Citations

ABSTRACT Background Sampling techniques have poor accuracy for classifying biliary strictures as benign or malignant. Previously, a cholangioscopy artificial intelligence (AI) outperfromed sampling techniques based solely on analysis of previously recorded cholangioscopy footage. The aim of this trial was to compare the performance of a real-time cholangioscopy AI to both sampling techniques and human observers for the task of biliary stricture classification. Methods A cholangioscopy AI computer connected directly to a cholangioscope console. The computer analyzed the cholangioscopy video stream during procedures for suspected biliary strictures. The primary outcome of the study was comparison of the performance of cholangioscopy AI to sampling techniques – brush cytology and transpapillary forceps biopsy – for biliary stricture classification. Secondary outcomes included comparison of the AI classification performance to that of human observers (separated into junior-level and experienced-level cohorts) who reviewed the cholangioscopy footage. Results A total of 41 patients were enrolled in the trial and had biliary strictures analyzed by cholangioscopy AI. For the classification of strictures, the AI had greater classification accuracy than standard sampling techniques (87.8% versus 67.4%; p = 0.043). Additionally, the cholangioscopy AI was significantly more accurate for biliary stricture classification than both junior-level (87.8% versus 61.5%; p = 0.001) and experienced endoscopists (87.8% versus 63.15%; p = 0.011). Conclusions This trial demonstrates that sampling techniques and human assessment of biliary strictures are flawed and there may be a benefit to the use of a cholangioscopy AI system to aid in biliary stricture classification.

Abstract Microglia are essential for maintaining brain homeostasis, including the sleep-wake cycle, but the underlying mechanisms remain unclear. Here, using in vivo two-photon imaging in both head-fixed and freely moving mice with simultaneous electroencephalogram–electromyogram (EEG–EMG) recording, we investigated microglial process dynamics and their interactions with locus coeruleus (LC) noradrenergic (NE) axons in the frontal cortex across sleep-wake states. During sleep or chemogenetic suppression of LC neurons, microglia enhanced their surveillance and increased interactions with NE axons. Correlative electron microscopy at nanometer resolution identified structural contacts between microglial process endings and NE boutons. Mechanistically, microglia-bouton interaction is primed by NE–β2-adrenergic receptor (β2AR) signaling, leading to enhanced Ca²⁺ activity in NE axons. These findings suggest that microglial interactions with NE axons promote cortical norepinephrine transmission and maintain stable wakefulness.

Abstract Background and Aims Celiac disease (CeD) is a chronic digestive autoimmune disorder affecting approximately 1% of the worldwide population. It is driven by T cells activated by specific HLA-DQ2 or HLA-DQ8 molecules leading to the destruction of intestinal villi. We aimed to characterize shared CeD-specific T cells in patients on and off a gluten-free diet (GFD) from a large cohort of cases and controls. Methods We performed bulk TCRβ immune sequencing of the peripheral blood of 1,604 biopsy-confirmed CeD patients (1,339 on GFD, 265 on normal diet) and 1,100 controls. We identified over 300 TCRβs enriched in CeD cases versus controls in an HLA-aware manner, controlling for CeD risk alleles. Results CeD-associated TCRβs were found to be more predictive of disease than previously characterized gliadin and glutenin-binding TCRs in a validation cohort. Furthermore, the clonal breadth of these TCRβs was associated with increased intestinal damage. Immune sequencing of the peripheral blood also uncovered repertoire-level differences between CeD patients and controls. CeD patients displayed significantly higher productive clonality compared to age-matched controls as well as expansion of TCRβs specific to cytomegalovirus (CMV) and Epstein-Barr Virus (EBV). Conclusions These findings underscore the value of unbiased immune repertoire sequencing to identify novel biomarkers for autoimmune disease and to discover new disease mechanisms which can improve both diagnosis and treatment of disease.

Abstract Pick’s disease (PiD) is a rare cause of sporadic frontotemporal dementia, neuropathologically defined by the presence of Pick bodies consisting of aggregates of 3-repeat tau. Given the genetic aetiology of PiD remains unresolved, we assembled the Pick’s disease International Consortium (PIC) to identify susceptibility loci through a genome-wide association study (GWAS). A GWAS was conducted in 294 autopsy confirmed PiD cases and 1,055 controls. Lead variants were annotated using the Functional Mapping and Annotation of GWAS (FUMA) platform, followed by co-localisation analyses using the METABRAIN dataset and statistical finemapping using FINEMAP and SuSiE. After exclusion of 3 cases of MAPT mutations, no variants were associated with risk of PiD at genome-wide significance ( p < 5 × 10 -8 ). The strongest association was on chromosome 4 (4p13, lead SNP rs112161979, OR = 7.53, 95% Confidence Interval (CI) = 3.62-15.65, p = 6.37 × 10 -8 ) followed by chromosome 11 (11p15.4, lead SNP rs66481907, OR = 2.10, 95% CI = 1.54-2.84, p = 1.83 × 10 -6 ). rs112161979 is an intronic SNP in the KCDT8 gene, encoding a potassium channel tetramerization domain that acts as an auxiliary subunit for GABA B receptors, whilst rs66481907 is an intronic SNP in TRIM22 , encoding an E3 ubiquitin-protein ligase. Our GWAS provides the first evidence of possible genetic risk for PiD that implicate the modulation of GABA B receptor signalling and inflammation, in disease pathogenesis. Replication of these findings will be important, but our results suggest that, if present, the genetic risk of PiD beyond MAPT mutations is low.

ABSTRACT Introduction Metabolic dysfunction‐associated steatotic liver disease (MASLD) and steatohepatitis (MASH) represent a spectrum of liver conditions that can gradually progress to cirrhosis. Sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors have shown benefits in reducing hepatic steatosis and liver‐related events in MASLD. This study aims to assess whether SGLT‐2 inhibitors are associated with a reduced risk of all‐cause mortality and disease‐specific outcomes in patients with MASH cirrhosis and type 2 diabetes (T2D). Methods A retrospective cohort study was performed using TriNetX. Patients with T2D and MASH cirrhosis on SGLT‐2 inhibitors were matched 1:1 with other glucose‐lowering drugs (oGLDs) based on demographics, comorbidities and medications. Primary outcomes included all‐cause mortality, hepatic decompensation and major adverse liver outcomes (MALO). Cox‐proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence interval (CI). Results A total of 51 427 patients with MASH cirrhosis and T2D were identified, of which 6833 (13.28%) were on SGLT‐2 inhibitors. Patients on SGLT‐2 inhibitors ( n = 6449, mean age 63.7 years, 52.9% female) were matched with 6449 individuals (mean age 63.9 years, 53.5% female) on oGLDs. The SGLT‐2 inhibitors cohort had statistically significantly lower risk of all‐cause mortality (HR: 0.58, 95% CI: 0.53–0.63), hepatic decompensation (HR: 0.85, 95% CI: 0.81–0.90) and MALO (HR: 0.88, 95% CI: 0.83–0.93). Conclusion SGLT‐2 inhibitors are associated with a reduced risk of all‐cause mortality in patients with MASH cirrhosis and T2DM, which may be partly attributable to a lower risk of hepatic decompensation and subsequent events. Further studies are warranted as SGLT‐2 inhibitors may serve as an adjunctive therapy for patients with MASH cirrhosis.

Abstract Background Healthy aging and cognitive decline in Alzheimer's Disease (AD) and its precursor, Mild Cognitive Impairment (MCI), are linked to changes in resting‐state EEG power spectral density (PSD). Theta band (3‐7 Hz) power decreases with normal aging but increases with cognitive decline. However, frequency content does not always indicate true oscillatory activity. Oscillations reflect power concentration at a specific frequency, appearing as peaks in the frequency domain and visible rhythms in the time domain. Rhythmicity analysis quantifies oscillation persistence (percentage of time observed) independently of power. This study examined Theta power and Theta rhythms in healthy controls (HC) versus individuals with MCI/AD. Method Participants included 32 AD, 88 MCI, and 115 and age‐ matched HC, who completed 5‐minutes of resting‐state eyes‐closed EEG at their baseline visit. PSD was computed for one‐second epochs. Relative Theta power was defined as the proportion of total power in the Theta band, averaging across epochs. Theta rhythm duration was defined as the percentage of epochs with Theta oscillations. Baseline differences and longitudinal changes were analyzed for a subset of participants: 28 MCI and 5 AD with at least one follow‐up visit, and 25 HC with at least two follow‐ups. Result At baseline, the MCI/AD group exhibited significantly higher relative Theta power ( p <0.01, df=233, ES=0.35 at T6) and a greater Theta rhythm duration ( p <0.01, df=231, ES=0.41 at T6) compared to HC. Longitudinally, HC exhibited a significant reduction in Theta power by the second follow‐up ( p <0.05, df=24, ES=0.51 at Cz), with no significant changes in Theta rhythms duration. In contrast, MCI/AD showed a significant increase in Theta rhythm duration (and not power) at first follow‐up visit ( p < 0.05, df =32, ES=0.30 at T3). Conclusion Theta power and Theta rhythm duration are both linked to cognitive decline in MCI and AD but differ from healthy aging patterns. While Theta power reflects age‐related changes, Theta rhythms duration may serve as a specific biomarker for disease progression in MCI and AD. These findings support the value of Rhythmicity analysis in EEG‐based biomarkers of cognitive decline.

Abstract Background TMEM106B encodes a lysosomal protein and is a genetic susceptibility factor for frontotemporal lobar degeneration (FTLD). Aptamer‐based proteomics quantifies TMEM106B protein levels in CSF. The associations of CSF TMEM106B with measures of disease severity have not been previously evaluated, and the value of CSF TMEM106B as a clinical biomarker is unknown. Method CSF TMEM106B and NfL protein levels were quantified with aptamer‐based proteomics in participants from two independent cohorts: sporadic FTLD with neuropathology‐confirmed FTLD‐tau and FTLD‐TDP, clinically diagnosed PSP‐Richardson Syndrome, and controls (UCSF MAC, n = 95; mean age = 69 ± 6 yrs; 48% female) and familial FTLD comprised of presymptomatic and symptomatic FTLD mutation carriers with family non‐carrier controls (ALLFTD, n = 179; mean age = 49 ± 13 yrs; 53% female). The association between biomarkers and diverse measures of disease severity, including the CDR®+NACC‐FTLD and CDR®+NACC‐FTLD sum of boxes, were determined with linear regressions or mixed linear models. Associations with brain volumes were determined within the framework of voxel‐based morphometry. Result In both cohorts, at baseline, CSF TMEM106B did not differ by sex, age, FTLD phenotype, or CSF NfL. CSF TMEM106B was lower in cases with worse disease severity (Figure 1) and in participants with the protective TMEM106B rs1990622 G/G genotype, regardless of pathological diagnosis or FTLD‐causing mutation. Low CSF TMEM106B was associated with more severe longitudinal worsening in FTLD disease severity (Figure 2), basic and instrumental function, global cognition, executive function, and depression scores. These associations were weaker than those of NfL. Low CSF TMEM106B was associated with low brain volumes in frontal, parietal, and temporal regions (FWE‐corrected p < 0.05) (Figure 3A). CSF NfL negatively correlated (FWE‐corrected p < 0.05) with brain volumes in frontotemporal regions (Figure 3B). Conclusion CSF TMEM106B concentrations are influenced by the TMEM106B rs1990622 genotype, and correlate with disease severity and brain volume in both genetic and sporadic FTLD. Lower levels of CSF TMEM106B correlate with more severe disease and brain atrophy. Disease severity is more strongly associated with CSF NfL, while brain volumes are more strongly associated with CSF TMEM106B. CSF TMEM106B may have value as a biomarker of neurodegeneration in FTLD.

Abstract Bone marrow is the primary immune organ responsible for stem cell maintenance and hematopoiesis. However, the contribution of the bone marrow niche for the generation of adaptive immune responses is less well-understood. We therefore assessed the capacity of virus antigen-specific CD8 T cells to be generated and expanded in bone marrow following acute neurotropic virus infection. Intracranial infection with the neurotropic Theiler’s Murine Encephalomyelitis Virus (TMEV) results in an acute infection in the C57BL/6 mouse which is cleared within 4 weeks post infection due to the generation of an antigen-specific CD8 T cell response against the immunodominant epitope VP2 121-130 . We determined that 1-10% of CD8 T cells present in the femoral, and sternal bone marrow were virus antigen-specific 5-7 days after intracranial TMEV infection. We determined that antigen-specific CD8 T cells were generated in the bone marrow with similar kinetics to that of conventional responses in the secondary lymphoid organs. Importantly, continuous treatment with FTY720, which sequesters T cells outside of the blood, did not eliminate antigen-specific CD8 T cells in the bone marrow compartment indicating generation within the bone marrow niche. Similarly, injection of Poly I:C admixed with fluorescently labeled ovalbumin into the brain generated a similar antigen-specific CD8 T cell response in the bone marrow indicating these responses occur following various brain insults. This model also identified the likely antigen presenting cell (APC) responsible for scavenging antigens from the brain and trafficking into the bone marrow as a migratory myeloid-derived APC. Moreover, following clearance of TMEV infection, CD8 T cells in the bone marrow established durable memory. Antigen-specific memory CD8 T cells in the bone marrow reactivated and expanded upon cognate antigen reencounter. Antigen-specific reactivation of memory CD8 T cells within the bone marrow caused a concurrent increase in Lineage-, Sca-1+, c-Kit+ (LSK) and CD11b+ MHCII+ myeloid cells. This increase in the LSKs and myeloid cells in the bone marrow niche was abrogated with CD8 T cell depletion. We conclude that brain viral infections induce in situ effector and memory T cell responses within the bone marrow compartment. Memory recall CD8 T cell responses induce niche dysregulation by expanding LSK cells and lead to an influx of MHCII+ myeloid cells. Our data pave the way for crucial studies of bone marrow resident antigen-specific CD8 T cells in health and diseases.

Objective: Age-related hearing loss is prevalent in a large proportion of older adults and is the largest modifiable risk factor of dementia. Previous studies have shown that hearing loss in older adults is associated with reductions in brain volume and alterations in brain connectivity, but there is a gap in our understanding of how hearing loss may impact brain activity, specifically while listening to speech. In this study, we hypothesized that hearing loss would be associated with (1) reduced activation within temporal auditory regions in response to speech presented with and without background noise, and (2) increased activation in the cingulo-opercular network in response to speech in noise. Design: Twenty-seven older adults (mean age = 68 yr, 17 women) recruited from the community completed a clustered sparse-sampling functional magnetic resonance imaging protocol while listening to speech presented with and without multi-talker background noise. Regions of interest–based and exploratory voxel-wise analyses were used to investigate correlations between functional magnetic resonance imaging activation to speech and hearing ability. Hearing was defined as the pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz from the better ear and ranged from normal to a moderate hearing loss. Results: Our results indicate that age-related hearing loss was associated with reduced activation in right Heschl’s gyrus and left middle temporal gyrus in response to speech. Exploratory voxel-wise analyses suggest that hearing loss may be associated with alterations in activation in other sensory cortical regions and portions of the frontal cortex, including left pars opercularis. Activation within the cingulo-opercular network was not associated with hearing loss. Conclusions: These findings suggest that age-related hearing loss in humans is associated with altered brain activity in response to speech, particularly within right Heschl’s gyrus. It further provides hypothesis-generating data for future studies on the effects of hearing loss on brain function.