Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis.

Importance: Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. Objective: To identify CSF biological measures associated with progressive MS pathobiology. Design, Setting, and Participants: This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Exposures: Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Main Outcomes and Measures: Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). Results: The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). Conclusions and Relevance: In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

No Evidence of Disease Activity (NEDA) as a Clinical Assessment Tool for Multiple Sclerosis: Clinician and Patient Perspectives [Narrative Review].

The emergence of high-efficacy therapies for multiple sclerosis (MS), which target inflammation more effectively than traditional disease-modifying therapies, has led to a shift in MS management towards achieving the outcome assessment known as no evidence of disease activity (NEDA). The most common NEDA definition, termed NEDA-3, is a composite of three related measures of disease activity: no clinical relapses, no disability progression, and no radiological activity. NEDA has been frequently used as a composite endpoint in clinical trials, but there is growing interest in its use as an assessment tool to help patients and healthcare professionals navigate treatment decisions in the clinic. Raising awareness about NEDA may therefore help patients and clinicians make more informed decisions around MS management and improve overall MS care. This review aims to explore the potential utility of NEDA as a clinical decision-making tool and treatment target by summarizing the literature on its current use in the context of the expanding treatment landscape. We identify current challenges to the use of NEDA in clinical practice and detail the proposed amendments, such as the inclusion of alternative outcomes and biomarkers, to broaden the clinical information captured by NEDA. These themes are further illustrated with the real-life perspectives and experiences of our two patient authors with MS. This review is intended to be an educational resource to support discussions between clinicians and patients on this evolving approach to MS-specialized care.

Recent progress in multiple sclerosis (MS) has led to the development of new treatments, known as high-efficacy therapies. Compared with previous treatments, high-efficacy therapies are better at managing visible inflammation of the central nervous system, a main cause of worsening symptoms early on in people living with MS. Treatment with high-efficacy therapies means many people with MS may achieve better outcomes than previously possible. One such outcome is the set of criteria known as no evidence of disease activity (NEDA). Achieving NEDA-3, the most commonly used NEDA criteria, means that people exhibit no clinical relapses, no worsening of physical symptoms, and no visible disease activity on a magnetic resonance imaging scan. Researchers have studied NEDA as an outcome in MS clinical trials, but it may be useful in clinical practice as a tool for doctors to measure a person's disease progression and response to treatment. This could help to inform important decisions around treatment selection and improve overall care for people with MS. This review explores the available information about NEDA to understand its potential to support clinical decision-making and patient evaluations. We discuss the barriers to NEDA being used in clinical practice and the ways the criteria may change to capture a broader range of clinical information from the patient. These topics are presented alongside the real-life perspectives and experiences of our two patient authors with MS. This review is meant to be an educational resource to assist conversations about NEDA between clinicians and patients in everyday clinical practice.

Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Disease correlates of rim lesions on quantitative susceptibility mapping in multiple sclerosis.

Quantitative susceptibility mapping (QSM), an imaging technique sensitive to brain iron, has been used to detect paramagnetic rims of iron-laden active microglia and macrophages in a subset of multiple sclerosis (MS) lesions, known as rim+ lesions, that are consistent with chronic active lesions. Because of the potential impact of rim+ lesions on disease progression and tissue damage, investigating their influence on disability and neurodegeneration is critical to establish the impact of these lesions on the disease course. This study aimed to explore the relationship between chronic active rim+ lesions, identified as having a hyperintense rim on QSM, and both clinical disability and imaging measures of neurodegeneration in patients with MS. The patient cohort was composed of 159 relapsing-remitting multiple sclerosis patients. The Expanded Disability Status Scale (EDSS) and Brief International Cognitive Assessment for Multiple Sclerosis, which includes both the Symbol Digit Modalities Test and California Verbal Learning Test-II, were used to assess clinical disability. Cortical thickness and thalamic volume were evaluated as imaging measures of neurodegeneration. A total of 4469 MS lesions were identified, of which 171 QSM rim+ (3.8%) lesions were identified among 57 patients (35.8%). In a multivariate regression model, as the overall total lesion burden increased, patients with at least one rim+ lesion on QSM performed worse on both physical disability and cognitive assessments, specifically the Symbol Digit Modalities Test (p = 0.010), California Verbal Learning Test-II (p = 0.030), and EDSS (p = 0.001). In a separate univariate regression model, controlling for age (p < 0.001) and having at least one rim+ lesion was related to more cortical thinning (p = 0.03) in younger patients (< 45 years). Lower thalamic volume was associated with older patients (p = 0.038) and larger total lesion burden (p < 0.001); however, the association did not remain significant with rim+ lesions (p = 0.10). Our findings demonstrate a novel observation that chronic active lesions, as identified on QSM, modify the impact of lesion burden on clinical disability in MS patients. These results support further exploration of rim+ lesions for therapeutic targeting in MS to reduce disability and subsequent neurodegeneration.

Quantitative susceptibility mapping versus phase imaging to identify multiple sclerosis iron rim lesions with demyelination.

BACKGROUND AND PURPOSE: To compare quantitative susceptibility mapping (QSM) and high-pass-filtered (HPF) phase imaging for (1) identifying chronic active rim lesions with more myelin damage and (2) distinguishing patients with increased clinical disability in multiple sclerosis. METHODS: Eighty patients were scanned with QSM for paramagnetic rim detection and Fast Acquisition with Spiral Trajectory and T2prep for myelin water fraction (MWF). Chronic lesions were classified based on the presence/absence of rim on HPF and QSM images. A lesion-level linear mixed-effects model with MWF as the outcome was used to compare myelin damage among the lesion groups. A multiple patient-level linear regression model was fit to establish the association between Expanded Disease Status Scale (EDSS) and the log of the number of rim lesions. RESULTS: Of 2062 lesions, 188 (9.1%) were HPF rim+/QSM rim+, 203 (9.8%) were HPF rim+/QSM rim-, and the remainder had no rim. In the linear mixed-effects model, HPF rim+/QSM rim+ lesions had significantly lower MWF than both HPF rim+/QSM rim- (p < .001) and HPF rim-/QSM rim- (p < .001) lesions, while the MWF difference between HPF rim+/QSM rim- and HPF rim-/QSM rim- lesions was not statistically significant (p = .130). Holding all other factors constant, the log number of QSM rim+ lesion was associated with EDSS increase (p = .044). The association between the log number of HPF rim+ lesions and EDSS was not statistically significant (p = .206). CONCLUSIONS: QSM identifies paramagnetic rim lesions that on average have more myelin damage and stronger association with clinical disability than those detected by phase imaging.

Lesion features on magnetic resonance imaging discriminate multiple sclerosis patients.

BACKGROUND: Magnetic resonance imaging (MRI) provides insight into various pathological processes in multiple sclerosis (MS) and may provide insight into patterns of damage among patients. OBJECTIVE: We sought to determine if MRI features have clinical discriminative power among a cohort of MS patients. METHODS: Ninety-six relapsing remitting and seven progressive MS patients underwent myelin water fraction (MWF) imaging and conventional MRI for cortical thickness and thalamic volume. Patients were clustered based on lesion level MRI features using an agglomerative hierarchical clustering algorithm based on principal component analysis (PCA). RESULTS: One hundred and three patients with 1689 MS lesions were analyzed. PCA on MRI features demonstrated that lesion MWF and volume distributions (characterized by 25th, 50th, and 75th percentiles) accounted for 87% of the total variability based on four principal components. The best hierarchical cluster confirmed two distinct patient clusters. The clustering features in order of importance were lesion median MWF, MWF 25th, MWF 75th, volume 75th percentiles, median individual lesion volume, total lesion volume, cortical thickness, and thalamic volume (all p values <0.01368). The clusters were associated with patient Expanded Disability Status Scale (EDSS) (n = 103, p = 0.0338) at baseline and at 5 years (n = 72, p = 0.0337). CONCLUSIONS: These results demonstrate that individual MRI features can identify two patient clusters driven by lesion-based values, and our unique approach is an analysis blinded to clinical variables. The two distinct clusters exhibit MWF differences, most likely representing individual remyelination capabilities among different patient groups. These findings support the concept of patient-specific pathophysiological processes and may guide future therapeutic approaches.

Brachial plexopathy as a complication of COVID-19.

COVID-19 affects a wide spectrum of organ systems. We report a 52-year-old man with hypertension and newly diagnosed diabetes mellitus who presented with hypoxic respiratory failure due to COVID-19 and developed severe brachial plexopathy. He was not treated with prone positioning respiratory therapy. Associated with the flaccid, painfully numb left upper extremity was a livedoid, purpuric rash on his left hand and forearm consistent with COVID-19-induced microangiopathy. Neuroimaging and electrophysiological data were consistent with near diffuse left brachial plexitis with selective sparing of axillary, suprascapular and pectoral fascicles. Given his microangiopathic rash, elevated D-dimers and paucifascicular plexopathy, we postulate a patchy microvascular thrombotic plexopathy. Providers should be aware of this significant and potentially under-recognised neurologic complication of COVID-19.

QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions.

BACKGROUND: Inflammation in chronic active lesions occurs behind a closed blood-brain barrier and cannot be detected with MRI. Activated microglia are highly enriched for iron and can be visualized with quantitative susceptibility mapping (QSM), an MRI technique used to delineate iron. OBJECTIVE: To characterize the histopathological correlates of different QSM hyperintensity patterns in MS lesions. METHODS: MS brain slabs were imaged with MRI and QSM, and processed for histology. Immunolabeled cells were quantified in the lesion rim, center, and adjacent normal-appearing white matter (NAWM). Iron+ myeloid cell densities at the rims were correlated with susceptibilities. Human-induced pluripotent stem cell (iPSC)-derived microglia were used to determine the effect of iron on the production of reactive oxygen species (ROS) and pro-inflammatory cytokines. RESULTS: QSM hyperintensity at the lesion perimeter correlated with activated iron+ myeloid cells in the rim and NAWM. Lesions with high punctate or homogenous QSM signal contained no or minimally activated iron- myeloid cells. In vitro, iron accumulation was highest in M1-polarized human iPSC-derived microglia, but it did not enhance ROS or cytokine production. CONCLUSION: A high QSM signal outlining the lesion rim but not punctate signal in the center is a biomarker for chronic inflammation in white matter lesions.

Impact of Lesion Location on Longitudinal Myelin Water Fraction Change in Chronic Multiple Sclerosis Lesions.

BACKGROUND AND PURPOSE: To examine the impact of lesion location on longitudinal myelin water fraction (MWF) changes in chronic multiple sclerosis (MS) lesions. Relative hypoxia, due to vascular watershed regions of the cerebrum, has been implicated in lesion development but impact on ongoing demyelination is unknown. METHODS: Forty-eight patients with relapsing-remitting and secondary progressive MS had two MWF scans with fast acquisition, spiral trajectory, and T2prep (FAST-T2) sequence, at an interval of 2.0 (±.3) years. Lesion location was identified based upon cerebral lobe and relation to the ventricles. Change in MWF was assessed using a mixed effects model, controlling for lesion location and patient covariates. RESULTS: Average age was 42.3 (±12) years, mean disease duration was 9.7 (±9.1) years, and median Expanded Disability Status Score (EDSS) was 2.5 (±2.3). The majority of 512 chronic lesions was located in the frontal and parietal lobes (75.6%) and more often periventricular (44.7%). All occipital lesions were periventricular. The average lesion MWF decreased from baseline (.07 ± .03) to 2 years (.06 ±.03) P < .01. Lesions within the occipital lobe showed a significant reduction in MWF as compared to other lobes. CONCLUSIONS: Chronic lesions in the occipital lobe showed the greatest reduction in MWF. Neuroanatomical localization of lesions to the occipital horns of the lateral ventricles, a watershed region, may contribute to ongoing demyelination in this lesion type.

A Multi-Ligand Imaging Study Exploring GABAergic Receptor Expression and Inflammation in Multiple Sclerosis.

PURPOSE: The γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter and essential for normal brain function. The GABAergic system has been shown to have immunomodulatory effects and respond adaptively to excitatory toxicity. The association of the GABAergic system and inflammation in patients with multiple sclerosis (MS) remains unknown. In this pilot study, the in vivo relationship between GABAA binding and the innate immune response is explored using positron emission tomography (PET) with [11C] flumazenil (FMZ) and [11C]-PK11195 PET (PK-PET), a measure of activated microglia/macrophages. PROCEDURES: Sixteen MS patients had dynamic FMZ-PET and PK-PET imaging. Ten age-matched healthy controls (HC) had a single FMZ-PET. GABAA receptor binding was calculated using Logan reference model with the pons as reference. Distribution of volume ratio (VTr) for PK-PET was calculated using image-derived input function. A hierarchical linear model was fitted to assess the linear association between PK-PET and FMZ-PET among six cortical regions of interest. RESULTS: GABAA receptor binding was higher throughout the cortex in MS patients (5.72 ± 0.91) as compared with HC (4.70 ± 0.41) (p = 0.002). A significant correlation was found between FMZ binding and PK-PET within the cortex (r = 0.61, p < 0.001) and among the occipital (r = 0.61, p = 0.012), parietal (r = 0.49, p = 0.041), and cingulate (r = 0.32, p = 0.006) regions. CONCLUSIONS: A higher GABAA receptor density in MS subjects compared with HC was observed and correlated with innate immune activity. Our observations demonstrate that immune-driven GABAergic abnormalities may be present in MS.

Black African and Latino/a identity correlates with increased plasmablasts in MS.

OBJECTIVE: To determine the influence of self-reported Black African and Latin American identity on peripheral blood antibody-secreting cell (ASC) frequency in the context of relapsing-remitting MS. METHODS: In this cross-sectional study, we recruited 74 subjects with relapsing-remitting MS and 24 age-, and self-reported ethno-ancestral identity-matched healthy donors (HDs) to provide peripheral blood study samples. Subjects with MS were either off therapy at the time of study draw or on monthly natalizumab therapy infusions. Using flow cytometry, we assessed peripheral blood mononuclear cells for antibody-secreting B-cell subsets. RESULTS: When stratified by self-reported ethno-ancestry, we identified significantly elevated frequencies of circulating plasmablasts among individuals with MS identifying as Black African or Latin American relative to those of Caucasian ancestry. Ethno-ancestry-specific differences in ASC frequency were observed only among individuals with MS. By contrast, this differential was not observed among HDs. ASCs linked with poorer MS prognosis and active disease, including IgM+- and class-switched CD138+ subsets, were among those significantly increased. CONCLUSION: The enhanced peripheral blood plasmablast signature revealed among Black African or Latin American subjects with MS points to distinct underlying mechanisms associated with MS immunopathogenesis. This dysregulation may contribute to the disease disparity experienced by patient populations of Black African or Latin American ethno-ancestry.

Quantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions.

Chronic active multiple sclerosis lesions, characterized by a hyperintense rim of iron-enriched, activated microglia and macrophages, have been linked to greater tissue damage. Post-mortem studies have determined that chronic active lesions are primarily related to the later stages of multiple sclerosis; however, the occurrence of these lesions, and their relationship to earlier disease stages may be greatly underestimated. Detection of chronic active lesions across the patient spectrum of multiple sclerosis requires a validated imaging tool to accurately identify lesions with persistent inflammation. Quantitative susceptibility mapping provides efficient in vivo quantification of susceptibility changes related to iron deposition and the potential to identify lesions harbouring iron-laden inflammatory cells. The PET tracer 11C-PK11195 targets the translocator protein expressed by activated microglia and infiltrating macrophages. Accordingly, this study aimed to validate that lesions with a hyperintense rim on quantitative susceptibility mapping from both relapsing and progressive patients demonstrate a higher level of innate immune activation as measured on 11C-PK11195 PET. Thirty patients were enrolled in this study, 24 patients had relapsing remitting multiple sclerosis, six had progressive multiple sclerosis, and all patients had concomitant MRI with a gradient echo sequence and PET with 11C-PK11195. A total of 406 chronic lesions were detected, and 43 chronic lesions with a hyperintense rim on quantitative susceptibility mapping were identified as rim+ lesions. Susceptibility (relative to CSF) was higher in rim+ (2.42 ± 17.45 ppb) compared to rim- lesions (-14.6 ± 19.3 ppb, P < 0.0001). Among rim+ lesions, susceptibility within the rim (20.04 ± 14.28 ppb) was significantly higher compared to the core (-5.49 ± 14.44 ppb, P < 0.0001), consistent with the presence of iron. In a mixed-effects model, 11C-PK11195 uptake, representing activated microglia/macrophages, was higher in rim+ lesions compared to rim- lesions (P = 0.015). Validating our in vivo imaging results, multiple sclerosis brain slabs were imaged with quantitative susceptibility mapping and processed for immunohistochemistry. These results showed a positive translocator protein signal throughout the expansive hyperintense border of rim+ lesions, which co-localized with iron containing CD68+ microglia and macrophages. In conclusion, this study provides evidence that suggests that a hyperintense rim on quantitative susceptibility measure within a chronic lesion is a correlate for persistent inflammatory activity and that these lesions can be identified in the relapsing patients. Utilizing quantitative susceptibility measure to differentiate chronic multiple sclerosis lesion subtypes, especially chronic active lesions, would provide a method to assess the impact of these lesions on disease progression.

Comparison of two different methods of image analysis for the assessment of microglial activation in patients with multiple sclerosis using (R)-[N-methyl-carbon-11]PK11195.

Chronic active multiple sclerosis (MS) lesions have a rim of activated microglia/macrophages (m/M) leading to ongoing tissue damage, and thus represent a potential treatment target. Activation of this innate immune response in MS has been visualized and quantified using PET imaging with [11C]-(R)-PK11195 (PK). Accurate identification of m/M activation in chronic MS lesions requires the sensitivity to detect lower levels of activity within a small tissue volume. We assessed the ability of kinetic modeling of PK PET data to detect m/M activity in different central nervous system (CNS) tissue regions of varying sizes and in chronic MS lesions. Ten patients with MS underwent a single brain MRI and two PK PET scans 2 hours apart. Volume of interest (VOI) masks were generated for the white matter (WM), cortical gray matter (CGM), and thalamus (TH). The distribution volume (VT) was calculated with the Logan graphical method (LGM-VT) utilizing an image-derived input function (IDIF). The binding potential (BPND) was calculated with the reference Logan graphical method (RLGM) utilizing a supervised clustering algorithm (SuperPK) to determine the non-specific binding region. Masks of varying volume were created in the CNS to assess the impact of region size on the various metrics among high and low uptake regions. Chronic MS lesions were also evaluated and individual lesion masks were generated. The highest PK uptake occurred the TH and lowest within the WM, as demonstrated by the mean time activity curves. In the TH, both reference and IDIF based methods resulted in estimates that did not significantly depend on VOI size. However, in the WM, the test-retest reliability of BPND was significantly lower in the smallest VOI, compared to the estimates of LGM-VT. These observations were consistent for all chronic MS lesions examined. In this study, we demonstrate that BPND and LGM-VT are both reliable for quantifying m/M activation in regions of high uptake, however with blood input function LGM-VT is preferred to assess longitudinal m/M activation in regions of relatively low uptake, such as chronic MS lesions.

Induction of disease remission with one cycle of alemtuzumab in relapsing-remitting MS.

OBJECTIVE: To investigate a single-course treatment with alemtuzumab in patients with relapsing-remitting multiple sclerosis. METHODS: We performed a retrospective chart review of all patients diagnosed with RRMS who were treated with alemtuzumab at our MS center and who had at least 12 month follow-up since the first dose. Data on radiological and clinical relapse were collected for the 2 years prior to patients' first dose of alemtuzumab and were tracked until the time of analysis. RESULTS: In the 2 years prior to first dose of alemtuzumab, 82.8% of the 29 patients had a new lesion on MRI and/or a clinical relapse, with an ARR of 0.67. In the mean 24.7 month follow-up after the first dose of alemtuzumab, 17.2% of patients displayed new disease activity and the ARR was 0.08. 4 out of 5 patients who relapsed did so within 12 month post-first infusion and received a second dose. Of the 24 patients who did not relapse, 8 received a second dose at 1 year and 16 did not. 5 out of all 29 patients developed thyroid disorder. CONCLUSIONS: Given that 96% of patients who did not relapse in the first 12 months following the initial dose of alemtuzumab remained relapse-free regardless of receiving a second course of drug, our data suggests that induction of disease remission for some patients might occur following just one dose of alemtuzumab. With further study, these data could support modification of the current therapy regimen.

Reduction of PK11195 uptake observed in multiple sclerosis lesions after natalizumab initiation.

OBJECTIVE: The objective of this study is to longitudinally analyze the uptake of [11C]PK11195-PET in multiple sclerosis patients after 3 and 6 months of natalizumab treatment. METHODS: Eighteen MS patients, starting treatment with monocloncal anti-VLA-4, were enrolled in a longitudinal PK-PET study. PK uptake was quantified by volume of distribution (VT) calculation using image-derived input function at baseline, 3 and 6 months. Pharmacokinetic quantification was done using a segmented MRI, and selected areas included white matter, gadolinium enhancing lesions, non-enhancing lesions, cortical grey matter and thalamus. VTs of lesions were calculated in reference to each patient's white matter (VT ratio=VTr), to consider physiologic variability. RESULTS: Test-retest variability was stable for healthy control (HC). Quantification of PK uptake was completed in 18 patients, and baseline uptake was compared to 6-month uptake. After the start of natalizumab VTr significantly decreased in 13 individual enhancing lesions present within 5 patients (p=0.001). Moreover, VTr of the sum of non-enhancing lesions showed a moderate decrease (p=0.03). No longitudinal changes were detected in normal appearing white matter, the thalamus and cortical grey matter. CONCLUSION: A reduction in PK11195 uptake was observed in both enhancing and chronic lesions after the start of natalizumab. PK11195 PET can be used as tool to assess the longitudinal change in MS lesions.

MRI in the assessment and monitoring of multiple sclerosis: an update on best practice.

Magnetic resonance imaging (MRI) has developed into the most important tool for the diagnosis and monitoring of multiple sclerosis (MS). Its high sensitivity for the evaluation of inflammatory and neurodegenerative processes in the brain and spinal cord has made it the most commonly used technique for the evaluation of patients with MS. Moreover, MRI has become a powerful tool for treatment monitoring, safety assessment as well as for the prognostication of disease progression. Clinically, the use of MRI has increased in the past couple decades as a result of improved technology and increased availability that now extends well beyond academic centers. Consequently, there are numerous studies supporting the role of MRI in the management of patients with MS. The aim of this review is to summarize the latest insights into the utility of MRI in MS.

Defining Disease Activity and Response to Therapy in MS.

OPINION STATEMENT: Disease activity in multiple sclerosis (MS) has classically been defined by the occurrence of new neurological symptoms and the rate of relapses. Definition of disease activity has become more refined with the use of clinical markers, evaluating ambulation, dexterity, and cognition. Magnetic resonance imaging (MRI) has become an important tool in the investigation of disease activity. Number of lesions as well as brain atrophy have been used as surrogate outcome markers in several clinical trials, for which a reduction in these measures is appreciated in most treatment studies. With the increasing availability of new medications, the overall goal is to minimize inflammation to decrease relapse rate and ultimately prevent long-term disability. The aim of this review is to give an overview on commonly used clinical and imaging markers to monitor disease activity in MS, with emphasis on their use in clinical studies, and to give a recommendation on how to utilize these measures in clinical practice for the appropriate assessment of therapeutic response.

An Acute Disseminated Encephalomyelitis-Like Illness in the Elderly: Neuroimaging and Neuropathology Findings.

INTRODUCTION: Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease of the central nervous system (CNS) that classically occurs in children and adolescents. It characteristically presents with acute inflammation, resulting in demyelination, often following an infectious disease. ADEM has been described in adult patients, but the incidence in the adult and especially elderly population is low. CASES: We describe five older adults (age 57 to 85) who presented with acute neurological symptoms. Three patients presented with an infectious illness preceding the event, 4 patients were encephalopathic, and oligoclonal bands (OCBs) were negative in all tested cases. The clinical scenario and imaging studies suggested alternative diagnoses, such as metastasis, primary CNS tumor, or stroke. Two patients had contrast enhancing lesions, two other patients had lesions with restricted diffusion on diffusion-weighted imaging. Neuropathologic diagnostic from biopsy or autopsy was eventually conclusive, showing perivascular zones of myelin loss with relative axonal sparing in all five cases. CONCLUSION: Each of these patients was found to have pathological findings of acute demyelination on tissue diagnosis, suggesting ADEM or ADEM-like disease. The initial presentation and imaging was pointing toward other diagnoses. Broad differential diagnosis is important, especially for older patients, and pathological proof might be warranted for a conclusive diagnosis.

A study of patients with aggressive multiple sclerosis at disease onset.

OBJECTIVE: Identify aggressive onset multiple sclerosis (AOMS) and describe its clinical course. METHODS: AOMS patients were identified from a multiple sclerosis (MS) database based on a set of criteria. The subsequent clinical course of AOMS patients was then reviewed with the goal of potentially identifying the best approaches to manage these patients. RESULTS: Fifty-eight of 783 (7.4%) patients in the MS database met the criteria for AOMS, and 43 patients who had complete data for the duration of their follow-up were included in the subsequent analysis. The mean duration of the follow-up was 54 months. Thirty-five patients (81%) were started on a conventional first-line agent (injectable therapies for MS). Only two of these 35 patients (5.7%) had no evidence of disease activity. Twenty-two of 35 patients suffering from refractory disease were switched to a more aggressive treatment (natalizumab, rituximab, alemtuzumab, cyclophosphamide). Eight patients were started on aggressive treatment as their initial therapy, and seven of these eight (87.5%) patients showed no evidence of disease activity. CONCLUSION: With recognition of the crucial significance of early optimal treatment during the potential window of opportunity for best long-term outcomes, we describe AOMS within 1 year of disease onset and discuss possible treatment considerations for these patients.