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MRI, rates of atrophy and Alzheimer’s disease

MRI, rates of atrophy and Alzheimer’s disease. Nick Fox Dementia Research Group Institute of Neurology, UCL Queen Square, London England. Atrophy rates and AD: overview. The relationship of atrophy rates to pathological and clinical progression in untreated patients

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MRI, rates of atrophy and Alzheimer’s disease

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

  2. Atrophy rates and AD: overview • The relationship of atrophy rates to pathological and clinical progression in untreated patients • Disease modification vs. symptomatic effect? • 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?

  3. 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

  4. H Time 0 18months 36months Serial coronal MRI of an individual with initially mild AD

  5. MCI Scan 1

  6. MCI Scan 2

  7. AD Scan 1

  8. AD Scan 2 6 months later

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

  10. Reproducibility • Scan-rescan (a real test of reproducibility) • Acquire a single scan and then two further scans on the same day one year later BBSIAB Scan B Scan A Scan C BBSIAC

  11. 30 20 10 0 -10 0 10 20 30 40 -10 Repeat measure / cc y = 1.00x - 1.08 R > 0.9 RMS Error = 1.6 cc First measure / cc

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

  13. Brain volume vs. time At risk F206 (well) 101.0 99.0 97.0 95.0 % 93.0 91.0 89.0 0 500 1000 1500 Days from first scan

  14. AD: brain volume vs. time 100 % 98 96 94 92 90 88 86 0 500 1000 1500 Days from first scan

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

  16. 94 95 93 4/97 96 11/97 AD: At risk subject - serial scans registered to 1993 baseline

  17. 93 11/97 Red = loss

  18. 90% 85 Normal range: 95%CI 80 symptoms symptoms 75 Brain Volume as percentage of TIV 70 65 0 500 1000 1500 2000 2500 Time since first scan (days)

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

  20. Cerebral atrophy rates on MRI and clinical progression in AD • Atrophy progression in untreated AD • Is inexorable • And correlates with cell loss • MR-based measures are reliable and sensitive to change at a clinically meaningful level • Rates 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

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

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

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

  24. Neurones Protein Water Other cells Could volume change occur without neuronal loss in AD? 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

  25. Atrophy and progression • Neuronal changes are neither necessary nor sufficient to produce volume changes • However progressive volume loss is more likely to be related to progression in neuronal loss • >2 imaging time points • Including off treatment % 85 80 50 100 150 200

  26. It is reasonably likely that • A 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 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 improved Dementia Research Group

  27. Summary • Atrophy rates correlate with and predict progression in untreated patients • The 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 benefit • Inevitably disease modifying drug(s) are required to strengthen the link between atrophy rates and disease modification Dementia Research Group

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