Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with an ambiguous etiology, whose onset may be linked to innate immune system activation outside the central nervous system (CNS). We investigated the association between peripheral blood and CNS inflammatory parameters in 45 sporadic ALS patients compared to 30 controls, analyzing peripheral blood tests (C-reactive protein [CRP], blood count, fibrinogen) and cerebrospinal fluid (CSF) immunological measures (Tumor Necrosis Factor alpha [TNF-α], TNF receptor type 1 [TNFR-1], CRP) alongside clinical characteristics. Results revealed significantly higher concentrations of TNFR-1 in the CSF of ALS patients compared to the control group (1,029.5 ± 176.0 vs. 846.1 ± 167.5 pg/ml; p < 0.0001). This difference remained significant in multivariable logistic regression adjusting for age and sex (OR 1.82 per 100 pg/ml increment, 95% CI 1.26-2.63; p = 0.0015). In an exploratory ROC analysis, CSF TNFR-1 discriminated patients from controls with an AUC of 0.78 (95% CI 0.67-0.88). TNFR-1 correlated with age (R = 0.32, p = 0.038), associations with disease severity and a lower concentration in bulbar-onset disease were exploratory and not robustly significant. Plasma and CSF CRP concentrations did not differ significantly between groups, but strongly correlated with each other in both ALS (R = 0.83) and control (R = 0.82) cohorts, indicating a disease-non-specific relationship. CSF TNFR-1 is independently associated with sporadic ALS and warrants further investigation as a candidate disease-associated inflammatory biomarker. Given the limitations, our findings do not prove diagnostic accuracy or causality. Longitudinal studies with disease controls and blood-CSF barrier integrity measures are needed.

Neuropsychological assessment largely depends on normative data to interpret an individual's test performance. In Italy, the Equivalent Scores (ES) system is a widely adopted non-parametric method to classify adjusted scores into five ordinal categories, on the basis of tolerance limits. Although the ES system provides a clear and rapid categorization of individuals' performance, it has several limitations. In contrast, percentile ranks could represent a valid alternative scoring approach to ES. Indeed, percentile ranks precisely indicate how rare or common a score is within the normative sample. Moreover, percentile ranks are non-parametric and are widely used, internationally, in the fields of neuropsychology, healthcare, and education. The finer resolution of percentiles allows the detection of small changes in individuals' performance and facilitates the communication of results to both professionals and non-experts. Importantly, the availability of confidence intervals (CIs), around percentile ranks, allows clinicians to better quantify sampling uncertainty. Different methods could be used to calculate CIs (the Binomial distribution method, the Beta distribution method, and the Bootstrap method). We calculate percentile values and their CI on the Italian MoCA 8.1 norms. The results showed that CIs based on the Binomial and the Beta distribution methods were similar, whereas the Bootstrap method yielded narrower CIs. After comparing ES to percentiles, the ES0-ES1 cutoff corresponded approximately to the 3[rd] -4[th] percentile rank. Overall, we recommend that neuropsychologists routinely consider percentile ranks, including the respective CIs, when interpreting individuals' test scores to provide a finer and more detailed approach to the diagnostic decision-making process.

Pathogenic variants in the OPHN1 gene are associated with X-linked intellectual developmental disorder, Billuart type (OMIM #300486), characterized by intellectual disability, distinctive facial features, cerebellar abnormalities, ventriculomegaly, epilepsy, and variable neuropsychiatric manifestations. In this study, four male individuals from four unrelated families presenting with intellectual disability and developmental delay were evaluated. Comprehensive clinical, neuroimaging, and molecular genetic data were collected. Genetic analyses were performed using whole-exome or clinical exome sequencing. Hemizygous OPHN1 variants were identified in all individuals. Two variants, a nonsense variant, c.226del (p.Leu76Ter), and a frameshift variant, c.226_227del (p.Leu76AspfsTer2), were predicted to introduce premature termination codons resulting in loss of protein function and were classified as pathogenic or likely pathogenic. Additionally, two intronic splice-site variants (c.1527-3 C > G and c.2158 + 5G > A) were classified as variants of uncertain significance; however, in silico analyses strongly supported their potential to disrupt normal splicing. The clinical features observed in the affected individuals, including developmental delay, intellectual disability of variable severity, characteristic facial features, and cerebellar and ventricular abnormalities, were consistent with previously reported OPHN1-associated phenotypes. Neuropsychiatric features, including autism spectrum disorder and hyperactivity, were also observed, highlighting phenotypic variability. This study reports the first OPHN1-related cases from Türkiye and expands the molecular and phenotypic spectrum of OPHN1-associated neurodevelopmental disorders by identifying three novel variants. Our findings support the pathogenic relevance of both loss-of-function and splice-site variants and contribute to improved genotype-phenotype correlation and diagnostic evaluation.

This report describes a 79-year-old woman with biomarker-confirmed Alzheimer's disease who developed progressive vasogenic edema initially interpreted as amyloid-related imaging abnormalities (ARIA) with edema during lecanemab therapy, but was ultimately found to have multifocal intracranial metastases from recurrent papillary thyroid carcinoma. The serial neuroimaging highlights the diagnostic challenge of distinguishing ARIA from alternative causes of vasogenic edema in the era of anti-amyloid monoclonal antibody treatment. In addition, this case raises an important and underexplored question regarding whether anti-amyloid therapies may alter blood-brain barrier integrity in a manner that could influence metastatic spread in susceptible patients.

Parkinson disease is an ongoing neurodegenerative disorder, and both motor and non-motor symptoms are involved with the existing therapies having minimal effects on the disease but only symptom alleviation. The goal of this systematic literature review was to generalize up-to-date evidence on the next-generation pharmacological strategies to manage the symptoms and the disease in a patient with Parkinson disease. The review was based on PRISMA 2020 and included the analysis of peer-reviewed studies of human research published in 2015-2026 and retrieved in the key databases, such as PubMed, Scopus, Web of Science, and Cochrane Library. This included 30 eligible studies consisting of randomized studies, observational studies, and early clinical trials. The results show that, although dopaminergic treatment continues to play a central role in managing motor symptoms, new methods such as gene therapy, gene editing, stem cell-based regeneration, nanomedicine delivery systems, repurposed drugs, artificial intelligence-based precision medicine approaches have a good neuroprotective and disease-modifying potential. Nonetheless, the majority of new interventions are still in preclinical or first line clinical phase, with a defined subset of emerging gene-, cell-, and nanotechnology-based approaches evaluated only in animal or in-vitro models rather than in PD patients and associated with small sample size, invasive delivery, limited follow-up and lack of long-term safety information. In general, the review concludes by stating that there has been significant advancement in diversification of therapeutic targets and mechanisms, but rigorous large-scale biomarker-directed clinical trials are needed to translate these advances to effective and sustainable treatment of the Parkinson disease.