Anti-CD20 therapy depletes activated myelin-specific CD8+ T cells in multiple sclerosis.

CD8+ T cells are believed to play an important role in multiple sclerosis (MS), yet their role in MS pathogenesis remains poorly defined. Although myelin proteins are considered potential autoantigenic targets, prior studies of myelin-reactive CD8+ T cells in MS have relied on in vitro stimulation, thereby limiting accurate measurement of their ex vivo precursor frequencies and phenotypes. Peptide:MHC I tetramers were used to identify and validate 5 myelin CD8+ T cell epitopes, including 2 newly described determinants in humans. The validated tetramers were used to measure the ex vivo precursor frequencies and phenotypes of myelin-specific CD8+ T cells in the peripheral blood of untreated MS patients and HLA allele-matched healthy controls. In parallel, CD8+ T cell responses against immunodominant influenza epitopes were also measured. There were no differences in ex vivo frequencies of tetramer-positive myelin-specific CD8+ T cells between MS patients and control subjects. An increased proportion of myelin-specific CD8+ T cells in MS patients exhibited a memory phenotype and expressed CD20 compared to control subjects, while there were no phenotypic differences observed among influenza-specific CD8+ T cells. Longitudinal assessments were also measured in a subset of MS patients subsequently treated with anti-CD20 monoclonal antibody therapy. The proportion of memory and CD20+ CD8+ T cells specific for certain myelin but not influenza epitopes was significantly reduced following anti-CD20 treatment. This study, representing a characterization of unmanipulated myelin-reactive CD8+ T cells in MS, indicates these cells may be attractive targets in MS therapy

Migraine and psychiatric comorbidity: a review of clinical findings.

Migraine is an extremely common disorder. The underlying mechanisms of this chronic illness interspersed with acute symptoms appear to be increasingly complex. An important aspect of migraine heterogeneity is comorbidity with other neurological diseases, cardiovascular disorders, and psychiatric illnesses. Depressive disorders are among the leading causes of disability worldwide according to WHO estimation. In this review, we have mainly considered the findings from general population studies and studies on clinical samples, in adults and children, focusing on the association between migraine and psychiatric disorders (axis I of the DSM), carried over after the first classification of IHS (1988). Though not easily comparable due to differences in methodology to reach diagnosis, general population studies generally indicate an increased risk of affective and anxiety disorders in patients with migraine, compared to non-migrainous subjects. There would also be a trend towards an association of migraine with bipolar disorder, but not with substance abuse/dependence. With respect to migraine subtypes, comorbidity mainly involves migraine with aura. Patients suffering from migraine, however, show a decreased risk of developing affective and anxiety disorders compared to patients with daily chronic headache. It would also appear that psychiatric disorders prevail in patients with chronic headache and substance use than in patients with simple migraine. The mechanisms underlying migraine psychiatric comorbidity are presently poorly understood, but this topic remains a priority for future research. Psychiatric comorbidity indeed affects migraine evolution, may lead to chronic substance use, and may change treatment strategies, eventually modifying the outcome of this important disorder

A magnetization transfer study of mild and advanced Parkinson's disease

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Normal endothelial function in carriers of the apolipoprotein A-IMilano mutant despite low HDL-cholesterol levels

Carriers of the apolipoprotein A-IMilano (apoA-IM) mutant show severe reductions in the plasma concentration of antiatherogenic HDL but do not present with preclinical atherosclerosis and premature CHD. Aim of the present study was to investigate endothelial function in A-IM carriers, since low HDL-C levels have been associated with features of endothelial dysfunction. Plasma concentrations of soluble cell adhesion molecules (sCAMs) and forearm arterial compliance (FAC) during reactive hyperemia were evaluated in 21 A-IM carriers, 21 healthy subjects with low HDL-C, and 42 controls. Low HDL-C subjects had significantly higher plasma sCAM levels than controls (sVCAM-1: 656.3\ub149.3 vs 502.6\ub125.5 ng/ml; sICAM-1: 335.6\ub121.5 vs 267.0\ub18.9 ng/ml; sE-selectin: 62.9\ub14.1 vs 47.9\ub13.0 ng/ml); on the contrary, no differences were detected between A-IM carriers (sVCAM-1: 550.6\ub132.1 ng/ml; sICAM-1: 309.8\ub126.9 ng/ml; sE-selectin: 52.3\ub14.3 ng/ml) and controls. Low HDL-C subjects had lower FAC than controls, while no differences were detected between A-IM carriers and controls. These results suggest that HDL from A-IM carriers may be more efficient than control HDL in modulating endothelial function. To test this hypothesis, plasma HDL were isolated from 6 A-IM carriers and 6 controls, and their ability to inhibit VCAM-1 expression and to induce eNOS was tested in cultured endothelial cells. A-IM HDL were two times more effective than control HDL in reducing TNFalpha-induced VCAM-1 expression; the inhibition occurred at a transcriptional level, as demonstrated by RT-PCR. In addition, cells exposed to A-IM HDL showed higher expression of eNOS than cells treated with control HDL. In conclusion, despite the very low HDL-C levels, A-IM carriers do not display features of endothelial dysfunction, such as the increase of circulating sCAM levels and the impairment of arterial compliance, probably because of a superior ability of A-IM HDL to protect the endothelium

Neurology and the COVID-19 emergency

Following the COVID-19 outbreak, significant changes have been implemented on a national level in the organization of neurology units and associated stroke units. Regionallydesignated COVID-19 hospitals have implemented an aggressive policy to relocate as many beds as possible to COVID-19 patients. In order to do so, the preferred strategy has been to reduce the number of beds in neurology units, and in some cases several units have been consolidated into one. In other cases, particularly in the northern regions

c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo.

Altered synaptic function is considered one of the first features of Alzheimer disease (AD). Currently, no treatment is available to prevent the dysfunction of excitatory synapses in AD. Identification of the key modulators of synaptopathy is of particular significance in the treatment of AD. We here characterized the pathways leading to synaptopathy in TgCRND8 mice and showed that c-Jun N-terminal kinase (JNK) is activated at the spine prior to the onset of cognitive impairment. The specific inhibition of JNK, with its specific inhibiting peptide D-JNKI1, prevented synaptic dysfunction in TgCRND8 mice. D-JNKI1 avoided both the loss of postsynaptic proteins and glutamate receptors from the postsynaptic density and the reduction in size of excitatory synapses, reverting their dysfunction. This set of data reveals that JNK is a key signaling pathway in AD synaptic injury and that its specific inhibition offers an innovative therapeutic strategy to prevent spine degeneration in AD