VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an adult-onset “hemato-autoinflammatory” disease provoked by somatic mutations in the UBA1 gene within hematopoietic progenitor cells. While dermatologic, rheumatologic and hematologic manifestations are well-documented, its neurological and cognitive implications remain poorly characterized. Given the chronic inflammatory burden of VEXAS, this study aimed to explore cognitive functioning in affected individuals. In this retrospective pilot study, we performed a neuropsychological assessment in patients with genetically confirmed VEXAS, VEXAS-like individuals (VEXAS-compatible symptoms without UBA1 variations), patients with mild cognitive impairment (MCI), and healthy controls (HC). Participants underwent computerized attention testing (Cognitrone) and multidomain cognitive evaluation (ENB-2), with analyses adjusted for age and education. Thirty-four participants were included: 7 patients with genetically confirmed VEXAS syndrome, 5 VEXAS-like patients, 11 individuals with mild cognitive impairment (MCI), and 11 healthy controls (HC). Mean age ranged from 63.3 ± 10.3 years in the VEXAS-like group to 75.7 ± 6.9 years in the VEXAS group. After adjustment for age and education, VEXAS-like patients showed cognitive performances broadly comparable to those of healthy controls. Patients with VEXAS demonstrated lower performance on selected measures of attentional control and response monitoring, whereas individuals with MCI showed broader cognitive impairment. Measures related to memory interference and complex attention displayed limited differences across groups. This pilot study represents the first standardized neuropsychological evaluation of patients with VEXAS syndrome. The findings suggest the presence of subtle differences in selected cognitive domains, warranting confirmation in larger longitudinal studies integrating inflammatory biomarkers and neuroimaging measures.

PURPOSE:To study COVID-19-associated coagulopathy and the clinical outcomes across different COVID-19 pandemic waves. METHODS:We retrospectively analyzed n 344 patients hospitalized for acute COVID-19 to Padova University Hospital between March 2020-March 2023, grouped by variants: Wild-type (G1, n 155; March 2020-January 2021), Alpha (G2, n 79; February-May 2021), Delta (G3, n 50; May-December 2021), and Omicron (G4, n 60; December 2021-March 2023). We compared traditional coagulation tests, thromboelastometry and impedance aggregometry. Clinical outcomes were also considered. RESULTS:Factor VIII decreased progressively from G1 (195%, IQR 149-227) to G4 (156%, IQR 128-197; p < 0.05), as did von Willebrand factor (343%, IQR 244-407 to 235%, IQR 216-247; p < 0.05). Thromboelastometry showed a significantly and progressively: i) prolonged INTEM and EXTEM clot formation time (p < 0.05 in all comparisons); ii) reduced INTEM, EXTEM and FIBTEM maximum clot firmness (p < 0.05 in all comparisons). Platelet aggregation significantly decreased from G1 to G4 (p < 0.05 in all comparisons). VTE occurred in 18.1% of G1 and 19.0% of G2 patients vs. 6.0% and 6.7% in G3 and G4, respectively (p < 0.05 in all comparisons). The 28-day mortality was 15.5% in G1 and 15.2% in G2 vs. 4.0% and 1.7% in G3 and G4, respectively (p < 0.05 in all comparisons). CONCLUSIONS:We observed a significant and progressive decrease in hypercoagulability across the four COVID-19 variants. A parallel decline in VTE incidence and 28-day mortality was also observed. Larger studies are needed to ascertain the pathophysiological mechanisms underlying the changes in coagulative profiles and their clinical implications.

BACKGROUND:Plasma phosphorylated-tau at threonine-217 (p-tau217) and threonine-181 (p-tau181) are scalable, minimally invasive biomarkers of Alzheimer's disease (AD) pathology. In Parkinson's disease (PD), AD co-pathology may contribute to its clinical heterogeneity. However, the existing literature has predominantly focused on p-tau181, with comparatively limited investigation of p-tau217. OBJECTIVE:The aim is to evaluate plasma p-tau217 and p-tau181 as biomarkers of AD co-pathology across the PD cognitive spectrum, relative to a cohort of dementia-free older adults. METHODS:Plasma p-tau217 and p-tau181 were measured in 70 PD patients and 83 older adults. Associations with cognitive impairment, disease severity (Hoehn-and-Yahr), and neurostructural measures-including global atrophy, hippocampal volume, and a magnetic resonance imaging-based AD signature-were assessed using correlation and dominance analyses. RESULTS:Both p-tau217 and 181 were higher in PD with cognitive impairment and dementia compared with cognitively normal PD. P-tau217 showed stronger associations than p-tau181 with AD-like neurostructural changes, multidomain cognitive deficits, greater disease severity, and reduced functional independence. CONCLUSIONS:Plasma p-tau217 and p-tau181 may serve as scalable markers of AD-related processes associated with neurostructural, clinical, and cognitive outcomes in PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

INTRODUCTION:Non-pharmacological interventions are increasingly relevant in neurocognitive disorders (NCDs) management. Cognitive training (CT) may benefit early stages, when functional resources allow targeted stimulation. However, its long-term effects and interaction with acetylcholinesterase inhibitors (AChEI) remain underexplored. This study aimed to investigate the 30-month efficacy of CT, alone or combined with AChEI, in older adults with mild NCD, considering the moderating role of cognitive reserve (CR) and individual characteristics. METHODS:A total of 108 individuals (mean age = 75.1 ± 6.5; 56.5% females) received either repeated CT alone (n = 69) or CT+AChEI (n = 39). Cognition was assessed at baseline and every 6 months using the Mini-Mental State Examination (MMSE) and Brief Neuropsychological Examination-2 (ENB-2). CR was measured with the Cognitive Reserve Index questionnaire (CRIq). Linear mixed models evaluated longitudinal changes, stratified by CR and sex. RESULTS:CT-only individuals showed greater and more consistent cognitive improvements over time compared to the CT+AChEI group (MMSE: β = 0.50, 95% CI: 0.04 to 0.96, p = 0.03). Improvements were also evident in specific measures tapping executive and memory functions. Participants with lower CR benefited most from CT (β = 0.86, 95% CI: 0.16 to 1.55, p = 0.02), while higher CR was associated with higher baseline and stability. Males showed more pronounced gains, particularly in the CT-only group. DISCUSSION:Sustained CT supports cognition in NCDs, particularly for those with lower CR. The combination with AChEI did not provide additional benefit and may reduce long-term effectiveness, warranting further investigation. Findings emphasize the importance of tailored, long-term approaches accounting for individual profiles. Highlights:Cognitive training improved cognition over 30 months in mild NCDs.CT alone outperformed combined CT+AChEI treatment in long-term cognitive outcomes.Individuals with lower CR benefited most from CT.Males showed greater cognitive gains, particularly in the CT-only group.Long-term CT efficacy supports real-world applicability in early NCD care.

For decades the cerebellum has been conceived as an organ chiefly involved in motor control, gait and posture. However, more recent and increasing evidence shows that the cerebellum is also involved in cognition and affection, and that damage to this structure may significantly compromise the overall neuropsychological functioning. Here we report we report the evolution along time of a possible congenital cerebellar atrophy and its effects on gross motor and cognitive functioning in a 41-years old man. Advanced neuroimaging analyses are also provided in order to understand the anatomo-functional correlates of cerebellar damage, with a novel focus on its different lobules. It is hypothesized that congenital cerebellar atrophy, initially compromising motor control, gradually brings to cognitive frailties. Findings related to neuroimaging, neuropsychological and postural data reveal a progressive decline in cognitive and gross motor capacities, particularly affecting executive and attentional functions. Neuroimaging results suggest specific gray matter volume reductions within cerebellar regions known to influence cognitive processes. This case report provides a nuanced look into the neuropsychological impact of cerebellar atrophy over time, shedding light on the elusive cognitive role of the cerebellum and its potential link to cerebellar cognitive affective syndrome.

ABSTRACT Background Lung transplant recipients are at increased risk of sarcopenia and osteoporosis, which may negatively influence respiratory outcomes. Although muscle health is known to affect lung function, little is known about the long‐term interplay between muscle parameters and pulmonary volumes, especially across sexes. The objective of this study is to evaluate the longitudinal relationship between muscle mass and strength and respiratory function in lung transplant patients, with sex‐specific analysis. Methods This prospective cohort included three assessments (baseline ≥ 3 months after transplant, ~1 year and 2–3 years). The primary outcome was the longitudinal change in pulmonary function (VC, FVC, FEV1 and TLC) in relation to appendicular skeletal muscle mass index (ASMMI) and handgrip strength (HGS). Associations at baseline were tested with multivariable linear regression. Analyses were performed with linear mixed‐effects models (LMM) including random intercepts for subject, time as a fixed effect and interactions between time and muscle parameters, adjusted for age, ADL, corticosteroid dose, vertebral fractures, osteoporosis, comorbidities and time since transplant. Results We studied 155 recipients (43.2% women, age 48.7 ± 13.3 years). Primary indications were cystic fibrosis (30.1%), restrictive (22.2%), obstructive (15.7%), miscellaneous (26.8%) and vascular diseases (5.2%). At baseline, HGS was independently associated with higher VC (R2: 0.63, β = 0.35, p = 0.001 in women; R2: 0.58, β = 0.16, p < 0.001 in men) and FEV1 (R2: 0.51, β = 0.08, p = 0.020 in women; R2: 0.57, β = 0.19, p = 0.009 in men). ASMMI was independently associated with VC in both sexes (women: R2: 0.58, β = 0.31, p = 0.003; men: R2: 0.40, β = 0.16, p = 0.023). Longitudinally, LMMs showed that higher HGS was associated with more favourable trajectories of pulmonary function over follow‐up. Specifically, among women with restrictive disease, lower ASMMI predicted higher FEV1 (β = −4.95, 95% CI −6.93 to −2.97, p = 0.007) and higher TLC (β = −2.22, 95% CI −4.56 to −1.12, p = 0.04) over time. In women with cystic fibrosis, stronger HGS was associated with improved TLC (β = 0.38, p = 0.04). All associations persisted after full adjustment. Conclusion Muscle mass and strength are associated with lung function after lung transplantation. These findings underscore the clinical importance of muscle health and support its integration into post‐transplant management.

Despite growing evidence that the cerebellum contributes to sensory, motor, cognitive, and affective domains, its role in chronic pain remains poorly understood. Fibromyalgia (FM), a rheumatological condition in which chronic pain is a hallmark feature, offers a paradigmatic model. Although neuroimaging studies have reported increased cerebellar activity in response to nociceptive stimuli, its contribution to pain chronification has been largely overlooked. This perspective paper proposes that the cerebellum may play a central role in FM by generating persistent prediction errors. Dysregulation of this mechanism may result in a mismatch between sensorimotor inputs and expected outcomes, for both noxious and innocuous stimuli, progressively disrupting error-based learning. We term this hypothesized state ‘cerebellar fragility’, where the system becomes locked into maladaptive loops. Reconceptualizing cerebellar involvement in chronic pain opens new perspectives for research and therapeutic strategies.

OBJECTIVES:Elevated cortisol levels are linked to a greater risk and faster progression of neurocognitive disorders (NCDs). While interventions such as exercise and mindfulness have shown benefits in reducing cortisol, the impact of cognitive training (CT) on cortisol regulation remains unexplored. This study investigated whether CT affects cortisol levels and secretion patterns in individuals with minor or major NCD and compared its effects with those of pharmacological treatment. METHODS:Sixty-two older adults with NCD and 43 healthy controls were recruited from the University Hospital of Padua in Italy. Among patients with NCD, 34 underwent CT (CT-NCD group), and 28 received pharmacological treatment (PH-NCD group). Salivary cortisol was measured at six points during the day, at baseline, and at 3 months (T1) and 6 months (T2) post-intervention. RESULTS:Compared with pharmacological treatment (PH), CT showed a larger percentage decrease of daily cortisol exposure area under the curve (AUC) from baseline; however, the between-group difference did not remain statistically significant after covariate adjustment, and the only robust time-point effect was in the afternoon (F(1,47)=5.13; p = .028). Morning values decreased within groups, but between-group differences in the CAR were not significant; at bedtime, CT showed only a trend towards lower cortisol than PH (p = .071). Median morning values changed from 7.75 to 6.20 in CT and from 5.80 to 5.15 in PH. DISCUSSION:Cognitive training may help lower cortisol levels and enhance cognitive function in NCD patients, suggesting its potential as a nonpharmacological tool to modulate hypothalamic-pituitary-adrenal axis activity. Larger randomized studies are needed to confirm and extend these findings.

BACKGROUND AND AIMS:Alcohol use disorder (AUD) is a mental disorder that affects up to 10.7% of the European population. There is historically a higher prevalence in male patients. Despite evidence supporting sex-related differences in AUD patients, to date, research has focused predominantly on patients of male sex. METHODS:We conducted a retrospective analysis of 907 patients (Females n 238, 26.2%) with AUD admitted to a tertiary Alcohol-related Disease Unit between 2004 and 2022. We collected demographics and clinical manifestations associated with AUD, including psychiatric disorders and alcohol withdrawal syndrome (AWS). RESULTS:Male and female patients showed similar prevalences of atrial fibrillation, ischemic cardiomyopathy, alcohol-related cognitive impairment, and AWS severity, whereas psychiatric disorders, particularly depressive disorders, eating disorders, and personality disorders, were significantly more frequent in female patients. Mild AWS was independently associated with increased long-term mortality (HR 1.625, 95% CI 1.041-2.536, p = 0.033). Sex-stratified analyses showed that age and neurovascular disease were independent predictors of mortality in male patients, whereas pulmonary and gastrointestinal diseases were independent predictors of mortality in female patients. DISCUSSION AND FUTURE DIRECTIONS:These findings support the presence of sex-related differences in the clinical and prognostic profile of patients with AUD, despite a similar distribution of AWS severity. Our results support the integration of sex-specific risk stratification and comprehensive multidisciplinary management, with particular attention to mental health and systemic comorbidities to improve long-term outcomes.

In transgender adults, reference-gender choice alters Z-scores and fracture-risk estimates. Z-scores differ by 0.4–0.6 SD, with male references identifying more individuals with low BMD for age, especially in those assigned male at birth. Dual-reference reporting is advisable until further evidence becomes available. Transgender individuals, especially those assigned male at birth (AMAB), exhibit lower bone mineral density (BMD) compared with the cisgender population. Interpretation of densitometric data is challenging, as the choice of reference gender can significantly influence Z-scores and fracture risk scores. This study aims to evaluate the impact of the gender reference database (male or female) on the assessment of BMD and fracture risk in transgender adults prior to gender-affirming hormone therapy (GAHT). We conducted a cross-sectional analysis of 249 transgender individuals (153 assigned female at birth – AFAB and 96 AMAB) aged 18–43 years, recruited in the Hospitals of Padua and Brescia (Italy). Z-scores were calculated using both male and female reference databases and FRAX scores were computed using both gender inputs. Associations with anthropometric, biochemical, and hormonal parameters were explored. Z-scores differed systematically depending on the reference gender, with mean ΔZ ranging 0.4–0.6 SD across skeletal sites. Switching reference databases frequently led to reclassification of BMD status. AMAB individuals showed a higher prevalence of low BMD for age, particularly when assessed against male references (27.1

BACKGROUND:Age-related decline in physical performance may reflect early loss of physiological reserve and increased vulnerability to adverse outcomes. We examined whether longitudinal decline across one or multiple physical performance domains predicts short- and long-term mortality in older adults. METHODS:We analysed data from 1967 community-dwelling participants in the Progetto Veneto Anziani (Pro.V.A.) cohort. Physical functional decline between baseline and first follow-up was defined across three domains (handgrip strength, gait speed, chair stand performance) and categorized as decline in 0, 1, or ≥ 2 domains. Landmark Cox models estimated 2- and 8-year mortality risk, adjusting for sociodemographic, clinical, cognitive and baseline functional parameters. RESULTS:During follow-up, decline in one domain was associated with increased mortality at both 2 years (HR 1.73, 95% CI 1.20-2.51) and 8 years (HR 1.49, 95% CI 1.26-1.78). Decline in ≥2 domains conferred similar risk estimates (2-year HR 1.77; 8-year HR 1.78). No significant interaction by sex was observed. Sensitivity analyses excluding early deaths yielded consistent results. CONCLUSIONS:These results suggest that even decline confined to a single physical performance domain may signal an early transition toward increased vulnerability. Monitoring trajectories of physical performance may therefore help identify older adults at increased mortality risk before more widespread functional deterioration becomes apparent.

BACKGROUND:Type 2 diabetes mellitus (T2DM) is frequently associated with cognitive decline in the older population. Although optimal glycemic control is known to be essential for disease management, the impact of hypoglycemic agents on cognitive function remains poorly investigated. METHODS:This retrospective study included 93 geriatric outpatients with T2DM. Hypoglycemic treatments consisted of metformin, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors, and insulin. Patient evaluations included glycated hemoglobin (HbA1c) measurements, Standardized Mini-Mental State Examination (MMSE), and Mini Nutritional Assessment (MNA). RESULTS:After one year of treatment, patients exhibited a significant reduction in HbA1c levels (from 8.06% [±1.19] to 7.19% [±0.84], P<0.001), improvement of MMSE scores (from 25.87 [±3.09] to 27.47 [±2.9], P<0.001). Regression analysis identified GLP-1RAs as the most effective agent in improving glycemic control (P<0.001) and cognitive function (P=0.016). Treatment with GLP-1RAs was associated with a reduction in MNA scores (P<0.001), though these remained above the malnutrition threshold. CONCLUSIONS:Our findings suggest that improved glycemic control may help slow cognitive decline in older patients with T2DM. Among the drug classes examined, GLP-1RAs showed the largest reductions in HbA1c and were linked to greater MMSE score gains.

Physical frailty is a prevalent geriatric syndrome associated with reduced physiological resilience and adverse outcomes. Beyond classical inflammaging, age-related changes in immune regulation and tissue repair may contribute to frailty pathophysiology. Biomarkers involved in adaptive immune responses and remodeling pathways, such as IL-17 and TGF-β1, may help characterize the inflammatory-regenerative milieu associated with frailty. We therefore investigated the association between circulating immune biomarkers and physical frailty severity in older adults. In this cross-sectional analysis, 167 community-dwelling outpatients aged ≥ 65 years (mean age 75.2 ± 6.4 years; 54.5

ObjectiveAlzheimer’s disease (AD) co-pathology may contribute to cognitive decline and faster progression in Parkinson’s disease (PD). Although blood-based biomarkers enable biological staging along the AD continuum, their contribution in the clinical-biological characterization of PD phenotypes remains unclear. We investigated associations between plasma biomarkers of AD-pathology [phosphorylated-tau-217(p-tau217), amyloid-beta-42/40 (Aβ42/40)], neurodegeneration [neurofilament light chain (NfL)], and neuroinflammation [glial fibrillary acidic protein (GFAP)] with MRI-derived neurostructural indices, cognition, functional independence, and neuropsychiatric symptoms across the PD cognitive spectrum, compared with dementia-free older adults.MethodsFifty-eight PD patients and 76 older adults underwent brain MRI, neuropsychological assessment, and plasma biomarker quantification. Multiple linear regressions examined associations between plasma biomarkers and MRI-derived measures (global atrophy, hippocampal volume, AD-specific signature) and clinical measures.ResultsAD-pathology markers (p-tau217 and Aβ42/40) showed stronger associations with neurostructural and clinical/cognitive measures than NfL and GFAP. In both cohorts, higher p-tau217 was associated with AD-like MRI alterations and worse global cognition. Further, in PD, p-tau217 reflected memory and executive dysfunctions, while lower Aβ42/40 was associated with reduced functional independence, visuospatial, and socio-cognitive deficits. In older adults, elevated p-tau217 was linked to subjective cognitive decline, language/memory deficits; lower Aβ42/40 to global atrophy, attention, visuospatial and memory deficits. Neuropsychiatric symptoms in PD (depressive mood, anxiety, apathy) were primarily associated with AD-pathology markers, whereas depressive symptoms in older adults were linked to higher NfL.ConclusionPlasma p-tau217 and Aβ42/40 were associated with neurostructural and cognitive impairment in PD and older adults, supporting the potential utility of AD-related plasma biomarkers—particularly p-tau217—for the clinical-biological characterization of cognitive decline in PD.

Hip fractures (HF) are among the most serious consequences of osteoporosis. Many individuals who subsequently sustain a HF may already fulfill recognized criteria for fracture risk assessment, bone mineral density (BMD) evaluation, or anti-osteoporosis treatment before the event occurs, yet remain unidentified and untreated. We aimed to quantify these missed opportunities for osteoporosis management prior to fragility HF occurrence. We performed a cross-sectional analysis of 1,103 patients aged ≥ 50 years hospitalized for fragility HF and evaluated within a Fracture Liaison Service. Pre-fracture fracture risk was retrospectively estimated using FRAX® based on clinical risk factors only, excluding the index HF. Eligibility for anti-osteoporosis treatment and BMD assessment was evaluated according to international recommendations and national reimbursement criteria. Only 82 patients (7.4

Behçet’s syndrome (BS) is a chronic multisystemic inflammatory disorder with a heterogeneous clinical course. A severe subset with central nervous system involvement (neuro-Behçet’s syndrome, NBS) carries substantial morbidity. While disease activity often decreases with age, the long-term neurological and cognitive outcomes remain poorly defined. Emerging evidence indicates that vascular insufficiency, chronic inflammation, and central nervous system involvement may contribute to cognitive decline in BS, even in the absence of frank neurological symptoms, suggesting a broader and underrecognized impact on brain function. These processes overlap with mechanisms implicated in age-related cognitive decline and dementia, bringing up the hypothesis that BS may accelerate neurodegenerative trajectories in older adults. However, this population remains underrepresented in research. Clarifying whether BS constitutes an overlooked cause or modifier of late-life cognitive decline is clinically urgent. A coordinated agenda spanning neuropsychology, advanced imaging, and biomarkers can deliver diagnostic pathways and testable prevention/management strategies for aging BS populations.

Glycaemic variability (GV) has emerged as a potential marker of adverse outcomes in hospitalised patients with diabetes, yet its clinical impact in older adults and the role of sex differences remain unclear. To evaluate the association between in-hospital GV and length of stay (LOS) and one- and two-year all-cause mortality in older adults with type 2 diabetes, and to explore sex-specific patterns. Retrospective observational study of patients aged ≥ 65 years with type 2 diabetes admitted to a geriatric unit (2018–2020). GV was assessed using the coefficient of variation (CV) of point-of-care glucose measurements (POCT). Multivariable linear regression and Cox proportional hazards models were applied, adjusting for relevant confounders, with analyses stratified by sex. A total of 283 patients (59.7