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

dia

l Te

mp

ora

l A

tro

ph

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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?