Elevated plasma p-tau181 levels unrelated to Alzheimer's disease pathology in amyotrophic lateral sclerosis.

BACKGROUND: Phosphorylated-tau181 (p-tau181), a specific marker of Alzheimer's disease (AD) pathology, was found elevated in plasma but not in cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). We expanded these findings in a larger patient cohort, exploring clinical/electrophysiological associations, prognostic value and longitudinal trajectories of the biomarker. METHODS: We obtained baseline plasma samples from 148 ALS, 12 spinal muscular atrophy (SMA), and 88 AD patients, and 60 healthy controls. Baseline CSF and longitudinal plasma samples were from 130 and 39 patients with ALS. CSF AD markers were measured with the Lumipulse platform, and plasma p-tau181 with SiMoA. RESULTS: Patients with ALS showed higher plasma p-tau181 levels than controls (p<0.001) and lower than AD participants (p=0.02). SMA patients had higher levels than controls (p=0.03). In patients with ALS, CSF p-tau and plasma p-tau181 did not correlate (p=0.37). Plasma p-tau181 significantly increased with the number of regions showing clinical/neurophysiological lower motor neurons (LMN) signs (p=0.007) and correlated with the degree of denervation in the lumbosacral area (r=0.51, p<0.0001). Plasma p-tau181 levels were higher in classic and LMN-predominant than in bulbar phenotype (p=0.004 and p=0.006). Multivariate Cox regression confirmed plasma p-tau181 as an independent prognostic factor in ALS (HR 1.90, 95% CI 1.25 to 2.90, p=0.003). Longitudinal analysis showed a significant rise in plasma p-tau181 values over time, especially in fast progressors. CONCLUSIONS: Plasma p-tau181 is elevated in patients with ALS, independently from CSF levels, and is firmly associated with LMN dysfunction. The finding indicates that p-tau181 of putative peripheral origin might represent a confounding factor in using plasma p-tau181 for AD pathology screening, which deserves further investigation.

Antibiotic Use and Risk of Multiple Sclerosis: A Nested Case-Control Study in Emilia-Romagna Region, Italy.

INTRODUCTION: Known risk factors for multiple sclerosis (MS) include smoking, a low vitamin D status, obesity, and EBV, while the inflammatory feature of the disease strongly suggests the presence of additional infectious agents. The association between use of antibiotics and MS risk that could shed light on these factors is still undetermined. We aimed to evaluate the association between antibiotics and MS risk, in the Emilia-Romagna region (RER), Italy. METHODS: All adult patients with MS seen at any RER MS center (2015-2017) were eligible. For each of the 877 patients included, clinical information was collected and matched to 5 controls (RER residents) (n = 4,205) based on age, sex, place of residence, and index year. Information on antibiotic prescription was obtained through the linkage with the RER drug prescription database. RESULTS: Exposure to any antibiotic 3 years prior to the index year was associated with an increased MS risk (OR = 1.52; 95% CI = 1.29-1.79). Similar results were found for different classes. No dose-response effect was found. DISCUSSION/CONCLUSIONS: Our results suggest an association between the use of antibiotics and MS risk in RER population. However, further epidemiological studies should be done with information on early life and lifestyle factors.

Combination of Genomic and Transcriptomic Approaches Highlights Vascular and Circadian Clock Components in Multiple Sclerosis.

Aiming at exploring vascular components in multiple sclerosis (MS) with brain outflow disturbance, we combined transcriptome analysis in MS internal jugular vein (IJV) wall with WES in MS families with vertical transmission of disease. Main results were the differential expression in IJV wall of 16 MS-GWAS genes and of seven genes (GRIN2A, GRIN2B, IL20RB, IL26, PER3, PITX2, and PPARGC1A) not previously indicated by GWAS but encoding for proteins functionally interacting with MS candidate gene products. Strikingly, 22/23 genes have been previously associated with vascular or neuronal traits/diseases, nine encoded for transcriptional factors/regulators and six (CAMK2G, GRIN2A, GRIN2B, N1RD1, PER3, PPARGC1A) for circadian entrainment/rhythm components. Among the WES low-frequency (MAF ≤ 0.04) SNPs (n = 7) filtered in the 16 genes, the NR1D1 rs17616365 showed significantly different MAF in the Network for Italian Genomes affected cohort than in the 1000 Genome Project Tuscany samples. This pattern was also detected in five nonintronic variants (GRIN2B rs1805482, PER3 rs2640909, PPARGC1A rs2970847, rs8192678, and rs3755863) in genes coding for functional partners. Overall, the study proposes specific markers and low-frequency variants that might help (i) to understand perturbed biological processes in vascular tissues contributing to MS disease, and (ii) to characterize MS susceptibility genes for functional association with disease-pathways.

Effects of Venous Angioplasty on Cerebral Lesions in Multiple Sclerosis: Expanded Analysis of the Brave Dreams Double-Blind, Sham-Controlled Randomized Trial.

PURPOSE: To evaluate if jugular vein flow restoration in various venographic defects indicative of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis (MS) patients can have positive effects on cerebral lesions identified using magnetic resonance imaging (MRI). MATERIALS AND METHODS: The Brave Dreams trial ( ClinicalTrials.gov identifier NCT01371760) was a multicenter, randomized, parallel group, double-blind, sham-controlled trial to assess the efficacy of jugular venoplasty in MS patients with CCSVI. Between August 2012 and March 2016, 130 patients (mean age 39.9±10.6 years; 81 women) with relapsing/remitting (n=115) or secondary/progressive (n=15) MS were randomized 2:1 to venography plus angioplasty (n=86) or venography (sham; n=44). Patients and study personnel (except the interventionist) were masked to treatment assignment. MRI data acquired at 6 and 12 months after randomization were compared to the preoperative scan for new and/or >30% enlargement of T2 lesions plus new gadolinium enhancement of pre-existing lesions. The relative risks (RR) with 95% confidence interval (CI) were estimated and compared. In a secondary assessment, venograms of patients who underwent venous angioplasty were graded as "favorable" (n=38) or "unfavorable" (n=30) for dilation according to the Giaquinta grading system by 4 investigators blinded to outcomes. These subgroups were also compared. RESULTS: Of the 130 patients enrolled, 125 (96%) completed the 12-month MRI follow-up. Analysis showed that the likelihood of being free of new cerebral lesions at 1 year was significantly higher after venoplasty compared to the sham group (RR 1.42, 95% CI 1.00 to 2.01, p=0.032). Patients with favorable venograms had a significantly higher probability of being free of new cerebral lesions than patients with unfavorable venograms (RR 1.82, 95% CI 1.17 to 2.83, p=0.005) or patients in the sham arm (RR 1.66, 95% CI 1.16 to 2.37, p=0.005). CONCLUSION: Expanded analysis of the Brave Dreams data that included secondary/progressive MS patients in addition to the relapsing/remitting patients analyzed previously showed that venoplasty decreases new cerebral lesions at 1 year. Secondary analysis confirmed the efficacy of the Giaquinta grading system in selecting patients appropriate for venoplasty who were more likely to be free from accumulation of new cerebral lesions at MRI.

Exacerbation of myasthenia gravis after amoxicillin therapy: a case series.

INTRODUCTION: Myasthenia gravis (MG) can be aggravated by several classes of drugs, including antibiotics. Penicillins are considered safe drugs for the management of infectious disease in patients with MG. However, a few cases of MG exacerbations after penicillin treatment have been reported in literature. CASE REPORTS: We report six patients with MG developing acute worsening of symptoms after amoxicillin or amoxicillin/clavulanate treatment. In most of the cases, symptoms started in a few days after antibiotic administration. In all cases, we observed a worsening of the Myasthenia Gravis Foundation of America (MGFA) clinical classification. Most patients required a therapeutic intervention with dosage increase of the previous therapy or the introduction of new drugs for MG. All patients had a full recovery to baseline neurological conditions within 1-2 months. CONCLUSIONS: We concluded that patients receiving amoxicillin should be closely monitored for possible acute relapse.

Prevalence and Psychopathological Determinants of Sexual Dysfunction and Related Distress in Women With and Without Multiple Sclerosis.

INTRODUCTION: Sexual dysfunction (SD) is common but still underdiagnosed in women with multiple sclerosis (MS); in fact, the lack of a consistent use of validated diagnostic tools makes the prevalence of SD and related distress difficult to define precisely. AIM: To assess the prevalence of SD in Italian women with MS compared with age-matched healthy control subjects (HC) and the association with demographic, psychological, and MS-related characteristics. METHODS: The Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale were administered to 153 women with MS and 153 HC. Demographic, gynecologic, and neurologic data were obtained. Disability was assessed using the Expanded Disability Status Scale. Psychological symptoms were evaluated in MS patients with Profile of Mood State and the Beck Depression Inventory II. MAIN OUTCOMES MEASURES: Prevalence of SD and sexual distress in women with MS compared with HC. RESULTS: Among women sexually active in the last month, we found an increased prevalence of SD in MS patients compared with HC subjects (42.0% vs 16.0%, P = .0001). The prevalence of dysfunctional FSFI global scores (<26.55) was higher in women with MS compared with HC (49.6% vs 33.6%, P = .014). In the MS group, the prevalence of SD was similar between pre- and post-menopausal women. Both premenopausal and postmenopausal MS women presented a greater prevalence of SD if compared with the premenopausal and postmenopausal HC groups (30/79 [37.9%] vs. 5/74 [6.8%], P = .0001 and 20/40 [50.0%] vs 16/57 [28.1%], P = .03, respectively). A negative correlation was observed between the FSFI global score and age and Expanded Disability Status Scale. Depressive symptoms were more common in women with MS and SD than in those without. CLINICAL IMPLICATIONS: This study suggests that sexual function investigation should always be a standard part of the consultation with healthcare professionals for MS. STRENGTH & LIMITATIONS: The strength of this study was the comparison with an age-matched healthy control group and the use of validated questionnaires to assess both sexual function and sexual distress. Larger and multicenter studies may further support our findings. CONCLUSION: In our cohort, the prevalence of SD and sexual distress was higher in women with MS compared to the HC group. Age, disability, and depressive symptoms were associated with increased SD. Gava G, Visconti M, Salvi F, et al. Prevalence and Psychopathological Determinants of Sexual Dysfunction and Related Distress in Women With and Without Multiple Sclerosis. J Sex Med 2019;16:833-842.

Changes in expression profiles of internal jugular vein wall and plasma protein levels in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disorder of the central nervous system (CNS). Several observations support interactions between vascular and neurodegenerative mechanisms in multiple sclerosis (MS). To investigate the contribution of the extracranial venous compartment, we analysed expression profiles of internal jugular vein (IJV), which drains blood from CNS, and related plasma protein levels. METHODS: We studied a group of MS patients (n = 19), screened by echo-color Doppler and magnetic resonance venography, who underwent surgical reconstruction of IJV for chronic cerebrospinal venous insufficiency (CCSVI). Microarray-based transcriptome analysis was conducted on specimens of IJV wall from MS patients and from subjects undergoing carotid endarterectomy, as controls. Protein levels were determined by multiplex assay in: i) jugular and peripheral plasma from 17 MS/CCSVI patients; ii) peripheral plasma from 60 progressive MS patients, after repeated sampling and iii) healthy individuals. RESULTS: Of the differentially expressed genes (≥ 2 fold-change, multiple testing correction, P < 0.05), the immune-related CD86 (8.5 fold-change, P = 0.002) emerged among the up regulated genes (N = 409). Several genes encoding HOX transcription factors and histones potentially regulated by blood flow, were overexpressed. Smooth muscle contraction and cell adhesion processes emerged among down regulated genes (N = 515), including the neuronal cell adhesion L1CAM as top scorer (5 fold-change, P = 5 × 10- 4). Repeated measurements in jugular/peripheral plasma and overtime in peripheral plasma showed conserved individual plasma patterns for immune-inflammatory (CCL13, CCL18) and adhesion (NCAM1, VAP1, SELL) proteins, despite significant variations overtime (SELL P < 0.0001). Both age and MS disease phenotypes were determinants of VAP1 plasma levels. Data supported cerebral related-mechanisms regulating ANGPT1 levels, which were remarkably lower in jugular plasma and correlated in repeated assays but not between jugular/peripheral compartments. CONCLUSIONS: This study provides for the first time expression patterns of the IJV wall, suggesting signatures of altered vascular mRNA profiles in MS disease also independently from CCSVI. The combined transcriptome-protein analysis provides intriguing links between IJV wall transcript alteration and plasma protein expression, thus highlighting proteins of interest for MS pathophysiology.

Failure of Tafamidis to Halt Progression of Ala36Pro TTR Oculomeningovascular Amyloidosis.

Oculomeningovascular amyloidosis is a variant of transthyretin (TTR) amyloidotic polyneuropathy, which is associated with blindness and brain ischemia, microhemorrages, and siderosis due to prominent production of the abnormal TTR in the eye and in the choroid plexuses. Tafamidis is a TTR stabilizer that is orally administered and, by interfering with amyloid fibril formation and deposition, is capable of slowing progression of TTR polyneuropathy and of early-stage cardiomyopathy. However, the ocular manifestations of amyloid deposition progressed despite tafamidis therapy in Val30Met TTR amyloidosis, and the effects of tafamidis on meningovascular amyloidosis are unknown. We observed failure of tafamidis to halt progression of oculomeningovascular amyloid deposition in a patient with familial Ala36Pro TTR amyloidosis. She received molecular diagnosis at age 24 and presented at age 26 with paresthesias of the lower limbs and bowel dysfunction. Echography showed minimal amyloid opacities in the corpus vitreum. Treatment with tafamidis meglumine was started. Sixteen months later, she complained of severe headache followed by left hemiparesthesias and numbness lasting 20 minutes. Magnetic resonance imaging showed multiple focal and diffuse hemosiderin deposits compatible with microbleeds and early siderosis. Echography showed a marked increase of "vitreal opacities." Our observation confirms that tafamidis fails in halting increase of vitreal amyloid deposits and indicates that it is presumably ineffective in preventing clinical onset due to progression of meningovascular amyloidosis. These failures may be due to the incapability of tafamidis to cross the blood-retina and blood-brain barriers. Therapeutic options targeting oculomeningovascular TTR amyloidoses in humans are required.

Amyotrophic lateral sclerosis and myasthenia gravis: association or chance occurrence?

Very few cases of patients with myasthenia gravis (MG) who later developed amyotrophic lateral sclerosis (ALS) have been described, although some studies showed that significantly more cases than expected have ALS associated with a prior diagnosis of autoimmune diseases. Our aim was to investigate whether the association of ALS and MG was higher than expected in a population-based study and to describe the clinical features characterizing these patients. In Emilia Romagna Region of Italy, a prospective registry has been collecting all incident ALS cases since 1.1.2009. For each patient, detailed clinical information is collected by caring physicians, including comorbidities. From 1.1.2009 to 31.12.2014, 671 patients were diagnosed with ALS; five patients (0.75%) were also affected by MG. Considering Western Countries incidence rates the occurrence of both the diseases should be a really exceptional event (7.5/109), compared to our findings (1.87/107) (p < 0.01). Patients with ALS and MG had more frequently a bulbar onset and a fast progressive course. These cases of ALS after MG raise the possibility of potential shared immunological dysfunctions, which may be expression of common pathogenic mechanisms, as well as of shared disease-course modulating events.

Diffuse Brain Hypoperfusion in Advanced Leukoencephalopathy with Calcifications and Cysts.

Leukoencephalopathy with calcifications and cysts (LCC) is an uncommon condition of unknown etiology occurring in children and adults. Pathological findings include obliterative hyalinosis of the small vessels, myelin loss, intense gliosis, Rosenthal fiber formation, microcalcifications, and hemosiderin deposits. Herein we report a 55-year-old man with LCC documented 10 years ago, in whom we examined brain perfusion by pseudocontinuous arterial spin labeling technique. We demonstrated diffused hypoperfusion of the affected white matter (WM) and of the subcortical gray matter (GM) and cortical GM in the patient in comparison to a group of healthy control subjects, using both qualitative evaluation and region of interest analysis. WM and subcortical GM hypoperfusion reflects the known distribution of LCC microangiopathy. We speculate that cortical hypoperfusion may be related to cerebral atrophy or may reflect deafferentation secondary to severe leukoencephalopathy, and may possibly contribute to severe motor and cognitive impairment. Further studies addressing cerebral blood flow in LCC are necessary.

Cardiac amyloidosis: the great pretender.

Cardiac amyloidosis (CA) is often misdiagnosed because of both physician-related and disease-related reasons including: fragmented knowledge among different specialties and subspecialties, shortage of centres and specialists dedicated to disease management, erroneous belief it is an incurable disease, rarity of the condition, intrinsic phenotypic heterogeneity, genotypic heterogeneity in transthyretin-related forms and the necessity of target organ tissue histological diagnosis in the vast majority of cases. Pitfalls, incorrect beliefs and deceits challenge not only the path to the diagnosis of CA but also the precise identification of aetiological subtype. The awareness of this condition is the most important prerequisite for the management of the risk of underdiagnoses and misdiagnosis. Almost all clinical, imaging and laboratory tests can be misinterpreted, but fortunately each of these diagnostic steps can also offer diagnostic "red flags" (i.e. highly suggestive findings that can foster the correct diagnostic suspicion and facilitate early, timely diagnosis). This is especially important because outcomes in CA are largely driven by the severity of cardiac dysfunction and emerging therapies are aimed at preventing further amyloid deposition.

Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study.

OBJECTIVE: To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS). METHODS: Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40,000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91. RESULTS: We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes. CONCLUSIONS: RhEPO 40,000 IU fortnightly did not change the course of ALS.

Heterogeneity in ALSFRS-R decline and survival: a population-based study in Italy.

Very few studies examined trend over time of the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and factors influencing it; previous studies, then, included only patients attending tertiary ALS Centres. We studied ALSFRS-R decline, factors influencing this trend and survival in a population-based setting. From 2009 onwards, a prospective registry records all incident ALS cases among residents in Emilia Romagna (population: 4.4 million). For each patient, demographic and clinical details (including ALSFRS-R) are collected by caring physicians at each follow-up. Analysis was performed on 402 incident cases (1279 ALSFRS-R assessments). The average decline of the ALSFRS-R was 0.60 points/month during the first year after diagnosis and 0.34 points/month in the second year. ALSFRS-R decline was heterogeneous among subgroups. Repeated measures mixed model showed that ALSFRS-R score decline was influenced by age at onset (p < 0.01), phenotype (p = 0.01), body mass index (BMI) (p < 0.01), progression rate at diagnosis (ΔFS) (p < 0.01), El Escorial Criteria-Revised (p < 0.01), and FVC% at diagnosis (p < 0.01). Among these factors, at multivariate analysis, only age, site of onset and ΔFS independently influenced survival. In this first population-based study on ALSFRS-R trend, we confirm that ALSFRS-R decline is not homogeneous among ALS patients and during the disease. Factors influencing ALSFRS-R decline may not match with those affecting survival. These disease modifiers should be taken into consideration for trials design and in clinical practice during discussions with patients on prognosis.

Brain Microbleeds 12 Years after Orthotopic Liver Transplantation in Val30Met Amyloidosis.

Unexplained focal neurologic episodes (FNEs) can occur in patients with transthyretin-related familial amyloidotic polyneuropathy (TTR-FAP) after orthotopic liver transplantation (OLT). A patient with Val30Met FAP underwent OLT at age 34 years. Twelve years after transplantation, she presented with recurrent FNEs lasting from 10 minutes to 8 hours each, with nonuniform deficitary clinical features and variably associated with headache. Magnetic resonance imaging showed multiple brain microbleeds and diffuse contrast enhancement of the craniospinal leptomeninges consistent with amyloid deposits. Our observation suggests that microbleeds associated with meningovascular amyloidosis can underlie FNEs in TTR-FAP. Moreover, it confirms that OLT does not halt progression of leptomeningeal and vascular amyloid deposition due to TTR production in the choroid plexuses. Such a progression might compromise the good long-term prognosis of patients with TTR-FAP due to increased risk of intracranial hemorrhages. Pharmacologic therapies targeting brain TTR production may modify this scenario.

Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective.

AIMS: Hereditary transthyretin (TTR)-related amyloidosis (ATTR) is mainly considered a neurologic disease. We assessed the phenotypic and genotypic spectra of ATTR in a Caucasian area and evaluated the prevalence, genetic background, and disease profile of cases with an exclusively cardiac phenotype, highlighting possible hints for the differential diagnosis with hypertrophic cardiomyopathy (HCM) and senile systemic amyloidosis (SSA). METHODS AND RESULTS: In this Italian multicentre study, 186 patients with ATTR were characterized at presentation. Thirty patients with SSA and 30 age-gender-matched HCM patients were used for comparison. Phenotype was classified as exclusively cardiac (n = 31, 17%), exclusively neurologic (n = 46, 25%), and mixed cardiac/neurologic (n = 109, 58%). Among the eight different mutations responsible for an exclusively cardiac phenotype, Ile68Leu was the most frequent. Five patients with an exclusively cardiac phenotype developed mild abnormalities at neurological examination, but no symptoms during a 36-month follow-up (range: 14-50). Exclusively cardiac phenotype was characterized by male gender, age >65 years, heart failure symptoms, symmetric left ventricular (LV) 'hypertrophy', and moderately depressed LV ejection fraction. This profile was similar to SSA, but relatively distinct from HCM. Compared with patients with a mixed phenotype, patients with an exclusively cardiac phenotype showed a more pronounced cardiac involvement on both echocardiogram and electrocardiogram (ECG). CONCLUSION: A clinically relevant subset of Caucasian ATTR patients present with an exclusively cardiac phenotype, mimicking HCM or SSA. Echocardiographic and ECG findings are useful to differentiate ATTR from HCM but not from SSA. The role of liver transplantation in these patients should be reconsidered.

Changes of cine cerebrospinal fluid dynamics in patients with multiple sclerosis treated with percutaneous transluminal angioplasty: a case-control study.

PURPOSE: To investigate characteristics of cine phase contrast-calculated cerebrospinal fluid (CSF) flow and velocity measures in patients with relapsing-remitting (RR) multiple sclerosis (MS) receiving standard medical treatment who had been diagnosed with chronic cerebrospinal venous insufficiency (CCSVI) and underwent percutaneous transluminal angioplasty (PTA). MATERIALS AND METHODS: This case-controlled, magnetic resonance (MR) imaging-blinded study included 15 patients with RR MS who presented with significant stenoses (≥50% lumen reduction on catheter venography) in the azygous or internal jugular veins. Eight patients underwent PTA in addition to medical therapy immediately following baseline assessments (case group) and seven had delayed PTA after 6 months of medical therapy alone (control group). CSF flow and velocity measures were quantified over 32 phases of the cardiac cycle by a semiautomated method. Outcomes were compared between groups at baseline and at 6 and 12 months of the study by mixed-effect model analysis. RESULTS: At baseline, no significant differences in CSF flow or velocity measures were detected between groups. At month 6, significant improvement in flow (P<.001) and velocity (P = .013) outcomes were detected in the immediate versus the delayed group, and persisted to month 12 (P = .001 and P = .021, respectively). Within-group flow comparisons from baseline to follow-up showed a significant increase in the immediate group (P = .033) but a decrease in the delayed group (P = .024). Altered CSF flow and velocity measures were associated with worsening of clinical and MR outcomes in the delayed group. CONCLUSIONS: PTA in patients with MS with CCSVI increased CSF flow and decreased CSF velocity, which are indicative of improved venous parenchyma drainage.

Muscle oxygen consumption by NIRS and mobility in multiple sclerosis patients.

BACKGROUND: The study of muscle metabolism by near-infrared spectroscopy (NIRS) has been poorly implemented in multiple sclerosis (MS). Aims of the study were to compare resting muscle oxygen consumption (rmVO2) at gastrocnemius in MS patients and in age-matched healthy controls (HC) measured using NIRS, and to evaluate its possible relationship with patients' mobility. METHODS: Twenty-eight consecutively enrolled MS patients (male, n = 16; age = 42.7 ± 14.0 y, Relapsing-Remitting, n = 19; Primary-Progressive, n = 9) and 22 HC (male, n = 13; age = 36.0 ± 8.2 y) were studied during rest applying the NIRS probes at gastrocnemius, producing a venous occlusion at the thigh using a cuff, and analyzing the slope of the total hemoglobin to calculate rmVO2. Mobility was assessed by a 6-Minute Walking Test and 6-Minute Walking Distance (6MWD) was recorded. RESULTS: rmVO2 was higher in MS compared to HC (0.059 ± 0.038 vs 0.039 ± 0.016 mlO2/min/100 g, P < 0.003), not different in clinical subtypes, not correlated to patients' characteristics (age, disease duration, Expanded Disability Status Scale, resting heart rate, skinfold thickness), and significantly higher in patients with lower walking ability (6MWD < 450 m, n = 12) compared to those at better performance (respectively, 0.072 ± 0.043 vs 0.049 ± 0.032 mlO2/min/100 g, P = 0.03). CONCLUSION: rmVO2 values, significantly higher in MS patients compared to HC, and in low versus high performing patients, might represent a marker of peripheral adaptations occurred to sustain mobility, as observed in other chronic diseases.

Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72.

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ~40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ~60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.

Thoracic Radiotherapy in Extensive Disease Small Cell Lung Cancer: Multicenter Prospective Observational TRENDS Study.

(1) Introduction: Small cell lung cancer (SCLC) is an aggressive tumor type, accounting for about 15% of all lung cancers. Radiotherapy (RT) plays a fundamental role in both early and advanced stages. Currently, in advanced disease, the use of consolidative chest RT should be recommended for patients with good response to platinum-based first-line chemotherapy, but its use has not yet been standardized. The present prospective study aims to evaluate the pattern of care of consolidative chest RT in patients with advanced stage SCLC, and its effectiveness in terms of disease control and tolerability. (2) Materials and methods: This study was a multicenter prospective observational trial, proposed and conducted within the AIRO lung study group to evaluate the pattern of care of consolidative chest RT after first-line chemotherapy in patients with advanced SCLC. The patient and tumor characteristics, doses, fractionation and volumes of thoracic RT and prophylactic cranial irradiation (PCI), as well as the thoracic and extrathoracic response to the treatment, toxicity and clinical outcomes, were collected and analyzed. (3) Results: From January 2017 to December 2019, sixty-four patients were enrolled. Median follow-up was 33 months. The median age was 68 years (range 42-81); 38 patients (59%) were male and 26 (41%) female. Carboplatin + etoposide for 6 cycles was the most commonly used first-line therapeutic scheme (42%). With regard to consolidative chest RT, 56% of patients (35) received 30 Gy in 10 factions and 16 patients (26%) received 45 Gy in 15 sessions. The modulated intensity technique was used in 84.5% of cases, and post-chemotherapy macroscopic residual disease was the target volume in 87.5% of patients. Forty-four patients (69%) also underwent PCI. At the last follow-up, over 60% of patients did not experience chest disease progression, while 67% showed extrathoracic progression. At the first radiological evaluation after RT, complete response and stable disease were recorded in 6% and 46% of the cases, respectively. Two patients had a long-term complete response to the combined treatment. The brain was the first site of extrathoracic progression in 28%. 1y and 2y OS and PFS were 67%, 19%, 28% and 6%, respectively. Consolidative chest RT was well-tolerated in the majority of patients; it was interrupted in three cases (due to G2 pulmonary toxicity, disease progression and clinical decay, respectively). Only 1 patient developed G3 asthenia. (4) Conclusions: Consolidative chest RT has been shown to be useful in reducing the risk of thoracic disease progression and is absolutely well-tolerated in patients with advanced stage SCLC with good response after first-line chemotherapy. Among the Italian centers that participated in this study, there is still variability in the choice of fractionation and target volumes, although the guidelines contain clear recommendations. The aim of future research should be to clarify the role and modalities of chest RT in the era of immunotherapy in advanced-stage SCLC.

The HFE p.H63D (p.His63Asp) Polymorphism Is a Modifier of ALS Outcome in Italian and French Patients with SOD1 Mutations.

Background: Data from published studies about the effect of HFE polymorphisms on ALS risk, phenotype, and survival are still inconclusive. We aimed at evaluating whether the p.H63D polymorphism is a modifier of phenotype and survival in SOD1-mutated patients. Methods: We included 183 SOD1-mutated ALS patients. Mutations were classified as severe or mild according to the median survival of the study population. Patients were screened for the HFE p.H63D polymorphism. Survival was calculated using the Kaplan-Meier modeling, and differences were measured by the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model (stepwise backward). Results: SOD1 severe mutation carriers show more frequent familial history for ALS and shorter survival compared to mild mutation carriers. Carriers and non-carriers of the p.H63D polymorphism did not differ in terms of sex ratio, frequency of positive familial history, age at onset, and bulbar/spinal ratio. In univariate and in Cox multivariable analysis using sex, age at onset, site of onset, family history, country of origin, and mutation severity as covariates, p.H63D carriers had a longer survival (p = 0.034 and p = 0.004). Conclusions: We found that SOD1-mutated ALS patients carrying the p.H63D HFE polymorphism have a longer survival compared to non-carriers, independently of sex, age and site of onset, family history, nation of origin, and severity of mutations, suggesting a possible role as disease progression modifier for the p.H63D HFE polymorphism in SOD1-ALS.