Primary angiitis of the central nervous system.

Primary angiitis of the central nervous system (CNS) is an uncommon inflammatory disorder, with highly variable clinical presentation. It needs to be differentiated from several mimickers, such as CNS involvement in systemic vasculitides, connective tissue disorders, infectious disease, and leukodystrophy as well as neoplastic diseases. The diagnosis requires a combination of clinical and laboratory investigations, multimodal imaging, and histopathological examination, which should be available for confirmation. In the present paper, the histopathological features of primary angiitis of the CNS are described and highlighted to help pathologists avoid misdiagnosis of a treatable acquired disease.

Promises and pitfalls of topological data analysis for brain connectivity analysis.

Developing sensitive and reliable methods to distinguish normal and abnormal brain states is a key neuroscientific challenge. Topological Data Analysis, despite its relative novelty, already generated many promising applications, including in neuroscience. We conjecture its prominent tool of persistent homology may benefit from going beyond analysing structural and functional connectivity to effective connectivity graphs capturing the direct causal interactions or information flows. Therefore, we assess the potential of persistent homology to directed brain network analysis by testing its discriminatory power in two distinctive examples of disease-related brain connectivity alterations: epilepsy and schizophrenia. We estimate connectivity from functional magnetic resonance imaging and electrophysiology data, employ Persistent Homology and quantify its ability to distinguish healthy from diseased brain states by applying a support vector machine to features quantifying persistent homology structure. We show how this novel approach compares to classification using standard undirected approaches and original connectivity matrices. In the schizophrenia classification, topological data analysis generally performs close to random, while classifications from raw connectivity perform substantially better; potentially due to topographical, rather than topological, specificity of the differences. In the easier task of seizure discrimination from scalp electroencephalography data, classification based on persistent homology features generally reached comparable performance to using raw connectivity, albeit with typically smaller accuracies obtained for the directed (effective) connectivity compared to the undirected (functional) connectivity. Specific applications for topological data analysis may open when direct comparison of connectivity matrices is unsuitable - such as for intracranial electrophysiology with individual number and location of measurements. While standard homology performed overall better than directed homology, this could be due to notorious technical problems of accurate effective connectivity estimation.

Functional conserved non-coding elements among tunicates and chordates.

Non-coding regions with dozens to several hundred base pairs of extreme conservation have been found in all metazoan genomes. The distribution of these conserved non-coding elements (CNE) within and across genomes has suggested that many of them may have roles as transcriptional regulatory elements. A combination of bioinformatics and experimental approaches can be used to identify CNEs with regulatory activity in phylogenetically distant species. Nevertheless, the high divergent rate of genomic sequences of several organisms, such as tunicates, complicates the characterization of these conserved elements and very few examples really may prove their functional activity. We used a comparative approach to facilitate the identification of CNEs among distantly related or highly divergent species and experimentally demonstrated the functional significance of these novel CNEs. We first experimentally tested, in C. robusta and D. rerio transgenic embryos, the regulatory activity of conserved elements associated to genes involved in developmental control among different chordates (Homo sapiens and Danio rerio for vertebrates, Ciona robusta and Ciona savignyi for tunicates and Branchiostoma floridae for cephalochordates). Once demonstrated the cross-species functional conservation of these CNEs, the same gene loci were used as references to locate homologous regions and possible CNEs in available tunicate genomes. Comparison of tunicate-specific and chordate-specific CNEs revealed absence of conservation of the regulatory elements in spite of conservation of regulatory patterns, likely due to evolutionary specification of the respective developmental networks. This result highlights the importance of an integrative in-silico/in-vivo approach to CNEs investigation, encompassing both bioinformatics, essential for putative CNEs identification, and laboratory experiments, pivotal for the understanding of CNEs functionality.

Meta-Omics Reveals Genetic Flexibility of Diatom Nitrogen Transporters in Response to Environmental Changes.

Diatoms (Bacillariophyta), one of the most abundant and diverse groups of marine phytoplankton, respond rapidly to the supply of new nutrients, often out-competing other phytoplankton. Herein, we integrated analyses of the evolution, distribution, and expression modulation of two gene families involved in diatom nitrogen uptake (DiAMT1 and DiNRT2), in order to infer the main drivers of divergence in a key functional trait of phytoplankton. Our results suggest that major steps in the evolution of the two gene families reflected key events triggering diatom radiation and diversification. Their expression is modulated in the contemporary ocean by seawater temperature, nitrate, and iron concentrations. Moreover, the differences in diversity and expression of these gene families throughout the water column hint at a possible link with bacterial activity. This study represents a proof-of-concept of how a holistic approach may shed light on the functional biology of organisms in their natural environment.

The EJC component Magoh in non-vertebrate chordates.

Earliest craniates possess a newly enlarged, elaborated forebrain with new cell types and neuronal networks. A key question in vertebrate evolution is when and how this cerebral expansion took place. The exon-junction complex (EJC) plays an essential role in mRNA processing of all Eukarya. Recently, it has been proposed that the EJC represses recursive RNA splicing in Deuterostomes, with implication in human brain diseases like microcephaly and depression. However, the EJC or EJC subunit contribution to brain development in non-vertebrate Deuterostomes remained unknown. Being interested in the evolution of chordate characters, we focused on the model species, Branchiostoma lanceolatum (Cephalochordata) and Ciona robusta (Tunicata), with the aim to investigate the ancestral and the derived expression state of Magoh orthologous genes. This study identifies that Magoh is part of a conserved syntenic group exclusively in vertebrates and suggests that Magoh has experienced duplication and loss events in mammals. During early development in amphioxus and ascidian, maternal contribution and zygotic expression of Magoh genes in various types of progenitor cells and tissues are consistent with the condition observed in other Bilateria. Later in development, we also show expression of Magoh in the brain of cephalochordate and ascidian larvae. Collectively, these results provide a basis to further define what functional role(s) Magoh exerted during nervous system development and evolution.

Into the bloom: Molecular response of pelagic tunicates to fluctuating food availability.

The planktonic tunicates appendicularians and thaliaceans are highly efficient filter feeders on a wide range of prey size including bacteria and have shorter generation times than any other marine grazers. These traits allow some tunicate species to reach high population densities and ensure their success in a favourable environment. However, there are still few studies focusing on which genes and gene pathways are associated with responses of pelagic tunicates to environmental variability. Herein, we present the effect of food availability increase on tunicate community and gene expression at the Marquesas Islands (South-East Pacific Ocean). By using data from the Tara Oceans expedition, we show that changes in phytoplankton density and composition trigger the success of a dominant larvacean species (an undescribed appendicularian). Transcriptional signature to the autotroph bloom suggests key functions in specific physiological processes, i.e., energy metabolism, muscle contraction, membrane trafficking, and proteostasis. The relative abundance of reverse transcription-related Pfams was lower at bloom conditions, suggesting a link with adaptive genetic diversity in tunicates in natural ecosystems. Downstream of the bloom, pelagic tunicates were outcompeted by copepods. Our work represents the first metaomics study of the biological effects of phytoplankton bloom on a key zooplankton taxon.

Neurovascular Perfusion Study With DynaPBV During Preoperative Balloon Test Occlusion: A Feasibility Study on Aneurysm and Tumor Lesions.

To report feasibility, safety, and technical advantages of flat-detector computed tomography perfusion (FD-CTP) during balloon test occlusion (BTO) angiography studies, 10 patients patients scheduled for BTO were evaluated. Cerebral blood volume maps were extracted from FD-CTP images acquired during the test. The FD-CTP perfusion combined with BTO is feasible and safe in intracranial tumor, and aneurysm cases in which vessel sacrifice should be considered.

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

BACKGROUND: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. METHODS: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. RESULTS: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. CONCLUSION: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.

Correction: Sciacca, F. L., et al. Microduplication of 15q13.3 and Microdeletion of 18q21.32 in a Patient with Moyamoya Syndrome. Int. J. Mol. Sci. 2018, 19, 3675.

The authors wish to make the corrections to this paper [...].

Microduplication of 15q13.3 and Microdeletion of 18q21.32 in a Patient with Moyamoya Syndrome.

Moyamoya angiopathy (MA) is a cerebrovascular disease determining a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and their proximal branches and the compensatory development of abnormal "moyamoya" vessels. MA occurs as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes) including several heritable conditions such as Down syndrome, neurofibromatosis type 1 and other genomic defects. Although the mechanism that links MA to these genetic syndromes is still unclear, it is believed that the involved genes may contribute to the disease susceptibility. Herein, we describe the case of a 43 years old woman with bilateral MA and peculiar facial characteristics, having a 484-kb microduplication of the chromosomal region 15q13.3 and a previously unreported 786 kb microdeletion in 18q21.32. This patient may have a newly-recognized genetic syndrome associated with MA. Although the relationship between these genetic variants and MA is unclear, our report would contribute to widening the genetic scenario of MA, in which not only genic mutation, but also genome unbalances are possible candidate susceptibility factors.

Carotid Artery Stenting With Proximal Embolic Protection via a Transradial or Transbrachial Approach: Pushing the Boundaries of the Technique While Maintaining Safety and Efficacy.

PURPOSE: To compare the feasibility and safety of proximal cerebral protection to a distal filter during carotid artery stenting (CAS) via a transbrachial (TB) or transradial (TR) approach. METHODS: Among 856 patients who underwent CAS between January 2007 and July 2015, 214 (25%) patients (mean age 72±8 years; 154 men) had the procedure via a TR (n=154) or TB (n=60) approach with either Mo.MA proximal protection (n=61) or distal filter protection (n=153). The Mo.MA group (mean age 73±7 years; 54 men) had significantly more men and more severe stenosis than the filter group (mean age 71±8 years; 100 men). Stent type and CAS technique were left to operator discretion. Heparin and a dedicated closure device or bivalirudin and manual compression were used in TR and TB accesses, respectively. Technical and procedure success, crossover to femoral artery, 30-day major adverse cardiovascular/cerebrovascular events (MACCE; death, all strokes, and myocardial infarction), vascular complications, and radiation exposure were compared between groups. RESULTS: Crossover to a femoral approach was required in 1/61 (1.6%) Mo.MA patient vs 11/153 (7.1%) filter patients mainly due to technical difficulty in engaging the target vessel. Five Mo.MA patients developed acute intolerance to proximal occlusion; 4 were successfully shifted to filter protection. A TR patient was shifted to filter because the Mo.MA system was too short. CAS was technically successful in the remaining 55 (90%) Mo.MA patients and 142 (93%) filter patients. The MACCE rate was 0% in the Mo.MA patients and 2.8% in the filter group (p=0.18). Radiation exposure was similar between groups. Major vascular complications occurred in 1/61 (1.6%) and in 3/153 (1.96%) patients in the Mo.MA and filter groups (p=0.18), respectively, and were confined to the TB approach in the early part of the learning curve. Chronic radial artery occlusion was detected by Doppler ultrasound in 2/30 (6.6%) Mo.MA patients and in 4/124 (3.2%) filter patients by clinical assessment (p=0.25) at 8.1±7.5-month follow-up. CONCLUSION: CAS with proximal protection via a TR or TB approach is a feasible, safe, and effective technique with a low rate of vascular complications.

Regulatory elements retained during chordate evolution: coming across tunicates.

Understanding the role of conserved noncoding elements (CNEs) throughout the genome is taking advantage of the improved efficiency of genome-sequencing techniques and bioinformatics tools. Tunicates diverged before the vertebrate whole genome duplications and, therefore, represent an optimal model system to study the evolution of complex regulatory networks. Here, we review the current knowledge on the characterization of CNEs during embryonic development, focusing on the evolutionary similarity and divergence between tunicates and other chordates. Many vertebrate specific CNEs that regulate developmental processes were identified based on high level of sequence conservation, but only few of them have been recognized in tunicates or other invertebrates because of genomic sequences divergence. We discuss recent studies demonstrating that a combination of different methodologies, based not only on high sequence identity, can collectively be used to identify CNEs with regulatory activity in phylogenetically distant species. Here, a low sequence constraints approach was successfully used to search orthologous chordate gene regions for cross-species conserved regulatory elements that control developmental genes.

Carotid artery stenting in patients with left ICA stenosis and bovine aortic arch: a single-center experience in 60 consecutive patients treated via the right radial or brachial approach.

PURPOSE: To assess the safety and efficacy of carotid artery stenting (CAS) of the left internal carotid artery (LICA) from a right radial/brachial approach in patients with bovine aortic arch. METHODS: Among 505 consecutive CAS patients treated at our facility between June 2007 and December 2012, 60 (11.9%) patients (44 men; mean age 73±9 years) with LICA stenosis and bovine arch were treated from a right radial (n=32) or brachial (n=28) approach. Three quarters of the patients had characteristics qualifying them at high surgical risk; 52 were asymptomatic. The types of cerebral protection (a distal filter or proximal MO.MA system), stent, and technique were at the operation's discretion. RESULTS: The radial/brachial approach was successful in 59 (98.3%) of 60 procedures; 1 case was converted to a femoral approach. Proximal protection was used in 15 cases (11 brachial, 4 radial) with severe, soft plaques, although the MO.MA system proved too short in a tall patient having a radial approach and a filter was used. Clinical success with no adverse events was 96.7% owing to 1 retinal embolism and 1 minor stroke. Vascular complications occurred in 2 (3.3%) brachial group patients. No major bleeding was encountered. Over a mean follow-up of 18.7±17.5 months, midterm event-free survival was 93%. No target vessel revascularization was necessary. CONCLUSION: CAS via a right radial or brachial approach is safe and effective in patients with LICA stenosis and types 1 or 2 bovine arch.

The Hemorrhagic Side of Primary Angiitis of the Central Nervous System (PACNS).

Primary Angiitis of the Central Nervous System (PACNS) is a rare cerebrovascular disease involving the arteries of the leptomeninges, brain and spinal cord. Its diagnosis can be challenging, and the current diagnostic criteria show several limitations. Among the clinical and neuroimaging manifestations of PACNS, intracranial bleeding, particularly intracerebral hemorrhage (ICH), is poorly described in the available literature, and it is considered infrequent. This review aims to summarize the available data addressing this issue with a dedicated focus on the clinical, neuroradiological and neuropathological perspectives. Moreover, the limitations of the actual data and the unanswered questions about hemorrhagic PACNS are addressed from a double point of view (PACNS subtyping and ICH etiology). Fewer than 20% of patients diagnosed as PACNS had an ICH during the course of the disease, and in cases where ICH was reported, it usually did not occur at presentation. As trigger factors, both sympathomimetic drugs and illicit drugs have been proposed, under the hypothesis of an inflammatory response due to vasoconstriction in the distal cerebral arteries. Most neuroradiological descriptions documented a lobar location, and both the large-vessel PACNS (LV-PACNS) and small-vessel PACNS (SV-PACNS) subtypes might be the underlying associated phenotypes. Surprisingly, amyloid beta deposition was not associated with ICH when histopathology was available. Moreover, PACNS is not explicitly included in the etiological classification of spontaneous ICH. This issue has received little attention in the past, and it could be addressed in future prospective studies.

Residual shunt after patent foramen ovale closure: preliminary results from Italian patent foramen ovale survey.

BACKGROUND: Percutaneous patent foramen ovale (PFO) closure is accepted as treatment for cryptogenic ischemic stroke/transient ischemic attack in young subjects. However, a thorough evaluation of residual right-to-left shunt (rRLS) after PFO closure is needed. Our aims were to analyze the characteristics related to PFO diagnosis and closure, focusing on rRLS and clinical recurrences until 24-month follow-up. Data were extrapolated from the 12-month Italian PFO Survey. METHODS: In all, 1035 patients were included. PFO diagnosis and right-to-left shunt (RLS) were assessed by contrast-enhanced transesophageal and/or transthoracic echocardiography and/or transcranial Doppler. RESULTS: PFO diagnosis with RLS data were available in 894 of 1035 (86.4%) patients. rRLS was investigated in 49.6% (6 months), 27.1% (12 months), and 3.5% (24 months), and observed in 19.5% (6 months) and 18.2% (12 months) of subjects. Large permanent rRLS was observed in less than 3% of RLS-positive patients after 1 year. Eleven of 14 and 3 of 14 neurological recurrences were observed in 10 of 444 (2.25%) and 2 of 243 (0.8%) patients within the 6- and 12-month follow-up, respectively. Among these, no large rRLS was reported. There were no neurological events at 2-year follow-up. Forty of 444 subjects had non-neurological complications, mostly cardiac arrhythmias within the sixth month. CONCLUSIONS: PFO closure is a safe procedure. rRLS is not uncommon but large rRLS is rare. Clinical complications, mostly related to cardiac arrhythmias, are not unusual. Evaluation of the data of the whole survey is underway.

Diverse eukaryotic phytoplankton from around the Marquesas Islands documented by combined microscopy and molecular techniques.

Oceanic phytoplankton serve as a base for the food webs within the largest planetary ecosystem. Despite this, surprisingly little is known about species composition, function and ecology of phytoplankton communities, especially for vast areas of the open ocean. In this study we focus on the marine phytoplankton microflora from the vicinity of the Marquesas Islands in the Southern Pacific Ocean collected during the Tara Oceans expedition. Multiple samples from four sites and two depths were studied in detail using light microscopy, scanning electron microscopy, and automated confocal laser scanning microscopy. In total 289 taxa were identified, with Dinophyceae and Bacillariophyceae contributing 60% and 32% of taxa, respectively, to phytoplankton community composition. Notwithstanding, a large number of cells could not be assigned to any known species. Coccolithophores and other flagellates together contributed less than 8% to the species list. Observed cell densities were generally low, but at sites of high autotrophic biomass, diatoms reached the highest cell densities (1.26 × 104 cells L-1). Overall, 18S rRNA metabarcode-based community compositions matched microscopy-based estimates, particularly for the main diatom taxa, indicating consistency and complementarity between different methods, while the wide range of microscopy-based methods permitted several unknown and poorly studied taxa to be revealed and identified.

Differential regulation of HCN channel isoform expression in thalamic neurons of epileptic and non-epileptic rat strains.

Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels represent the molecular substrate of the hyperpolarization-activated inward current (I(h)). Although these channels act as pacemakers for the generation of rhythmic activity in the thalamocortical network during sleep and epilepsy, their developmental profile in the thalamus is not yet fully understood. Here we combined electrophysiological, immunohistochemical, and mathematical modeling techniques to examine HCN gene expression and I(h) properties in thalamocortical relay (TC) neurons of the dorsal part of the lateral geniculate nucleus (dLGN) in an epileptic (WAG/Rij) compared to a non-epileptic (ACI) rat strain. Recordings of TC neurons between postnatal day (P) 7 and P90 in both rat strains revealed that I(h) was characterized by higher current density, more hyperpolarized voltage dependence, faster activation kinetics, and reduced cAMP-sensitivity in epileptic animals. All four HCN channel isoforms (HCN1-4) were detected in dLGN, and quantitative analyses revealed a developmental increase of protein expression of HCN1, HCN2, and HCN4 but a decrease of HCN3. HCN1 was expressed at higher levels in WAG/Rij rats, a finding that was correlated with increased expression of the interacting proteins filamin A (FilA) and tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Analysis of a simplified computer model of the thalamic network revealed that the alterations of I(h) found in WAG/Rij rats compensate each other in a way that leaves I(h) availability constant, an effect that ensures unaltered cellular burst activity and thalamic oscillations. These data indicate that during postnatal developmental the hyperpolarizing shift in voltage dependency (resulting in less current availability) is compensated by an increase in current density in WAG/Rij thereby possibly limiting the impact of I(h) on epileptogenesis. Because HCN3 is expressed higher in young versus older animals, HCN3 likely does not contribute to alterations in I(h) in older animals.

Transradial/brachial carotid artery stenting with proximal protection: technical instructions, acute results and long-term outcomes.

BACKGROUND: The aim of this study was to evaluate the feasibility, safety and efficacy of transradial/brachial (TR/TB) carotid artery stenting (CAS) with proximal cerebral protection (PCP) as a first line of treatment of carotid artery stenosis. METHODS: Among 556 patients with significant (>50% if symptomatic or >70% if asymptomatic by Doppler US) unilateral, lipid-rich carotid artery stenosis undergoing TR/TB CAS, 137 (24.5%) deemed at high-risk for periprocedural cerebral embolization were scheduled for PCP with Mo.MA Ultra or Mo.MA mono-balloon. In patients with very complex anatomy the standard technique was modified loading the Mo.MA catheter without mandrel on two-wire system (so called 'No MAndrel 2 wire' technique, No.MA2) to increase support and deliverability. Device, technical and procedural successes both acute and at follow-up were the main outcomes. RESULTS: Mean patients' age was 74±7 years (93% male), 15% were symptomatic and 59.6% owned 'high-surgical-risk' features. Stenosis degree was 85±7% with soft composition in all (by CT-angiography). TR and TB approach were selected in 92 (67%) and 45 (33%) patients, respectively. Target carotid axes were right, left bovine and left non bovine in 55%, 38% and 7% of patients. Procedures were successfully completed in all patients (intention-to-treat basis) with the standard Mo.MA Ultra system in 129 patients and the Mo.MA mono-balloon in 8 patients. No.MA2 technique was succesfully used in 16 patients as 'bailout' and in 27 patients as 'first line'). Device and technical success was 97% (133/137 patients) due to crossover to femoral access in 3 cases, and Mo.MA too short to engage the ECA in 1 patient. The procedural success was 96.7% (131/137, two minor strokes). Procedural time and fluoroscopy time were increased with No.MA2 technique. One major vascular complication occurred, in the TB group, while chronic radial occlusion was detected by Doppler ultrasound in 7/92 patients (7.1%) at 372±163 days of follow-up. The event-free survival was 91% and the stroke rate was 0%. CONCLUSIONS: TR/TB CAS with proximal protection is a feasible, safe and effective strategy and may be considered a first line strategy in all comer patients.

The complete mitochondrial genome of the zebra seabream Diplodus cervinus (Perciformes, Sparidae) from the Mediterranean Sea.

The complete nucleotide sequence of the mitochondrial (mt) genome of the demersal zebra seabream Diplodus cervinus (Lowe, 1838) was determined for the first time. The double stranded circular molecule is 16,559 base pairs (bp) in length and encodes for the typical 37 metazoan mitochondrial genes, and 2 non-coding regions (D-loop and L-origin). The gene arrangement of the D. cervinus mt genome follows the usual one for fishes. The nucleotide sequences of the mt protein coding and ribosomal genes of D. cervinus mt genome were aligned with orthologous sequences from representatives of the Sparidae family and phylogenetic relationships were inferred. Maximum likelihood analyses placed D. cervinus as a sister species of Diplodus sargus (Linnaeus, 1758).

Anti-Cyclic Citrullinated Peptide Antibody Index in the Cerebrospinal Fluid for the Diagnosis and Monitoring of Rheumatoid Meningitis.

Rheumatoid meningitis (RM) is a rare but often aggressive neurological complication of rheumatoid arthritis. The diagnosis of RM, besides the clinical, radiological, and laboratory criteria, usually requires a cerebral biopsy. Based on the two cases presented in this paper, we propose a new laboratory marker. Cerebrospinal fluid and serum anti-cyclic citrullinated peptide (CCP) IgG were measured, and the intrathecal synthesis of anti-CCP antibodies (anti-CCP antibody index) was calculated using the hyperbolic function. The anti-CCP antibody index was positive in both cases at first diagnosis and progressively decreased after treatments. Together with clinical and radiological criteria, the calculation of the anti-CCP intrathecal synthesis, more than the simple measurement of serum or cerebrospinal fluid anti-CCP antibody titers, may represent a useful tool for RM diagnosis and, possibly, for treatment response.