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Saturday, January 20, 2018

The History of Ocrevus’ - The Journey from Defiant Idea to Game-Changing Treatment

Information found below was acquired from MS NewsToday

Twenty years ago, the idea that B-cell depletion could treat multiple sclerosis would have been greeted with a hearty laugh by any well-respected neurologist or MS researcher — or perhaps a scoff. But times change and research advances.
Today, a medicine that gets rid of certain B-cells may be the most powerful drug yet developed against MS — even benefitting primary progressive patients who, until now, had no approved therapies for their condition.
With the approval of Ocrevus (ocrelizumab) now in hand, Multiple Sclerosis News Today looks at how this game changer of an MS drug came into being.

The early days

“The journey of ocrelizumab in MS started about 15 years ago,” Dr. Peter Chin, a neurologist and the principal medical director of Global Neuroscience Development at Genentech, said when Multiple Sclerosis News Today spoke to him in February.
For academic researchers, the work started even earlier. On a backdrop of skepticism, some began thinking outside the box. They had noted that autoantibodies seemed to be involved in MS disease processes, but only in conjunction with disease-causing T-cells.
But since the antibodies, seen in both human patients and animal models, were of so many different sorts, the researchers turned their sights to B-cells. A proportion of B-cells become antibody-producing plasma cells; by targeting these cells, the scientists reasoned, maybe it would be possible to get to the autoantibodies.
At that point, Genentech began to work with the academic researchers to launch a small clinical trial in patients.
The first small proof-of-concept studies yielded surprising results: It was apparent that B-cells carrying the CD20 molecule on their surface played a more prominent role in disease mechanisms than anyone had previously thought.
While the research community at large remained highly skeptical about treating MS with B-cell depleting drugs, the science began speaking for itself. The first clinical trial showed that a single administration of a B-cell depleting drug reduced the presence of inflammatory brain lesions by 91 percent, and significantly reduced relapses, measured six months after treatment.
First tested for MS was a different Genentech B-cell depleting compound — Rituxan (rituximab). It had been developed for B-cell cancers, and was gaining ground as a treatment for autoimmune conditions.
While study results showed that B-cells were, indeed, involved in MS, they largely excluded the possibility that antibodies were driving disease. The treatment effect was noted almost immediately, making it highly unlikely that the benefits were linked to reduced levels of antibodies, which take longer to control.
Genentech had initially judged the success rate for B-cell depletion in MS as “lower than 15 percent,” but quickly realized that a B-cell strategy could be more effective than any other approach taken so far.
“At that time, we had a number of B-cell targeted anti-CD20 molecules in our portfolio with different properties,” Chin said in the interview. “We advanced ocrelizumab, a humanized anti-CD20 antibody, into late-stage development because we believed it had the best potential for efficacy and safety in people with MS, a disease where long-term treatment is warranted.”
Ocrelizumab had failed in previous clinical trials involving patients with rheumatoid arthritis and systemic lupus erythematosus (both autoimmune conditions), but its path in MS would take another route.

Well-founded optimism

The first report of Ocrevus’ efficacy came in 2010, when an early analysis of a Phase 2 trial (NCT00676715) confirmed what researchers had seen with Rituxan. The study’s lead investigator called the results “among the most remarkable seen in a phase II RRMS study.”
A year later, Genentech reported that two-thirds of patients were free of disease activity in the form of brain lesions, relapses, or disability progression after being treated for nearly two years.
In addition to these preliminary, but very promising, effects, analyses showed that the treatment triggered only very low levels of anti-drug antibodies. Biological drugs, such as Ocrevus, always run the risk of becoming ineffective because of a neutralizing immune response, in which the body produces antibodies that prevent the drug from working.
These encouraging findings spurred Genentech to advance development. Not only did the company launch two Phase 3 trials — the OPERA I and OPERA II studies (NCT01247324 and NCT01412333) — in relapsing MS, it also started recruiting primary progressive patients into a third Phase 3 trial, named ORATORIO (NCT01194570).
The two relapsing MS studies compared Ocrevus with high doses of the standard-of-care drug Rebif (interferon beta-1a). Primary progressive patients were treated with either Ocrevus or placebo.

Finally, success

As researchers and patients kept working on the Phase 3 studies, several quiet years followed with few updates on the drug’s progress. Then, in 2015, Genentech released first results from the OPERA I and II trials.
Both studies had met primary and key secondary endpoints: Ocrevus reduced relapse rates, slowed the progression of disability, and minimized the number of brain lesions compared to Rebif-treated patients.
“Ocrelizumab showed remarkable improvements over a standard-of-care medicine across clinical and imaging endpoints in two pivotal studies,” said Sandra Horning, MD, chief medical officer and head of Global Product Development, at the time.
Later that year, Genentech caught the attention of primary progressive MS patients worldwide. A group that had grown accustomed to failed trials now learned that the ORATORIO trial was successful.
“This is an important moment for the MS community,” Xavier Montalban, MD, PhD, chair of the Scientific Steering Committee for the ORATORIO study and a professor of neurology and neuroimmunology at Vall d’Hebron University Hospital and Research Institute in Spain, said in a 2015 press release. “For decades, trial after trial has failed to show the benefit of any medicine for people with primary progressive MS. Now, for the first time, we have a positive Phase 3 study result for people with this debilitating form of the disease.”
For the first time in history, Genentech applied for FDA approval of Ocrevus to treat both relapsing and primary progressive MS. Today, its hard work has been rewarded.
“This pioneering science redefines our understanding of the underlying biology of MS and shows that B-cells, a type of immune system cell, play a central role in the disease,” Chin said.
In early 2016, the FDA acknowledged the impact Ocrevus had on primary progressive MS by designating it a Breakthrough Therapy. Later that year, the agency also granted Priority Review to Ocrevus’ Biologics License Application (BLA).

Final data

Genentech published data from the three Phase 3 trials — data that led to Ocrevus’ approval. The two December 2016 publications in the New England Journal of Medicine confirmed what the company had shared in various conference presentations.
In relapsing patients, the annualized relapse rates were 46% and 47% lower among the Ocrevus-group patients than among those treated with Rebif. Ocrevus-treated patients had 94% to 95% fewer new inflammatory brain lesions over the 96-week trial. The two trials also showed that 64% and 89% more patients receiving Ocrevus had “no evidence of disease activity,” or NEDA — a measure taking into account brain lesions, disability progression, and symptom relapses.
“The consistency of these pioneering data, the effect seen in these clinical studies and the favorable safety profile may support treating MS earlier with a high-efficacy disease-modifying medicine,” Stephen Hauser, MD, chair of the Scientific Steering Committee of the OPERA studies, director of the Weill Institute for Neurosciences, and chair of the Department of Neurology at theUniversity of California, San Francisco, said in a press release at the time. Hauser was among the researchers who first started exploring B-cell mechanisms in MS.
In primary progressive patients, Ocrevus lowered the risk of six-month disability progression by 25% over the 120-week trial compared to placebo. As in relapsing patients, the treatment also lowered the number of brain lesions, which were fewer at the trial’s end than at its start. Placebo-treated patients, however, continued with a steady increase in brain lesions throughout the study.
Genentech continued analyzing trial data after publication. At a recent ACTRIMS 2017 Forum, it revealed that NEDA rates in relapsing patients actually increased as treatment with Ocrevus lengthened, while no such increase was seen among Rebif-treated patients.
It also presented an analysis showing “no evidence of progression” (NEP) in patients with progressive disease. Ocrevus increased NEP by 47% compared to placebo, with a total of 42.7% of patients achieving NEP over the course of the trial.
The drug’s safety profile is surprisingly benign, given its effectiveness. The three trials found a similar extent of adverse events and infections, as well as serious adverse events and serious infections, in both Ocrevus-treated and control groups.
Its efficacy, along with this good safety profile, has people suggesting that Ocrevus should, in fact, be considered as a first-line treatment in MS, much as Hauser earlier hinted might be the case.
This optimism is, however, tempered by concerns of increased cancer risks. In all three trials, cancer rates were twice as high among those who received Ocrevus than among respective control group patients.
“Rates of malignancy with ocrelizumab treatment remain within epidemiological reports and no clear relationship between B-cell suppression and malignancy has been established,” said Chin, who also reassured patients that Genentech is working to understand why the rates were numerically higher.
“Patient safety is very important to us and we are committed to closely and continuously monitoring all safety data, including malignancy rates, in ongoing and future clinical studies.”
Orevus’ approval will also allow for the gathering of safety data beyond a clinical trial setting.
“The B-cell saga in MS has provided a cornucopia of surprises, thrilling insights, several disappointments, numerous still-to-be-solved conundrums, and also a few generic lessons,” Hauser wrote in a lecture on the topic in 2015, voicing perhaps what is now obvious: The last word has yet to be said when it comes to B-cell depletion in MS.
Or, indeed, when it comes to Ocrevus itself.


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Spoon Theory: Making Sense of Fatigue in Multiple Sclerosis

Published on Jan 20, 2018

Fatigue is one of the most common, most debilitating, and least understood of MS symptoms.
Here we discuss ways of better understanding MS pathologic fatigue.
Concepts of functional reserve and spoon theory are discussed.



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U.S. Government Shutdown's Impact on People with MS

Information provided below was made possible from The National Multiple Sclerosis Society

January 20, 2018
The federal government and its programs were operating under a continuing resolution that extended existing funding levels—but the resolution expired at midnight Eastern, January 19, 2018. Congress has not passed any of the 12 individual spending bills for FY 2018. Congressional leaders are negotiating an extension of the resolution that would fund the government at current levels through either January 23 or February 16—to give them more time to reach a bipartisan budget deal. Since the continuing resolution was not extended past January 19 and a new budget agreement was not reached, the federal government has shut down.

Government shutdown means all non-essential federal government operations are shut down until Congress passes a stopgap funding bill and/or comes to consensus on final funding levels for FY 2018. The National Multiple Sclerosis Society continues to urge Congress to take a balanced approach to resolving budgetary issues in order to get the government working again and ensure that Americans living with multiple sclerosis are not negatively impacted.

While Social Security checks and disability benefits will continue to be issued, processing of benefits may be slowed because of Social Security employees being furloughed. Another agency of utmost importance to the MS community is the National Institutes of Health (NIH). The NIH Clinical Center will continue care for current patients, but will not admit new patients unless deemed medically necessary. Funding supporting FY 2018 research grants will not be paid, slowing the momentum of vital medical research.

This document provides guidance based on the best available information about how a shutdown may impact people with MS. The National MS Society is not a government agency and does not rely on government funding. Therefore, there will be no direct impact to the Society. If you have specific questions, please contact the Society’s MS Navigators at 1-800-344-4867 (regular business hours) or online.

About Multiple Sclerosis

Multiple sclerosis is an unpredictable, often disabling disease of the central nervous system that disrupts the flow of information within the brain, and between the brain and body. Symptoms range from numbness and tingling to blindness and paralysis. The progress, severity and specific symptoms of MS in any one person cannot yet be predicted, but advances in research and treatment are leading to better understanding and moving us closer to a world free of MS. Most people with MS are diagnosed between the ages of 20 and 50, with at least two to three times more women than men being diagnosed with the disease. MS affects more than 2.3 million people worldwide.


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Friday, January 19, 2018

Things that might be causing - uh, er, uh - Brain Fog

You might feel forgetful or find it hard to focus. Maybe you can't put your thoughts into words. Could one of these things be to blame?

The Term: “Brain fog” isn’t a medical condition. It’s a term used for certain symptoms that can affect your ability to think. You may feel confused or disorganized or find it hard to focus or put your thoughts into words.

Multiple Sclerosis - This disease affects your central nervous system and can change the way your brain “talks” to the rest of your body. About half the people who have MS have issues with memory, attention, planning, or language. Learning and memory exercises can help, and a therapist can give you new ways to handle the tasks you have trouble with. 

Brain fog, also commonly known as brain fatigue, can be a mild to severe episode of mental confusion that can strike without warning. When this occurs, it is common to experience a lack of focus, poor memory recall and reduced mental acuity.

Read more


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Neuroprotective effects of testosterone treatment in men with multiple sclerosis - Low "T" can make you feel quite miserable and fatigued

Testosterone treatment is known to improve depression, decrease fatigue

1. Introduction

Multiple sclerosis (MS) is a putative autoimmune disease characterized by a relapsing–remitting disease course leading to progressive disability, inflammation, and neurodegeneration (). MS relapses are associated with inflammation and the development of white matter lesions. As a result, anti-inflammatory treatments have been developed based on their ability to reduce relapses and white matter lesions. However, inflammatory activity and white matter lesion burden are only weakly correlated with clinical disease progression (). Gray matter (GM) atrophy correlates strongly with clinical disability () and neurodegeneration in MS (). This atrophy is evident from the earliest stages of disease, even before a clinically definite diagnosis can be made () and continues throughout the disease course (). Consequently, GM atrophy has been suggested as a surrogate marker for disease progression and neurodegeneration in MS (). GM atrophy has produced different results than inflammatory markers as outcome measures in clinical trials: while anti-inflammatory treatments in MS have been shown to reduce the occurrence of inflammatory markers such as new white matter lesions or relapse rates, their effects on GM atrophy and permanent disability have been modest (). To effectively target gray matter atrophy and diminish or prevent permanent disability in MS, neuroprotective therapies are needed.
Testosterone has been shown to be neuroprotective in animal studies () including the most widely used MS model, experimental autoimmune encephalomyelitis (EAE) (). Analogously, we hypothesized that testosterone treatment in human disease may be neuroprotective and this would be reflected as a slowing of gray matter atrophy. Thus, the aim of the current study was to evaluate the effects of testosterone treatment on local changes in gray matter volume in MS. Changes in local gray matter volume were quantified using voxel-based morphometry (VBM), a sophisticated, objective whole-brain analysis technique (). Ten male patients with MS were enrolled in an open-label phase II clinical trial. The patients were observed prior to treatment for 6 months (observation phase), followed by a 12-month period of treatment with testosterone. To account for “wash-in effects”, this 12-month treatment period was divided into an initial 6-month transition phase, which allowed the drug to take action, followed by a 6-month protection phase. Statistically significant changes in GM concentration were mapped for each phase and the GM volume of these localized changes was plotted as a percent change. In addition, the annualized whole-brain GM atrophy rate was calculated in a supplementary analysis.

2. Material and methods

2.1. Study design and subjects

Participants were eligible if they met the criteria for clinically definite relapsing–remitting MS, had had at least one clinical relapse or the appearance of at least one enhancing lesion on MRI over the preceding two years, but were not receiving disease-modifying treatment. The original study has been described in detail (). Briefly, this study was an open label phase II trial to assess the safety and tolerability of testosterone treatment using 10 g of gel containing 100 mg of testosterone (Androgel) applied topically daily for one year. The ten men enrolled had a median Expanded Disability Status Scale (EDSS) score of 2.0 (range: 1.5–2.5), a median disease duration of 12.5 years (range: 0.5–25.0 years), and a mean age of 46 years (range: 29–61 years). A cross-over trial design was chosen, where subjects served as their own controls. The protocol was approved by the University of California Los Angeles (UCLA) Human Subjects Protection Committee and the institutional review board of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center.
Contrast-enhanced, FLAIR, and high-resolution T1-weighted brain MRIs were obtained every month from baseline (month 0) until the end of the trial (month 18). All ten subjects completed all nineteen monthly scans (baseline plus monthly scans for 18 months) and were included in the current analysis. Testosterone treatment started at the end of month six. To allow the drug enough time to work (“wash-in”), we divided the trial into three parts: an untreated observation phase, a transition phase, and a protection phase. The observation phase was between baseline and end of month six. The transition phase was defined as end of month six through end of month twelve, leaving the last six months of the trial as the protection phase.

2.2. Image acquisition and processing

Magnetic resonance imaging (MRI) data was acquired on a 1.5 T Siemens Sonata scanner using a T1-weighted sequence (MPRAGE) with the following parameters: TR = 1900 ms, TE = 4.38 ms, flip angle = 15°, 128 sagittal slices, matrix: 256 × 256, and voxel dimensions: 0.9375 × 0.9375 × 1.2 mm3. In addition, a Fluid Attenuated Inversion Recovery (FLAIR) sequence was obtained during the same session using the following parameters: TR = 9140 ms, TE = 100 ms, flip angle = 180°, 50 axial slices, matrix: 256 × 256, and voxel dimensions: 0.9375 × 0.9375 × 3 mm3. Brain images were processed and examined using SPM8, the LST toolbox, and the VBM8 Toolbox following previously described methods (). This processing consisted of lesion in-painting to prevent a possible confound of white matter lesions on tissue segmentation, followed by tissue-segmentation and normalization to a common reference space that allows for voxel-wise testing. Briefly, white matter lesions were automatically delineated using a lesion-growing algorithm () that used information from both the FLAIR and T1-weighted images simultaneously. The lesion growing algorithm was validated and fine-tuned using manual delineations of lesions as described (). Based on these delineations, the lesions were in-painted as white matter in the T1-weighted scans () and the in-painted images were quality controlled to assure accuracy. To accommodate for the longitudinal design of this study, the lesion in-painted images were subsequently realigned for each subject using half-way registrations and corrected for bias-field inhomogeneities using the VBM8 Toolbox (see
Further preprocessing with this toolbox included tissue-classification into gray matter, white matter, and cerebrospinal fluid followed by a registration to MNI space using linear and non-linear transformations (). More specifically, the tissue segmentation algorithm accounted for partial volume effects (), and was based on adaptive maximum a posteriori estimations (), a spatially adaptive non-local means denoising filter (), as well as a hidden Markov random field model (). This tissue classification was independent of tissue probability maps (), thus acting as an additional safeguard against a potential influence of lesions and altered geometry. Using affine registration and the non-linear DARTEL algorithm (), the individual GM and WM segments in native-space were then normalized to the DARTEL-Template supplied with the VBM8 Toolbox (see This allowed for a comparison between time-points and subjects on voxel-level, yielding an extremely high regional specificity. A quality check was performed using tools from the VBM8 Toolbox and individual visual assessment, which yielded no artifacts or failed segmentation/normalization of the data. Finally, the gray matter segments were smoothed with a Gaussian kernel (12 mm full width at half maximum). These smoothed gray matter segments constituted the input for the statistical model. For visualization, a mean template from all subjects was created using normalized whole-brain images. This way, significant results from the statistical analysis were directly superimposed on the subjects' mean anatomy for anatomic localization of significant changes in local gray matter volume.

2.3. Statistical analyses

The statistical model included all ten subjects and their smoothed gray matter segments from four time points: at baseline, after 6 months (i.e. at the end of the observation phase), after 12 months (i.e. at the end of the transition phase), and after 18 months (i.e. at the end of the protection phase). This selection allowed us to investigate the voxel-wise volume changes over the three phases of the trial. Specifically, a “subject × condition” model was generated (with condition being the four time points). In this model the inter-individual differences between subjects were modeled by the subject factor, while changes between the time points were modeled for each subject by the condition factor. To control for false positives, threshold-free cluster enhancement (TFCE) () in conjunction with family-wise error correction was used to detect significant clusters at p≤ 0.05.
Patterns of significant local change (i.e. significant gray matter decrease and increase) were visualized on a series of maximum intensity projections illustrating significant changes during the observation, transition, and protection phases. In a subsequent step, the exact locations of gray matter change during the observation and protection phases were mapped on the mean template, as described above. The time course of the volumetric changes for each significance cluster was extracted over all eighteen months of the trial and plotted as percent change to better assess the effects of testosterone therapy on gray matter volume.

2.4. Supplemental analyses

For the supplemental analysis of gray matter changes, lesion in-painted images for each time-point were corrected for bias-field inhomogeneities using the VBM8 Toolbox. Whole-brain masks were generated using the Brain Surface Extractor and manually corrected by a single investigator (AMG) in BrainSuite 13 (). Whole-brain masks were applied to the lesion in-painted images and segmented into cerebrospinal fluid, gray matter, and white matter using the FSL Automated Segmentation Tool (FAST) (), the segmentation tool used in SIENA and SIENAX (). Annualized gray matter atrophy rates were calculated for each treatment phase for each patient by calculating the best-fit line through the gray matter volume measures during the treatment period and multiplying the slope of the line (change in gray matter volume/month) by 12 months. Differences in gray matter atrophy rates between the observation, transition, and protection phases were assessed using paired t-tests.
For the supplemental analysis of white matter changes, lesion masks for each time-point were warped to MNI space and their overlap calculated. In addition, lesion volumes in native space were calculated for every subject and month (months 0–18) to assess a change in lesion volume over time. Differences in overall lesion volume between the observation and protection phases were assessed using paired t-tests. Finally, the number of gadolinium-enhancing lesions was assessed for every subject and month (months 0–18). A non-parametric Friedman test was applied to test for differences in the number of enhancing lesions between the observation and protection phases (Supplement 2).

2.5. Scan–rescan reliability

To assess the scan–rescan reliability of our measurements, ten patients were scanned within two weeks of each other and had no clinical change in their disease between scans. We determined that the average GM volume difference was 0.22% (1.2 ± 1.8 cm3).

3. Results

During the observation phase, i.e. when patients received no treatment, we observed a significant voxel-wise GM loss across the entire brain (Fig. 1aTable 1). This loss was widespread throughout cortical, subcortical, and cerebellar structures, extending from its maximum in the paracentral lobe along the central sulcus to the inferior frontal and superior parietal regions (p= 0.0004 at its maximum). The thalamus and basal ganglia also showed highly significant effects (Fig. 2a). Measurement of GM volume changes within this cluster over time demonstrated a significant decrease in the observation phase (p= 0.00006), which leveled off completely during the protection phase (Fig. 2b).
Fig. 1
Regional gray matter volume increase in testosterone treated men with MS. (a) Significant gray matter changes during the observation phase, (b) the transition phase, and (c) the protection phase, threshold at p≤ 0.05, FWE-corrected for ...
Fig. 2
Regional volume changes over time. (a) Regional GM decreases during the observation phase. Heat maps visualize regional differences in the level of significance, thresholded at p≤ 0.05, FWE-corrected for multiple comparisons. (b) The widespread ...
Table 1
Cluster-specific descriptors.
During the transition phase, substantially less GM loss was observed and instead of one large, diffuse cluster, we observed several discrete clusters (Fig. 1bTable 1). In the protection phase, essentially no further atrophy occurred. Instead, a significant increase in GM was observed in a cluster within the right frontal cortex (Fig. 1c), with a maximum located in the right middle frontal gyrus (p= 0.011) (Fig. 2cTable 1). The posterior portion of this cluster of significant gray matter increase included the motor and premotor regions, while the maximum of significance was located anterior to these regions. Measurement of GM volume changes within this cluster over time demonstrated a significant decrease in the observation phase (p= 0.00034), followed by a significant increase in the protection phase (p= 0.002) (Fig. 2d). Overall, the cluster's volume at month 18 was not statistically different from the volume at baseline (p= 0.7048).
Whole-brain gray matter changes over the course of the trial were consistent with our findings of decreased localized gray matter atrophy (Supplement 1). The annualized gray matter atrophy rate in these untreated MS patients during the observation phase (2.87%) was consistent with previous reports of gray matter atrophy rates in similar untreated or placebo-treated MS populations, specifically annualized gray matter atrophy rates of 0.86%–3.57% in the context of 0.47%–0.94% annualized percent brain parenchymal volume atrophy rates have been reported (). This pretreatment atrophy was halted in the protection phase (0.18%).
The number and volume of enhancing lesions in white matter were low in the majority of subjects, consistent with the relatively benign clinical course of the subjects choosing to not take DMTs in this trial. Given the low level of enhancement at baseline in the cohort, it was not surprising that a reduction in enhancing lesions was not observed with testosterone treatment. In fact, neither the number of enhancing lesions nor the volume of FLAIR lesions changed significantly over time. Further, no temporal or spatial relationship between lesions and GM changes was observed (Supplement 2).

4. Discussion

The widespread GM loss observed herein by VBM during the observation phase is consistent with previous observations (). Specifically, regional GM atrophy in MS has previously been shown in frontal cortical regions (), subcortical structures such as the thalamus () and caudate (), as well as in the cerebellum (). However, during testosterone treatment this GM loss was stalled diffusely and even reversed in the right frontal cortex, suggesting a treatment-related recovery of the volume loss. To our knowledge, this is the first report of a treatment-induced GM volume increase in MS, which stands in stark contrast to previous outcomes on gray matter atrophy in anti-inflammatory treatment trials (). This observation is particularly interesting since we found no significant correlations between gray matter loss and changes in white matter lesion volume or in newly occurring lesions during testosterone treatment. Since lesions are thought to be a marker of inflammatory activity, this is consistent with testosterone's effects being neuroprotective rather than anti-inflammatory. This observation also supports the notion that MS pathogenesis consists of relatively distinct inflammatory and neuroprotective components. This in turn may explain why anti-inflammatory treatments prevent relapses and newly occurring lesions, but fail to exhibit a similar impact on long-term disability and gray matter atrophy ().



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