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Publication Quantitative Contribution of Clinical Attacks to Residual Disability in Patients With AQP4-Antibody Neuromyelitis Optica Spectrum Disorder(Lippincott, Williams & Wilkins, 2024-12-12) Chen, Bo; Francis, Anna; Cooper, Sarah; Dobson, Ruth; Hacohen, Yael; Halfpenny, Christopher; Hemingway, Cheryl; Hobart, Jeremy; O'Sullivan, Eoin; Rashid, Waqar; Martin, Roswell; Williams, Victoria; Ramdas, Sithara; Geraldes, Ruth; Leite, Maria; Palace, Jacqueline; Martin, Roswell; Medical and DentalBackground and objectives: Disease-related disability in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) is solely attributed to clinical attacks. However, few studies have assessed the relationship between attacks and residual disability in NMOSD. Thus, we aimed to quantify the contribution of clinical attacks to the residual disability in patients with AQP4-NMOSD. Methods: This retrospective observational single-center study enrolled patients from the Oxford National NMO Service, with the inclusion criteria as (1) AQP4-NMOSD diagnosis and (2) availability of at least 1 disability score (Expanded Disability Status Scale [EDSS] or logarithm of the minimum angle of resolution [LogMAR] score) recorded ≥6 months after attack (defined as residual disability). The outcome measures were EDSS and LogMAR scores. Univariable and multivariable linear mixed-effect models were used to quantify the effect of clinical relapses on the outcomes. Results: A total of 165 patients with AQP4-NMOSD (median onset age, 43 years, range 2-84; women, 140 [84.8%]; White European patients, 92 [55.8%]; African or African British patients, 40 [24.2%]; Asian or Asian British patients, 20 [12.1%]; multiracial or unknown racial patients, 13 [7.9%]) were included, with the median time of disability measurement since the last attack being 32 months (range 6-197). The mean increase in the EDSS score per relapse was 0.304 (95% CI 0.074-0.553, p < 0.001), with individual relapse phenotypes showing different effects: the transverse myelitis (TM) + optic neuritis (ON) phenotype contributed most, with an increase of 1.290 (95% CI 0.233-2.207, p = 0.017) per relapse, followed by brain plus other phenotypes (β = 0.782, 95% CI 0.029-1.03, p < 0.001) and isolated TM (β = 0.295, 95% CI 0.074-0.549, p < 0.001), while neither brain nor optic nerve relapse alone was associated with a residual change in the EDSS score. Older onset age was correlated with more severe motor disability where this mainly occurred early in the disease course while younger patients exhibited mild initial disability that worsened more significantly with relapses. Each ON attack led to a mean increase of 0.464 (95% CI 0.199-0.741, p < 0.001) in the LogMAR score. Race, sex, and timing of acute treatment did not significantly affect these disability outcomes (EDSS and LogMAR scores). Discussion: The quantitative contribution of relapse to the residual disability in patients with AQP4-NMOSD varies across phenotypes, and this relapse-related disability progression may also vary by the onset age. Although this retrospective single-center study may need validation in other data sets, these findings may help predict disability and provide a modeling tool for longer term disability in the cost-effective analysis of newer interventions.Publication Plectin plays a role in the migration and volume regulation of astrocytes: a potential biomarker of glioblastoma(BioMed Central, 2024-01-23) Žugec, Maja; Furlani, Borut; Castañon, Maria; Rituper, Boštjan; Fischer, Irmgard; Brogi, Giuseppe; Caltabiano, Rosario; Barbagallo, Giuseppe; Di Rosa, Michelino; Tibullo, Daniele; Parenti, Rosalba; Vicario, Nunzio; Simčič, Saša; Pozo Devoto, Victorio Martin; Stokin, Gorazd Bernard; Wiche, Gerhard; Jorgačevski, Jernej; Zorec, Robert; Potokar, Maja; Stokin, Gorazd Bernard; Medical and DentalBackground: The expression of aquaporin 4 (AQP4) and intermediate filament (IF) proteins is altered in malignant glioblastoma (GBM), yet the expression of the major IF-based cytolinker, plectin (PLEC), and its contribution to GBM migration and invasiveness, are unknown. Here, we assessed the contribution of plectin in affecting the distribution of plasmalemmal AQP4 aggregates, migratory properties, and regulation of cell volume in astrocytes. Methods: In human GBM, the expression of glial fibrillary acidic protein (GFAP), AQP4 and PLEC transcripts was analyzed using publicly available datasets, and the colocalization of PLEC with AQP4 and with GFAP was determined by immunohistochemistry. We performed experiments on wild-type and plectin-deficient primary and immortalized mouse astrocytes, human astrocytes and permanent cell lines (U-251 MG and T98G) derived from a human malignant GBM. The expression of plectin isoforms in mouse astrocytes was assessed by quantitative real-time PCR. Transfection, immunolabeling and confocal microscopy were used to assess plectin-induced alterations in the distribution of the cytoskeleton, the influence of plectin and its isoforms on the abundance and size of plasmalemmal AQP4 aggregates, and the presence of plectin at the plasma membrane. The release of plectin from cells was measured by ELISA. The migration and dynamics of cell volume regulation of immortalized astrocytes were assessed by the wound-healing assay and calcein labeling, respectively. Results: A positive correlation was found between plectin and AQP4 at the level of gene expression and protein localization in tumorous brain samples. Deficiency of plectin led to a decrease in the abundance and size of plasmalemmal AQP4 aggregates and altered distribution and bundling of the cytoskeleton. Astrocytes predominantly expressed P1c, P1e, and P1g plectin isoforms. The predominant plectin isoform associated with plasmalemmal AQP4 aggregates was P1c, which also affected the mobility of astrocytes most prominently. In the absence of plectin, the collective migration of astrocytes was impaired and the dynamics of cytoplasmic volume changes in peripheral cell regions decreased. Plectin's abundance on the plasma membrane surface and its release from cells were increased in the GBM cell lines. Conclusions: Plectin affects cellular properties that contribute to the pathology of GBM. The observed increase in both cell surface and released plectin levels represents a potential biomarker and therapeutic target in the diagnostics and treatment of GBMs.Publication Non hepatic hyperammonaemia: a case series(BMJ Publishing Group, 2024-11-07) Nye, Charles; di Mambro, Alex; Renowden, Shelley; Rice, Claire; Nye, Charles; di Mambro, Alex; Medical and DentalHyperammonaemia is a reversible cause of encephalopathy and can mimic of several neurological conditions. The diagnosis may be delayed, particularly if liver function tests are normal. We present a case series of adult non-hepatic hyperammonaemia patients highlighting the importance of testing ammonia levels in patients with cryptogenic neurological disease and the consideration of multiple causes including iatrogenic elevation secondary to sodium valproate, gastrointestinal and urinary causes of hyperammonaemia. None had a urea cycle disorder, as such there is little evidence on how best to manage these patients. We summarise the treatments used in these cases and the patient’s outcome.Publication Nerve biopsy in T-cell lymphoma with neurolymphomatosis: where and when(BMJ Publishing Group, 2024-01-25) Pipis, Menelaos; Jaunmuktane, Zane; Marafioti, Teresa; Brandner, Sebastian; Smith, Elaine; D'Sa, Shirley; Lunn, Michael; Cwynarski, Kate; Fialho, Doreen; Shah, Sachit; Fuller, Geraint; Reilly, Mary; Smith, Elaine; Fuller, Geraint; Allied Health Professional; Medical and DentalPeripheral T-cell lymphomas are rare heterogeneous haematological malignancies that may also involve peripheral nerves in a very small subset of cases. We report a patient with a diagnostically challenging cutaneous T-cell lymphoma and multifocal mononeuropathies in whom a targeted nerve biopsy identified lymphomatous infiltration of nerves and expedited combination treatment with chemotherapy and an autologous stem cell transplant. She showed an excellent response with a complete metabolic response on positron emission tomography imaging and significant clinical improvement, maintained 5 years post-treatment.Publication Emotion regulation shows an age- and sex-specific moderating effect on the relationship between chronic stress and cognitive performance(Nature Research, 2024-02-06) Novotny, Jan; Srt, Luka; Stokin, Gorazd Bernard; Stokin, Gorazd Bernard; Medical and DentalDespite the extensive knowledge about the effects of chronic stress on cognition, the underlying mechanisms remain unclear. We conducted a cross-sectional moderation analysis on a population-based sample of 596 adults to examine the age- and sex-specific role of emotion regulation (ER) in the relationship between chronic stress and cognitive performance using validated self-report questionnaires. While women showed no direct or moderated relationship between stress and cognition, men displayed a distinct age-related pattern where stress was negatively associated with poorer cognitive performance at older ages, and the onset of this relationship was detected earlier in men with ER problems. These results showed that suppression of emotions and lack of executive control of ER amplify the negative consequences of chronic stress and suggest that there are sex-specific differences in the decline of ability to cope with long-term exposure to stressors.Publication IgG4-Related Disease in the Nervous System(BMJ Publishing Group, 2024-09-12) Yang, Lu; Smith, Paul; Scolding, Neil; Rice, Claire; Scolding, Neil; Medical and DentalIgG4-related disease (IgG4-RD) is a recently described multisystemic disorder with a spectrum of manifestations that continue to be described. Nonetheless, there are recognised distinct patterns of disease. Neurological involvement is rare, particularly in isolation, but IgG4-RD may present with orbital disease, hypophysitis or pachymeningitis. Typically, it is highly responsive to treatment. This review highlights neurological manifestations of IgG4-RD and emphasises the importance of a high index of clinical suspicion to facilitate investigation and appropriate management, avoiding irreversible tissue damage and neurological dysfunction. We present a treatment algorithm for suggested management of IgG4-RD affecting the nervous system.Publication Internal carotid artery aneurysm causing Horner’s syndrome with the Harlequin sign(BMJ Publishing Group, 2024-11-07) Monks, Kimberley Rose; Jawaheer, Aminah Iffah; Nowak, Victoria; Monks, Kimberley Rose; Medical and DentalNo abstract availablePublication Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial(BMJ Publishing Group, 2024-02-05) Brittain, Gavin; Petrie, Jennifer; Duffy, Kate; Glover, Rachel; Hullock, Katie; Papaioannou, Diana; Roldan, Elisa; Beecher, Colette; Bursnall, Matthew; Ciccarelli, Olga; Coles, Alasdair; Cooper, Cindy; Giovannoni, Gavin; Gabriel, Ian; Kazmi, Majid; Kyriakou, Charalampia; Nicholas, Richard; Paling, David; Peniket, Andy; Scolding, Neil; Silber, Eli; de Silva, Thushan; Venneri, Annalena; Walters, Stephen; Young, Carolyn; Muraro, Paolo; Sharrack, Basil; Snowden, John; Scolding, Neil; Medical and DentalIntroduction: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. Methods and analysis: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs.Publication Amyloid precursor protein induces reactive astrogliosis(Wiley, 2024-04-08) Velezmoro Jauregui, Gretsen; Vukić, Dragana; Onyango, Isaac; Arias, Carlos; Novotný, Jan; Texlová, Kateřina; Wang, Shanshan; Locker Kovačovicova, Kristina; Polakova, Natalie; Zelinkova, Jana; Čarna, Maria; Lacovich, Valentina; Head, Brian; Havas, Daniel; Mistrik, Martin; Zorec, Robert; Verkhratsky, Alexei; Keegan, Liam; O'Connell, Mary; Rissman, Robert; Stokin, Gorazd; Stokin, Gorazd; Medical and DentalAim: Astrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in reactive astrogliosis. Methods: We investigated whether APP instigates reactive astroglios by examining in vitro and in vivo the morphology and function of naive and APP-deficient astrocytes in response to APP and well-established stressors. Results: Overexpression of APP in cultured astrocytes led to remodeling of the intermediate filament network, enhancement of cytokine production, and activation of cellular programs centered around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion abrogated remodeling of the intermediate filament network and blunted expression of IFN-stimulated gene products in response to lipopolysaccharide. Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein observed canonically in astrocytes in response to TBI. Conclusions: The APP thus represents a candidate molecular inducer and regulator of reactive astrogliosis. This finding has implications for understanding pathophysiology of neurodegenerative and other diseases of the nervous system characterized by reactive astrogliosis and opens potential new therapeutic avenues targeting APP and its pathways to modulate reactive astrogliosis.