The NHLBI LAM Registry: Prognostic Physiologic and Radiologic Biomarkers Emerge From a 15-Year Prospective Longitudinal Analysis.

BACKGROUND: The natural history of lymphangioleiomyomatosis (LAM) is mainly derived from retrospective cohort analyses, and it remains incompletely understood. A National Institutes of Health LAM Registry was established to define the natural history and identify prognostic biomarkers that can help guide management and decision-making in patients with LAM. METHODS: A linear mixed effects model was used to compute the rate of decline of FEV1 and to identify variables affecting FEV1 decline among 217 registry patients who enrolled from 1998 to 2001. Prognostic variables associated with progression to death/lung transplantation were identified by using a Cox proportional hazards model. RESULTS: Mean annual decline of FEV1 was 89 ± 53 mL/year and remained remarkably constant regardless of baseline lung function. FEV1 decline was more rapid in those with greater cyst profusion on CT scanning (P = .02) and in premenopausal subjects (118 mL/year) compared with postmenopausal subjects (74 mL/year) (P = .003). There were 26 deaths and 43 lung transplantations during the evaluation period. The estimated 5-, 10-, 15-, and 20-year transplant-free survival rates were 94%, 85%, 75%, and 64%, respectively. Postmenopausal status (hazard ratio, 0.30; P = .0002) and higher baseline FEV1 (hazard ratio, 0.97; P = .008) or diffusion capacity of lung for carbon monoxide (hazard ratio, 0.97; P = .001) were independently associated with a lower risk of progression to death or lung transplantation. CONCLUSIONS: The median transplant-free survival in patients with LAM is > 20 years. Menopausal status, as well as structural and physiologic markers of disease severity, significantly affect the rate of decline of FEV1 and progression to death or lung transplantation in LAM.

Long-Term Magnetization Transfer Ratio Evolution in Multiple Sclerosis White Matter Lesions.

BACKGROUND AND PURPOSE: Magnetization transfer ratio (MTR), a magnetic resonance imaging technique used to assess tissue integrity, correlates with demyelination and axonal loss in multiple sclerosis (MS) lesions. In acute white matter lesions, short-term MTR changes mainly reflect demyelination and remyelination, in addition to edema and axonal and glial changes. Long-term MTR changes in MS lesions have not been studied extensively. METHODS: A new quantitative image analysis method was developed to measure long-term MTR changes in MS lesions. The method was applied to a group of 59 patients and 14 healthy control subjects followed for 4 years. MTR changes in white matter lesions were analyzed, where lesion voxels were classified into six categories based on starting MTR and change over time. For each patient, the proportion of lesion voxels in each MTR-change category was calculated. Correlations between long-term MTR evolution, disability progression, and brain atrophy were investigated. RESULTS: The proportion of lesion voxels in the high stable category correlated with less atrophy progression, while the proportion with low and increasing MTR correlated with increased atrophy. The proportion of lesion voxels in the high and stable MTR lesion category was significantly different between MS disease subgroups. The group with disability progression had a higher proportion of lesion voxels with low and increasing MTR. CONCLUSIONS: These results suggest that long-term changes in MTR in white matter lesions can be used to distinguish lesion subtypes associated with MS disease progression and improve understanding of the temporal evolution of MS pathology.

The Multiple Sclerosis Performance Test (MSPT): an iPad-based disability assessment tool.

Precise measurement of neurological and neuropsychological impairment and disability in multiple sclerosis is challenging. We report a new test, the Multiple Sclerosis Performance Test (MSPT), which represents a new approach to quantifying MS related disability. The MSPT takes advantage of advances in computer technology, information technology, biomechanics, and clinical measurement science. The resulting MSPT represents a computer-based platform for precise, valid measurement of MS severity. Based on, but extending the Multiple Sclerosis Functional Composite (MSFC), the MSPT provides precise, quantitative data on walking speed, balance, manual dexterity, visual function, and cognitive processing speed. The MSPT was tested by 51 MS patients and 49 healthy controls (HC). MSPT scores were highly reproducible, correlated strongly with technician-administered test scores, discriminated MS from HC and severe from mild MS, and correlated with patient reported outcomes. Measures of reliability, sensitivity, and clinical meaning for MSPT scores were favorable compared with technician-based testing. The MSPT is a potentially transformative approach for collecting MS disability outcome data for patient care and research. Because the testing is computer-based, test performance can be analyzed in traditional or novel ways and data can be directly entered into research or clinical databases. The MSPT could be widely disseminated to clinicians in practice settings who are not connected to clinical trial performance sites or who are practicing in rural settings, drastically improving access to clinical trials for clinicians and patients. The MSPT could be adapted to out of clinic settings, like the patient's home, thereby providing more meaningful real world data. The MSPT represents a new paradigm for neuroperformance testing. This method could have the same transformative effect on clinical care and research in MS as standardized computer-adapted testing has had in the education field, with clear potential to accelerate progress in clinical care and research.

Differential roles of microglia and monocytes in the inflamed central nervous system.

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.

Cognitive impairment in multiple sclerosis: An 18 year follow-up study.

BACKGROUND: Cognitive impairment occurs in 40-65% of patients with multiple sclerosis (MS). Less is known about the rate and pattern of cognitive decline over the course of the illness. OBJECTIVE: To examine long-term changes in cognition among patients enrolled in the phase III clinical trial of intramuscular interferon beta-1a (IM IFNß-1a). METHODS: Twenty-two patients underwent a longitudinal investigation comparing neuropsychological test performance at study entry and 18-year follow-up. RESULTS: Over the 18 year interval, significant declines were observed on measures of information processing speed, simple and complex auditory attention, episodic learning and memory, and visual construction. Nine patients (41%) were found to be cognitively impaired at study entry. At follow-up 13 patients (59%) were cognitively impaired. While both the impaired and unimpaired patients at baseline experienced declines on these measures, only one measure, the Symbol Digit Modalities Test (SDMT), demonstrated a group (cognitively impaired versus intact at baseline)×time interaction. This interaction was characterized by a steeper decline in the unimpaired than the impaired group at baseline. CONCLUSIONS: Over an 18 year period, our results suggest that cognitive impairment in MS progresses, with declines being most evident on measures known to be most sensitive to MS-related cognitive difficulties both cross-sectionally and longitudinally.

Reliability of classifying multiple sclerosis disease activity using magnetic resonance imaging in a multiple sclerosis clinic.

OBJECTIVE: To assess the reliability of new magnetic resonance imaging (MRI) lesion counts by clinicians in a multiple sclerosis specialty clinic. DESIGN: An observational study. SETTING: A multiple sclerosis specialty clinic. PATIENTS: Eighty-five patients with multiple sclerosis participating in a National Institutes of Health­supported longitudinal study were included. INTERVENTION: Each patient had a brain MRI scan at entry and 6 months later using a standardized protocol. MAIN OUTCOME MEASURES: The number of new T2 lesions, newly enlarging T2 lesions, and gadolinium-enhancing lesions were measured on the 6-month MRI using a computer-based image analysis program for the original study. For this study, images were reanalyzed by an expert neuroradiologist and 3 clinician raters. The neuroradiologist evaluated the original image pairs; the clinicians evaluated image pairs that were modified to simulate clinical practice. New lesion counts were compared across raters, as was classification of patients as MRI active or inactive. RESULTS: Agreement on lesion counts was highest for gadolinium-enhancing lesions, intermediate for new T2 lesions, and poor for enlarging T2 lesions. In 18% to 25% of the cases, MRI activity was classified differently by the clinician raters compared with the neuroradiologist or computer program. Variability among the clinical raters for estimates of new T2 lesions was affected most strongly by the image modifications that simulated low image quality and different head position. CONCLUSIONS: Between-rater variability in new T2 lesion counts may be reduced by improved standardization of image acquisitions, but this approach may not be practical in most clinical environments. Ultimately, more reliable, robust, and accessible image analysis methods are needed for accurate multiple sclerosis disease-modifying drug monitoring and decision making in the routine clinic setting.

Multiple sclerosis normal-appearing white matter: pathology-imaging correlations.

OBJECTIVE: The study was undertaken to determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal-appearing white matter (NAWM) in multiple sclerosis brains. METHODS: Brain tissues were obtained through a rapid postmortem protocol that included in situ magnetic resonance imaging (MRI). Four types of MRI-defined regions of interest (ROIs) were analyzed: (1) regions that were abnormal on all images (T2T1MTR lesions); (2) NAWM regions with slightly abnormal MTR located close to white matter lesions (sa-WM Close); (3) NAWM regions with slightly abnormal MTR located far from lesions (sa-WM Far); and (4) NAWM regions with normal MTR (NAWM). Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia/macrophages, astrocytes, plasma proteins, and blood vessels. RESULTS: Forty-eight ROIs from 4 secondary progressive MS brains were analyzed. sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged major histocompatibility complex II(+) microglia and macrophages detected in sa-WM Far, sa-WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area, and axonal counts. Excluding T2T1MTR lesions from analysis revealed that MTR and DTI measures in nonlesional white matter (WM) were correlated with activated microglia, but not with axonal or myelin integrity. INTERPRETATION: The pathologic substrates for MRI abnormalities in NAWM vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities.

Excessive biologic response to IFNß is associated with poor treatment response in patients with multiple sclerosis.

BACKGROUND: Interferon-beta (IFNß) is used to inhibit disease activity in multiple sclerosis (MS), but its mechanisms of action are incompletely understood, individual treatment response varies, and biological markers predicting response to treatment have yet to be identified. METHODS: The relationship between the molecular response to IFNß and treatment response was determined in 85 patients using a longitudinal design in which treatment effect was categorized by brain magnetic resonance imaging as good (n = 70) or poor response (n = 15). Molecular response was quantified using a customized cDNA macroarray assay for 166 IFN-regulated genes (IRGs). RESULTS: The molecular response to IFNß differed significantly between patients in the pattern and number of regulated genes. The molecular response was strikingly stable for individuals for as long as 24 months, however, suggesting an individual 'IFN response fingerprint'. Unexpectedly, patients with poor response showed an exaggerated molecular response. IRG induction ratios demonstrated an exaggerated molecular response at both the first and 6-month IFNß injections. CONCLUSION: MS patients exhibit individually unique but temporally stable biological responses to IFNß. Poor treatment response is not explained by the duration of biological effects or the specific genes induced. Rather, individuals with poor treatment response have a generally exaggerated biological response to type 1 IFN injections. We hypothesize that the molecular response to type I IFN identifies a pathogenetically distinct subset of MS patients whose disease is driven in part by innate immunity. The findings suggest a strategy for biologically based, rational use of IFNß for individual MS patients.

Web-based self-management for patients with multiple sclerosis: a practical, randomized trial.

OBJECTIVE: No studies have addressed the use of electronic personal health records (e-PHRs) for self-management in complex neurological disorders. We assessed and tested an Internet-based self-management system that utilized the e-PHR and determined its impact on self-assessed well-being, clinician-assessed well-being, and healthcare utilization in patients with multiple sclerosis (MS). MATERIALS AND METHODS: Subjects were randomized to usual care (a secure Web-based messaging system) or active intervention, which included secure messaging, self-monitoring, self-management of MS symptoms, and communication about upcoming clinic visits. Computers and Internet access were provided. Subjects were included if they had MS, lived within the county or region surrounding our MS center, had at least two appointments at our center in the previous 12 months, and demonstrated basic typing and computer skills. Study duration was 12 months. RESULTS: Of 220 subjects completing informed consent, 206 met the inclusion criteria. At the study's end, 83 subjects remained in the usual care group and 84 in the enhanced care group. Both groups used the available system components. The groups did not significantly differ on the primary endpoints or healthcare utilization. CONCLUSIONS: Self-management support is an emerging aspect of chronic care management. We established the feasibility of conducting a randomized, controlled trial using e-PHRs for patient self-management. We did not find that e-PHR-enabled self-management augmented multidisciplinary MS center-based care, possibly because the differences between interventions were not great enough.

Disability progression in a clinical trial of relapsing-remitting multiple sclerosis: eight-year follow-up.

OBJECTIVE: To investigate the value of Expanded Disability Status Scale (EDSS) worsening sustained for at least 6 months and other parameters as predictors for disability status. DESIGN: Retrospective analysis of the Multiple Sclerosis Collaborative Research Group study data. SETTING: The intramuscular interferon beta-1a pivotal trial was a double-blind, placebo-controlled phase 3 study. PARTICIPANTS: Patients with relapsing-remitting multiple sclerosis who received at least 2 years of treatment and completed an EDSS evaluation 8 years postrandomization. INTERVENTION: Thirty micrograms of intramuscular interferon beta-1a or placebo once weekly during the 2-year clinical trial. MAIN OUTCOME MEASURES: Positive predictive values for 6-month sustained progression during 2 years were calculated to determine the ability to predict disability status at 8 years. A multivariate logistic regression model was used to assess the relationship between predictors and EDSS milestones at follow-up. RESULTS: Forty-five patients had sustained 6-month EDSS progression during the clinical trial and 115 did not. Progression during the trial was the strongest predictor of reaching EDSS milestones at the follow-up visit, 8 years after randomization. Other independent predictors were treatment arm assignment and baseline EDSS score. CONCLUSION: In this phase 3 clinical trial of intramuscular interferon beta-1a, compared with effects of treatment, baseline EDSS score, and number of relapses during the study, worsening of 1 point or more on EDSS from baseline lasting 6 months was the strongest predictor of clinically significant disability 8 years after randomization into the clinical trial.

Heterogeneous, longitudinally stable molecular signatures in response to interferon-beta.

Interferons (IFNs) are widely used in therapy for viral, neoplastic, and inflammatory disorders, but clinical response varies among patients. The biological basis for variable clinical response is not known. We determined the primary molecular response to IFN-beta (IFN-beta) injections in 35 treatment-naïve multiple sclerosis (MS) patients using a customized cDNA macroarray with 186 interferon-stimulated genes (ISGs). Our results revealed striking interindividual heterogeneity, both in the magnitude as well as the nature of the primary molecular response to IFN-beta injections. Despite marked between-subject variability in the molecular response, responses within individual subjects were stable over a 6-month interval. Our data suggest that clinical response to IFN-beta therapy for MS differs among patients because of qualitative rather than quantitative variability in the primary molecular response to the drug.

Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS.

BACKGROUND: Gray matter (GM) pathology is an important component of the multiple sclerosis (MS) disease process. Accelerated gray matter atrophy has been observed in MS patients, but its relationship to neurological disability is not defined. This study was done to determine the relationship between whole brain, GM, and white matter (WM) atrophy and MS disability progression. METHODS: Patients with MS and Clinically Isolated Syndromes (CIS), and age- and gender-matched healthy controls were entered into an observational protocol. Baseline brain parenchymal fraction (BPF), GM fraction, and WM fraction, and change over 4 years were correlated with sustained disability progression over the entire study duration. Disability progression was measured using the Multiple Sclerosis Functional Composite (MSFC) and the Expanded Disability Status Scale (EDSS). RESULTS: Seventy MS and CIS patients and 17 HCs were studied for an average of 6.6 years (range, 3.6-7.8 years). At the final visit, 7 patients were classified as CIS, 36 as relapsing-remitting MS (RRMS), and 27 as secondary progressive MS (SPMS). Baseline whole brain, GM, and WM atrophy predicted EDSS >6.0 at the last study visit. Twenty-one (33%) patients worsened using the EDSS to define disability progression; 29 (46%) worsened using MSFC to define disability progression. Patients with MSFC progression had significantly higher GM atrophy rates compared with patients who were stable on MSFC. White matter atrophy was similar in patients with and without disability progression. Atrophy rates were not different in patients with or without disability progression defined using EDSS. CONCLUSIONS: Whole brain, GM, and WM atrophy predicted MS disability progression observed over the next 6.6 years. Gray matter atrophy rates over 4 years correlated with disability progression measured with the MSFC, but not EDSS. This indicates that MSFC defined disability progression is more closely linked to brain atrophy than EDSS defined disability progression, and provides important new insight into the poor correlation between MRI and clinical disability in MS. The findings confirm the clinical relevance of gray matter atrophy in MS.

A preliminary validation study of diffusion tensor imaging as a measure of functional brain injury.

BACKGROUND: Diffusion tensor imaging (DTI) characterizes multiple sclerosis (MS) tissue injury, although it has remained unproven whether DTI changes in disease have functional consequences. The medial longitudinal fasciculus (MLF) is a key brainstem pathway for ocular adduction and is commonly injured in patients with MS, typically resulting in internuclear ophthalmoparesis. OBJECTIVE: To validate DTI as a physiologically relevant measure of brain tissue integrity. DESIGN: A correlation study of ocular dysmotility and DTI conducted between January 2004 and September 2004. SETTING: Multiple Sclerosis Center, University of Texas Southwestern Medical Center, Dallas. Patients Six patients with chronic, unilateral, or bilateral internuclear ophthalmoparesis and 10 healthy control subjects. Main Outcome Measure We used infrared oculography to correlate the velocity versional dysconjugacy index, defined as the ratio of the velocity of the abducting to adducting eye movements during horizontal saccades, and DTI measures within the MLF as measured through an anatomical overlay. Overall diffusion was measured by mean diffusivity, and anisotropy was measured by the lattice index. RESULTS: Within the pontine MLF, the mean diffusivity was increased compared with healthy controls (P < .005), whereas the pontine lattice index was decreased (P < .03). Correlations were observed between the velocity versional dysconjugacy index and the mean diffusivity (left: r = 0.65, P < .01; right: r = 0.46, P = .07). Similar correlations were found between the versional dysconjugacy index and the lattice index (left: r = -0.43, P = .09; right: r = -0.65, P <.01). CONCLUSIONS: We identified DTI evidence of pathologic disruption of a small brainstem fiber pathway, which is crucial for accurate horizontal eye movements. In this small study, we observed correlations between the DTI changes and oculomotor dysfunction. Our preliminary observations provide criterion validity of DTI as a surrogate marker of brain tissue integrity.

Efficacy and safety of a hip flexion assist orthosis in ambulatory multiple sclerosis patients.

OBJECTIVE: To evaluate the efficacy and safety of a hip flexion assist orthosis (HFAO) in ambulatory patients with multiple sclerosis (MS). DESIGN: Fourteen week pre- and postintervention uncontrolled trial. SETTING: Outpatient rehabilitation clinic within an MS center. PARTICIPANTS: Ambulatory MS patients (N=21) with unilateral (or unilateral predominant) hip flexor weakness. INTERVENTION: Subjects were fitted with the HFAO on the weaker side, trained to use the device, and given a wear schedule. Subjects completed 2 baseline evaluations and follow-up testing at 8 and 12 weeks. MAIN OUTCOME MEASURES: Lower-extremity manual muscle testing, pain, and gait performance (Timed 25-Foot Walk, Timed Up & Go, 6-minute walk test, Mellen Center Gait Test). Subject satisfaction was evaluated by using a 9-item custom questionnaire. RESULTS: There was a statistically significant improvement of strength in the affected lower extremity at 8 and 12 weeks (effect size [ES]=0.63; ES=1.32, respectively), of pain at 12 weeks only (ES=-0.64), and of all gait tests at 8 and 12 weeks (ES range, 0.38-1.33). The overall mean satisfaction score at 12 weeks was 39 (maximum score, 45). No serious adverse events were recorded during the study. The most frequent side effect of the HFAO was low back pain (19%). No side effects led to discontinuation of the HFAO use during the study. CONCLUSIONS: The HFAO was safe and well tolerated. HFAO use was associated with significant improvement of gait performance as well as improvement of strength in the lower extremity fitted with the HFAO. Subjective reports suggest that there was an increase in daily life activity level.

Gray matter atrophy in multiple sclerosis: a longitudinal study.

OBJECTIVE: To determine gray matter (GM) atrophy rates in multiple sclerosis (MS) patients at all stages of disease, and to identify predictors and clinical correlates of GM atrophy. METHODS: MS patients and healthy control subjects were observed over 4 years with standardized magnetic resonance imaging (MRI) and neurological examinations. Whole-brain, GM, and white matter atrophy rates were calculated. Subjects were categorized by disease status and disability progression to determine the clinical significance of atrophy. MRI predictors of atrophy were determined through multiple regression. RESULTS: Subjects included 17 healthy control subjects, 7 patients with clinically isolated syndromes, 36 patients with relapsing-remitting MS (RRMS), and 27 patients with secondary progressive MS (SPMS). Expressed as fold increase from control subjects, GM atrophy rate increased with disease stage, from 3.4-fold normal in clinically isolated syndromes patients converting to RRMS to 14-fold normal in SPMS. In contrast, white matter atrophy rates were constant across all MS disease stages at approximately 3-fold normal. GM atrophy correlated with disability. MRI measures of focal and diffuse tissue damage accounted for 62% of the variance in GM atrophy in RRMS, but there were no significant predictors of GM atrophy in SPMS. INTERPRETATION: Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disabillity. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS. These findings demonstrate the clinical relevance of gray matter atrophy in MS, and underscore the need to understand its causes.

Lung transplantation in the management of patients with lymphangioleiomyomatosis: baseline data from the NHLBI LAM Registry.

BACKGROUND: In 1997, the National Heart, Lung, and Blood Institute of the National Institutes of Health established a Registry to better characterize the demographic, clinical, physiologic and radiographic features of patients with lymphangioleiomyomatosis (LAM). Herein we report data collected at enrollment from patients who had either undergone transplant prior to enrollment, underwent transplant during the 5-year study, or were evaluated/wait-listed for lung transplant during the 5-year study. METHODS: The LAM Registry enrolled patients from six clinical centers between August 1998 and October 2001. On entry, patients filled-out questionnaires covering their medical history, symptoms, treatment and quality of life (SF-36 and St. George's Respiratory Questionnaire). Enrollees underwent blood laboratory work and testing for arterial blood gases and pulmonary function. Follow-up was done at 6-month and/or yearly intervals. Diagnoses were confirmed by biopsy or typical clinical presentation plus computerized tomography (CT) findings confirmed by independent expert radiologists. A total of 243 women were enrolled. Of these, 13 (5.3%) had been transplanted at time of entry (Group A), 21 (8.6%) were transplanted during the study (Group B), and 48 (19.8%) were either wait-listed for transplant or underwent evaluation after enrollment during the study period (Group C). The remaining 161 (66.3%) registrants were neither considered for nor listed for transplant during the Registry period (Group D). RESULTS: One-third of patients in a large sample of LAM patients had either been transplanted or were being considered for transplant. At enrollment, patients who had already been transplanted and those not in need of transplant (Groups A and D) had better pulmonary function and quality-of-life scores compared with patients who subsequently underwent lung transplant during the Registry period (Group B). CONCLUSIONS: In this large Registry of LAM patients, lung transplantation appears to be associated both with significantly improved lung function and quality of life compared with patients with advanced disease.

Chemokine receptors as biomarkers in multiple sclerosis.

Leukocyte infiltrates characterize tissue inflammation and are thought to be integral in the pathogenesis of multiple sclerosis (MS). This attribute underlines the importance of understanding mechanisms of leukocyte migration. Chemokines are secreted proteins which govern leukocyte trafficking into targeted organs. Chemokine receptors (CKR) are differentially expressed on leukocytes and their modulation is a potential target for MS disease modifying therapies. Chemokines and their receptors are also potential biomarkers of both disease activity and response to treatment. We describe the fluctuations in CKR expression on peripheral leukocytes in a group of MS patients followed longitudinally for up to 36 months. We observed little fluctuation in CKR expression within each patient over time, despite considerable variability in CKR expression between patients. These observations suggest that individual patients have a CKR set point, and this set point varies from one patient to another. Evaluation of chemokines or chemokine receptors as biomarkers in MS will need to account for this individual variability in CKR expression.

Significance of T2 lesions in multiple sclerosis: A 13-year longitudinal study.

OBJECTIVE: To evaluate the relation between T2 lesions and disease severity in relapsing-remitting multiple sclerosis (MS). METHODS: This article describes a 13-year longitudinal study in 30 patients. RESULTS: Patients were 36.3 +/- 6.0 years old, had MS for 6.1 +/- 5.8 years, Expanded Disability Status Scale was 2.2 +/- 0.8, and brain parenchymal fraction (BPF) was 0.825 +/- 0.015 at study entry. At last visit, Expanded Disability Status Scale was 4.4 +/- 1.95, Multiple Sclerosis Functional Composite was -0.34 +/- 1.7, and BPF was 0.774 +/- 0.037. Baseline T2 lesion volume correlated with the BPF of the last visit (r = -0.66; p < 0.0001), magnetization transfer ratio (MTR) in normal-appearing brain tissue (r = -0.52; p = 0.004), and lesion MTR (r = -0.76; p < 0.0001). Change in T2 lesion volume in the first 2 years correlated with BPF of the last visit (r = -0.40; p = 0.03), normal-appearing brain tissue MTR (r = -0.44; p = 0.015), lesion MTR (r = -0.46; p = 0.018), Multiple Sclerosis Functional Composite scores (r = -0.50; p = 0.005), and Paced Auditory Serial Addition Task scores (r = -0.52; p = 0.003). Age was a significant covariate for clinical but not magnetic resonance imaging outcomes. INTERPRETATION: T2 lesions in relapsing-remitting MS correlate strongly with brain tissue loss and brain tissue integrity 13 years later, and with clinical disease severity, though age significantly impacts the clinical correlation. The results provide direct evidence for the disability threshold hypothesis in MS and support monitoring T2 lesions in relapsing-remitting MS.

Control of microglial neurotoxicity by the fractalkine receptor.

Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.