Research Brief: Blood Flow Parallels Disease Severity in ALS

The Alzheimer’s Disease Neuroimaging Initiative has provided AD researchers with reams of data. Could imaging do the same for those studying amyotrophic lateral sclerosis? Some researchers hope so (see ARF related news story). The latest news in the effort to image ALS comes out of the University of California in San Francisco, with a paper published online by the journal Neurology on February 10. Randall Rule and colleagues, in the laboratory of Norbert Schuff, attempted to match ALS severity with the level of blood flow in the brain.

The researchers recruited 16 subjects with ALS. They analyzed brain blood flow, or perfusion, with arterial spin labeling, a non-invasive form of magnetic resonance imaging. To correlate the perfusion results with symptoms, they used the ALS Functional Rating Scale to categorize severity of motor symptoms, and forced vital capacity to measure breath volume. A decrease on the rating scale or breath capacity was correlated with a drop in brain perfusion. To measure upper motor neuron involvement, they asked participants to rapidly tap their fingers and toes. Similarly, this was also related to perfusion.

“The current findings, while preliminary, are promising,” the authors write. “Brain perfusion may be a useful tool for monitoring disease progression and assessing treatments in ALS.” Currently, lower motor neuron deficits can be measured clinically, but there is no reliable means of determining deficits of upper motor neurons, though several functional and structural imaging techniques are under evaluation. One caveat in this study is that there was no control group, so it is impossible to compare the results to brain perfusion in healthy individuals.

Arterial spin labeling is a more practical technique than some other imaging modalities, wrote Martin Turner of Oxford University, UK, in an e-mail to ARF. Turner was not involved with the study. For example, there is no need to inject radioactive tracers, as PET imaging requires. Turner called the results “encouraging” but said a larger, controlled study, following participants for multiple timepoints, is required.

Clinicians desperately need biomarkers to both diagnose ALS and to track its course in clinical trials (see ARF related news story). “The technique has not that much potential for anything more than making correlations…yet,” wrote Jonathan Katz of the California Pacific Medical Center in San Francisco in an e-mail to ARF. He also was not part of the current work. But if researchers could reduce the amount of noise in the signal, making it easier to see changes, it “holds some promise,” Katz wrote.—Amber Dance

Comments

  1. This comment was solicited by the Alzheimer Research Forum.

    There is a clear need for novel biomarkers that are sensitive to progression of disease in ALS and that could be used to facilitate monitoring in therapeutic trials and reduce the reliance on survival as the primary outcome measure. MRI, as a non-invasive technique with widespread availability for patients, has proved itself in providing several robust objective and quantitative markers of upper motor neuron involvement. There remain important challenges to apply it to the study of the lower motor neuron burden of disease which accounts for much of the disability in ALS.

    Arterial spin labeling is a novel MRI technique that allows non-invasive measurement of cerebral perfusion. This study by Rule et al. has a sound rationale given what has been demonstrated already about the wider extra-motor cerebral involvement in ALS, and the need to find a potentially “functional” correlate for the more 'structural' analysis that diffusion tensor tractography can offer. Their results are encouraging in that regional alterations in perfusion appear to be linked to the 'bedside' functional rating scale for disability in ALS (the ALSFRS-R).

    PET, involving radioactive tracers, has been the gold standard of perfusion imaging for many years. It is noteworthy, as a proof-of-concept, that this more practical, non-invasive MRI study confirms some of the regional resting-state findings of the PET study of blood flow in ALS undertaken by my predecessor John Kew in Professor Nigel Leigh's lab in London nearly 20 years ago, "Cortical function in amyotrophic lateral sclerosis. A positron emission tomography study" (see Kew et al., 1993).

    The authors acknowledge that there is no control group, and so this paper stands as a promising pilot study that needs repeating in a larger group of patients, with controls, and crucially with longitudinal data. Combination with diffusion imaging would also be useful. A wider point is that, despite the all-too-regular comments that MRI has had its day as a technology, it continues to be inventive and to push back the boundaries of neuroscience research. With high resolution cord imaging becoming a reality, there is much more to come in the next decade for MRI across a range of neurological disorders, and it is vital that the brightest physicists and image analysts continue to be drawn to the field.

    References:

    Kew JJ, Leigh PN, Playford ED, Passingham RE, Goldstein LH, Frackowiak RS, Brooks DJ. Cortical function in amyotrophic lateral sclerosis. A positron emission tomography study. Brain. 1993 Jun;116 ( Pt 3):655-80. PubMed.

    View all comments by Martin R. Turner

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References

News Citations

  1. Portrait of a Motor Neuron Disease: Focus on Imaging for ALS
  2. News Brief: Scientists Net Prizes for Progress Toward ALS Biomarker

Further Reading

Papers

  1. Rule RR, Suhy J, Schuff N, Gelinas DF, Miller RG, Weiner MW. Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Sep;5(3):141-9. PubMed.
  2. Agosta F, Rocca MA, Valsasina P, Sala S, Caputo D, Perini M, Salvi F, Prelle A, Filippi M. A longitudinal diffusion tensor MRI study of the cervical cord and brain in amyotrophic lateral sclerosis patients. J Neurol Neurosurg Psychiatry. 2009 Jan;80(1):53-5. PubMed.
  3. Wicks P, Turner MR, Abrahams S, Hammers A, Brooks DJ, Leigh PN, Goldstein LH. Neuronal loss associated with cognitive performance in amyotrophic lateral sclerosis: an (11C)-flumazenil PET study. Amyotroph Lateral Scler. 2008 Feb;9(1):43-9. PubMed.
  4. Grosskreutz J, Kaufmann J, Frädrich J, Dengler R, Heinze HJ, Peschel T. Widespread sensorimotor and frontal cortical atrophy in Amyotrophic Lateral Sclerosis. BMC Neurol. 2006;6:17. PubMed.
  5. Stanton BR, Shinhmar D, Turner MR, Williams VC, Williams SC, Blain CR, Giampietro VP, Catani M, Leigh PN, Andersen PM, Simmons A. Diffusion tensor imaging in sporadic and familial (D90A SOD1) forms of amyotrophic lateral sclerosis. Arch Neurol. 2009 Jan;66(1):109-15. PubMed.
  6. Assaf Y. Can we use diffusion MRI as a bio-marker of neurodegenerative processes?. Bioessays. 2008 Nov;30(11-12):1235-45. PubMed.

Primary Papers

  1. Rule RR, Schuff N, Miller RG, Weiner MW. Gray matter perfusion correlates with disease severity in ALS. Neurology. 2010 Mar 9;74(10):821-7. PubMed.

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