1. Investigating dementia
Dr Richard Perry
Consultant Neurologist
Imperial College Healthcare NHS Trust

3. Overview Structural imaging – CT and MRI MRI and vascular disease
MRI and focal atrophy
MRI and microhaemorrhages
CSF
Biomarkers -Tau and abeta
EEG
Functional imaging - 18 F FDG PET
Illustrative cases
Amyloid imaging

4. Structural brain imaging in cognitive impairment
MRI modality of choice
1.5 T or 3T
CT useful for acute presentations:
Hydrocephalus – acute
Haemorrhage
Mass lesions
If MRI unavailable, CT can give information on
Atrophy
Vascular load

5. Role of imaging in dementia diagnosis
NICE guidance: Structural imaging should be used in the assessment of people with suspected dementia to exclude other cerebral pathologies and to help establish the subtype diagnosis. Magnetic resonance imaging (MRI) is the preferred modality to assist with early diagnosis and detect subcortical vascular changes, although computed tomography (CT) scanning could be used.

6. MRI and cerebrovascular disease
Lacune
Leukoaraiosis
Small Vessel Disease
Large Vessel

7. White matter hyperintensities
Leukoaraiosis
T2 hyperintensities
Most consistent association is with hypertension
Visual rating – Scheltens scale, Fazekas scale

8. Cheese is yellow, the moon is yellow….
Cognitive impairment + WMH on imaging report ≠ vascular dementia
WMH responsible for minimal cognitive impairment
Often focal atrophy overlooked by radiologists
Usually co-existent degenerative disease that is responsible for the cognitive impairment
First symptoms and course of disease important e.g. early episodic memory impairment with progressive cognitive impairment and lack of neurological signs
Look for gait disorder
Frisoni et al 2007
Jack et al 2011

9. MRI and focal atrophy
More relevant to new diagnostic criteria for AD and MCI
Hippocampal atrophy – biomarker of neuronal degeneration in MCI secondary to AD diagnosis
≈73% sensitivity and ≈81% specificity for predicting whether patients with amnestic MCI will convert to dementia
Dependent on skill of radiologist
Visual rating scales
Quantitative analysis available

10. MRI and focal atrophy
MRI also part of diagnostic criteria for other forms of dementia
Temporal variant of Frontotemporal Dementia = Semantic Dementia
Behavioural Variant of FTD
Always interpret in light of clinical context

11. MRI and focal atrophy 62 yr old man Difficulty in proof reading
Difficulty in telling time from clock
Digital clock OK
Couldn’t see things right in front of him
Diagnosis – Posterior Cortical Atrophy

12. MRI – specific sequences
T2* - Gradient Echo or SWI – susceptibility weighted imaging
Good for detecting effects of iron deposition - haemosiderin
In effect, is detecting microhaemorrhages
Subcortical and basal ganglia microhaemorrhages related to HT
Lobar microhaemorrhages related to amyloid angiopathy

13. EEG NICE guidelines suggest not a routine investigation CJD
triphasic waves on EEG
MRI / CSF / Bx
Psychiatric disease or neurological disease?
If abnormal, then either brain disease or drugs
Loss of alpha waves
Asymmetry in accordance with clinical findings
If normal with significant cognitive disturbance then consider psychiatric cause

14. CSF LP quick and minimally invasive (?) Requires bed and operator
Exclude infection and inflammation
Now biomarkers for neurodegenerative disease available
A beta 1-42
Total tau
Phospho tau
Low abeta levels indicate amyloidopathy
Raised tau levels indicate ongoing neuronal damage
Sensitive and specific tests - require counselling prior to test
Processing of samples important as reliability of assay sub-optimal

15. AD or FTD, MRI or PET MRI may be sufficient
tvFTD highly specific MRI appearances
bvFTD MRI may be normal early in course

16. AD or FTD, MRI or PET
18F FDG PET adds value with normal MRI or lateralising clincial presentation

17. Investigations and cascade of events in neurodegenerative disease (AD)

18. Case 1 - GW Not repetitive 3 yr Hx disorganisation
Multiple episodes of depression over last 10 yrs
Performance IQ down to 81
3 yr Hx disorganisation
Word finding difficulty
Cant follow instructions
CSF analysis: A-beta 589, Tau 449
Diagnosis – Frontotemporal Lobar Degeneration

19. Case 2 - SN 2 yr Hx of decreasing verbal output Apathy and passivity
EEG showed L frontal slow wave activity
Diagnosis – Frontotemporal Dementia

20. Case 3 - BS CSF tau level = 1004 CSF abeta level = 379
49 yr old with progressive language impairment 2 yrs
Non-fluent aphasia
Mild apraxia
CSF tau level = 1004
CSF abeta level = 379
Genetic testing showed PS-1 mutation
Diagnosis – Familial Alzheimer’s Disease

21. Case 4 - AK EEG – loss of alpha rhythm and triphasic slow waves CSF
55 yr old woman
2 yr Hx of loss of confidence, anxiety
Good days and bad days
Unable to perform simple tasks in the workplace
Inconsistencies in neuropsych performance, v tearful
Put down to anxiety disorder
EEG – loss of alpha rhythm and triphasic slow waves
CSF
Tau 955 (high)
Abeta 176 (low)
Diagnosis - AD

22. Amyloid PET imaging
11C amyloid PET scans used in research – have to scan near cyclotron
18F compounds now available
20-30% of asymptomatic yr olds have positive scan
Increased risk of conversion from normal to MCI in amyloid positive healthy older controls 8% per year
86% of aMCI patients with positive amyloid PET develop clinical AD over 3 years

23. Amyvid Detection of amyloid plaques Half hour PET scan
Result positive or negative
Guidelines likely to suggest use by dementia experts in cases of possible AD where previous Ix inconclusive and where diagnostic clarity changes management
Only licensed in patients with cognitive impairment
Negative scan – highly unlikely that cognitive impairment due to AD pathology
Pivotal pathological study, Clarke et al Lancet Neurol 2012
59 end of life patients, sensitivity 92% and specificity 96%

24. Amyloid imaging ligands
Florbetapir – Amyvid
Flutemetamol – Vizamyl
Florbetaben - Neuraceq

25. Case 5 - RD 58 yr old district nurse
18/12 Hx of memory problems and organisational difficulties at work
Local memory clinic MMSE 30/30, ACE-R 97/100
MRI normal
SPECT reported as showing medial temporal hypoperfusion
Given diagnosis of AD and started on donepezil

26. Case 5 - RD Referred for second opinion Husband felt that memory OK
Daughter reported her as repetitive and more noticeable symptoms over last year
FDG – PET again reported as medial temporal hypometabolism
CSF analysis – tau 108 and abeta 874
ACE -96, MMSE 28 – one point on orientation and one on memory

27. Case 6 -VW 63 yr old woman – Editor for Mensa magazine
18/12 Hx of memory problems and oranisational difficulties
Collects things, less empathic
Likes eating biscuits
Non-fluent aphasia
Stimulus bound behaviour

28. Case 6 - VW

29. Case 7 - LC Progressive memory deficits corroborated by husband
Previous Hx of ME, anxiety, and depression
MMSE 26/30
Neuropsych showed memory deficits and attentional dysfunction consistent with MCI
MRI unremarkable

30. Case 8 - DT Walking memory speech
Emotional change after loosing son in RTA 8 yrs previously
Decreased motivation
Muddled
Not really forgetful
MMSE17/ , and 22/
Neuropsych showed reduced encoding but normal delayed recall, poor attentional and executive dysfunction – felt to be not consistent with AD but suggestive of frontal-subcortical dementia
Diagnosed VaD and depression

31. Case 8 DT

32. Case 9 - AH Retired policeman, 66 yrs ol
1 year Hx of memory deficits, repetitive
Scored 29/30 on MMSE
Neuropsych found patchy deficits on memory, - recommended therapy for symptoms of anxiety / depresion
MRI brain

33. Case 9 - AH CSF examination Evidence of neuronal loss – progressive
Abeta
Total tau 490
Evidence of neuronal loss – progressive
Not Alzheimer’s Disease
Some mild behavioural features
? Atypical presentation of Frontotemporal Dementia

34. Which patients are suitable for amyloid imaging?
It’s a new area, so we are still calibrating
Currently, we are focusing on:
Younger patients – less probability of ‘false positive’
Atypical AD presentations – e.g. PCA, Progressive Aphasia
AD / FTD differentiation
MCI if clarification helpful
Multiple possible causes of cognitive impairment e.g depression / vascular

35. Conclusions Investigations support clinical diagnosis
Investigations can be thought of as biomarkers that are:
Supportive of neurodegeneration and / or
Pathology or disease specific
Familiarity with Ix important and important to review actual pictures
Amyloid imaging e.g. Amyvid now available for use within guidelines