19 July 2008. Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Robert Bartha and colleagues at the Robarts Research Institute in London, Ontario, Canada, have evaluated the possibility that the rate of ventricular enlargement over six months could be a useful marker for Alzheimer disease progression. By comparing change in ventricle size with changes in two common psychometric tests, they found that absolute changes in ventricle size provided a more sensitive measure of disease progression than cognitive changes. Their results, published online in Brain on July 11, suggest that rates of ventricular enlargement, determined by serial MRI, could serve as a feasible short-term marker in multicenter clinical trials for AD. A second study on brain size, this one from Jeffrey Burns and colleagues at the University of Kansas in Kansas City, offers a possible modifier of brain tissue loss by showing that fitness level correlates with brain size in patients with early AD.
Researchers in the ADNI study, a multicenter, longitudinal imaging and biomarker discovery program, have accumulated thousands of MRI measures from hundreds of people with AD, mild cognitive impairment (MCI), and normal elderly controls. In the current study, first author Sean Nestor and colleagues applied an automated method of determining ventricular volume to ADNI MRI data from 504 subjects who had both baseline and six-month follow-up scans. Nestor and coworkers found that at baseline, absolute ventricular volume was highest in AD patients, and that in the MCI group it was also significantly elevated over controls. All of the groups showed further enlargement over six months, with the rate being greatest in the patients with AD, and also significantly elevated in the MCI group compared to normal controls. Among AD patients, the test was sensitive to ApoE allele status, where people with ApoE4 showed significantly more ventricular enlargement than those without.
In the MCI group, the change in ventricular volume tracked with cognitive changes and disease progression as measured by the Mini-Mental State Exam (MMSE), the ADAS-cog battery, and conversion to AD. For people with MCI, an increase in ventricular volume correlated with decline in MMSE score and increase in ADAS-cog. People with MCI who progressed to AD during the six-month follow-up showed twice the rate of ventricle enlargement than people with stable MCI.
Among anatomical measures, loss of hippocampal volume has been shown to predict the progression of AD (see ARF related news story). Ventricular enlargement is the flip side of brain shrinkage, and the authors speculate that their measure is so sensitive, in part, because it captures the loss of hippocampal volume. However, measuring ventricle volume has some advantages over determining hippocampal size, the authors write. The calculation of ventricular volume is easily automated because ventricle boundaries show up as a sharp line of contrast between tissue and cerebrospinal fluid in MRI. This automation may contribute to the high reproducibility of the measure even in a multicenter design.
The results suggest that changes in ventricular volume measured over time could provide a more sensitive read of the clinical progression of AD than the currently accepted endpoints of cognitive testing. By the authors’ calculations, the ability to measure significant (20 percent) changes in ventricle size in a clinical trial would require hundreds of subjects, versus thousands for the MMSE or ADAS-cog endpoints. “As a potential measure of disease progression for multicenter studies of both AD and MCI subjects, ventricular enlargement measures would significantly reduce the number of subjects required to demonstrate a change from the natural history of Alzheimer’s disease progression,” the authors conclude.
One finding of the Nestor study is that there are large variations in the rate of ventricular enlargement within the AD or MCI groups. That suggests a range of responses to AD pathology among individuals, which could be affected by environmental factors. The Burns study, which appeared in the July 15 issue of Neurology, asks whether fitness level affects brain changes seen early in AD. The researchers measured the fitness of 57 early-stage AD patients, and a similar number of non-demented subjects, during exercise on a treadmill, and determined whole brain volume by MRI. Their results indicate that subjects with AD had a modestly but significantly reduced maximum oxygen consumption (a measure of cardiorespiratory fitness) compared to non-demented subjects. Fitness level correlated with brain volume in the AD group, so that people with AD who were in better shape had more brain tissue. There was no such relationship in people without dementia, and there was no correlation between brain volume and cognitive measures after adjustment for age.
From the data, the authors conclude, “Increased cardiorespiratory fitness is associated with reduced brain atrophy in Alzheimer disease.” That does not mean keeping fit staves off brain loss, they caution. The association could just as likely result from a situation where loss of fitness accompanies AD, or where some underlying process affects both fitness and AD progression. Studies in mice support the appealing idea that fitness can moderate the attack of AD on the brain—exercise reduces amyloid pathology in mouse models of AD (see ARF related news story and Adlard et al., 2005) and stimulates learning and neurogenesis in normal adult mice (see ARF related news story). However, moving from association to causation in humans will require further studies.—Pat McCaffrey.
Nestor SM, Rupsingh R, Borrie M, Smith M, Accomazzi V, Wells JL, Fogarty J, Bartha R, and the Alzheimer's Disease Neuroimaging Initiative. Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging database. Brain. 2008 July 11, advance access. Abstract
Burns JM, Cronk BB, Anderson HS, Donnelly JE, Thomas GP, Harsha A, Brooks WM, Swerdlow RH. Cardiorespiratory fitness and brain atrophy in early Alzheimer disease. Neurology. 2008 Jul 15;71(3):210-216. Abstract