Gray matter brain disease

Contents

A View Into the MS Brain: What New Imaging Techniques Reveal

White Matter Consists Mainly of Nerve Fibers

White matter appears white because the protective wrapping around nerve fibers, or axons, is a pale, fatty tissue called myelin.

“Axons are like the electric wires of the brain,” says Rhonda Voskuhl, MD, professor of neurology at the UCLA Brain Research Institute and director of the UCLA Multiple Sclerosis Program in Los Angeles.

In MS, the immune system attacks the myelin in the brain, spinal cord, and optic nerves. The attack causes inflammation that eventually leads to sclerosis, which is the medical term for scarring. (That’s how MS got its name.)

“When MS attacks these parts of the brain, it’s like stripping the rubber off the wires. That slows down conduction speed and causes the types of MS symptoms that come and go,” says Dr. Voskuhl. “An attack may last for weeks or months, but then the inflammation cools off, and the area recovers completely or partially.”

Gray Matter Is Made of Nerve Cell Bodies, or Neurons

Gray matter, made up of the cells of the central nervous system called neurons, is thickly located in the outer areas of the brain, called the cortex. If you look at the outside of the brain, it looks gray.

“The white matter carries messages from point A to point B,” Stone says. “The gray matter is point A and point B.”

As MS progresses, changes occur in the gray matter that are different from those occurring in the white matter.

“If you cut off the connections between nerve cells, they eventually die,” Voskuhl explains. “This causes a shrinking of brain tissue, called gray matter atrophy. MS causes inflammation in white matter and atrophy in gray matter. You can measure atrophy by actual loss of brain volume.”

But demyelination and lesions can also happen in gray matter, even if this isn’t visible using conventional magnetic resonance imaging (MRI) scans, according to Léorah Freeman, MD, PhD, a neurologist and assistant professor at Dell Medical School at the University of Texas at Austin.

In fact, Dr. Freeman says, “We know from postmortem studies that in the most severe cases, up to 70 percent of the gray matter can be demyelinated” in people with MS.

Newer Types of MRI and PET Scans Reveal Disease Progression in the MS Brain

Researchers and doctors who treat MS commonly use MRI scans to study the brain. MRI is imaging created with computers and radio wave energy. New types of MRI provide more detail, making it easier to see gray matter.

Magnetic resonance spectroscopy shows areas of the brain where proteins found only inside neurons are located.

Functional MRI (fMRI) makes images of the brain while a person is doing a specific task, like reading. When fewer areas light up during this test, it may be a sign of gray matter atrophy.

Gray matter damage has been shown to play an important role in MS disease progression, according to a study study published in July 2013 in the journal Annals of Neurology that followed more than 400 people with relapsing-remitting MS.

Using a model that included a patient’s age, gray matter lesions, and gray matter atrophy, researchers were able to correctly predict MS progression in about 94 percent of participants who maintained relapsing-remitting MS status, and 88 percent of those who transitioned to the secondary-progressive stage.

Knowledge of how gray matter damage affects MS has lagged behind what’s known about white matter, due to the limitations of conventional imaging techniques.

“It’s easy to see white matter inflammation, because it lights up like a Christmas tree on MRI,” Stone says. “Gray matter atrophy is harder to see. Eventually, it shows up as an increase in the fluid-filled parts of the brain as the brain shrinks. But that can be confusing, because the truth is that everybody’s brain shrinks over time — with or without MS.”

Freeman notes that newer imaging techniques, like positron emission tomography (PET), can help identify gray matter changes that may not be visible on a conventional MRI.

In a small pilot study published in October 2015 in the journal Annals of Neurology, a research team led by Freeman found that PET scans could effectively map and reveal measurements of neuronal damage in the gray matter of people with various stages of MS.

Symptoms of Gray and White Matter Disease

“In general, white matter disease causes acute MS symptoms, like numbness and weakness,” Stone says. “Gray matter disease causes progressive symptoms, like fatigue and memory loss. These higher brain functions are called cognitive functions. Most MS disability actually comes from cognitive dysfunction.”

Voskuhl provides another angle: “I think it makes sense to think of some white matter damage like inflammation as temporary, and some gray matter damage like neuron loss as permanent,” she says. “It’s important to know that cognitive changes in MS are not like in Alzheimer’s disease. They don’t affect a person’s intelligence, long-term memory, or their ability to read or carry on a conversation.”

It’s the cumulative damage to both gray and white matter that adds up to MS symptoms, Stone adds. The problem is that even with increasingly detailed imaging techniques, visible changes in the brain don’t correlate exactly with symptoms like fatigue or cognitive impairment.

“Part of the whole discussion is that we are missing something in MS, and we are constantly trying to figure out what it is we are missing,” says Stone.

Freeman is optimistic that advances in imaging will make it easier to pinpoint how communication between different areas of the brain contributes to a wide range of MS symptoms. “We’re trying to make more correlations between specific symptoms and specific locations of lesions or damage,” she notes.

Better Imaging May Lead to Better Drugs for MS

Gaining a better understanding of how MS operates in the brain is critical to developing the next generation of MS drugs, according to Voskuhl.

“We have drugs that can suppress the immune system, reduce MS attacks, and decrease white matter damage. But what we need now are drugs that prevent or reverse long-term disability of all types, including not only cognition but also walking, balance, and vision,” Voskuhl says. “Research focused on gray matter protection may be the critical next step in this goal.”

Freeman notes that recent advances in imaging, and the better understanding of gray matter damage that they allow, are already affecting how trials of potential new MS drugs are conducted.

“Clinical trials are more consistently looking at the impact of the drug on brain atrophy” in different gray matter structures, Freeman says, “because those are meaningful end points” that the U.S. Food and Drug Administration (FDA) is interested in.

Aside from informing new drug development, advances in imaging may also prove useful to doctors in deciding what course of treatment is best for an individual patient, according to Freeman. Her lab is studying computing techniques to extract more meaningful information from conventional MRIs that are already part of the standard of MS care.

“Right now, the information we’re using from these MRIs to monitor therapy is patients develop new or active lesions within the white matter,” Freeman explains. “I think we could be using MRI in a different way, to maybe predict treatment response before we even start therapy.”

Artificial Intelligence Could Play a Role in MS Treatment Advances

This vision of MS imaging and treatment could involve using artificial intelligence (AI) technologies to look at the entire brain in MRI scans, and predict individual outcomes and responses to different MS drugs.

In this way, AI could help doctors know “what therapy we should initiate, or when it is time to switch, before patients fail their medication,” says Freeman, as part of a “move from a trial-and-error approach to therapy, and more into a personalized, precision-medicine approach to therapy.”

The best way to get there, the experts agree, is to keep developing and refining imaging techniques that advance our knowledge of the MS brain.

Additional reporting by Quinn Phillips.

Enhancing our understanding of white matter changes in early multiple sclerosis

This scientific commentary refers to ‘Permeability of the blood–brain barrier predicts conversion from optic neuritis to multiple sclerosis’, by Cramer et al. (doi:).

The cause of multiple sclerosis remains one of the great mysteries of neurology. Despite its clinico-neuropathological characterization almost 150 years ago by Charcot, we continue to gain fundamental knowledge about multiple sclerosis pathology. A major roadblock to the better understanding of multiple sclerosis, and many chronic CNS diseases, is the lack of adequate longitudinal histological analyses of the CNS. These are needed to show the early development of individual lesions as well as the changes in neuropathology over the years.

How do multiple sclerosis lesions begin? Neuroimaging has provided clues by revealing that lesions commence with blood–brain barrier (BBB) breakdown as indicated by gadolinium enhancement. In the BECOME study in which monthly gadolinium-enhanced brain MRIs were performed in 75 subjects with multiple sclerosis for 2 years, more than 95% of new lesions seen on T2-weighted/FLAIR magnetic resonance began with gadolinium enhancement (Cadavid et al., 2009). However, we do not know what precedes BBB breakdown. It is likely that subtle focal or global changes occur prior to gadolinium enhancement within the normal-appearing CNS. To understand early events in lesion development, investigators often focus on patients who are at the early stages of a single demyelinating event, so-called ‘clinically isolated syndrome’ (CIS). In this issue of Brain, Cramer and co-workers examine patients with CIS limited to the optic nerves to determine whether subtle changes in BBB permeability are also present elsewhere in the CNS (Cramer et al., 2015).

Previous studies have examined such patients with magnetic resonance spectroscopy, finding increases in myo-inositol (Fernando et al., 2004) and reductions in N-acetyl-aspartate within normal-appearing white matter that are predictive of subsequent conversion to multiple sclerosis (Wattjes et al., 2008). Such chemical shifts suggest glial cell activation and neuronal injury at the earliest stages of the disease. Evidence of altered tissue integrity in normal-appearing white matter of patients with CIS has been revealed by magnetization transfer (Fernando et al., 2005) and diffusion tensor imaging (Gallo et al., 2005). Studies using magnetization transfer imaging suggest loss of macromolecules such as myelin, while diffusion imaging measures correlate with injured structural components within the tissue, including axons, myelin, and the tissue matrix. A recent study using PET showed that microglia are globally activated in the normal-appearing white matter and deep grey matter of patients with CIS compared to control subjects (Giannetti et al., 2015), and that the global increase in microglial activation is predictive of earlier development of multiple sclerosis over the next 2 years. This PET study is in accord with studies of autopsied multiple sclerosis tissues that have revealed activated microglia throughout normal-appearing white matter.

Dynamic susceptibility contrast (DSC)-MRI assesses tissue perfusion based upon susceptibility effects on T2-weighted sequences associated with the first pass of gadolinium contrast through the cerebrum. DSC parameters of cerebral blood flow and volume have been shown to increase in the weeks prior to acute lesion development (Wuerfel et al., 2004). Haemodynamic changes as assessed by DSC have varied within normal-appearing white matter across studies. One study observed cerebral blood flow and transit time to be increased within normal-appearing white matter in patients with CIS compared to controls (Papadaki et al., 2012), although this and earlier studies observed a decrease in these parameters in the normal-appearing white matter of patients with established multiple sclerosis.

Dynamic contrast enhanced (DCE) MRI has been utilized to qualitatively evaluate temporal patterns of enhancement (signifying BBB permeability) for lesions in various stages (Gaitán et al., 2011). Newly enlarging lesions often enhance outwards from the centre, but over time, the enhancement appears from the peripheral portion of the lesion towards the centre. This suggests different patterns of permeability associated with lesion outgrowth.

In this issue of Brain, Cramer and co-workers use DCE imaging to estimate subtle differences in gadolinium enhancement throughout the brain in very early stages of CNS demyelination. Previously, this same group has demonstrated by using DCE that patients with established relapsing-remitting multiple sclerosis have higher BBB permeability than controls (Cramer et al., 2014). Not unexpectedly, permeability was greatest in association with relapse. Although still higher than in normal control subjects, DCE was lower among those patients who were receiving disease-modulating therapies.

In the present study, Cramer et al. have applied the DCE-MRI technique to 39 patients with a single acute optic neuritis attack in order to search for BBB permeability changes elsewhere in the CNS, and to determine whether such changes might be predictive of confirmed multiple sclerosis over the next 2 years. Periventricular permeability within normal-appearing white matter was increased by 50% compared to healthy controls in these patients with a single clinical demyelinating episode of the optic nerve. Among the 44% of patients who met 2010 McDonald criteria for diagnosis of multiple sclerosis during the 2-year follow-up, periventricular permeability was increased by 50% compared to those who did not subsequently meet multiple sclerosis criteria. Those who converted to multiple sclerosis also showed an ∼50% increase in permeability in the thalamus compared to both non-converters and controls. Those patients who did not convert to multiple sclerosis over the 2 years showed no permeability differences from controls in either periventricular white matter or thalamus. While having nine or more T2 lesions at baseline was a strong predictor of conversion as established previously, the addition of increased BBB permeability improved the predictive power for development of multiple sclerosis. Moreover, permeability by DCE MRI was not correlated with T2 lesion counts, suggesting that alterations of the BBB leading to increased permeability may also be independent of focal inflammatory plaques.

This study is notable for revealing subtle changes in BBB integrity that support the concept that multiple sclerosis is not just a disease of multiple focal lesions, but affects large regions of the CNS white matter at the earliest disease stages. The present study indicates that, in regions that appear normal based on FLAIR (fluid attenuation inversion recovery) and are located well away from the site of acute optic neuritis, there is nevertheless a global mild alteration in BBB integrity in normal-appearing white matter. The level of increased contrast leakage correlated with elevated CSF levels of the chemokine CXCL10 and of MMP9, and with increased CSF cells. Activated microglia, as well as infiltrating inflammatory cells, may be the source of chemokines and MMP9. Of note, the majority of the converters to multiple sclerosis in the present study had CSF oligoclonal bands (82%), the presence of which indicates that the CNS had already been infiltrated by B cells and/or plasma cells. One interpretation of this study, in the context of previous studies using other imaging techniques, is that in early CIS, there already exists a pervasive underlying CNS pathology that is invisible to many standard imaging modalities.

Future studies should evaluate DCE in a longitudinal setting, in concert with other quantitative imaging techniques. The potential of DCE as a long-term predictor of disease severity would be interesting to assess. The multiple sclerosis disease-modifying therapy natalizumab acts by blocking cellular transmigration into the CNS. Thus, the effect of natalizumab therapy on DCE would be of particular interest to help determine whether increased DCE requires cellular infiltration, which might help address the question of whether multiple sclerosis lesions initiate inside the CNS or are instigated from outside. However, examining CIS may not be early enough. To determine the very earliest events of multiple sclerosis, we may need to perform longitudinal imaging and CSF studies in young people who are at very high risk of developing multiple sclerosis based on genetics and demographics.

Cadavid D Wolansky L Skurnick J Lincoln J Cheriyan J Szczepanowski K et al. . Efficacy of treatment of MS with IFNβ-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology 2009; 72: 1976–83. Cramer SP Modvig S Simonsen H Frederiksen JL Larsson HBW . Permeability of the blood-brain barrier in normal appearing white matter predicts conversion from optic neuritis to multiple sclerosis. Brain 2015. Cramer SP Simonsen H Frederiksen JL Rostrup E Larsson HBW . Abnormal blood–brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI. Neuroimage 2014; 4: 182–9. Fernando KTM McLean MA Chard DT MacManus DG Dalton CM Miszkiel KA et al. . Elevated white matter myo-inositol in clinically isolated syndromes suggestive of multiple sclerosis. Brain 2004; 127: 1361–9. Fernando KTM Tozer DJ Miszkiel KA Gordon RM Swanton JK Dalton CM et al. . Magnetization transfer histograms in clinically isolated syndromes suggestive of multiple sclerosis. Brain 2005; 128: 2911–25. Gaitán MI Shea CD Evangelou IE Stone RD Fenton KM Bielekova B et al. . Evolution of the blood–brain barrier in newly forming multiple sclerosis lesions. Ann Neurol 2011; 70: 22–9. Gallo A Rovaris M Riva R Ghezzi A Benedetti B Martinelli V et al. . DIffusion-tensor magnetic resonance imaging detects normal-appearing white matter damage unrelated to short-term disease activity in patients at the earliest clinical stage of multiple sclerosis. Arch Neurol 2005; 62: 803–8. Giannetti P Politis M Su P Turkheimer FE Malik O Keihaninejad S et al. . Increased PK11195-PET binding in normal-appearing white matter in clinically isolated syndrome. Brain 2015; 138: 110–9. Papadaki EZ Mastorodemos VC Amanakis EZ Tsekouras KC Papadakis AE Tsavalas ND et al. . White matter and deep gray matter hemodynamic changes in multiple sclerosis patients with clinically isolated syndrome. Magn Reson Med 2012; 68: 1932–42. Wattjes MP Harzheim M Lutterbey GG Bogdanow M Schild HH Träber F . High field MR imaging and 1H-MR spectroscopy in clinically isolated syndromes suggestive of multiple sclerosis. J Neurol 2008; 255: 56–63. Wuerfel J Bellmann-Strobl J Brunecker P Aktas O McFarland H Villringer A et al. . Changes in cerebral perfusion precede plaque formation in multiple sclerosis: a longitudinal perfusion MRI study. Brain 2004; 127: 111–9. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]

Gray Matter vs White Matter

The brain is an immensely complex structure, but there are ways we can divide up its anatomical structure into more discrete parts; the left and right hemisphere, parietal, temporal, occipital and frontal lobes. Another common divider is to separate the brain’s gray and white matter. But what are these two structures? How different are they from each other? How significant, and physiologically relevant, is this divide? Read on to find out!

Differences between Gray and White Matter

What is gray matter?

Gray matter consists primarily of neuronal cell bodies, or soma. This a spherical structure that houses the neuron’s nucleus.

What is white matter?

White matter areas of the brain mainly consist of myelinated axons, which are long relays that extend out from the soma, and which are whiteish in color due to the relatively high lipid fat content of the myelin protein that sheathes them, These form connections between brain cells, and white matter is typically distributed into bundles called tracts.

Is it really that simple?

Not quite. Whilst the above division is physiologically accurate on a system level, there are a mix of cell types present in both gray and white matter.
Gray matter also contains:

  • Axon tracts
  • Glial cells
  • Capillary blood vessels
  • Neuropil – a mix of dendrites, unmyelinated axons, and glia

White matter also contains:

  • Oligodendrocytes – glial cells which produce myelin
  • Astrocytes

How are gray matter and white matter arranged in the CNS?

Both gray and white matter are spread throughout the human central nervous system – the brain and spinal cord

Figure 1: The arrangement of white and gray matter in the brain.

Gray Matter Location

Neuronal cell bodies are abundant in the cerebrum, brain stem and cerebellum. This latter structure, which makes up just 10% of brain volume, contains more neurons than the rest of the brain put together. In the spinal cord, gray matter forms a “butterfly” structure, which can be visualized below in figure 2.

So which regions of the central nervous system have an external layer of gray matter?

We can think of the cerebrum and cerebellum as the brain regions which have an external layer of gray matter (see figure 1). The brainstem’s gray matter is located in groups of neurons called nuclei which are embedded within white matter tracts.

White matter location

As previously mentioned, white matter is organized into tracts of axons. In the cerebrum and cerebellum, white matter is predominantly found in deeper areas – with gray matter coating the white matter – see figure 1. Other gray matter structures, like the basal ganglia, are embedded within this white matter core. The brain’s fluid-filled ventricles are also found within the white matter.
In the spinal cord, things are largely reversed – the white matter is distributed around the central gray matter “butterfly”.

Figure 2: The arrangement of white and gray matter in the spinal cord.

Gray matter and white matter: function

What is the function of gray matter?

Gray matter-heavy brain regions include those that control muscular and sensory activity.

  • Cerebral cortex – The outer layer of the brain, the cerebral cortex, consists of columns of gray matter neurons, with white matter located underneath. This area is essential to many facets of higher learning, including attention, memory, and thought.
  • Cerebellum – The cerebellum is essential for motor control, coordination, and precision.

What is the function of white matter?

Neuron-rich brain regions wouldn’t count for much without the rich veins of axonal connections contained within white matter to join them up.

The white fatty myelin that gives this tissue its name is also essential to its function – myelin insulates axons, letting the signal within travel far faster, enabling the nerve cell function that is essential to normal motor and sensory function.

Diseases of gray and white matter

Gray matter disease

Diseases that cause the loss of the neurons that make up gray matter are primarily called neurodegenerative diseases. These diseases, which include dementias like Alzheimer’s disease and frontotemporal dementia, affect millions of people worldwide. White matter alterations are often present in these diseases, but physiological hallmarks such as amyloid plaques and tau neurofibrillary tangles are located in the gray matter. As might be expected, the region where neurons are lost largely dictates disease progression – the motor symptoms of Parkinson’s disease are directly related to the loss of dopamine-producing neurons in the substantia nigra.

White matter disease

As James Balm phrases it in his article for the BMC, white matter tracts are the subways of the brain, vital connections that ensure the smooth operation of our nervous system. As such, disease that affects our white matter can disrupt this nerve signal transit and can be a serious issue.

  • Multiple sclerosis – In multiple sclerosis (MS) the white fatty myelin coating around axons is destroyed, leading to motor or sensory disruption. In relapsing-remitting multiple sclerosis, this myelin can be repaired and lost multiple times. In progressive multiple sclerosis, axonal damage is followed by neuron death, which is irreversible.
  • White matter disease – responsible for roughly a fifth of strokes worldwide, white matter diseases affect blood vessels buried within white matter. These harden, preventing oxygen and other nutrients from reaching the white matter.
  • Spinal cord injury – When the axon bundles in the spinal cord are damaged, the connection between the brain and spinal cord gray matter is lost. This can cause paralysis and sensory issues, which are often permanent if neuronal bodies are damaged.

The Role of Grey Matter in Alzheimer’s Disease

Learn more from Monica Gomez and her article about recent research into the role of grey matter in Alzheimer’s disease.

Research Reveals the Role of Grey Matter in Alzheimer’s

As Americans live longer, we are encountering a significant increase in the senior population who suffer from neurodegenerative conditions, including Alzheimer’s. The Alzheimer’s Association points out that experts believe Alzheimer’s is the result of various factors, including age and genetics, which are identified as major risk factors. Yet, many questions about the disease still remain open.

Two recent medical studies offer critical information about additional factors that may impact the development and treatment of Alzheimer’s. Scientists in the UK found that a specific network within grey matter was more vulnerable to age-related neurodegeneration, and that it degenerated sooner than other brain areas. Stateside, researchers discovered that a protein created under heat shock could improve a dysfunctional actin cytoskeleton, which is linked to neurodegenerative disorders.

Medical News Today first reported that scientists at the Oxford University Functional MRI of the Brain Centre, led by Dr. Gwenaelle Douaud, applied a theory called “retrogenesis” from the 1880s to current research on grey matter. Grey matter is the cortex of the brain, which is responsible for muscle control, memory, emotions, speech, decision-making, self-control and sensory perception. The “retrogenesis” theory of brain change suggests that brain ability declines in reverse order to how it develops.

Following this line of inquiry, the scientists relied on Magnetic Resonance Imaging (MRI) scans of 484 people aged 8-85 to look for age-related patterns. Their analysis revealed two important findings:

  1. A particular network within the grey matter links most of the higher order functions of the brain.
  2. This network develops later than the rest of the brain and is the first to show signs of degeneration with age.

Moreover, when the researchers compared the scans of healthy individuals with those of people who suffer from Alzheimer’s and schizophrenia, they found that this particular brain network might play a crucial role in these different diseases. It seems like this area of the brain is more vulnerable to both Alzheimer’s and schizophrenia.

This study further reconciles two hypotheses that have previously been discussed entirely separately in scientific literature, according to Dr. Douaud:

  • The brain damage caused by schizophrenia and Alzheimer’s are related to higher order parts of the brain
  • These parts of the brain are not as developed in other primates, which also don’t develop schizophrenia or Alzheimer’s, implying that these diseases are a result of human evolution and longer lifespans

According to Professor Perry, chairman of the Medical Research Council’s Neurosciences and Mental Health Board, which funded the research, there was no evidence that the same parts of the brain might be linked to such different diseases. Although doctors called schizophrenia “premature dementia” in the past.

“This large-scale and detailed study provides an important, and previously missing, link between development, aging, and disease processes in the brain. It raises important issues about possible genetic and environmental factors that may occur in early life and then have lifelong consequences,” Perry says.

Alzheimer’s and the HSF-1 Protein

While the findings from Oxford University research may provide us with new insights about the factors that contribute to Alzheimer’s, the discoveries made in a recent study from University of California, Berkeley, and University of Michigan could possibly lead to future treatments of this incurable disease.

The study was spearheaded by Andrew Dillin, who serves as the Thomas and Stacey Siebel Distinguished Chair of Stem Cell Research in the Department of Molecular and Cell Biology and the Howard Hughes Medical Institute investigator at the University of California, Berkeley.

Science Daily reports that a team of researchers challenges a long held scientific belief about how the brain reacts to misfolded proteins during heat shock. For over 30 years, scientists believed that cells exposed to heat, such as a fever, produced a protein called heat shock factor-1 (HSF-1), which would launch “chaperone” molecules to refold misfolded proteins. An accumulation of misfolded proteins has been associated with neurodegenerative diseases. Hence, scientists believed that artificially increasing HSF-1 would reduce misfolded proteins and thus protect the brain. Yet, this process had the unintended consequences of increasing cancer risk.

In the past, scientists believed that HSF-1 was simply responsible for releasing chaperone cells. However, Dillin and his team found in experiments that the protein plays a much bigger part:

  1. HSF-1 also stabilizes the cell’s cytoskeleton, which transports necessary supplies — including healing chaperones — throughout the cell.
  2. HSF-1 regulates a gene called pat-10, which produces a protein that stabilizes actin, a building block of the cytoskeleton.

As a result, Dillin and his colleagues’ research suggests that instead of increasing HSF-1 to release chaperone molecules, the protein ought to be used for strengthening the cytoskeleton in order to protect against neurodegenerative diseases. This alternative approach might also avoid the cancerous side effects of boosting HSF-1. Furthermore, Dillin and his team even suspect that the protein’s main function is actually reinforcing the cytoskeleton, rather than triggering the release of chaperones. They mutated HSF-1 so that it would no longer boost chaperones, showing that it was not essential to surviving heat stress as long as the cytoskeleton was stable.

Even though further experiments are needed to rule out errors, the University of California, Berkeley and the University of Michigan research teams hope that their findings will pave the way for novel treatments of neurodegenerative diseases.

As researchers learn more about how the brain develops and works at all ages, they are discovering links that they previously thought were unrelated. Further research into these connections may open new avenues for future preventative treatments.

Did you know about the research into the connection between grey matter and Alzheimer’s? What did you find most interesting about the results? Share your thoughts with us in the comments below.

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The Behavioral Neurology of White Matter: Diagnosis of Major Disordersand Syndromes

More than 100 neurologic diseases, injuries, and intoxications are known to prominently or exclusively involve the white matter of the brain.1,2 Without exception, these disorders have the potential to disrupt aspects of cognitive and emotional function and to lead to important syndromes related to white matter dysfunction. Although not as familiar as the diseases of gray matter that have dominated thinking in behavioral neurology, the white matter disorders are emerging as common problems that erode neurobehavioral function.

These disorders highlight the concept that white matter tracts provide the neuroanatomic connectivity between gray matter areas; thus, disruption of tracts produces neurobehavioral syndromes by disturbing the function of distributed neural networks that subserve higher brain function. In the era of MRI, which enables detailed imaging of white matter disorders, the diagnosis of neurobehavioral syndromes associated with these disorders is increasingly feasible and will lead to improved patient care. White matter constitutes nearly half of brain volume.1,2 Consisting of billions of myelinated axons that travel within and between the hemispheres to connect gray matter regions with each other, white matter occupies a central position that is important in both brain structure and function (Figure 1). In traditional neurologic teaching, white matter has been regarded as a component of the brain that is primarily dedicated to elemental sensory and motor function; thus, the major problems produced by white matter lesions include visu-al field deficits, hemihypesthesia, and hemiparesis. However, more recent information is justifying the view that white matter has neurobehavioral affiliations of its own and that a behavioral neurology of white matter can now reasonably be considered.3-5

Recognizing the clinical effects of white matter lesions helps illuminate the role of white matter tracts in the normal connectivity of the brain and illustrates how white matter makes an essential contribution to the distributed neural networks that subserve all higher functions. WHITE MATTER DISORDERS White matter disorders that affect the brain make up a widely diverse group of diseases, injuries, and intoxications (Table 1). The range of these disorders encompasses all major categories of neurologic illness, and the variety of white matter neuropathology is impressively broad. This review focuses on disorders that prominently or exclusively involve brain white matter.

Not surprisingly, many of these clinical entities display variable degrees of cortical or subcortical gray matter damage as well, and the combination of neuropathologic involvement often introduces additional complexity. Nevertheless, consideration of the disorders in which white matter is significantly affected serves to highlight both the frequency with which white matter lesions are encountered and the tendency of these lesions to produce patterns of neurobehavioral dysfunction similar to gray matter lesions. White matter disorders can be classified as genetic, demyelinative, infectious, inflammatory, toxic, metabolic, vascular, traumatic, neoplastic, or hydrocephalic (Table 1).1,2

Each category involves a distinct pathophysiologic basis. Further, the entities within these categories also vary considerably in many clinical and neuropathologic respects.2 A comprehensive account of all white matter disorders is beyond the scope of this article, but a brief survey can show the diversity of clinical and neuropathologic phenomena. White matter disorders can affect any age group; they may first come to the attention of neurologists, psychiatrists, pediatricians, internists, geriatricians, or psychologists.

In infants and children, genetic diseases, such as metachromatic leukodystrophy (MLD), demonstrate how the failure of brain myelin to develop normally produces dysmyelination that leads to early disability and death-or rarely, in older individuals, to a common sequence of psychosis followed by dementia.6,7 In contrast, young adults are most vulnerable to demyelinative diseases such as multiple sclerosis (MS), in which inflammatory destruction of myelin-and sometimes axons-leads to neurobehavioral and neurologic disability.8 MS is an example of how a white matter disease that was formerly regarded as having little significance for behavioral neurology has proved, with the application of modern neuroimaging and clinical assessment, to have major neurobehavioral sequelae.1,2,8

Infectious diseases may produce cognitive decline by involving the white matter, as illustrated by the AIDS dementia complex9 and by progressive multifocal leukoencephalopathy.10 Similarly, noninfectious inflammatory diseases, such as systemic lupus erythematosus, can have an impact on the white matter. Both immune-related and vascular pathology may be central in generating the multiple manifestations of neuropsychiatric lupus.11 One of the most interesting observations with MRI is in the category of toxic disorders. Among the large and growing number of white matter toxins recently identified, the common industrial and household solvent toluene has been correlated with a disabling leukoencephalopathy in solvent abusers that correlates with the severity of dementia in the abusers.12-14

Metabolic white matter disorders have been recognized as well, including dementia of vitamin B12 (cobalamin) deficiency15 that is regularly evaluated in the routine dementia workup. Among the most common white matter disorders is the subtype of vascular dementia known as Binswanger disease (BD).16,17 Closely related to BD is the recently described cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy,18,19 which may appear clinically identical to BD except for the absence of hypertension and other cerebrovascular risk factors.

Traumatic brain injury (TBI) qualifies as a white matter disorder because of the ubiquitous lesion, known as diffuse axonal injury, in the white matter of TBI patients.20 A variety of primary brain neoplasms also primarily affect white matter. Gliomatosis cerebri serves especially well to illustrate the adverse neurobehavioral consequences of neoplastic white matter infiltration.21 Finally, hydrocephalus from any cause exerts major effects on periventricular white matter. In children who have early hydrocephalus and in adults who have normal-pressure hydrocephalus, white matter damage of this type can result in major neurobehavioral sequelae.22,23

NEUROBEHAVIORAL SYNDROMES

White matter offers an excellent opportunity to study brain-behavior relationships.1-5 The key question is how myelinated systems participate in the networks on which all higher functions are thought to depend. The role of white matter tracts in human behavior can be directly addressed by evaluating individuals with white matter lesions who experience cognitive dysfunction, emotional distress, or both. For the neurologist, a thorough history taking and physical examination can be joined with neuroimaging and other tests to yield a powerful method of correlating the lesion with the behavioral alteration. In practice, a syndrome diagnosis is crucial, because it is important that syndromes such as dementia, amnesia, aphasia, agnosia, visuospatial dysfunction, neglect, and executive dysfunction be distinguished from one another before specific diagnostic tests and therapeutic modalities are recommended.

The syndrome approach proves particularly helpful in considering the white matter disorders, in which a surprising number of neurobehavioral syndromes-in addition to well-known elemental neurologic deficits-may be encountered. Many patients with white matter disorders, in fact, present with neurobehavioral issues even before other neurologic features come to clinical attention. A thorough review of the white matter disorders reveals that these syndromes can be classified as involving cognitive impairment, focal neurobehavioral disturbances, or neuropsychiatric dysfunction (Table 2).1,2

COGNITIVE IMPAIRMENT

Cognitive impairment, broadly defined as a deficit in intellectual function, is the most common neurobehavioral syndrome that can be related to white matter pathology. This syndrome may manifest as cognitive dysfunction that may be so subtle that distinguishing it from normal mentation may be difficult; in many cases, however, the disturbance is sufficiently florid to merit the term “dementia.”1,2 Cognitive impairment results from diffuse white matter involvement, reflecting the typically scattered distribution of white matter neuropathology that produces widespread dysfunction. In contrast, focal syndromes are far less common.1,2

The relative rarity of focal neurobehavioral syndromes is apparent from studies of MS, in which cognitive dysfunction or dementia may afflict as many as 65% of patients,24 whereas aphasia occurs in fewer than 1%.25 Similarly, although neuropsychiatric syndromes, such as depression, are frequent in patients with white matter disorders, the prevalence of these syndromes remains uncertain. Also, because they may stem from many etiologies, there is a less secure association with white matter pathology. Thus, cognitive impairment, especially when it reaches the stage of dementia, is the most important source of clinical distress and functional disability that results from white matter damage. White matter dementia, as a term, was introduced in 1988 to call attention to the morbidity caused by disabling cognitive impairment in patients with white matter disorders.26 Although cognitive dysfunction is more common than dementia in early stages of white matter dementia-and may be the presenting feature27-its severity as the disease progresses may justify a diagnosis of dementia. For example, an estimated 10% to 20% of patients with MS-a disease that typically involves little or no overt cognitive impairment initially-will develop dementia at some point in the disease course.28 The implication of this observation is that among the many benefits of developing effective interventions at an early stage may be the prevention of dementia.

Because understanding the origin of dementia and reducing its prevalence are such high priorities for neurologists, a justification for the concept of white matter dementia is to alert clinicians to the importance of early diagnosis and treatment. Despite the neuropathologic diversity of the white matter disorders, a remarkable similarity in the cognitive profiles of the many afflictions can be discerned.1,2 Only a general portrait of white matter disorders can be given currently; relevant clinical observations have been unsystematic and difficult to compare.

However, a preliminary profile of deficits and strengths seen in patients with white matter disorders has emerged that may prove useful in diagnosis, counseling, rehabilitation, and research on new therapeutic strategies.1,2 This profile consists of the following: sustained attention deficit, executive dysfunction, memory-retrieval deficit, visuospatial impairment, psychiatric dysfunction, and normal language; extrapyramidal function; and procedural memory. Sustained attention deficits, executive dysfunction, and memory-retrieval deficits may be especially salient. These problems are typical in patients with white matter disorders and relate to a slowing of cognition-what is often referred to neuropsychologically as impaired speed of information processing.2 Neuroanatomically, these disturbances are all closely associated with frontal lobe dysfunction, and most white matter disorders show a predilection for the frontal white matter.2 Even when white matter lesions are located in more posterior sites of the cerebrum, frontal lobe functions are still affected.29

This probably reflects the dense connectivity between the frontal and other regions. In contrast, language is usually normal or only mildly affected because the language-related cortex is spared,1,2 which may lead the clinician to overlook cognitive dysfunction involving nonlinguistic domains. The validity of the concept of white matter dementia is supported by substantial neuropsycho-logical, neuroimaging, and neuropathologic evidence. Neuropsychological studies have suggested that white matter dementia differs clinically from both the cortical and the subcortical dementias. In contrast to cortical dementias, such as Alzheimer disease, white matter dementia shows a retrieval deficit, but not an encoding deficit, in declarative memory; more impaired sustained attention; and relatively spared language. Unlike subcortical dementias, such as Huntington disease, white matter dementia shows spared procedural memory and extrapyramidal function.1,2 Neuroimaging studies have established at least modest correlations between cerebral white matter abnormality and the degree of dementia in white matter disorders, and more advanced MRI techniques promise to refine these investigations.1,2 Finally, neuropathologic observations, when available, have typically demonstrated that the degree of cerebral white matter pathology-of any type-predicts the severity of dementia.

FOCAL NEUROBEHAVIORAL SYNDROMES

In addition to cognitive loss and dementia, a wide range of focal neurobehavioral syndromes has been described (Table 2).2 The unique feature of these syndromes is that they identify a restricted area of the brain that has been damaged, thus producing an isolated neurobehavioral deficit. Classic focal syndromes in behavioral neurology, such as aphasia, apraxia, agnosia, and amnesia, have formed the foundation of brain-behavior relationships as currently understood.3-5 Although these syndromes are considered to be more common with cortical lesions, recent findings have confirmed that they also may occur after white matter damage.2 For example, conduction aphasia related to an acute MS plaque in the left arcuate fasciculus has been reported,30 which confirms the classic teaching on the role of this tract in language repetition.3

The critical point is that focal syndromes are associated with discrete, isolated white matter lesions; in contrast, white matter dementia results from the more typical widespread pathology of white matter disorders. Although less common than syndromes caused by diffuse white matter damage, the focal neurobehavioral syndromes illustrate the importance of white matter tracts in all mental domains.

NEUROPSYCHIATRIC SYNDROMES

Structural changes of white matter also have been associated with a wide spectrum of emotional disturbances, constituting a group that can be referred to as the neuropsychiatric syndromes.2 Neuropsychiatric dysfunction is a broad category that defies precise characterization, but many patients manifest clinically significant emotional disorders that may have a neurologic basis. New information indicates that these problems may be associated with abnormal white matter. These disturbances are less clearly defined than the neurobehavioral syndromes, because the correlation of white matter pathology with clinical syndromes is less defined. Some suggestion exists that the burden of white matter pathology contributes to emotional dysfunction, but other factors play a role as well, and the origin of psychiatric impairment must be considered multifactorial. It is useful to divide the neuropsychiatric syndromes into 2 general groups: psychiatric problems that may occur in patients with known white matter disorders and psychiatric diseases in which white matter abnormalities have been identified (Table 2).

Numerous reports have documented the presence of syndromes such as depression, mania, psychosis, and euphoria in patients with white matter disorders.2 In psychiatric diseases, typically considered idiopathic and unrelated to known structural brain damage, research with MRI techniques has disclosed subtle changes in the structure of white matter. In schizophrenia, for example, microstructural white matter abnormalities implying altered cerebral connectivity have been found.31 Evidence also is accumulating to support an association between white matter changes and geriatric depression.32 Detailed examination of the white matter may offer new insights into psychiatric disease by concentrating on disruption of the neural networks devoted to emotional function. MAGNETIC RESONANCE IMAGING Although the appearance of CT in the 1970s greatly improved the clinical imaging of the brain, it was the advent of MRI in the 1980s that first enabled the detailed visualization of white matter structure.2

In particular, the capacity of T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences to permit the viewing of myelinated regions led to MRI becoming the preferred method for imaging white matter and its disorders. Neurology has been changed as much by MRI as by its predecessor CT. MRI, for example, has become the most important diagnostic test for MS because of its excellent imaging of demyelinative lesions in the CNS. Old disorders became better understood with MRI, and new ones were soon discovered.2 The early use of MRI in patients presenting with neurobehavioral symptoms and signs suggesting white matter involvement often reveals these disorders when more effective intervention is still possible. After the detection of white matter lesions, the identification of individual white matter disorders can proceed using specific clinical features analysis, neuroimaging, selected blood and cerebrospinal fluid (CSF) studies, and other investigations as indicated by the neurologic picture.

To illustrate, a strong family history, widespread dysmyelination, and genetic testing may point to MLD.2,7 A history of episodic neurologic events, periventricular demyelination, and oligoclonal bands in the CSF may confirm MS.2,8 Infectious, inflammatory, toxic, metabolic, vascular, traumatic, neoplastic, and hydrocephalic disorders can be similarly diagnosed using a standard neurologic approach.2 In some cases, specific neurobehavioral syndromes can be detected by neuropsychological testing, a highly sensitive-but not necessarily specific-procedure. Neuropsychology is most helpful in detection of early or subtle cases of white matter dysfunction, such as toxic leukoencephalopathies,13 when standard medical or neurologic evaluation is inconclusive. The testing may be equally helpful in concluding that the patient has no deficits or in identifying psychiatric disease such as conversion disorder or malingering.

CLINICAL DECISION MAKING

The recognition of neurobehavioral dysfunction in white matter disorders may not be straightforward. Many patients present with subtle cognitive symptoms and signs, frequently commingled with other neurologic or medical features of their disease; this challenges the clinician to interpret the relationship of white matter burden to cognitive status. The range of clinical features heralding the onset of white matter involvement is impressively broad and may include inattention, executive dysfunction, confusion, memory loss, personality change, depression, somnolence, lassitude, or fatigue. The nonspecific clinical profile of many affected patients often suggests a primary psychiatric disorder. Indeed, many patients with white matter dementia had psychiatric dysfunction that antedated measurable cognitive impairment. This interplay of cognitive and emotional features may prove particularly perplexing. An awareness of the potential for white matter disorders to lead to neurobehavioral dysfunction is essential, and the early use of MRI and other tests is often definitive. Also frequent is the detection of unexpected white matter changes on MRI that introduce new complexities in the clinical picture.

Especially in older people, white matter hyperintensities on MRI are common but not always clinically relevant. Review of the history and physical examination in concert with specific features of the white matter abnormality can often reveal a likely etiology, and the evaluation can be directed accordingly. Clinicians should avoid the equally perilous pitfalls of ignoring potentially significant white matter abnormalities and, conversely, ascribing too much importance to trivial ones.

FUTURE DIRECTIONS

In recent years, the visualization of white matter has been improved by more sophisticated MRI techniques. Diffusion tensor imaging (DTI) is an ideal tool for this, because it can reveal the course and structural integrity of specific tracts and can permit investigation of their participation in cognitive and emotional operations.33-35 This technique is based on the principle of anisotropy, a term referring to the propensity for water to diffuse along the direction of white matter tracts. In contrast, damaged white matter is characterized by isotropic diffusion, which is correspondingly less directional and more random. DTI can thus better define the anatomy of normal white matter tracts, as well as the changes they undergo when subjected to various neuropathologic processes.33-35

The application of DTI to both normal and abnormal white matter may offer a major step forward for clinicians, who may soon be able to identify individual tracts with the same specificity with which clinicians identify cortical regions and basal ganglia today. By improving the understanding of the origin, course, and destination of white matter tracts, DTI may redefine the neuroanatomy of white matter. Paralleling advances in structural neuroimaging are technologies for the examination of brain function. The cerebral cortex has been the focus of these methods because of its high degree of metabolic activity. The 2 most familiar of these methods are positron emission tomography36 and single photon emission CT.37 More recently, functional MRI (fMRI) has been added to the armamentarium of functional neuroimag-ing methods. Although some technical issues remain problematic, fMRI potentially offers more refined analyses of brain-behavior relationships.38 Structural and functional neuroimaging are complementary in the pursuit of understanding the architecture of higher function. Gray matter, particularly of the cerebral cortex, is inextricably linked to white matter tracts in the distributed neural networks subserving all domains of mental activity.39 Functional neuroimaging can identify cortical regions involved in cognitive processing, while DTI and other related methods can establish the connectivity between these areas. A combination of techniques capable of characterizing gray and white matter components of distributed neural networks will help formulate a unifying picture,40 and in so doing, will advance the practice of neurology. CHRISTOPHER M. FILLEY, MD, is a professor in the departments of neurology and psychiatry, University of Colorado School of Medicine, and a neurologist at the Denver Veterans Affairs Medical Center. REFERENCES 1. Filley CM. The behavioral neurology of cerebral white matter. Neurology. 1998;50:1535-1540. 2. Filley CM. The Behavioral Neurology of White Matter. New York: Oxford University Press; 2001. 3. Geschwind N. Disconnexion syndromes in animals and man. Brain. 1965;88:237-294, 585-644. 4. Mesulam MM. Large-scale neurocognitive networks and distributed processing for attention, language, and memory. Ann Neurol. 1990;28:597-613. 5. Mesulam MM. Behavioral neuroanatomy: large-scale neural networks, association cortex, frontal syndromes, the limbic system, and hemispheric specializations. In: Mesulam MM. Principles of Behavioral and Cognitive Neurology. 2nd ed. New York: Oxford University Press; 2000. 6. Filley CM, Gross KF. Psychosis with cerebral white matter disease. Neuropsychiatry Neuropsychol Behav Neurol. 1992;5:119-125. 7. Hyde TM, Ziegler JC, Weinberger DR. Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. Arch Neurol. 1992;49:401-406. 8. Feinstein A. The Clinical Neuropsychiatry of Multiple Sclerosis. Cambridge: Cambridge University Press; 1999. 9. Bencherif B, Rottenberg DA. Neuroimaging of the AIDS dementia complex. AIDS. 1998;12:233-244. 10. Berger JR, Concha M. Progressive multifocal leukoencephalopathy: the evolution of a disease once considered rare. J Neurovirol. 1995;1:5-18. 11. West SG. Neuropsychiatric lupus. Rheum Dis Clin North Am. 1994;20:129-158. 12. Filley CM, Heaton RK, Rosenberg NL. White matter dementia in chronic toluene abuse. Neurology. 1990;40(3 pt 1):532-534. 13. Filley CM, Kleinschmidt-DeMasters BK. Toxic leukoencephalopathy. N Engl J Med. 2001;345:425-432. 14. Filley CM, Halliday W, Kleinschmidt-DeMasters BK. The effects of toluene on the central nervous system. J Neuropathol Exp Neurol. 2004;63:1-12. 15. Kealey SM, Provenzale JM. Tensor diffusion imaging in B12 leukoencephalopathy. J Comput Assist Tomogr. 2002;26:952-955. 16. Caplan LR. Binswanger’s disease-revisited. Neurology. 1995;45:626-633. 17. Kramer JH, Reed BR, Mungas D, et al. Executive dysfunction in subcortical ischaemic vascular disease. J Neurol Neurosurg Psychiatry. 2002;72:217-220. 18. Filley CM, Thompson LL, Sze CI, et al. White matter dementia in CADASIL. J Neurol Sci. 1999;163:163-167. 19. Harris JG, Filley CM. CADASIL: neuropsychological findings in three generations of an affected family. J Int Neuropsychol Soc. 2001;7:768-774. 20. Hurley RA, McGowan JC, Arfanakis K, Taber KH. Traumatic axonal injury: novel insights into evolution and identification. J Neuropsychiatry Clin Neurosci. 2004;16:1-7. 21. Filley CM, Kleinschmidt-DeMasters BK, Lillehei KO, et al. Gliomatosis cerebri: neurobehavioral and neuropathological observations. Cogn Behav Neurol. 2003;16:149-159. 22. Fletcher JM, Bohan TP, Brandt ME, et al. Cerebral white matter and cognition in hydrocephalic children. Arch Neurol. 1992;49:818-824. 23. Del Bigio MR. Neuropathological changes caused by hydrocephalus. Acta Neuropathol (Berl). 1993;85:573-585. 24. Rao SM. Cognitive function in patients with multiple sclerosis: impairment and treatment. Int J MS Care. 2004;1:9-22. 25. Lacour A, De Seze J, Revenco E, et al. Acute aphasia in multiple sclerosis: a multicenter study of 22 patients. Neurology. 2004;62:974-977. 26. Filley CM, Franklin GM, Heaton RK, Rosenberg NL. White matter dementia: clinical disorders and implications. Neuropsychiatry Neuropsychol Behav Neurol. 1988;1:239-254. 27. Franklin GM, Nelson LM, Filley CM, Heaton RK. Cognitive loss in multiple sclerosis. Case reports and review of the literature. Arch Neurol. 1989;46:162-167. 28. Rao SM. White matter disease and dementia. Brain Cogn. 1996;31:250-268. 29. Tullberg M, Fletcher E, DeCarli C, et al. White matter lesions impair frontal lobe function regardless of their location. Neurology. 2004;63:246-253. 30. Arnett PA, Rao SM, Hussain M, et al. Conduction aphasia in multiple sclerosis: a case report with MRI findings. Neurology. 1996;47:576-578. 31. Davis KL, Stewart DG, Friedman JI, et al. White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry. 2003;60:443-456. 32. Alexopoulos GS, Kiosses DN, Choi SJ, et al. Frontal white matter microstructure and treatment response of late-life depression: a preliminary study. Am J Psychiatry. 2002;159:1929-1932. 33. Wakana S, Jiang H, Nagae-Poetscher LM, et al. Fiber tract-based atlas of human white matter anatomy. Radiology. 2004;230:77-87. 34. Moseley M, Bammer R, Illes J. Diffusion-tensor imaging of cognitive performance. Brain Cogn. 2002;50:396-413. 35. Taylor WD, Hsu E, Krishnan K, MacFall JR. Diffusion tensor imaging: background, potential, and utility in psychiatric research. Biol Psychiatry. 2004;55:201-207. 36. Cabeza R, Nyberg L. Imaging cognition: an empirical review of PET studies with normal subjects. J Cogn Neurosci. 1997;9:1-26. 37. Alavi A, Hirsch LJ. Studies of central nervous system disorders with single photon emission computed tomography and positron emission tomography: evolution over the past 2 decades. Semin Nucl Med. 1991;21:58-81. 38. Prichard JW, Cummings JL. The insistent call from functional MRI. Neurology. 1997;48:797-800. 39. Mesulam MM. Brain, mind, and the evolution of connectivity. Brain Cogn. 2000;42:4-6. 40. Werring DJ, Clark CA, Parker GJ, et al. A direct demonstration of both structure and function in the visual system: combining diffusion tensor imaging with functional magnetic resonance imaging. Neuroimage. 1999;9:352-361.

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University Rutgers University, Stony Brook University

Multiple sclerosis may originate in a different part of the brain than previously believed, a finding that could explain why progress toward discovering the cause has been so elusive.

Until recently, most research on MS, a disease that affects up to half a million people in the United States, has focused on the brain’s white matter, which contains the nerve fibers.

And for good reason: symptoms of the disease, which include muscle weakness and vision loss, occur when there is deterioration of a fatty substance called myelin. The substance coats nerves contained in the white matter and acts as insulation for them.

When myelin in the brain is degraded, apparently by the body’s own immune system, and the nerve fiber is exposed, transmission of nerve impulses can be slowed or interrupted. So when patients’ symptoms flare up, the white matter is where the action in the brain appears to be.

But new research published in the journal PLOS ONE, suggests scientists should look more to the gray matter and less to the white. That approach could give physicians effective tools to treat MS far earlier than ever before.

Steven Schutzer, a a physician and scientist at Rutgers, attacked the problem from a new direction. He analyzed patients’ cerebrospinal fluid (CSF) by taking full advantage of a combination of technologies called proteomics and high-resolution mass spectrometry.

“Proteins present in the clear liquid that bathes the central nervous system can be a window to physical changes that accompany neurological disease,” he says, “and the latest mass spectrometry techniques allow us to see them as never before.”

In this study, he used that novel approach to compare the cerebrospinal fluid of newly diagnosed MS patients with that of longer term patients, as well as fluid taken from people with no signs of neurological disease.

What Schutzer found startled one of his co-investigators, Patricia K. Coyle of Stony Brook University. The proteins in the CSF of the new MS patients suggested physiological disruptions not only in the white matter of the brain where the myelin damage eventually shows up.

They also pointed to substantial disruptions in the gray matter, a different part of the brain that contains the axons and dendrites and synapses that transfer signals between nerves.

Several scientists have in fact hypothesized that there might be gray matter involvement in early MS, but the technology needed to test their theories did not yet exist.

The critical initial target

Schutzer’s analysis, which Coyle calls “exquisitely sensitive,” provides the solid physical evidence for the very first time.

It includes a finding that nine specific proteins associated with gray matter are far more abundant in patients who had just suffered their first attack than in longer term MS patients or in the healthy controls.

“This evidence indicates gray matter may be the critical initial target in MS rather than white matter,” says Coyle. “We may have been looking in the wrong area.”

That realization presents exciting possibilities, Coyle says. One is that patients who suffer attacks that appear related to MS could have their cerebrospinal fluid tested quickly. If proteins that point to early MS are found, helpful therapy could begin at once, before the disease can progress further.

The findings may also lead one day to more effective treatments for MS with far fewer side effects. Without specific knowledge of what causes multiple sclerosis, patients now need to take medications that can broadly weaken their immune systems.

These drugs slow the body’s destruction of myelin in the brain, but also degrade the immune system’s ability to keep the body healthy in other ways. The new research may set the stage for more targeted treatments that attack MS while preserving other important immune functions.

Schutzer sees an even broader future for the work he is now doing. He also has used advanced analysis of cerebrospinal fluid to identify physical markers for neurological ailments that include Lyme disease and chronic fatigue syndrome.

“When techniques are refined, more medical conditions are examined, and costs per patient come down, one day there could be a broad panel of tests through which patients and their doctors can get early evidence of a variety of disorders, and use that knowledge to treat them both more quickly and far more effectively than is possible now. ”

This National Institutes of Health funded the study.

Source: Rutgers

Celgene is now part of Bristol-Myers Squibb

For decades, researchers seeking to develop new treatment options for multiple sclerosis (MS) believed that it was primarily a disease of the brain’s white matter, but recent studies have highlighted that grey matter plays an important role as well. For instance, grey matter loss, known as atrophy, may be seen in early stages of the disease and is associated with worsening symptoms.

As part of this year’s efforts to raise awareness of the disease during World MS Day on May 30, Dr. Robert Zivadinov, professor of Neurology and director of the Buffalo Neuroimaging Analysis Center and Center for Biomedical Imaging at Clinical Translational Science Institute at the University of Buffalo, explains researchers’ evolving understanding of the role of grey matter damage in MS.

DR. ROBERT ZIVADINOV FROM THE UNIVERSITY OF BUFFALO BELIEVES UNRAVELING THE ROLE OF GREY MATTER IN MULTIPLE SCLEROSIS MAY HAVE IMPLICATIONS FOR FUTURE TREATMENTS.

MS was previously considered to affect white matter primarily. How has that understanding evolved to include grey matter?

“About 15 years ago, improved imaging techniques revealed that large areas of grey matter were affected in patients. This evidence helped explain why some patients had such severe disease but relatively few damaged areas in the white matter, known as lesions.”

Are there specific regions of grey matter that are affected by MS?

“Not all parts of the grey matter are equally affected. There’s definitely significant involvement of the cortical layers of the brain’s grey matter, which is linked to symptoms such as fatigue, cognitive changes and memory loss.

“The deep grey matter is also involved in MS as well, and in particular the thalamus, which relays motor signals and regulates things like consciousness, sleep and alertness.”

“Some studies have found that grey matter atrophy correlates with disability, cognitive impairment and disease progression better than white matter.”

What do researchers know about the connection between the loss of grey matter, cognitive dysfunction, disability and MS progression?

“Many studies have found links between grey matter damage with both physical and cognitive impairment in patients with MS, including symptoms such as muscle control, sensory perception and memory. Some studies have found that grey matter atrophy correlates with disability, cognitive impairment and disease progression better than white matter lesions do.

“Studies also suggest that grey matter lesions occur rather early on, particularly in relapsing-remitting MS, even before white matter lesions appear. It could very well be a potential marker for predicting disease progression.”

What is preventing it from becoming a more useful predictor of disease progression?

“Grey matter lesions are less pronounced than white brain lesions, so doctors have difficulty seeing them on typical MRIs. Instead, we have to use advanced, highly sensitive MRI techniques to measure changes in grey matter, but those techniques aren’t available everywhere. They require specialized equipment and expertise that is typically only found in academic research centers. That is one reason why grey matter atrophy has had limited use in the clinic.”

What do we still not understand about grey matter atrophy in people with MS?

“We still don’t understand what causes the damage. Grey matter atrophy is associated with several genetic, viral and environmental risk factors, but we haven’t pinpointed the mechanisms yet.”

What can be done to reduce the risk of damage to grey matter?

“That’s the holy grail. Most MS trials weren’t necessarily designed to answer that question. We are going to have to change the design of MS trials. Instead of only using MRIs of white matter lesions as an endpoint, we’ll need more sensitive imaging techniques to monitor grey matter changes over time as well.”

To learn more about how MS affects the brain over a lifetime, read “How Multiple Sclerosis Affects the Brain and CNS.”

Dr. Robert Zivadinov is a paid consultant for Celgene.

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