Giuseppe Salemi

Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial and peripheral myeloid cell function, with its soluble form (sTREM2) emerging as a biomarker of neuroinflammation. Although cerebrospinal fluid (CSF) sTREM2 is consistently elevated in neurodegenerative diseases, the clinical relevance of blood sTREM2 remains unclear. We performed a retrospective observational study including 547 individuals: Alzheimer's disease ( AD , n = 142), mild cognitive impairment (MCI, n = 42), multiple sclerosis (MS, n = 105), hereditary transthyretin amyloidosis with polyneuropathy (ATTR‐PN, n = 23), asymptomatic ATTR mutation carriers ( n = 25), and controls ( n = 210). Plasma sTREM2 concentrations were measured using Lumipulse automated chemiluminescent enzyme immunoassay platform (Fujirebio, Tokyo, Japan). Age‐adjusted multivariate analysis was performed to compare disease groups with controls. In controls, plasma sTREM2 levels increased with age, with a significant breakpoint at 68 years, after which the rate of increase markedly accelerated. Across diagnostic groups, AD , MCI, and MS patients exhibited significantly lower plasma sTREM2 levels (11%–18% reduction) compared to controls ( p < 0.05), independent of age. No significant differences were observed in ATTR‐PN patients or asymptomatic carriers. Age remained a strong positive predictor of sTREM2 levels across all groups. In conclusions, plasma sTREM2 levels are reduced in AD , MCI, and MS despite known elevations in CSF, indicating a divergence between peripheral and central TREM2 biology. The lack of alteration in ATTR‐PN suggests tissue‐specific regulation of sTREM2. These findings highlight that blood sTREM2 does not directly mirror central nervous system microglial activation but may reflect peripheral immune dynamics, warranting further investigation into its role as a biomarker of systemic immune dysfunction in neurodegenerative diseases.

Introduction: The significant impact of attention deficit/hyperactivity disorder (ADHD) on health in adult life has been widely recognized. Among the comorbidities of this disorder in later life, dementia is one of the most relevant ones. We performed a systematic review and meta-analysis to explore the impact of previous ADHD diagnosis on dementia risk. Materials and methods: We systematically searched Pubmed, Embase and Scopus for the relevant literature. Cohort and case–control studies were included in our review. Retrieved records were selected by title and abstract and then by full text reading. For quality appraisal, the Newcastle–Ottawa scale was used. A meta-analysis of hazard ratios (HRs) was performed for each type of dementia. Results: Four cohort studies and one case–control study were included, for a total of 3,703,877 and 400 participants, respectively. For all-cause dementia, the pooled HR was 2.52 (95%CI 1.51–4.22, p < 0.001), pointing out a significantly higher hazard in subjects with ADHD. For Alzheimer’s disease, vascular dementia and Lewy body dementia, no meta-analysis was performed due to the low number of available studies. Discussion and conclusions: Our results support a significant association between ADHD and risk of dementia. The results regarding specific types of dementia are more challenging to interpret and could have been influenced by sample size issues. These findings show that ADHD deserves attention in future research on cognitive disorders of the elderly; in particular, more studies are needed to reveal if a true causal relationship links ADHD and dementia.

Background/Objectives: Alzheimer’s disease (AD) is the most common cause of dementia. Among the various factors associated with the risk of AD, growing attention in recent years has focused on environmental influences, particularly air pollution. The association between air pollutants and AD remains inconclusive due to heterogeneity in available studies. Given these gaps, we performed a systematic review on the topic. Methods: We systematically searched Pubmed, Embase and Scopus. Retrieved records underwent screening by title and abstract and then in full text. We included studies quantitatively exploring the association between exposure to air pollutants and risk of AD. We performed a meta-analysis to identify a pooled estimate of the impact of each pollutant on the probability of developing AD. Results: We retrieved 1081 records and included 27 studies. We found a significant association between PM_2.5 levels and AD risk (HR 1.74, 95%CI 1.36–2.23). Our data did not support a relevant role for the other pollutants we analyzed (for PM₁₀ HR = 1.35, 95%CI: 0.86–2.11; for NO₂ HR = 1.34, 95%CI 0.96–1.86; and for O₃ HR = 1.03, 95%CI 0.68–1.57). Conclusions: PM_2.5 emerged as the pollutant most strongly and consistently associated with an increased risk of AD. This robust and statistically significant association underscores the potential neurotoxic effects of fine particulate matter. For other pollutants, a clear role was not found. These results should be interpreted with caution, due to high heterogeneity in the definition of AD in the included studies (in most cases, a clinical definition was used). More research will be needed in the future.

Multiple Sclerosis (MS) is a neuroinflammatory disorder in which genetic and environmental factors contribute to disease onset. Evidence implicates the inflammasome pathway in MS pathophysiology. However, the interaction between inflammasome-related genetic variants and 25-OH-vitamin D₃ (25(OH)D₃) levels remains unclear. 105 MS patients and 109 healthy controls were enrolled. Genotyping of NLRP3 (rs10754558, rs3806265) and NLRC4 (rs479333) polymorphisms was performed using real-time PCR. Serum 25(OH)D₃ levels were measured by high-performance liquid chromatography. Clinical severity was assessed using the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Score (MSSS), annualized relapse rate (ARR), and age at onset. MS patients showed significantly lower serum 25(OH)D₃ levels than controls. Genotype distributions did not differ significantly under an additive model; however, the NLRP3 rs10754558 GG genotype was more frequent in MS patients under a recessive model and was significantly associated with disease status after adjustment for sex. Subjects carrying the GG genotype also had significantly lower serum 25(OH)D₃ levels than CC/CG carriers, independently of sex. No significant associations were observed for NLRP3 rs3806265 or NLRC4 rs479333, and none of the investigated variants was associated with EDSS, MSSS, ARR, or age at onset. The NLRP3 rs10754558 polymorphism may be associated with MS susceptibility and reduced circulating vitamin D levels, suggesting a potential link between inflammasome-related genetic variability and immunometabolic regulation in MS.

Background/Objectives: At the international level, harmonized networks of dementia clinical studies are available, but Italian participation remains limited. This systematic review aims to define harmonization rules to facilitate the inclusion of Italian clinical studies in existing networks and to propose standardized data collection methods to enable comparison of the study results. Methods: A systematic review was conducted (January 2019–December 2024) to identify Italian clinical studies evaluating Alzheimer’s disease and other dementias as outcomes. Eight modifiable risk factors were extracted: BMI, arterial hypertension, diabetes, dietary patterns, alcohol consumption, smoking habits, depressive symptomatology, and physical activity. WHO definitions and internationally accepted criteria were used as reference standards. Variable harmonization potential was assessed using the DataSHaPER methodology and classified as complete, partial, or impossible, considering information loss across studies. Results: Of 365 records identified, 18 studies met the inclusion criteria. Obesity assessed via BMI showed the highest harmonization potential (44% complete, 33% partial), along with dietary habits measured by food frequency questionnaires (44% complete). Diabetes and physical inactivity followed (33% complete), assessed through fasting glucose or pharmacological treatment and the IPAQ, respectively. Smoking habits classified as current, former, or never smokers were reported in 28% of studies. Depression (assessed by GDS or CES-D) and hypertension (blood pressure measurement or antihypertensive treatment) showed complete harmonization in only 22% of studies. Conclusions: Italian studies show substantial limitations in the harmonization of modifiable risk factor data for Alzheimer’s disease, mainly due to heterogeneous and non-standardized data collection methods, highlighting the need for uniform research protocols.

Approximately 10% of ALS (amyotrophic lateral sclerosis) cases show a family history, and the remaining 90% are sporadic. In 2018, through genome sequencing using two independent approaches, KIF5A was described as a novel ALS-associated gene. To describe clinical and genetic characteristics of a series of patients with motor neuron disease (MND), diagnosed at University Hospital of Palermo, carrying KIF5A variants. During 2019–2023, two hundred twenty-four patients with MND and healthy subjects with familial history of MND, underwent next-generation sequencing (NGS) for molecular analysis, including genetic testing for C9orf72 hexanucleotide-repeat expansion. The most mutated ALS genes, including KIF5A, were included in a NGS panel. Of the entire tested population, eight patients (including a brother and a sister) were found to carry KIF5A variants. Four patients had familial ALS, the other four were sporadic. Six patients were females (75%). Mean age at ALS onset was 59 years (33–75). Patients were evaluated according to the ALSFRS-revisited during follow-up visits. According to disease progression rate, five patients were defined as ∆FS ≤ 0.5 (slow-progressors), the remaining three patients showed a ∆FS > 1 (fast-progressors). Of the seven KIF5A variants, three are not already described in literature (respectively c.170 C > T, p.Thr57Met; c.2920T > G, p.Ser974Ala and c.2732 A > C, p.Lys911Thr). Two patients showed the association of variations in KIF5A with variations or mutations in other ALS genes, one of them carried a pathogenic variant of FUS (P525L). This study demonstrates phenotypic variability related to mutations in different regions of the same gene resulting in a susceptibility for the disease spectrum with different characteristics.

Progression independent of relapse activity (PIRA) is the main driver of disability accumulation in relapsing multiple sclerosis (MS). We tested various PIRA definitions against the risk of long-term disability. Patients with relapsing MS, first visit ≥January 1, 2000, ≥3 visits with Expanded Disability Status Scale (EDSS), and ≥5-year follow-up were extracted from the Italian MS and Related Disorders Register on September 29, 2023. Eighteen PIRA definitions were obtained combining fixed or roving baseline, 24-week, 48-week confirmed or sustained disability accrual, no relapses ≤90 days before/≤30 days after the event (90d), ≤180 days before/≤30 days after the event, or absence of relapses from baseline to confirmation score (ABS). Predictive performance against the reaching of EDSS = 6.0 was calculated. A total of 30,203 patients were included. After a follow-up of 11.3 ± 4.3 years, PIRA ranged from 38.8% to 74.1%. EDSS = 6.0 was detected in 4,401 (15%) patients. Sensitivity of PIRA definitions against EDSS = 6.0 was higher using the 90d criterion (66.7%-69.4%), while the ABS criterion increased specificity (55.3%-62.2%). The definition of PIRA combining roving baseline, no relapses 90 days before and 30 days after the event and 24-week confirmation achieved the best predictive value and feasibility, supporting its use in routine practice and research.

Background/Objectives: Dementia is a major public health challenge, with age as its primary non-modifiable risk factor. Several modifiable conditions, such as hypertension, diabetes, and depression, have been identified as potential targets for prevention. The aim is to describe the methodology and preliminary results of a study that will be conducted within the Italian National Health Service (INHS), designed to assess the impact of hypertension, diabetes, depression, and their interactions on the onset of dementia. Methods: This population-based cohort study, part of the PREV-ITA-DEM project, was conducted using a Common Data Model (CDM) approach across five Italian regions and cities participating in the NeuroEpiNet network. Individuals aged ≥ 50 years without prior diagnoses of dementia, depression, diabetes, or hypertension were followed from cohort entry (2011–2013) until dementia diagnosis, death, emigration, or study end (2019–2022). Exposures were time-dependent and defined using validated algorithms applied to Healthcare Utilization Databases (HUDs). Associations between chronic conditions and dementia risk will be estimated using competing risks regression models adjusted for confounders. Results: The final cohort comprised more than 3 million individuals, with a mean baseline age of 63–65 years and a female proportion of 52–55%. On 1 January 2011, the prevalence of individuals aged ≥ 50 years with dementia ranged from 8.7 to 14.7 per 1000 population. A harmonized methodological framework based on a CDM was developed and implemented across all sites, incorporating a shared protocol, standardized local databases, and uniform analytic scripts, and the results will be pooled using meta-analytic techniques. Conclusions: Preliminary findings confirm the feasibility of a standardized, multi-regional CDM approach and the potential for HUDs to support large-scale dementia prevention studies in real-world settings.

We describe the case of a 65-year-old man with a medical history of smoking, hypertension, dyslipidaemia, gastroesophageal reflux disease, and anxiety-depressive disorder. The patient initially presented with dysuria and haematuria. Contrast-enhanced computerized tomography scan revealed a muscle-invasive bladder tumour and rectal wall thickening. Biopsies confirmed high-grade urothelial carcinoma (stage pT2) and rectal adenocarcinoma. The patient underwent radiotherapy and chemotherapy with gemcitabine plus cisplatin, which was later switched to carboplatin due to renal impairment. Chemotherapy was discontinued approximately 12 months after symptom onset, and immunotherapy with Avelumab was initiated. Four months following the start of immunotherapy, a fluorodeoxyglucose positron emission tomography-computed tomography scan showed no evidence of metastases. Shortly thereafter, he developed neck pain and postural instability. Brain magnetic resonance imaging scan revealed cerebellar oedema and leptomeningeal enhancement. Although neuroradiologists suggested carcinomatous leptomeningitis, oncological evaluation considered it unlikely. Alternative hypotheses included paraneoplastic cerebellitis and immunotherapy-induced leptomeningitis. Despite corticosteroid therapy, the patient’s condition worsened. Cerebrospinal fluid analysis revealed markedly elevated protein levels and the presence of epithelial cells, confirming leptomeningeal metastatic spread of urothelial origin. Leptomeningeal carcinomatosis is a rare manifestation of bladder cancer and is difficult to diagnose due to non-specific symptoms and potential overlap with immunotherapy-related side effects. Neuroimaging and CSF cytology remain essential for diagnosis. There is currently no standardized treatment for leptomeningeal carcinomatosis from urothelial carcinoma; management is palliative. In our case, the patient died shortly after diagnosis. This case highlights the importance of considering this diagnosis even in rare tumour types, particularly in patients receiving immunotherapy.

Background: The natural history of multiple sclerosis (MS) is highly heterogeneous and almost unpredictable since several factors may affect the disease course including comorbidities. The aims of this study were to predict the risk of disability worsening and disease progression at the first patient’s visit by using a modified version of the Charlson Comorbidity Index (mCCI). Methods: the mCCI was obtained by incorporating the grade of pyramidal functional system scores extracted by the Expanded Disability Status Scale (EDSS) into the original CCI version. The risk of reaching EDSS 4, EDSS 6, and secondary MS progression (SPMS) associated to mCCI classes was calculated by carrying out multivariable Cox-regression models and it was reported as hazard ratios (HRs) and 95% confidence intervals (95% CIs). The accuracy of mCCI for the recognition of individuals who reached the study milestones was estimated by building the receiving operator curves and the optimal cut-off values were estimated. Results: A total of n = 622 individuals were enrolled (72.7% women; median age 30.8 years [24–40]). Compared with patients with a mCCI equal to zero, the HRs for those with a mCCI comprised between 1 and 2 at the first visit were 1.53 (1.1–2.1), 2.17 (1.48–2.96), and 1.57 (1.16–2.1) for the reaching of EDSS 4, EDSS 6, and SPMS, respectively. Moreover, individuals with a mCCI equal or higher than 3 were at even higher risk of reaching EDSS 6 (HR = 2.34 [1.44–3.8]) and SPMS conversion (HR = 2.38 [1.29–4.01]). The mCCI cut-off value of 3 reached a sensitivity and specificity of 88.1% and 77.8%, respectively, for the recognition of EDSS 4, while the mCCI cut-off of 4 reached a sensitivity of 83.1% and a specificity of 80.7% for the recognition of EDSS 6 and a sensitivity and a specificity of 76.8% and 87.5%, respectively, for the recognition of SPMS conversion. Conclusion: mCCI appeared a simple and fast tool for the prediction of MS prognosis since the first patient’s visit and its best cut-off values showed higher sensitivity and specificity for the recognition of patients who undergo disability worsening and SPMS conversion.