Citations

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 Background A hexanucleotide repeat expansion in C9orf72 is the leading genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. There remains a critical need for biomarkers that track disease progression across clinical stages. Cross‐sectionally, intrinsic connectivity networks (ICNs) derived from task‐free fMRI (tf‐fMRI) detects abnormalities in C9orf72 expansion carriers ( C9orf72+ ), even when brain structural differences are subtle (Lee et al. , 2017). Few studies have examined longitudinal connectivity changes in C9orf72+ , however. Methods We analyzed longitudinal structural and tf‐fMRI data and plasma neurofilament light chain (NfL) concentrations of C9orf72+ recruited from UCSF and the ALLFTD Consortia. Mean time from first to last scan was 2.4±1.3 years. Participants included 36 asymptomatic (aSx‐ C9 ), 17 prodromal (prodromal‐ C9 ), 29 symptomatic (Sx‐ C9 ) carriers, and 107 healthy controls (HC). For structural MRI analyses, smoothed gray matter maps were parcellated into 246 regions‐of‐interest based on the Brainnetome atlas. We conducted voxelwise seed‐based tf‐fMRI analyses to examine ICNs showing alterations C9orf72+ based on previous literature: salience network (SN), sensorimotor network (SMN), default mode network (DMN), and a medial pulvinar thalamus network (pulvinar). General linear models and linear mixed models (LMM) compared C9orf72+ groups to HC in baseline and longitudinal gray matter and functional connectivity, as well as examined associations between longitudinal functional connectivity changes and baseline NfL concentrations. Results Despite a lack of longitudinal gray matter decline, aSx‐ and Sx‐ C9orf72+ showed functional connectivity changes. Compared to HC, aSx‐ C9 had baseline hypoconnectivity in the SN, SMN, and pulvinar network. Longitudinally, this group showed declines in the SN and pulvinar network, alongside DMN increases. Prodromal‐ C9 exhibited baseline SMN hypoconnectivity and hyperconnectivity in the DMN and pulvinar network, but no significant longitudinal changes. Sx‐ C9 showed baseline hypoconnectivity in SN, SMN, and DMN, with additional regions of DMN hyperconnectivity, while longitudinally, SN and SMN connectivity increased. In aSx‐ C9 , higher baseline NfL concentrations correlated with regions of SMN decreases over time and both increases and decreases in the pulvinar network. In prodromal‐ C9 and Sx‐ C9 combined, higher NfL was associated with DMN increases longitudinally. Conclusions Though gray matter declines were undetectable over a span of several years, functional connectivity networks changed dynamically in C9orf72+ .

Abstract Background Plasma neurofilament light chains (NfL) and glial fibrillary acidic protein (GFAP) are blood‐based biomarkers of axonal injury and astrocytic activation, respectively, that are elevated in those with Alzheimer's disease (AD) and mild cognitive impairment (MCI) relative to cognitively unimpaired (CU) individuals. Neurite orientation dispersion and density imaging (NODDI) is a multishell diffusion MRI method capable of evaluating tissue microstructure at the axonal and dendritic level. We evaluated associations between temporal cortex orientation dispersion index (ODI), neurite density index (NDI) and isotropic volume fraction (ISOVF) and plasma NfL and GFAP concentrations. Method We included Mayo Clinic Study of Aging (MCSA) participants (ages 60‐95 years) with diagnoses or CU ( n = 356) or MCI ( n = 60), and Alzheimer's Dementia Research Center (ADRC) participants with dementia ( n = 51). NODDI imaging was obtained on a 3T Siemens Prisma scanner with 2 mm isotropic resolution. NfL and GFAP were measured using the Simoa® Neurology 4‐Plex E Advantage kit. We fit separate linear regression models within each MCALT_ADIR122 cortical ROI with regional NODDI as the primary predictor and log‐transformed plasma concentration as the outcome. Models were adjusted for age, sex, BMI, cortical thickness (or hippocampal & amygdalar volume) and total intracranial volume. Result The Table displays demographic data. Figures 1 and 2 show the relationship of NDI and ISOVF measures to plasma NfL concentrations across participants in individual ROIs (similar findings were noted with GFAP). A significant inverse relationship between NfL concentrations and NDI was observed in hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus as well as all temporal neocortical regions except the superior temporal gyrus ( p <0.001) (Figure 1), whereas higher NfL concentrations were associated with higher ISOVF in all regions ( p <0.001) (Figure 2). Fewer significant associations were also seen with ODI. After adjusting for age, cortical thickness/volume and other confounds, significant associations with NDI remain, particularly in hippocampal and amygdalar regions. Conclusion NODDI‐derived measures (NDI and ISOVF) within the temporal lobe cortical regions demonstrate significant associations with plasma biomarkers of axonal and astrocytic dysfunction that are elevated during cognitive decline. This association provides preliminary validation of the utility of NODDI in assessing cortical microstructural changes associated with cognitive decline.

ABSTRACT Objectives T‐cell large granular lymphocytic leukemia (T‐LGLL), reported in up to 58% of inclusion body myositis (IBM) patients, is a rare leukemia of cytotoxic or less commonly helper T cells. The range of myopathies in T‐LGLL and the impact of coexisting T‐LGLL in IBM are not well understood. Our objectives are to investigate the spectrum of myopathies in patients with T‐LGLL and compare the clinical, serological, pathological, and transcriptomic features of IBM patients with and without T‐LGLL. Methods We reviewed two Mayo Clinic cohorts: (1) T‐LGLL patients evaluated for myopathies (2003–2018), and (2) IBM patients tested for T‐LGLL via T‐cell receptor gene rearrangement or flow cytometry (2016–2022). We also compared transcriptomic profiles of IBM muscle biopsies with and without T‐LGLL. Results Of 447 T‐LGLL patients, 13 (2.9%) had myopathies, IBM being the most common ( n = 7). Of 43 IBM patients, 9 (20.9%) had T‐LGLL, with 5 diagnosed prior to the onset of weakness. Clinical and pathological features were largely similar between IBM patients with and without T‐LGLL, except for milder finger flexor weakness and more frequent neutropenia (55.6% vs. 0%, p < 0.001) in the T‐LGLL group. However, transcriptomic analysis of muscle tissues revealed a more immunologically active profile, with upregulation of T‐cell and macrophage markers, elevated levels of IFN‐γ gene and IFN‐γ–inducible genes, heightened cytokine activity, and enhanced immunoglobulin production in IBM patients with T‐LGLL. Interpretation IBM is the most common myopathy in T‐LGLL patients. While clinico‐sero‐pathological features were largely similar, transcriptomic differences suggest IBM with T‐LGLL may represent a distinct, more immune‐driven subtype.

Living donor liver transplantation (LDLT) is an established therapy with curative intent for pediatric and adult patients with acute liver failure and end-stage liver disease. Donor safety remains paramount and commences during preoperative evaluation and assessment. Given the importance of the topic, the International Liver Transplantation Society and International Living Donor Liver Transplantation Group consensus conference on Living Liver Donor Safety was convened in March 2025 (Toronto, Canada). Recommendations were based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus was followed. This report presents 28 recommendations from the working group focused on addressing clinically relevant questions related to the preoperative aspects of living donor safety including assessment of donor acceptability (age, body mass index and hepatic steatosis; medical conditions and contraindications), medical and surgical workup (liver function and procoagulant workup; anatomical considerations and safe remnant), and psychosocial evaluation (timing and team; underlying conditions; non-directed, paired, and anonymous directed donors; urgent living donor workups for acute liver failure).

Background Costosternal cartilages and the costal margin, collectively termed costal cartilage, are hyaline cartilage connecting ribs to the sternum and to adjacent ribs, respectively. Presence of intact costal cartilage is essential for elasticity of the chest wall. Anecdotally, costal cartilage injuries are underdiagnosed on trauma CT scan in patients with rib fractures. Our aim was to determine a baseline frequency of acute costal cartilage injury among patients presenting with rib fractures. Methods We performed a retrospective cohort study of injured adult patients admitted to Level I/II trauma centers with rib fractures from January 2020 to July 2024. CT images obtained at admission were manually reviewed by chest wall surgeons for presence of costal cartilage injury. Concordance with the original radiology report was obtained. Multivariable regression was used to analyze factors associated with costal cartilage injury and missed cartilage fractures. Results 1441 patients were identified; 197 (14%) had a costal cartilage fracture. A plurality of injuries included falls (n=667, 46%). Median ISS (Injury Severity Score) was 13 (IQR: 9 to 21), median Abbreviated Injury Scale thorax score was 3 (IQR: 3 to 3), and median number of fractured ribs was 3 (IQR: 3 to 7). 294 (21%) patients had radiographic flail segments, and 136 (9%) had sternal fractures. 172 (87%) patients had a costal cartilage fracture missed on initial trauma chest CT. On multivariable analysis, ISS (adjusted OR (aOR) 1.02 (95% CI 1.01 to 1.04), radiographic flail segment (aOR 1.6 (95% CI 1.10 to 2.31)) and presence of sternal fracture (aOR 1.85 (95% CI 1.19 to 2.89)) were associated with costal cartilage fractures. Only the total number of rib fractures was associated with a missed costal cartilage fracture on univariate analysis (OR 1.17 (95% CI 1.01 to 1.36)). Conclusions Costal cartilage injuries are common and frequently are not identified during interpretation of the initial trauma CT. A higher index of suspicion is warranted for costal cartilage fractures among patients with greater injury burden, radiographic flail segment, and sternal fractures. Level of evidence Level III.

BACKGROUND AND OBJECTIVES: Minimum clinically important differences (MCIDs) for patient-reported outcome metrics (PROMs) in patients with cervical spondylotic myelopathy (CSM) lack consensus on the most appropriate calculation method. This retrospective study aimed to identify the optimal MCIDs for commonly used PROMs in CSM. METHODS: The CSM database from the Quality Outcomes Database SpineCORe Study Group was analyzed. Baseline, 3-month, and 24-month PROM values for Neck Disability Index (NDI), 5-dimension Euro-quality of life (EQ-5D) in quality-adjusted life years, modified Japanese Orthopaedic Association (mJOA) score, and neck/arm pain numeric rating scale (NRS) were collected. MCIDs were calculated for each PROM using previously validated techniques. MCID values were compared using the area under the curve (AUC) with the North American Spine Society satisfaction scale as an anchor. RESULTS: A total of 1141 patients with CSM undergoing surgery were included in this analysis. Improvement of ≥30% from baseline was the optimal MCID for NDI and neck/arm NRS. At 24 months, the optimal percentage cutoff MCID for these instruments resulted in AUCs of 0.76, 0.72, and 0.67, similar to the 30% improvement method, with AUCs of 0.73, 0.71, and 0.67, respectively. Numeric cutoffs (0.065 at 3 months; 0.149 at 24 months) were the superior MCIDs for EQ-5D. For mJOA score, a severity-adjusted MCID outperformed other methods, yielding an AUC of 0.67 at 24 months. MCIDs were achieved in 63% of patients for NDI, 59% for neck pain NRS, 61% for arm pain NRS, 52% for EQ-5D, and 59% for mJOA score at 24 months. CONCLUSION: Using the Quality Outcomes Database SpineCORe data set, we defined optimal MCIDs for key PROMs in CSM. A ≥30% improvement from baseline was optimal in NDI and arm/neck NRS. An absolute numeric cutoff was superior for EQ-5D (0.149 at the 24-month follow-up). A severity-adjusted MCID performed best for mJOA score. These redefined benchmarks better capture the treatment impact and guide care decisions for patients with CSM.

Patzelt et al. previously characterized dermal-binding autoantibodies using an indirect immunofluorescence (IIF) mosaic assay with cells transfected with p200-laminin β4, laminin-332 or collagen VII subunits among specimens showing a dermal pattern on IIF using salt-split skin (IIF-SSS) and IgG. This study expanded testing to include specimens with either a dermal or mixed pattern on IIF-SSS and demonstrated improved test sensitivity with modified testing methods.