1. Dementia Research Group MRI, rates of atrophy and Alzheimer’s disease Nick Fox Dementia Research Group Institute of Neurology, UCL Queen Square, London England

2. Is it reasonably likely that a change in atrophy rate would predict clinical outcome in AD?

3. Atrophy rates and AD: overview The relationship of atrophy rates to pathological and clinical progression in untreated patientsThe relationship of atrophy rates to pathological and clinical progression in untreated patients Disease modification vs. symptomatic effect?Disease modification vs. symptomatic effect? Is it reasonably likely that atrophy rate changes would predict clinical benefit in treated patients?Is it reasonably likely that atrophy rate changes would predict clinical benefit in treated patients? How might atrophy rates be uncoupled from clinical benefit? Can this be protected against?How might atrophy rates be uncoupled from clinical benefit? Can this be protected against?

4. AD is characterised pathologically by neurofibrillary tangles, neuritic amyloid plaques, synapse loss, dendritic pruning,cell loss and atrophy… MRI can visualise and measure atrophy rates

5. Time 0 18months36months H Serial coronal MRI of an individual with initially mild AD

7. MCI Scan 1

8. MCI Scan 2

9. AD Scan 1

10. AD Scan 2 6 months later

11. 0 1 2 3 4 5 Controls AD Rate of brain volume loss %/yr 2.8% (+/-1) 0.2% (+/-0.3)

12. Reproducibility Scan-rescan (a real test of reproducibility)Scan-rescan (a real test of reproducibility) Acquire a single scan and then two further scans on the same day one year laterAcquire a single scan and then two further scans on the same day one year later Scan A Scan C Scan B BBSI AB BBSI AC

13. y = 1.00x - 1.08 R > 0.9 -10 0 10 20 30 -10010203040 First measure / cc Repeat measure / cc RMS Error = 1.6 cc

14. y = 0.48x + 0.34 R = 0.8 0 2 4 6 8 10 12 024681012 Fall in MMSE % LOSS OF BRAIN VOLUME Cognitive decline in AD correlates with rate of cerebral atrophy Fox et al Neurology 1999;52:1687-9

16. At risk F206 (well) Brain volume vs. time 89.0 91.0 93.0 95.0 97.0 99.0 101.0 050010001500 Days from first scan %

17. AD: brain volume vs. time 86 88 90 92 94 96 98 100 050010001500 Days from first scan %

18. Rate of atrophy predicts conversion to AD in at-risk subjects Fox et al The Lancet 1999; 353:2125

19. 93 9495 96 4/97 11/97 AD: At risk subject - serial scans registered to 1993 baseline

20. 93 11/97 Red = loss

21. 65 70 75 80 85 90% 05001000150020002500 Time since first scan (days) Brain Volume as percentage of TIV symptomssymptoms Normal range: 95%CI

22. Normal control range Symptom onset Fulfils clinical criteria for AD Scahill et al PNAS 2001

23. Cerebral atrophy rates on MRI and clinical progression in AD Atrophy progression in untreated ADAtrophy progression in untreated AD –Is inexorable –And correlates with cell loss MR-based measures are reliable and sensitive to change at a clinically meaningful levelMR-based measures are reliable and sensitive to change at a clinically meaningful level Rates of cerebral atrophy on MRRates of cerebral atrophy on MR –Are increased in AD –Predict conversion to AD –Correlate with cognitive decline –Biologically plausible: regional specific atrophy reflects pathological and clinical progression

24. Differentiating Disease Slowing From Symptomatic Benefit Is benefit sustained?Is benefit sustained? Are all disease effects modified?Are all disease effects modified? Disease modifying effects take place nearer the causal end of the processDisease modifying effects take place nearer the causal end of the process Disease process Disease effects Clinical outcomes

25. Dementia Research Group “a surrogate … should capture the full effects… …on the clinical outcome” Can change in one happen without change in the other?Can change in one happen without change in the other? Are changes correlated?Are changes correlated? Clinically meaningful?Clinically meaningful? Are measures sensitive?Are measures sensitive? Feasible?Feasible?

26. Neuronal degeneration is closely linked to progression of cognitive decline Pathological process Cell loss Cognitive decline and death Synapse loss Destruction of neuronal networks

27. Could volume change occur without neuronal loss in AD? Neurones Other cells Water Protein Yes – neuronal loss is not the sole determinate of cerebral volume – e.g. inflammation, hydration, osmotic effects… 3% cerebral volume change after haemodialysis Walters, Fox et al Nephron 2001;87:143-7

28. Atrophy and progression Neuronal changes are neither necessary nor sufficient to produce volume changesNeuronal changes are neither necessary nor sufficient to produce volume changes However progressive volume loss is more likely to be related to progression in neuronal lossHowever progressive volume loss is more likely to be related to progression in neuronal loss >2 imaging time points>2 imaging time points Including off treatmentIncluding off treatment 80 85 % 50100150200

29. Dementia Research Group It is reasonably likely that A measure of slowed neuronal loss would predict clinical outcome and that slowing would constitute disease modificationA measure of slowed neuronal loss would predict clinical outcome and that slowing would constitute disease modification A slowed rate of neuronal loss would result in reduced atrophy ratesA slowed rate of neuronal loss would result in reduced atrophy rates If the reduction in atrophy rate followed the region- and time-related pattern of the pathology then it would be reasonable to conclude that clinical outcome would also be improvedIf the reduction in atrophy rate followed the region- and time-related pattern of the pathology then it would be reasonable to conclude that clinical outcome would also be improved

30. Dementia Research Group Summary Atrophy rates correlate with and predict progression in untreated patientsAtrophy rates correlate with and predict progression in untreated patients The causality of the link between neurodegeneration and atrophy is plausibleThe causality of the link between neurodegeneration and atrophy is plausible It may be reasonable, with appropriate study designs, to suggest changes in rate of atrophy are due to reduced neuronal degeneration and are likely to predict clinical benefitIt may be reasonable, with appropriate study designs, to suggest changes in rate of atrophy are due to reduced neuronal degeneration and are likely to predict clinical benefit Inevitably disease modifying drug(s) are required to strengthen the link between atrophy rates and disease modificationInevitably disease modifying drug(s) are required to strengthen the link between atrophy rates and disease modification