageing, University of Edinburgh Chair: Scottish Dementia Research Consortium Director: Brain Health Scotland
Is Dementia Preventable?
Prof Craig RitchieProfessor: Psychiatry of Ageing, University of EdinburghChair: Scottish Dementia Research ConsortiumDirector: Brain Health Scotland
Key questions:
• Can we detect neurodegenerative diseases at a stage their course can be impacted upon?
• Can we develop accurate prediction models and implement them in practice?
• Can we map this onto the individual to put in place personal prevention plans?
• Can we instigate public health initiatives to improve brain health?
The world (until now) has only seen Neurodegenerative Brain Disease through the ‘peep hole’ of ‘Dementia’
MEMORY ++++
In the very near future we will have a service for people with much earlier stages of neurodegenerative brain disease…
Behavioural, Other Cognitive & Patient Related Outcomes
and BIOMARKERS
RISKS
DISEASE(Biomarkers)
DISEASE(Cognition et al)
TIME(Changes in other 3
factors)
Four Factor Modeling
Overall Modeling Approach
• What is modeling?
1. Using data to create representations of what is happening at a biological level
2. Turn the real world into data
• (create a digital representation of the world/system)
3. Turn the data into statistical or mathematical models
4. Use these models to represent the real world for
• Risk prediction
• Success of an intervention
5. The more accurate the model the more likely that its use will yield the desired outcomes (back) in the real world
Risk Factors – Complex Interplay
• Complex interaction of risks
• Fixed Risks (e.g. genetics)
• Modifiable risks (e.g. diet)
– High potency acute risks (e.g.
head injury)
– Low potency chronic risks (e.g.
obesity)
• Critical period of risk on disease
– Precipitation
– Perpetuation
– Prevention
Model of brain function - cognition
• What does the brain do?
– Senses
– Assimilates
– Processes
– Acts
• A marker of brain function/action is cognitive abilities
– These are testable
Model of brain function - disease
• What does the brain look like?
– Structure
– Function
– Pathological changes
• A marker of brain function are Biomarkers– Neuroimaging
– Retinal imaging
– CSF and Blood
Sources of Data
• European Prevention of Alzheimer’s Dementia
• PREVENT Dementia
• Scottish Brain Health Register
• Other
• Data interoperability
WWW.EP-AD.ORG @IMI_EPAD SLIDE 11
The EPAD consortium
WWW.EP-AD.ORG @IMI_EPAD
COGNITIVE OUTCOMES
PRIMARY: RBANS
– Verbal Episodic Memory: List Learning & Story Memory
– Visual Episodic Memory: Figure recall
– Visuospatial/Constructional: Figure Copy & Line Orientation
– Language: Picture Naming
– Attention/Executive Functioning: Semantic Fluency, Digit Span, Coding
SECONDARY:
– Dot Counting
– Flanker
– Name/Face Pairs
– Four Mountains Task
– Virtual Reality Supermarket Trolley
BIOMARKER OUTCOMES
– CSF biomarker outcomes: Aβ, t-tau, p-tau Blood, urine, saliva for genomics and assessment of emerging biomarkers
– Neuroimaging outcomes
• Structural MRI
• Functional MRI
• PET Amyloid Imaging (AMYPAD)
OTHER
– Risk Factors: including genomics (NeuroX)
– Lifestyle
– Physical comorbidities (includingl TBI)
– Demographics
– Mood, anxiety, sleep, apathy
https://www.youtube.com/watch?v=Ec5bei45ko4
The PREVENT Dementia Project
Sub-studies• AIP (Amyloid Imaging in PREVENT) Capacity n=300
• 7T MRI Study (Cambridge) n=50 (Scanned) and n=300 (VR) (6/12/18 ethics)
• Retinal Imaging (Edinburgh Only) n=61 (95% agree) target 100+
• Language analysis
– Dialogue (Edinburgh MRC Fellowship) n=11
– Syntax (Cardiff) n= 115
• Digital Technology (Oxford) n=32
• Lab work (Edinburgh) Funding secure for Proteomics and Genomics (n=700)
Risk Factor Assessment in PREVENT Dementia Programme
Domain Risk Measurement
Principal Risk Model ApoE Genotype
Family History
Genetic ApoE and GWAS*
Environmental Diet Scottish Food Frequency Questionnaire
Life-events Life Stressor Checklist
Sleep Pittsburgh Sleep Evaluation
Exercise Study Proforma
Clinical Head Injury Brain Injury Screening Questionnaire
Inflammation Biomarkers
Cardiovascular/Metabolic Syndrome Biomarkers*/ECG/History and Examination
Depression CED-D
Respiratory Spirometry/History and Examination
Stress Salivary Cortisol/Resilience Questionnaire
Endocrine Haematology/Biochemistry and History & Examination
* Subject to additional funding
Expressions of disease state in PREVENT Dementia Programme
• Imaging
– fMRI with task, Magnetic Resonance Spectroscopy, Diffusion Tensor Imaging, vMRI, WML volume
– Amyloid PET imaging via Alliance (n=300)
• Cerebrospinal Fluid (40%)
• Blood (Whole blood and plasma)
• Saliva
• Urine
• Cognition: COGNITO, Four Mountain Test, Supermarket Trolley, Verbal Short Term Memory Binding Paradigm
Cognitive testing – detecting disease
• What is the date today?
• What is this called?
• Starting at 100; I want you to take 7 away and keep taking 7 away from the answer you give until I ask you to stop.
Alzheimer’s disease ‘starts’ in the Hippocampus
Testing the hippocampus….
Alzheimer’s disease ‘starts’ in the Hippocampus
Testing the hippocampus….
Hippocampal Subfields….
Alzheimer’s disease ‘starts’ in the Hippocampus
Testing the hippocampus….
Hippocampal Subfields….
Hippocampal Place Cells….
A
DC
B
Alzheimer’s disease starts in the Hippocampus
Ritchie K. et al., 2018
‘A significant negative association was found between the DRS and 4MT (Spearman Correlation – 0.26, p-00006)’
CAIDE SCORE*• Weight• Age• Sex• Education• ApoE• Systolic Blood Pressure• BMI• Total Cholesterol• Physical Activity
Neuroimaging: Split into …..
• Structural – MRI/CT
– Connectivity e.g. Diffusion Tensor Imaging
• Functional
– Blood flow (Arterial Spin Labelling)
• Metabolic – Positron Emission Tomography
– Amyloid, Tau, Dopamine Receptors, Glucose
WWW.EP-AD.ORG @IMI_EPAD SLIDE 25
MRI Visual Rating: Atrophy Scales
Me
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CAIDE SCORE*: >6 (High)
• Weight• Age• Sex• Education• ApoE• Systolic Blood Pressure• BMI• Total Cholesterol• Physical Activity
Retinal imaging in PREVENT Dementia
Dr Tom MacGillivray
Senior Research Fellow
Modality Resolution (mm)
CT 0.2
MRI 0.5
PET 3
Modality Resolution (µm)
Fundus camera 7
OCT 5
Human hair: 60-80 µm
33
Optos Ultra-widefield SLO
Retinal Biomarker Discovery
Aim: characterize & validate retinal changes with disease pathology → biomarkers
1. Mid-life cohort good health with spectrum of AD risk (ApoE status/family hist.)
2. Older asymptomatic persons genetically high & low risk (ApoE status)
3. Prodromal group with & without AD pathology on PET/CSF
4. Patients with AD, MCI & healthy control group
CSF and Blood
• Cerebrospinal Fluid (CSF) ‘bathes’ the brain and spinal cord.
• Proteins in CSF are from the cells in the brain – neurones and glial cells.
• Abnormal CSF could represent abnormal neuronal integrity or function
Blood Based Biomarkers
• Some proteins from neurones also appear in the blood
• Recent research is showing very good correlation between PET-Amyloid and Blood A-Beta levels (and sAPP)
• Blood tests will prove to be the best way of detecting abnormalities in the brain related to Alzheimer’s disease in the (very) near future
• Can we develop accurate prediction models and implement them in practice?
Personalised
Prevention Plan
10-year
Dementia Risk
73%
Dietary Advice
Lose Weight
Optimal
Management of
Diabetes
STEP 1 STEP
2
Targeted
Drug
Therapy
LS
Diabetes
Biology
Genetic
60 Year Old
LS
Genetic
Biology
Diabetes
70 Year Old
LS
Genetic
Diabetes
Biology
80 Year Old
10-year
Dementia Risk
51% 10-year
Dementia Risk
37%
What role do Old Age Psychiatrists as individuals and as a specialty want to have in achieving and then delivering this?