The study aimed to evaluate the effects of monoclonal antibodies (mAbs) acting on the calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP/R mAbs) on migraine comorbidities of depression, anxiety, and fatigue in patients resistant to traditional therapies. The issue addressed in this study is pivotal to unveiling the role of this neurotransmitter beyond pain processing. We conducted an open-label prospective study assessing comorbidities in patients with high frequency (HFEM) and chronic migraine (CM), medication overuse headache (MOH), and resistance to traditional prophylaxis. All patients were treated with anti-CGRP/R mAbs for 3 months. Seventy-seven patients were enrolled with either HFEM (21%) or CM (79%) with or without MOH (56% and 44%, respectively). We identified 21 non-responders (27%) and 56 responders (73%), defined on the reduction ≥50% of headache frequency. The two groups were highly homogeneous for the investigated comorbidities. Disease severity in terms of headache frequency, migraine-related disability, and affective comorbid symptoms was reduced in both groups with different thresholds; allodynia and fatigue were ameliorated only in responders. We found that anti-CGRP/R antibodies improved pain together with affection, fatigue, and sensory sensitization in a cohort of migraine patients resistant to traditional prophylaxis. Our results offer novel perspectives on the early efficacy of anti-CGRP/R mAbs in difficult-to-treat patients focusing on clinical features other than pain relief.

Background and Objectives: The incidence of urothelial cancer in males is higher than in females; however, females have a higher risk of recurrence and progression. The aim of our study was to report the effect of gender on the oncological outcome in advanced urothelial cancer. Materials and Methods: In our retrospective study, all patients had undergone primary surgical treatment for urothelial cancer and were affected by stage IV disease at the time of chemotherapy. Response to therapy and toxicity were evaluated. Subgroups were analyzed for tumour presentation, first- and second-line treatment response, progression-free survival (PFS) and overall survival (OS). Results. Seventy-five patients, 18 (24%) females and 57 (76%) males, were considered. Investigation into the distribution of individual characteristics according to gender revealed a significant difference only for smoking, with a prevalence of smokers in women (p = 0.029). At the end of follow-up, OS was higher in females (27.5% vs. 17.4%; p = 0.047). Smoking did not significantly influence OS (p = 0.055), while univariate Cox regression analysis confirmed that males had a higher risk of death (HR = 2.28, 95% CI 0.99–129 5.25), with borderline statistical significance (p = 0.053). Men showed higher PFS than women both after first-line (p = 0.051) and second-line chemotherapy (p = 0.018), with a lower risk of progression (HR = 0.29, 95% CI 0.10–0.86; p = 0.026). No differences were found between genders with regard to toxicity. Conclusions. In our series, PFS rates following first- and second-line therapies for advanced urothelial carcinoma confirmed that females have a greater risk of progression than males.

Objective: The study aimed to evaluate the effects of monoclonal antibodies (mAbs) acting on the calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP/R mAbs) on comorbid symptoms of depression, anxiety, and fatigue in migraine patients resistant to traditional prophylaxis. Methods: The study was an open-label prospective study assessing comorbidities in patients with high frequency (HFEM) and chronic migraine (CM), medication overuse headache (MOH), and resistance to traditional prophylaxis treated with anti-CGRP/R mAbs for 3 months. Results: 77 patients were enrolled with either HFEM (21%) or CM (79%) with or without MOH (56% and 44% respectively). We identified 21 non-responders (27%) and 56 responders (73%), defined on the reduction ≥ 50% of headache frequency. The two groups were highly homogeneous for investigated comorbidities. Disease severity in terms of headache frequency, migraine-related disability, and affective comorbid symptoms were reduced in both groups with different thresholds; allodynia and fatigue were ameliorated only in responders. Conclusion: anti-CGRP/R antibodies improve pain together with affection, fatigue, and sensory sensitization in migraine patients.

Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders characterized by progressive weakness and spasticity of lower limbs. SPG15 is a rare form of autosomal recessive HSP due to mutations in ZFYVE26 gene, which encodes for spastizin, involved in autophagy and endocytosis ( 1 ). Here we describe the case of a 56 years old man who presented to our clinic in November 2020 referring a progressive motor clumsiness of both legs and walking instability during the last five years. No motor impairment at upper limb, no bulbar nor respiratory symptoms. These symptoms had a progressive evolution. In anamnesis only high blood pressure. No familiar history of neurodegenerative diseases. Neurological examination showed a spastic gait, a light hypotrophy and hyposthenia of the left leg, brisk reflexes at lower limb, no Hoffmann nor Babinski signs, no urinary nor intestinal problems. He underwent: blood examination (resulted normal, no HIV, HTLV infections), electroneurography/electromyography study (signs of chronic neurogenic muscle damage at lower limbs), brain MRI (normal), cervical MRI (normal medulla, small discal hernias without radicular or medulla compression), neuropsychological tests (executive and visuo-spatial impairments). On the basis of these examinations, we suspected a primary form of upper motor neuron disease. Therefore, we prescribed rehabilitation (with partial improvement of gait disturbances) and we executed a genetic examination in the suspect of a rare form of HSP. We observed a homozygous mutation in ZFYVE26 gene, which is the cause of a rare form of HSP (the SPG15). In detail, the mutation we found (c.195-1G>A) is a novel deletion in ZFYVE26 gene, never described in literature. This is a mutation in a splicing site and an in-silico evaluation demonstrated its pathogenic role. The clinical features of our patient are superimposable to other cases of SPG15. Background: Nicotinamide adenine dinucleotide (NAD+) is a central component for cell metabolism, and a vital factor for function of various groups of enzymes involved in pathways such as DNA repair, inflammation, genomic stability and stress resistance. NAD + is synthesised through three pathways; the Kynurenine, Preiss-Handler and salvage pathways. Conversely, NAD + is consumed to its reduced form nicotinamide adenine dinucleotide (NADH) via poly (ADP-ribose) polymerases (PARPs), sirtuins (SIRTs), ADP-ribosyl cyclases (CD38/CD157), and Sterile alpha and TIR motif containing 1 (SARM1). Reduced NAD + levels caused by impairment of enzymes involved in NAD + biosynthesis or up-regulation of enzymes that consume NAD + have been associated with aging and several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). While gene mutations are known to cause ALS, the genetics of ALS is highly complex, whereby only approximately 60–70% of familial and 10% of sporadic ALS cases have a known genetic cause. In additional to causal gene mutations, multiple gene variants may also act synergistically, with or without environmental influence, to cause or confer risk to the development of ALS. Objectives: We aimed to determine the genetic contribution of 36 genes involved in NAD + biosynthesis (focusing on Preiss handler and Salvage pathway, Kynurenine pathways), and NAD + consumption (PARPs, SIRTs, CD38/CD157, SARM1) by identification of novel gene variants and gene burden in a large cohort of Australian sporadic ALS cases. Methods: Whole-genome sequencing data from 609 Australian sporadic ALS cases was screened through the 36 genes. Novel variants absent in public control databases, and rare protein-altering variants (for gene burden analysis) were identified. For burden analysis, variants in genes involved in NAD + synthesis and each consumption pathway were grouped, and compared to two independent control databases. Results: Forty-two novel variants identified in 26/36 genes were identified. Burden analysis of rare variants performed on genes in combined Preiss-handler and Salvage pathway (NAD + synthesis), and genes belonging to the SIRT family (NAD + consumption) was statistically significant (p = 0.0014 and p = 0.006 respectively) when compared to Project MinE controls. Discussion: Some of these variants may represent ALS risk factors that disrupt NAD + biosynthesis or consumption, hence altering NAD + levels in ALS patients. Overall, our genetic findings suggest that rare genetic mutations in genes that alter NAD + levels may be associated with sporadic ALS in Australia. There is potential for therapeutic drugs that boost NAD + levels in ALS patients, and future studies can assess the specific pathogenic role of novel variants identified in patients to improve our understanding underlying the mechanisms of disease. SINE-VNTR-Alu (SVA) retrotransposons are transposable elements which are capable of propagating throughout the genome and hence represent a source of genetic variation. We previously demonstrated that presence or absence of a human-specific SVA, termed SVA_67, correlated with both isoform- and tissue-specific expression of multiple genes at the MAPT locus, a locus associated with several neurodegenerative diseases including frontotemporal dementia and other tauopathies. A problem in defining regulatory associations is that this region is contained within a large genomic inversion termed H1/H2. We have identified that SVA _67 tags the H1 inversion and we are extending our analysis to distinguish the SVA specific regulation from that associated with the inversion. In the current study we show that SVA_67 is not only a retrotransposon insertion polymorphism (RIP), but also variable in the size of its variable number tandem repeat (VNTR) domain. Four different alleles of the SVA_67 VNTR were identified which demonstrated differential properties of a regulatory domain in a reporter gene assay. We expanded these findings by...

Amyotrophic Lateral Sclerosis (ALS) is increasingly recognized as a multisystem disorder. However, SOD1-associated ALS has traditionally been regarded as an exclusively motor phenotype. This systematic review challenges that paradigm by characterizing the cognitive and behavioural profiles of SOD1 mutation-related ALS. Following PRISMA guidelines, a systematic PubMed search identified 17 eligible studies. Across the included studies, encompassing 222 patients with SOD1 variants, three of the analyzed subjects fulfilled the diagnostic criteria for frontotemporal dementia (FTD), and a larger proportion exhibited multidomain cognitive deficits, including executive dysfunction, language impairment, and working memory decline. Behavioural disturbances, such as apathy, emotional lability, and mental rigidity, were also prominent. The historical assumption that SOD1 mutations completely spare cognitive networks likely reflects an under-recognition of subtle manifestations, compounded by the limited sensitivity of earlier screening tools. These findings indicate that cognitive and behavioural involvement can occur in SOD1-ALS, highlighting a highly heterogeneous phenotype. Encompassing varying degrees of severity—from subtle differences in neuropsychological test scores to formal FTD diagnoses—the current evidence points towards possible variant-specific phenotypes rather than a uniform cognitive syndrome. Routine multidomain cognitive screening is crucial in this population. Properly characterizing these non-motor features allows for more accurate disease staging, better monitoring of clinical progression, and the implementation of truly personalized care strategies.