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The presence of Epstein-Barr Virus (EBV) DNA in cerebrospinal fluid (CSF) and peripheral blood (PB) samples collected from 55 patients with clinical and radiologically-active relapsing-remitting MS (RRMS) and 51 subjects with other neurological diseases was determined using standardized commercially available kits for viral nucleic acid extraction and quantitative EBV DNA detection. Both cell-free and cell-associated CSF and PB fractions were analyzed, to distinguish latent from lytic EBV infection. EBV DNA was detected in 5.5% and 18.2% of cell-free and cell-associated CSF fractions of patients with RRMS as compared to 7.8% and 7.8% of controls; plasma and peripheral blood mononuclear cells (PBMC) positivity rates were 7.3% and 47.3% versus 5.8% and 31.4%, respectively. No significant difference in median EBV viral loads of positive samples was found between RRMS and control patients in all tested samples. Absence of statistically significant differences in EBV positivity rates between RRMS and control patients, despite the use of highly sensitive standardized methods, points to the lack of association between EBV and MS disease activity.

Objective: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid β (Aβ) autoantibodies in the acute and remission phases of CAA-ri. Methods: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau, and APOE genotype were also investigated. Results: During the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel. Interpretation: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aβ, directly related to autoantibody concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.

Objective: Cerebral amyloid angiopathy (CAA) is characterized by the progressive deposition of amyloid-β (Aβ) protein in the walls of small/medium sized arteries of cerebral cortex and leptomeninges, representing an important cause of spontaneous intracerebral haemorrhage and cognitive impairment. A subgroup of CAA patients develop perivascular inflammation linked to the Aβ laden vessels, associated with vasogenic edema (VE) and to a rapid cognitive decline, leading to a condition known as CAA-related inflammation (CAA-ri). This syndrome has parallels with what observed in about 10% of patients affected by Alzheimer's disease (AD) who developed reversible VE after immunization with the anti-Aβ antibody bapineuzumab, where postmortem examination revealed inflammation and/or vasculitis associated with CAA, implying the discontinuation of therapeutic protocols. Recent MRI data have also shown that up to 17% of the treated patients have signs of VE directly related to the drug dose, even if in the absence of clinical correlates. Methods: thanks to a novel technique for the ultra sensitive evaluation (patent application pending), we followed the concentration of anti-Aβ antibodies in the CSF of 10 CAA-ri patient during the acute phase (acCAA-ri) and after the remission phase (rpCAA-ri), compared to 8 non-inflammatory CAA, 10 AD, 10 MS and 20 healthy control subjects. Results: we demonstrated that the concentration of anti-Aβ antibodies is specifically increased in the CSF of acCAA-ri patients, followed by a progressive reduction of their concentration after steroid treatment, accordingly to clinical-radiological improvements. Moreover, we observed a spontaneous decrease of these autoantibodies in rpCAA-ri patients without any immunosuppressant treatment, finally proving that the event is not secondary to an unspecific effect of treatment, but strictly related to disease progression. Conclusions: our data support the hypothesis that the pathogenesis of CAA-ri is caused by a specific autoimmune reaction against Aβ, directly mediated by anti-Aβ autoantibodies. Since an invasive procedure such as brain biopsy is still needed for a definite diagnosis of CAA-ri, the outcomes implied by anti-Aβ dosage in CSF may be proposed to support future targets for early diagnosis and follow-up, in association with clinical and radiological features, and as a surrogate biomarker for clinical trials of disease modifying therapies