1. Chris Hyde
Exeter Test Group

2. Cochrane Dementia and Cognitive Improvement Group
Report work on a series of reviews on diagnostic accuracy of diagnostic tools for dementia
PET-CT : PIB PET; FDG PET; F PET with flutemetamol or flobetapen or flobetapir
Cerebrospinal fluid (CSF) analysis of Abeta and tau.
Structural magnetic resonance imaging (sMRI).
Fluoropropil-carbomethoxy-iodophenil-tropane single photon emission tomography (FP-CIT SPECT).
ApoE4.
Neuropsychological tests (Mini-Mental State Examination (MMSE); MiniCOG; Montreal Cognitive Assessment (MoCA)).
Informant interviews (Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE); AD8).

3. Cochrane Dementia and Cognitive Improvement Group
Report work on a series of reviews on diagnostic accuracy of diagnostic tools for dementia
PET-CT : PIB PET; FDG PET; F PET with flutemetamol or flobetapen or flobetapir
Support was methodological
Reprise with a view to considering research implications
Offer some examples of some of the methodological problems we encounter in evaluating tests

4. Cochrane Dementia and Cognitive Improvement Group
18F-FDG PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI)
11C-PIB-PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI)
18F PET with florbetaben for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI)
18F PET with florbetapir for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI)
18F PET with flutemetamol for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI)

5. PET-CT Combines structure and function
CT provides structural information
Markers provide information function
Different markers provide information on different aspects of function
18 F-2-fluoro-2-deoxy-D-glucose (18 F-FDG)-PET – glucose metabolism
11C-labelled Pittsburgh Compound-B (11C-PIB) – beta amyloid deposition
18F-florbetaben - [18F]BAY , trans-4-(N-methyl-amino)-4’-2-[2-(2-[18F]fluoro-ethoxy)-ethoxy]-ethoxy-stilbene– beta amyloid deposition
18F-florbetapir -(E)-4-(2-(6-(2-(2-(2[18F]fluoroethoxy)ethoxy)ethoxy)pyridine-3-yl)vinyl)-Nmethylbenzamine - beta amyloid deposition
18F-flutemetamol - 6-benzothiazolol, 2-[3-[18F]fluoro-4-(methylamino)phenyl] - beta amyloid deposition

7. Systematic reviews of test accuracy
Same principles as systematic reviews of RCTs
Cochrane has taken the lead in developing the methods for applying principles to test accuracy
The accuracy studies in dementia are peculiar even by standard of accuracy studies
Population – MCI – cognitive decline without signs of functional problems
Test results with PET-CT of various types
Reference standard – follow-up for signs of progression to dementia over the next few years [National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDSADRDA) criteria (McKhann 1984), the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria (APA 1987; APA 1994), and the International Classification of Diseases (ICD) (ICD-10) criteria for ADD
Atypical accuracy studies
Longitudinal component – delayed verification
Nested case-control design

8. 2x2 table Sensitivity Specificity a/a+c d/b+d Gold standard + - a b
Test c d
c +d -
a + c
b +d
Sensitivity
a/a+c
Specificity
d/b+d

9. Results F PET with flutemetamol or flobetapen or flobetapir
F PET with flobetapen – 1 study 45 participants
F PET with flobetapir – 3 studies 448 participants
F PET with flutemetamol – 2 studies 243 participants
Limited conclusions because of small numbers of studies
Not directly involved in these reviews
Focus on
F-FDG-PET – 14 studies 421 participants
C-PIB-PET – 9 studies 274 participants

10. Results F-FDG-PET (glucose metabolism)
14 studies
421 participants
Search to Jan 2013

11. Results C-PIB-PET (amyloid deposition)
– 9 studies
- 274 participants
Search to Jan 2013

12. Bottom-line
The empirical evidence does not support PET CT being of much value clinically in the routing management of MCI
Much uncertainty
… and so opportunity to for further research

13. Research agenda Overview/umbrella review would be useful
More systematic reviews
Up-dates
Additional data from investigators would be helpful
Better investigation of heterogeneity
However, real opportunity to do some definitive studies on accuracy
Evaluate as they would be used in the clinical pathway
Consider comparative data
Use optimal image interpretation
Deal with methodological difficulties associated with delayed verification
Deal with other methodological shortcomings identified in the reviews
Primary studies on clinical utility and cost-effectiveness

14. General challenge Failing to take heterogeneity seriously
Creating a summary estimate is not an appropriate response to this pattern of data

15. Hope this quick run through has been helpful and stimulating
Get in touch
Chris Hyde
Exeter Test Group