# Presentation: 645941

## MRI, rates of atrophy and Alzheimer’s disease

**Nick Fox**
**Dementia Research Group **
**Institute of Neurology, UCL**
**Queen Square, London**
**England**

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

## 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? **

## AD is characterised pathologically by neurofibrillary tangles, neuritic amyloid plaques, synapse loss, dendritic pruning,cell loss and atrophy...

**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**

## Time 0			    18months			36months

- Time 0			    18months			36months

- H

- Serial coronal MRI of an individual with initially mild AD

## Slide 6

## MCI

- Scan 1

## MCI

- Scan 2

## AD

- Scan 1

## AD

- Scan 2
- 6 months later

## Slide 11

## Reproducibility

**Scan-rescan (a real test of reproducibility)**
**Acquire a single scan and then two further scans on the same day **_**one year later**_

**Scan A**

**Scan C**

**Scan B**

**BBSI****AB**

**BBSI****A**C

## First measure / cc

- y = 1.00x - 1.08
- R > 0.9

**First measure / cc**

**Repeat measure / cc**

**RMS Error = 1.6 cc**

## Cognitive decline in AD

**y = 0.48x + 0.34**

**R**

** ****= 0.8**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**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

## <footer> Dementia Research Group

- <date/time>

## At risk F206 (well) 

**At risk ****F206**** (well)**** **

**Brain volume vs. time**

- 89.0

- 91.0

- 93.0

- 95.0

- 97.0

- 99.0

- 101.0

- 0

- 500

- 1000

- 1500

**Days from first scan**

**%**

## Slide 17

## Rate of atrophy predicts conversion to AD in at-risk subjects

- Fox et al The Lancet 1999; 353:2125

## 93

- 94

- 95

- 96

- 4/97

- 11/97

**AD: At risk subject - serial scans registered to 1993 baseline**

## 93

- 11/97

**Red = loss**

## symptoms

- 65

- 70

- 75

- 80

- 85

- 90%

- 0

- 500

- 1000

- 1500

- 2000

- 2500

**Time since first scan (days)**

**Brain Volume as percentage of  TIV**** **

**symptoms**

**symptoms**

- Normal range: 95%CI

## Normal control range

- <date/time>

- Symptom onset

- Fulfils clinical criteria for AD

- Scahill et al PNAS 2001

## 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**

## 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**
**process**

**Disease**
**effects**

**Clinical outcomes**

## “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?**

## Neuronal degeneration is closely linked to progression of cognitive decline

**Pathological **
**process**

**Cell loss**

**Cognitive decline and death**

**Synapse loss**

- Destruction of neuronal networks

## 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**

## 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**

- 80

- 85

- %

- 50

- 100

- 150

- 200

## 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**

## 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**