Categories: Biomarker Central

MRI, Make That A Double

clock December 21, 2011

MRI

 

MRI double-take. Oxford researchers developed a new MRI program (set of sequences) based on structural and functional measures that may help diagnose people with ALS. Image: NIAMS, NIH.

People with ALS experience muscle weakness and ultimately paralysis in part due to the crumbling of neuromuscular junctions, disconnecting their muscles from the motor nerves.

But some neurologists suspect that at least some of the earliest seeds of ALS lie instead within the motor cortex – the motor centers of the brain which tell these muscles to relax or contract – which are also damaged in people with the disease.  And by zeroing in on these signs of cerebral deterioration using magnetic resonance imaging (MRI), ALS may be diagnosed more rapidly and treated more effectively.

Reporting in 2010, researchers from the Oxford Motor Neuron Disease Care and Research Centre in England found using diffuse tensor imaging (DTI) potentially early structural changes in the very center of the brain (the corpus callosum) in people with limb and spinal-onset ALS. But although these changes appeared consistently in patients, these kinds of changes were also previously associated with other outwardly similar diseases.

Now in a study that included 25 people with ALS, the Oxford team identified by MRI a network of regions within the brain that may be specifically altered in people with ALS. And, by taking a look at the structural and functional integrity of this network using these MRI measures, the researchers could distinguish people with ALS from those without the disease with more than 90% accuracy.

The study suggests that these combined MRI measures may have the potential to help diagnose people with ALS more rapidly. And at the same time these results indicate that the disease may indeed be due to a cerebral system failure.

“There is no question this is a whole brain disease,” said University of Oxford neurologist Martin Turner MA PhD MRCP who led the study. 

The study appears this month in the research journal Brain.

Whole Brain Catalog

 

Making tracts. Researchers use DTI coupled to tractography to create a wiring diagram of the brain. Video: Luis Concha MD PhD and Daniel Torres MSc, University of Alberta.

The Oxford team identified a network within the brain likely affected by ALS by first zeroing in on deteriorating white matter regions in people with ALS by DTI and subsequently using tractography identified grey matter likely also involved in the disease. The researchers then deduced the functional connectedness within this network by resting-state functional MRI (rs-fMRI).

Their results confirm that the areas of cortical structural damage extended throughout the brain in people with ALS - well outside of the motor cortex which tells the muscles to move.  And, the functional connectedness within this network appeared to be increased in those with more rapidly progressive disease.

“We can’t think of ALS as simply a motor system problem within the corticospinal tract,” says Turner. “We need to look at the whole brain.”

Early next year, in collaboration with the University of Miami’s Michael Benatar MBChB PhD MS, the Oxford researchers are going to examine people at high risk for developing a familial form of ALS (fALS) to see whether such changes could be used to identify people before they show the first signs of the disease. And at the same time, the Oxford researchers are continuing to monitor people with ALS to determine whether these functional MRI-based measures can be used to track the progression of the disease.

See The Neurochemicals

Meanwhile, neurologists such as the University of Alberta’s Sanjay Kalra MD are turning to a related MRI-based technique called magnetic resonance spectroscopy (MRS) to try and monitor the disease. MRS enables neurologists to track ALS by measuring chemical changes in the brain that may occur due to the disease.  

In the mid 1990s, researchers began to explore the the use of MRS to monitor ALS by measuring levels of n-acetyl aspartate (NAA) to estimate neuronal loss in the motor regions of the brain.  Produced by healthy neurons, NAA is significantly reduced in many regions of the brain in people with ALS.  But the levels of NAA can be variable and unreliable. And in some people with ALS, there may not be enough change in these levels to monitor the disease.

 

Astrocyte explosion. In people with ALS, astrocytes proliferate and produce cytotoxic substances that further injure and/or destroy the motor nerves. Called astrocytosis, this explosion of astrocytes is thought to be triggered by the immune response in patients during the course of the disease.  Image: National Research Council of Canada.

To boost the reliability of these neurochemical measures, Kalra's team in 2006 turned their attention toward another key aspect of ALS – astrocytosis – by measuring levels of myo-inositol in the motor centers of the brain.  Produced by astrocytes, myo-inositol allows researchers to track this rise in so-called reactive astrocyte populations in people with ALS which contributes to the destruction of the motor nerves. 

Their strategy: estimate the extent of both neurodegeneration and astrocytosis in people with ALS by measuring the ratio of levels of NAA to myo-inositol to more effectively monitor the progression of the disease.

Reporting in 2006 and 2011, Kalra's team found that the ratios of these metabolites are reduced in people with ALS including in regions outside the motor centers of the brain.  And at least in the spinal cord, researchers at the University of Miami are now monitoring these levels in people at high risk for developing fALS to determine whether these changes can predict the onset and monitor the course of the disease.

“I am thinking about therapies,” says Kalra. “If we envision therapies that are directed at neural functioning then we will be able to monitor neural function by MRS. If we are looking at therapies directed at astrocytosis, then [myo-inositol] could be the marker to monitor the effects of a therapy on the astrocyte population. That’s the hope.”

Losing Inhibitions?

MRI technologies, however, may hold the potential to do much more than facilitate the development of new ALS medicines. By understanding the changes in the brain identified by these imaging tools, neurologists might also have a better idea how to more effectively treat the disease.

ALS Brain MRI

 

Making more connections. Oxford researchers discovered that regions of the brain that sustained the greatest structural damage (blue) overlapped with the areas of highest functional connectivity (yellow) suggesting that the loss of inhibitory signals may contribute to ALS. Adapted from Douaud et al. (2011), Brain. Copyrighted and reproduced with permission from Oxford Press. All rights reserved.

Peering more deeply into the brain in people with ALS, the Oxford team noticed that the areas of brain hardest hit structurally exhibited the greatest functional connectedness. The researchers speculate that this spike in network activity may be due to the loss of so-called GABAergic inhibitory neurons in people with ALS. The resulting so-called cortical excitability has been observed previously just prior to symptom onset in people at high risk for developing ALS and is characteristic of the disease.

The ALS ravaged-brain, explains Turner, may be like a Ferrari with inadequate brakes.  If critical inhibitory neurons are indeed lost, potentially toxic brain activity cannot be kept in check.

How can neurologists help put the brakes back on in people with ALS?   Anti-epileptic drugs might be one possibility at least theoretically, according to Turner.  But many of these medications have been evaluated in ALS patients and found to be ineffective.  Turner, however, says that this loss of inhibitory neurons might occur very early in the disease process, and therefore for such strategies to be effective these medicines might need to be administered before significant weakness develops. This means identifying and treating people at high risk for ALS well before they show the first signs of the disease.

“I think we will have to study [fALS] gene carriers much more now,” says Turner.  “That’s going to require great sensitivity but I think that is the only way.”

With the recent discovery that an expansion in the C9ORF72 gene may be the most common cause of inherited forms of ALS frontotemporal dementia (FTD) and ALS-FTD, ALS is indeed emerging at least in part, as a whole brain disease.  Understanding how these changes in the brain can inform new therapies therefore remains an important goal.

“I think this is one of the biggest discoveries in the last decade,” says Kalra, “We need to pursue it.”

References

Douaud, G., Filippini, N., Knight, S., Talbot, K., and Turner, M.R. (2011) Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis. Brain doi: 10.1093/brain/awr279.  Abstract Full Text (Subscription Required)

Filippini, N., Douaud, G., Mackay, C.E., Knight, S., Talbot, K., and Turner, M.R. (2010) Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis. Neurology, 75(18), 1645-52. Abstract Full Text (Subscription Required)

Kalra S., Hanstock, C.C., Martin, W.R., Allen, P.S., Johnston, W.S. (2010) Detection of cerebral degeneration in amyotrophic lateral sclerosis using high-field magnetic resonance spectroscopy. Archives of Neurology, 63(8), 1144-1148. Abstract Full Text

Sudharshan, N., Hanstock, C., Hui, B., Pyra, T., Johnston, W. and Kalra S. (2011) Degeneration of the mid-cingulate cortex in amyotrophic lateral sclerosis detected in vivo with MR spectroscopy. American Journal of Neuroradiology, 32(2), 403-407. Abstract Full Text (Subscription Required)

Usman, U., Choi, C., Camicioli, R., Seres, P., Lynch, M., Sekhon, R., Johnston, W. and Kalra S. (2011) Mesial prefrontal cortex degeneration in amyotrophic lateral sclerosis: a high-field proton MR spectroscopy study. American Journal of Neuroradiology, 32(9), 1677-1680. AbstractFull Text (Subscription Required)

Further Reading

Bowser R, Turner M.R., and Shefner J. (2011) Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations. Nature Reviews Neurology, 7(11), 631-8. Full Text (Subscription Required)

Turner, M.R. et al. (2011). Towards a neuroimaging biomarker for ALS. Lancet Neurology, 10(5), 400-403.  Full Text (Subscription Required)

Turner, M.R. and Modo, M. (2010) Advances in the application of MRI to amyotrophic lateral sclerosis. Expert Opinion in Medical Diagnostics 4(6), 483-496. Abstract Full Text

Verstraete E, van den Heuvel MP, Veldink JH, Blanken N, Mandl RC, Hulshoff Pol HE, van den Berg LH. (2010) Motor network degeneration in amyotrophic lateral sclerosis: a structural and functional connectivity study. PLoS One, 5(10), e13664. Abstract Full Text

Patient Resources

The Oxford Study for Biomarkers in MND/ALS (BioMOx).  Contact Website

The Pre-Familial Amyotrophic Lateral Sclerosis (Pre-fALS) StudyContact Website

 

 

 

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Categories: Biomarker Central

NAA MaRkS the Spot

clock October 24, 2011

 

N-acetyl aspartate (NAA). The second most abundant metabolite produced by the neurons of the brain and spinal cord, NAA is routinely used by neuroimaging experts to determine the levels of neuronal loss in people with multiple sclerosis. Neurologists are currently looking towards NAA levels as a means to monitor the progression of neurodegenerative diseases including ALS.

Without a single diagnostic test for ALS, physicians can spend one year on average to arrive at a diagnosis clinically.  But people with ALS may not have that time to waste.  With 30% of neurons lost by some estimates before patients show signs of the disease, the deterioration of the motor nerves, according to some experts, may simply be too difficult to completely reverse.

To speed up the diagnosis, researchers at the University of Miami launched a study in 2006 to in part, find biomarkers that can be used to identify people at the earliest stage of disease.  Called the pre-familial ALS study, the project looks for tell-tale changes in people who because of inherited mutations in ALS-associated genes are at high risk to get the disease.

Now, in a study of 76 participants using magnetic resonance spectroscopy (MRS), the University of Miami team reports that the biomarker n-acetyl aspartate (NAA) in combination with other vital neuronal substances may have the potential to identify people with mutations in the superoxide dismutase gene who are likely to develop ALS. 

These findings also suggest that the motor nerves may start to deteriorate in people at high risk for ALS well before they show any signs of the disease.

“I have long worried that ALS like other neurodegenerative diseases begins before symptoms appear,” says University of Miami neurologist Michael Benatar, MBChB, MS, PhD. “That makes therapy development that much more difficult and that much more challenging.”

The study is published this month in the journal Neurology.

The University of Miami researchers measured the ratios of NAA to other metabolites in the cervical spinal cord of people who are at high risk for developing ALS or who have the disease and compared them to those in healthy people.  The scientists found about a 40% reduction in these ratios in both groups, suggesting that considerable degeneration of the motor nerves occurred before the onset of symptoms of the disease.

Now, the team is monitoring study participants annually to determine whether or not changes in the levels of these ratios of metabolites in combination with other clinical and functional measures can be used to predict which people at high risk actually develop ALS.  The researchers however caution that these changes may simply be indicative of their high susceptibility of developing the disease.

“We need the longitudinal data to distinguish between the two,” says Benatar.  “I think that will come hopefully in the next couple of years.”



ALS: A MRI Investigation. An averaged cross-sectional view of the brain from a group of people with ALS showing areas of most significant change in the descending motor nerve tracts in patients with the disease, as detected by diffusion tensor MRI. This non-invasive way of studying the central nervous system may be sensitive to very early changes when combined with other structural and functional MRI measurements. Courtesy of Martin Turner, MA, PhD, MRCP.

MRI Multitasking

Originally developed to detect neuronal damage in patients with multiple sclerosis, scientists in the mid 1990s turned to MRS in hopes to objectively measure the progression of ALS to develop better treatments for the disease.  But researchers hit a serious roadblock.  They could detect changes in metabolites that correlated with ALS but due to the variability of the levels of these substances they were unable to monitor in individual patients the progression of the disease.

“You can’t at the moment take a single patient and be sure that you are going to see enough change over time,” explains neurologist Martin Turner, MA, PhD, MRCP, co-director of the Oxford Motor Neuron Disease Care and Research Centre in England.

Now, Turner’s team is developing tests based on multiple MRI-based screening tools to more reliably diagnose and monitor the progression of people with the disease.  Last November, his team demonstrated that using both structural and functional connectivity MRI-based brain measures they could distinguish, in a study of 48 participants, people with ALS from healthy people with more than 90% accuracy.  Called BioMOx, the Oxford study remains ongoing.

In future, in collaboration with the University of Miami team, Oxford researchers are going to use some of these same MRI-based tests in hopes to identify changes in individuals at high risk that could be used to determine whether or not they develop the disease and monitor their progression.

“I think we might be able to detect very early changes,” says Dr. Turner.  “Once we develop effective therapeutics for ALS patients, treating those at risk of the disease but not yet showing symptoms then becomes a viable strategy to pursue.”

 

References

Carew J.D., Nair G., Andersen P.M, Wuu J., Gronka S., Hu X., and Benatar, M. Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS.  Neurology. 77(14), 1370-1375.  Abstract Full Text (Subscription Required)

Filippini, N., Douaud, G., Mackay, C.E., Knight, S., Talbot, K., and Turner, M.R. (2011). Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis. Neurology, 75(18), 1645-1652.  Abstract Full Text (Subscription Required)

Turner, M.R. et al. (2011). Towards a neuroimaging biomarker for ALS. Lancet Neurology. 10(5), 400-403.  Full Text (Subscription Required)

Further Reading

Bowser, R., Turner, M.R., and Shefner J. (2011). Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations. Nature Reviews. Neurology. doi: 10.1038/nrneurol.2011.151 Abstract Full Text (Subscription Required)

Turner, M.R. and Modo, M. (2010). Advances in the application of MRI to amyotrophic lateral sclerosis. Expert Opinion on Medical Diagnostics, 4(6), 483-496.  Abstract Full Text

Patient Resources

The Pre-Familial Amyotrophic Lateral Sclerosis (Pre-fALS) StudyContact Website

The Oxford Study for Biomarkers in MND/ALS (BioMOx).  Contact Website

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