Citations

Abstract Background Frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominant atrophy is an emerging area of interest. Recent findings by the International Working Group (IWG) have identified this subtype as having a distinct clinical profile within the FTD spectrum (Ulugut et al., 2024, A&D). However, its genetic and pathological underpinnings remain unexplored in large, multicultural cohorts. Methods Retrospective analyses encompassing clinical, genetic, pathological, and neuroimaging data from 23 IWG sites across 13 countries in Asia, Middle East, Europe, North and South America were conducted. The study included 444 patients with FTD exhibiting predominant RATL atrophy. Results Genetic screening was performed on 51% ( n = 225) of the cohort for at least the major frontotemporal lobar degeneration (FTLD) mutations including microtubule‐associated protein tau ( MAPT ), progranulin ( GRN ), and chromosome 9 open reading frame 72 ( C9orf72 ), or dementia panels encompassing extended sets of genes. Of these, 81% were sporadic, showing negative results for the screened genes and a modified Goldman Score of ≥ 3, indicating a negative family history for dementia. The MAPT mutation was the most common genetic variant, identified in 7% of the screened cases (Figure 1). Pathological confirmation was available for 63 patients. Among the sporadic cases, transactive response DNA‐binding protein 43 type C (TDP‐C) pathology was most prevalent (60%, n = 32), while tau‐MAPT pathology was most common in the genetic cases (38%, n = 16). Fifteen cases did not fit neatly into genetic or sporadic categories, displaying heterogeneous pathologies (Figure 2). At the initial visit, compared to genetic cases, patients with TDP‐C pathology were older, and more frequently exhibited semantic deficits, with less frequent attention difficulties and executive dysfunction. No differences were observed in sex distribution, symptom duration or disease severity between genetic and sporadic TDP‐C cases. However, left handedness was more common in TDP‐C cases (14%) compared to genetic cases (5%). Conclusion While FTD with RATL atrophy primarily appears sporadic, a significant proportion of cases exhibit genetic variants. These sporadic and genetic subtypes display distinct neuropathological features and clinical manifestations. Given the implications for therapeutic strategies, precise clinical and molecular subtyping is critical for enhancing patient management and ensuring appropriate enrollment in clinical trials.

Abstract Background The interplay between vascular dysfunction and brain amyloidosis in driving Alzheimer's disease (AD) pathogenesis and cognitive decline is increasingly recognized. The retina, sharing an embryonic origin with the brain, offers an accessible CNS organ for high‐resolution, noninvasive imaging of AD‐related vascular pathology. However, the exact nature of retinal vascular damage in AD—especially in early disease stages—and its relationship with cerebral amyloid angiopathy (CAA) and cognitive impairment remain understudied. Method We examined vascular abnormalities in retinas of MCI and AD via histopathology and in‐vivo imaging studies. Postmortem retinas from 53–62 individuals (CN: 22; MCI/AD: 31–40) underwent immunohistochemistry for pericyte integrity, vascular Aβ42/40, and endothelial TJ proteins, with dysregulated proteins quantified by mass spectrometry in 12 additional AD/CN cases. Retinal curcumin‐amyloid imaging by scanning‐laser ophthalmoscope in 28–34 live participants (CN[MOCA>26]: 8–15; MCI/AD[MOCA≤26]: 13–19) assessed peri‐arteriolar/venular amyloid plaques (APs). Perivascular AP burden was correlated with MRI measures (hippocampal volume, WMH lesions) and cognitive/neuropsychiatric parameters. Result Retinal pericyte loss, reflected by PDGFRβ deficiency and apoptosis, was evident in MCI and AD patients and correlated with vascular Aβ42/40 accumulation and CAA severity (r=0.68–0.84; p <0.01–0.0001). Retinal endothelial ZO‐1 and claudin‐5 levels were significantly reduced, correlating with arteriolar Aβ40 deposition, suggesting impaired retinal Aβ clearance. Retinal capillary claudin‐5 and arteriolar Aβ40 strongly associated with CAA (r=0.75–0.77, p <0.0001), while ZO‐1 moderately correlated with brain amyloidosis/tauopathy, CAA, and cognitive decline (r=0.43–0.57, p <0.01–0.001). Both histological and in‐vivo imaging studies revealed greater Aβ deposition in retinal arterioles, particularly in secondary and tertiary branches, compared to venules or capillaries ( p <0.01–0.0001). Retinal perivascular APs in secondary/tertiary branches imaged in living patients correlated with cognitive impairment (global CDR, MOCA), hippocampal atrophy, and WMH lesions (r=0.51–0.66, p <0.05–0.001). Perivascular APs in the secondary (β=0.397, p = 0.033) and tertiary (β=0.756, p = 0.017) arteriolar branches showed significant interactions with hippocampal volumetry for visual memory. Conclusion Retinal arteriolar Aβ accumulation, pericyte loss, and TJ dysfunction contribute to early AD vascular pathology. If validated in larger cohorts, these findings support retinal vascular biomarkers as tools for predicting cognitive decline, monitoring AD progression, and assessing CAA severity.

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer’s disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.

Abstract Context Adult growth hormone (GH) deficiency (GHD) is characterized by metabolic abnormalities caused by insufficient GH production. Lonapegsomatropin, a prodrug administered once weekly, was designed to provide sustained release of unmodified somatropin to reduce the burden of daily somatropin injections. Objective This work aimed to evaluate the efficacy and safety of lonapegsomatropin vs placebo as treatment for adults with GHD. Methods The foresiGHt trial was a multicenter, randomized, parallel-arm, placebo-controlled (double-blind) and active-controlled (open-label) trial (NCT04615273) conducted at 116 centers in North America, Europe, and Asia-Pacific. The trial randomly assigned and dosed 259 adults with GHD. Participants were randomly assigned 1:1:1 to receive once-weekly lonapegsomatropin, once-weekly placebo, or daily somatropin for 38 weeks. The primary efficacy end point was change from baseline in trunk percent fat at week 38. Secondary efficacy end points included change from baseline in trunk fat mass and total body lean mass. Results At week 38, lonapegsomatropin significantly reduced trunk percent fat (−1.68% vs +0.37%; least squares [LS] mean difference −2.04%; P &lt; .001), increased total body lean mass (+1.60 kg vs −0.11 kg; LS mean difference 1.70 kg; P &lt; .0001), and reduced trunk fat mass (−0.48 kg vs +0.22 kg; LS mean difference −0.70 kg; P = .0053) vs placebo. The safety and tolerability profile of lonapegsomatropin was comparable to somatropin. Conclusion The foresiGHt trial met its primary efficacy end point by demonstrating superiority of lonapegsomatropin vs placebo with similar safety and tolerability, supporting its potential as a once-weekly treatment option for adults with GHD.

Living donor liver transplantation (LDLT) is a life-saving procedure for patients with end-stage liver disease. As its use expands worldwide, ensuring the safety and well-being of live liver donors (LLD) is of paramount importance. Published evidence on early postoperative complications after living donor hepatectomy—those occurring within 90 days of surgery—is limited, and standardized postoperative care protocols are lacking. The International Liver Transplantation Society (ILTS) and the International Living Donor Liver Transplantation Group (iLDLT Group) convened a consensus conference in Toronto in March 2025 to develop guidelines for the safe care of the LLDs. This manuscript details the recommendations on early postoperative considerations for the safety of LLDs developed by Working Group III (WGIII) of the Consensus Scientific Committee, using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus. WGIII addressed four key areas: (1) standardized postoperative care, (2) early biliary complications, (3) early postoperative liver dysfunction, and (4) early postdischarge follow-up. This report emphasizes the need for vigilant postoperative monitoring in specialized units, with access to experienced providers and defined clinical pathways. Structured clinical and psychosocial follow-up protocols, perioperative prophylaxis for surgical site infections and venous thromboembolism, and management of early biliary and vascular complications are discussed. These may help standardize care, reduce complications and improve short-term outcomes in LLDs.

Living liver donation is a critical component for addressing organ shortage and improving outcomes for patients with end-stage liver disease. As the prevalence of living donor liver transplantation (LDLT) increases worldwide, understanding and optimizing long-term donor health is paramount. The 2025 International Liver Transplantation Society and International Living Donor Liver Transplantation Society (ILTS-iLDLT) Consensus Conference convened experts in the field of liver transplantation to establish evidence-based guidelines focused on the long-term medical, psychological, and social considerations following living liver donation. The aim of this working group was to integrate current evidence and expert consensus on donor follow-up protocols, risk assessment, and management strategies to promote long-term donor health, quality of life, and living liver donor programs globally to safeguard the welfare of this unique population.

Abstract Aims Pre-capillary pulmonary hypertension (PHTN), typically due to intrinsic pulmonary pathology, requires right heart catheterization (RHC) for diagnosis. ePLAR, the echocardiographic pulmonary to left atrial ratio [calculated: tricuspid regurgitation maximum velocity (TRVmax) divided by mitral valve E to e′ wave ratio (E/e′)], has been demonstrated as a promising non-invasive surrogate for characterization of pre-capillary PHTN. As such, this study aimed to further evaluate the diagnostic utility of ePLAR in a large cohort of patients with PHTN. Methods and results All RHCs between 2018 and 2023 across three tertiary centres were retrospectively reviewed. Patients with PHTN were characterized as pre-capillary or post-capillary (isolated or combined). Concurrent ePLAR was calculated. ROC analysis evaluated the accuracy of ePLAR in detecting pre-capillary PHTN. Overall, 2235 patients had PHTN by RHC, mean age 63.5 ± 14.7 years, 53.5% male. Of these, 43.3% had pre-capillary PHTN. ROC analysis demonstrated ePLAR to have good accuracy in detection of pre-capillary PHTN (AUC 0.760), with a cutoff of 0.20 m/s demonstrating a sensitivity and specificity of 77% and 60% respectively. This persisted on sensitivity analysis for contemporaneous investigations and for right ventricular function. Conclusion In this large cohort, ePLAR was validated as an accurate tool for identifying patients with pre-capillary PHTN. This widely available, non-invasive, and reproducible parameter can have an important role in the work up of PHTN and may guide the need for invasive testing.

Autoantibodies contribute to many autoimmune diseases, yet there is no approved therapy to neutralize them selectively. A popular mouse model, experimental autoimmune encephalomyelitis (EAE), could serve to develop such a therapy, provided we can better understand the nature and importance of the autoantibodies involved. Here, we report the finding of autoantibody-secreting extrafollicular plasmablasts in EAE induced with specific myelin oligodendrocyte glycoprotein (MOG) antigens. Single-cell RNA sequencing reveals that these cells produce nonaffinity-matured IgG antibodies. These include pathogenic antibodies competing for shared binding space on MOG’s extracellular domain. Interestingly, the synthetic anti-MOG antibody 8-18C5 can prevent the binding of pathogenic antibodies from either EAE mice or people with MOG antibody disease. Moreover, an 8-18C5 variant carrying the NNAS mutation, which inactivates its effector functions, can reduce EAE severity and promote functional recovery. In brief, this study provides not only a comprehensive characterization of the humoral response in EAE models but also a proof of concept for a therapy to antagonize pathogenic anti-MOG antibodies.

An ST-segment elevation myocardial infarction is a life-threatening condition within the spectrum of acute coronary syndrome, with well-recognized implications for short-term and long-term health outcomes. Retrospective review of our institutional electronic health records identified patterns of inaccurate acute coronary syndrome diagnostic assignment, including the presence of erroneous ST-segment elevation myocardial infarction diagnoses in discharge records. Such erroneous diagnoses in the durable health record may increase risk to patients through inadequate risk assessment and inappropriate follow-up care. Misapplication of a shortcut in our electronic health record system for rapidly ordering emergent cases was identified as a potential cause of the quality gap. To address this issue, a nurse-led quality improvement project was developed by using the define, measure, analyze, improve, and control framework. The project intervention decreased the percentage of patients with erroneous diagnoses from 24% to 7% and marginally improved nursing staff satisfaction. Our project successfully addressed an institutional quality concern. Our goal of reducing erroneous discharge diagnoses with minimal disruption to our existing practice was achieved, positively affecting our patients. Including both nurse leaders and frontline health care workers ensured the success of our project.

Abstract The Mayo Clinic Center for Clinical and Translational Science Rural Health Research Core emphasizes community engagement to address healthcare access and delivery. In 2023, the Midwest Rural Health Research Community Advisory Board (CAB) was established to guide research. Eleven of 13 researchers presenting to the CAB in 2023 completed a survey assessing influence of CAB feedback across seven domains. All reported >1 domain influenced by CAB feedback, most commonly on study design, pre-research activities and implementation. CAB feedback shaped many aspects of the rural health research process. CAB members valued seeing how their input contributed to the research process.