Radiological Changes in the Spinal Cord and Brain of Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP).

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neurological disorder and shares many radiological and clinical features with other more prevalent myelopathies. Here, we quantified spinal cord and brain volumes in adults with HAM/TSP in comparison with healthy volunteers (HVs) and individuals diagnosed with relapsing-remitting or progressive multiple sclerosis (RRMS or P-MS). Clinical disability and MRI were assessed in 24 HVs, 43 HAM/TSP subjects, and 46 MS subjects.

Multiple sclerosis patient-derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease.

Epstein-Barr virus (EBV) is an aetiologic risk factor for the development of multiple sclerosis (MS). However, the role of EBV-infected B cells in the immunopathology of MS is not well understood. Here we characterized spontaneous lymphoblastoid cell lines (SLCLs) isolated from MS patients and healthy controls (HC) ex vivo to study EBV and host gene expression in the context of an individual's endogenous EBV.

Viral Immune signatures from cerebrospinal fluid extracellular vesicles and particles in HAM and other chronic neurological diseases.

Background And Objectives: Extracellular vesicles and particles (EVPs) are released from virtually all cell types, and may package many inflammatory factors and, in the case of infection, viral components. As such, EVPs can play not only a direct role in the development and progression of disease but can also be used as biomarkers. Here, we characterized immune signatures of EVPs from the cerebrospinal fluid (CSF) of individuals with HTLV-1-associated myelopathy (HAM), other chronic neurologic diseases, and healthy volunteers (HVs) to determine potential indicators of viral involvement and mechanisms of disease.

EBNA1 Inhibitors Block Proliferation of Spontaneous Lymphoblastoid Cell Lines From Patients With Multiple Sclerosis and Healthy Controls.

Background And Objectives: Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that establishes lifelong latency in memory B cells and has been identified as a major risk factor of multiple sclerosis (MS). B cell depletion therapies have disease-modifying benefit in MS. However, it is unclear whether this benefit is partly attributable to the elimination of EBV B cells.

Unstable EBV latency drives inflammation in multiple sclerosis patient derived spontaneous B cells.

Epidemiological studies have demonstrated that Epstein-Barr virus (EBV) is a known etiologic risk factor, and perhaps prerequisite, for the development of MS. EBV establishes life-long latent infection in a subpopulation of memory B cells. Although the role of memory B cells in the pathobiology of MS is well established, studies characterizing EBV-associated mechanisms of B cell inflammation and disease pathogenesis in EBV (+) B cells from MS patients are limited.

The repertoire of CSF antiviral antibodies in patients with neuroinflammatory diseases.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Although various viruses have been proposed to contribute to MS pathology, the etiology of MS remains unknown. Since intrathecal antibody synthesis is well documented in chronic viral infection and neuroinflammatory diseases, we hypothesized whether the patterns of antigen-specific antibody responses associated with various viral exposures may define patients with CNS chronic immune dysregulation.

Lesion size and shape in central vein sign assessment for multiple sclerosis diagnosis: An in vivo and postmortem MRI study.

Background: The "central vein sign" (CVS), a linear hypointensity on T2*-weighted imaging corresponding to a central vein/venule, is associated with multiple sclerosis (MS) lesions. The effect of lesion-size exclusion criteria on MS diagnostic accuracy has not been extensively studied.

Objective: Investigate the optimal lesion-size exclusion criteria for CVS use in MS diagnosis.

Cortical lesion hotspots and association of subpial lesions with disability in multiple sclerosis.

Background: Dramatic improvements in visualization of cortical (especially subpial) multiple sclerosis (MS) lesions allow assessment of impact on clinical course.

Objective: Characterize cortical lesions by 7 tesla (T) T-/T-weighted magnetic resonance imaging (MRI); determine relationship with other MS pathology and contribution to disability.

Methods: Sixty-four adults with MS (45 relapsing-remitting/19 progressive) underwent 3 T brain/spine MRI, 7 T brain MRI, and clinical testing.

Central Vein Sign Profile of Newly Developing Lesions in Multiple Sclerosis: A 3-Year Longitudinal Study.

Background And Objectives: The central vein sign (CVS), a central linear hypointensity within lesions on T2*-weighted imaging, has been established as a sensitive and specific biomarker for the diagnosis of multiple sclerosis (MS). However, the CVS has not yet been comprehensively studied in newly developing MS lesions. We aimed to identify the CVS profiles of new white matter lesions in patients with MS followed over time and investigate demographic and clinical risk factors associated with new CVS+ or CVS- lesion development.

Clinical trial of raltegravir, an integrase inhibitor, in HAM/TSP.

Objective: Human T-cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive myelopathy. A high proviral load (PVL) is one of the main risk factors for HAM/TSP. Recently, it was shown that raltegravir could inhibit cell-free and cell-to-cell transmission of HTLV-1 in vitro.

Complement component 3 from astrocytes mediates retinal ganglion cell loss during neuroinflammation.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by varying degrees of secondary neurodegeneration. Retinal ganglion cells (RGC) are lost in MS in association with optic neuritis but the mechanisms of neuronal injury remain unclear. Complement component C3 has been implicated in retinal and cerebral synaptic pathology that may precede neurodegeneration.

BK virus-specific T cells for immunotherapy of progressive multifocal leukoencephalopathy: an open-label, single-cohort pilot study.

Background: Progressive multifocal leukoencephalopathy, a rare disease of the CNS caused by JC virus and occurring in immunosuppressed people, is typically fatal unless adaptive immunity is restored. JC virus is a member of the human polyomavirus family and is closely related to the BK virus. We hypothesised that use of partly HLA-matched donor-derived BK virus-specific T cells for immunotherapy in progressive multifocal leukoencephalopathy would be feasible and safe.

Cervical and thoracic cord atrophy in multiple sclerosis phenotypes: Quantification and correlation with clinical disability.

Objective: We sought to characterize spinal cord atrophy along the entire spinal cord in the major multiple sclerosis (MS) phenotypes, and evaluate its correlation with clinical disability.

Methods: Axial T-weighted images were automatically reformatted at each point along the cord. Spinal cord cross-sectional area (SCCSA) were calculated from C1-T10 vertebral body levels and profile plots were compared across phenotypes.

Effect of Teriflunomide on Cells From Patients With Human T-cell Lymphotropic Virus Type 1-Associated Neurologic Disease.

Objective: To test the hypothesis that teriflunomide can reduce ex vivo spontaneous proliferation of peripheral blood mononuclear cells (PBMCs) from patients with human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

Methods: PBMCs from patients with HAM/TSP were cultured in the presence and absence of teriflunomide and assessed for cell viability, lymphocyte proliferation, activation markers, HTLV-1 and HTLV-1 messenger ribonucleic acid (mRNA) expression, and HTLV-1 Tax protein expression.

Results: In culture, teriflunomide did not affect cell viability.

Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease.

In this study, we examined and characterized disease-specific TCR signatures in cerebrospinal fluid (CSF) of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). TCR β libraries using unique molecular identifier-based methodologies were sequenced in paired peripheral blood mononuclear cells (PBMCs) and CSF cells from HAM/TSP patients and normal healthy donors (NDs). The sequence analysis demonstrated that TCR β repertoires in CSF of HAM/TSP patients were highly expanded and contained both TCR clonotypes shared with PBMCs and uniquely enriched within the CSF.

Progressive multifocal leukoencephalopathy lesion and brain parenchymal segmentation from MRI using serial deep convolutional neural networks.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic brain infection caused by the JC virus and associated with substantial morbidity and mortality. Accurate MRI assessment of PML lesion burden and brain parenchymal atrophy is of decisive value in monitoring the disease course and response to therapy. However, there are currently no validated automatic methods for quantification of PML lesion burden or associated parenchymal volume loss.

Paramagnetic Rim Lesions are Specific to Multiple Sclerosis: An International Multicenter 3T MRI Study.

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on magnetic resonance imaging by their paramagnetic rims, and increasing evidence supports their association with severity of clinical disease. We studied their potential role in differential diagnosis, screening an international multicenter clinical research-based sample of 438 individuals affected by different neurological conditions (MS, other inflammatory, infectious, and non-inflammatory conditions). Paramagnetic rim lesions, rare in other neurological conditions (52% of MS vs 7% of non-MS cases), yielded high specificity (93%) in differentiating MS from non-MS.

Association of Chronic Active Multiple Sclerosis Lesions With Disability In Vivo.

Importance: In multiple sclerosis (MS), chronic active lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based magnetic resonance imaging (MRI) in vivo as non-gadolinium-enhancing lesions with paramagnetic rims. Pathologically, they feature smoldering inflammatory demyelination at the edge, remyelination failure, and axonal degeneration. To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine their contribution to disability and value as a treatment target.

Clinical trial of a humanized anti-IL-2/IL-15 receptor β chain in HAM/TSP.

Objective: Human T cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neurological disease. Chronic activation of CD8 T cells, as evidenced by increased spontaneous lymphoproliferation and HTLV-1-specific cytotoxic T cells, has been demonstrated in HAM/TSP patients. Since IL-2 and IL-15 stimulate memory CD8 T cell activity, these cytokines have been implicated in the immunopathogenesis of HAM/TSP.

Pembrolizumab Treatment for Progressive Multifocal Leukoencephalopathy.

Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection that is caused by the JC virus and is typically fatal unless immune function can be restored. Programmed cell death protein 1 (PD-1) is a negative regulator of the immune response that may contribute to impaired viral clearance. Whether PD-1 blockade with pembrolizumab could reinvigorate anti-JC virus immune activity in patients with PML was unknown.

Robust, atlas-free, automatic segmentation of brain MRI in health and disease.

Background: Brain- and lesion-volumes derived from magnetic resonance images (MRI) serve as important imaging markers of disease progression in neurodegenerative diseases and aging. While manual segmentation of these volumes is both tedious and impractical in large cohorts of subjects, automated segmentation methods often fail in accurate segmentation of brains with severe atrophy or high lesion loads. The purpose of this study was to develop an atlas-free brain Classification using DErivative-based Features (C-DEF), which utilizes all scans that may be acquired during the course of a routine MRI study at any center.

Comprehensive Analysis of TCR-β Repertoire in Patients with Neurological Immune-mediated Disorders.

In this study we characterized the TCR repertoire profiles in patients with chronic progressive inflammatory neurological disorders including HAM/TSP, associated with human T-cell lymphotropic virus type I (HTLV-I) infection, and multiple sclerosis (MS), an inflammatory, demyelinating disease of the CNS of unknown etiology. We hypothesized that a T-cell receptor (TCR) clonal repertoire 'signature' could distinguish HAM/TSP patients from healthy controls, as well as from patients with a more heterogeneous CNS-reactive inflammatory disease such as MS. In this study, we applied an unbiased molecular technique - unique molecular identifier (UMI) library-based strategy to investigate with high accuracy the TCR clonal repertoire by high throughput sequencing (HTS) technology.

Immunophenotypic characterization of CSF B cells in virus-associated neuroinflammatory diseases.

Intrathecal antibody synthesis is a well-documented phenomenon in infectious neurological diseases as well as in demyelinating diseases, but little is known about the role of B cells in the central nervous systems. We examined B cell and T cell immunophenotypes in CSF of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) compared to healthy normal donors and subjects with the other chronic virus infection and/or neuroinflammatory diseases including HIV infection, multiple sclerosis (MS) and progressive multifocal leukoencephalopathy. Antibody secreting B cells (ASCs) were elevated in HAM/TSP patients, which was significantly correlated with intrathecal HTLV-1-specific antibody responses.

Imaging spinal cord atrophy in progressive myelopathies: HTLV-I-associated neurological disease (HAM/TSP) and multiple sclerosis (MS).

Objective: Previous work measures spinal cord thinning in chronic progressive myelopathies, including human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Quantitative measurements of spinal cord atrophy are important in fully characterizing these and other spinal cord diseases. We aimed to investigate patterns of spinal cord atrophy and correlations with clinical markers.

Leptomeningeal gadolinium enhancement across the spectrum of chronic neuroinflammatory diseases.

Objective: To assess the prevalence and the specificity of leptomeningeal enhancement (LME) on postcontrast T2-fluid-attenuated inversion recovery (FLAIR) MRI in multiple sclerosis (MS) compared to a variety of inflammatory and noninflammatory neurologic conditions assessed in 2 academic research hospitals.

Methods: On 3T postcontrast T2-FLAIR images, the presence of focal gadolinium enhancement was evaluated in the leptomeningeal compartment in 254 people with non-MS neurologic conditions or neurotropic viral infections. Based on their clinical diagnosis, patients were grouped as follows: (1) other-than-MS inflammatory neurologic diseases; (2) noninflammatory neurologic diseases; (3) human T-lymphotropic virus (HTLV)-infected; (4) HIV-infected; (5) healthy volunteers.