Neurobiology of Disease

A critical challenge in endocrine neurosurgery is intraoperative discrimination between normal pituitary tissue and pituitary neuroendocrine tumors (PitNETs). Suggesting the universal persistence of near-infrared autofluorescence (NIRAF) in endocrine organs and inspired by routine clinical use of NIRAF for parathyroid gland identification, we discovered that pituitary NIRAF can be employed for label-free transsphenoidal surgery guidance. Ex vivo confocal spectral imaging of 33 specimens identified secretory granules as the dominant long-wavelength fluorescence source and showed that normal pituitary had higher granule content than PitNETs. For the first time, we made use of the pituitary NIRAF during surgery and assessed its performance for pituitary/adenoma separation in vivo for 27 surgeries and showed near-perfect separability between pituitary and non-pituitary measurement sites with ROC-AUC of 0.98. The obtained results clearly demonstrate that the suggested method, based on the solid microscopic background, has the potential for clinical translation and paves the way for enhanced gland preservation during resection.

ObjectiveBrain branks preserve extensive material relevant to neurodegenerative disease research. As these collections age, tissue becomes archival, raising the question of whether long-term fixed and stored human brain tissue remains suitable for contemporary immunohistochemical analyses. Materials and MethodsForty-one autopsy brains collected between 1946 to 1980 were examined. For each case, midbrain and hippocampus were available both as original paraffin-embedded blocks and as tissue stored long term in fixative. New paraffin blocks were prepared from the long-term fixated tissue. Sections from original and newly prepared blocks were immunohistochemically stained for -synuclein, hyperphosphorylated tau and amyloid-{beta}. Immunoreactivity was assessed using semi-quantitative scoring. ResultsOriginal blocks consistently showed good staining intensity and morphological preservation for each protein pathology. Newly prepared blocks showed slightly lower semi-quantitative scores for Lewy-related pathology, without statistically significant differences, except for astrocytic -synuclein in the substantia nigra in cases from the 1960s. Tau pathology displayed modestly reduced labelling, particularly of the neuropil threads and neurofibrillary tangles, most evident in cases from the 1950s. Amyloid-{beta}-positive senile plaques showed similar or slightly higher scores in newly prepared blocks, with no significant differences across regions. ConclusionHuman brain tissue preserved as paraffin-embedded blocks or stored in fixative for up to 78 years remains suitable for immunohistochemical analyses. Adequate-to-good detection of aggregated of -synuclein, hyperphosphorylated tau and amyloid-{beta} is achievable, indicating preserved pathological hallmarks of Lewy Body Disease and Alzheimers Disease in archival tissue.

2- AbstractO_ST_ABSOBJECTIVEC_ST_ABSTo compare, in a Brazilian population, the clinical efficacy and quality-of-life (QoL) impact of one-stage bilateral thoracic sympathectomy (BTS) versus unilateral sympathectomy on the dominant side (UniS), with additional analysis of patients who later underwent contralateral surgery (two-stage bilateral, 2stS). METHODSProspective, randomized, controlled, multicenter trial (11 centers) including 163 adults with primary palmar hyperhidrosis. Participants were randomized 1:1 to BTS or UniS. From 6 months onward, UniS patients could elect contralateral sympathectomy (2stS). Sweating severity was assessed using the Hyperhidrosis Disease Severity Scale (HDSS) across 18 anatomical sites at each visit. Compensatory sweating (CS) was defined as new sweating in previously unaffected areas (preoperative HDSS = 1) and graded by the magnitude of HDSS increase. QoL was measured with two complementary validated instruments: HidroQOL and the Horn questionnaire. RESULTSBaseline characteristics were similar between groups, with most participants presenting severe preoperative disease. Improvement in the operated (dominant) hand was comparable after BTS and UniS, whereas control of the non-operated hand favored BTS. In the UniS group, spontaneous contralateral improvement occurred in approximately one-seventh of untreated hands. The proportion of patients without CS was similar in both groups ([~]25%), but severe CS was more frequent after BTS (40.4% vs 21.0%, p = 0.0344). QoL improved in both groups, with larger and more sustained reductions in Horn and HidroQOL scores after BTS (p < 0.001). In the 2stS subgroup, contralateral surgery produced a consistent HDSS decrease and marked QoL improvement, with predominantly mild additional CS. CONCLUSIONSBTS provides more complete symptom control and greater QoL improvement, but at the cost of more severe CS. UniS offers excellent control on the treated side, may reduce severe CS, and supports a staged strategy in which some patients avoid a second procedure (requested by 22.5% in this study); when needed, contralateral completion tends to restore additional clinical and QoL gains.

Olfactory decline is a well-established aspect of Parkinsons disease (PD) and is considered one of its earliest signs, often preceding motor symptoms by years to decades. However, because olfactory impairment is also common in healthy aging and other medical conditions, current olfactory tests that score performance (odor detection, discrimination, and identification) lack disease specificity. In contrast to performance scores, olfactory perceptual fingerprints are derived from odor ratings and sniffing behavior, and provide a stable measure of how the world smells to an individual. To test the hypothesis that olfactory perceptual fingerprints may provide a disease-specific marker, we obtained them in three cohorts: Individuals with PD (n=33), healthy age-matched controls (n=33), and critically, in participants with non-PD olfactory dysfunction (n=28). Consistent with previous results, a standard clinical olfactory test detected impairment in both PD and non-PD olfactory dysfunction, but failed to distinguish between these two groups. In contrast, olfactory perceptual fingerprints detected impairment, and distinguished PD from non-PD olfactory dysfunction at 88% accuracy (SVM classification, leave-one-out cross validation, 90% sensitivity, 85% specificity, P=3.2x10-4), or 94% accuracy after matching age and sex (SVM classification, leave-one-out cross-validation, 100% sensitivity, 88% specificity, P=0.0047). The difference between PD related and unrelated olfactory decline was particularly evident in sniffing behavior: Whereas both healthy participants and non-PD olfactory decline groups decreased sniff duration in response to unpleasant odors (-12.5% and -11.36% respectively), individuals with PD paradoxically increased sniff duration (+1.69%; P=4.5x10-5). Thus, PD was marked not by loss of olfactory performance, but by a distinct shift in olfactory perception. These findings imply that olfactory perceptual fingerprints provide for a disease-specific marker in PD.

SignificanceMastectomy skin flap necrosis remains a major complication in implant-based breast reconstruction due to inadequate tissue blood flow. Existing diagnostic technologies are limited by shallow depth sensitivity, dye-related risks, contact requirements, and an inability to continuously assess blood flow. AimThis study aimed to translate a noncontact, dye-free, depth-sensitive speckle contrast diffuse correlation tomography (scDCT) technique to a clinically relevant porcine skin flap model for assessing flap blood flow and viability. ApproachThe scDCT system was optimized to image blood flow over seven days in four porcine skin flaps including Sham (SH), Implant (IM), Half Necrosis (HN), and Full Necrosis (FN). Measurements were compared with indocyanine green angiography (ICG-A) as a reference standard. ResultsscDCT enabled longitudinal monitoring of flap blood flow, revealing significant flow differences among flap types and over time. FN flaps consistently exhibited the most severe flow impairment, while other flap types showed partial or complete recovery over time, distinguishing nonviable from viable tissue. scDCT measurements demonstrated moderate to strong correlations with ICG-A across time points. ConclusionsThe findings support scDCT as a promising perioperative imaging modality for improving flap necrosis risk stratification and surgical decision-making, with future work focused on large-scale validation and clinical translation.

IntroductionGenome-wide association studies (GWAS) have identified over 130 risk loci for Parkinsons disease (PD), yet the majority derive from studies performed in European ancestry populations. African (AFR) and African admixed (AAC) ancestry individuals remain underrepresented in PD genetics research, limiting our understanding of ancestry-specific genetic architecture and the generalizability of known risk factors. MethodsWe conducted GWAS in AFR and AAC populations by integrating individual-level genotype data from the Global Parkinsons Genetics Program (GP2) with summary statistics from 23andMe Research Institute and the Million Veterans Program. The combined dataset included 3,975 cases and 319,883 controls, representing a 64% increase in total sample size compared with prior analyses. We performed separate GWAS for AFR and AAC cohorts as well as a combined AFR/AAC meta-analysis. ResultsThe intronic GBA1 variant rs3115534 was the most significant association across all analyses, reaching genome-wide significance in AAC individuals for the first time. In the AFR-only analysis, five loci achieved genome-wide significance: GBA1 (rs3115534), the SNCA signal previously reported in European ancestry GWAS (rs356182), a new protein-coding association at LRRK2 (rs72546327, p.T1410M), a non-coding RPL10P13 variant (rs12302417), and a novel signal on chromosome 16 (rs113244182). The combined AFR/AAC meta-analysis identified four genome-wide significant associations at GBA1 (rs3115534), SNCA (rs356182), SCARB2 (rs11547135), and LRRK2 (rs139283662, which is in LD with p.T1410M). ConclusionsThis study reports the largest GWAS of PD in AFR and AAC populations to date. Our findings confirm trans-ancestry risk loci (GBA1 and SCARB2) and identify an ancestry-enriched coding variant at LRRK2. This convergence of evidence around genes involved in glucocerebrosidase (GCase) trafficking and alpha-synuclein clearance supports current therapeutic strategies targeting this pathway and provides critical targets for developing precision medicine in African ancestry populations. Importantly, the identification of a novel association between a LRRK2 coding variant with disease in the AFR and AAC populations opens up a traditionally underrepresented population for ongoing LRRK2 targeted trials. Furthermore, the identification of novel ancestry-specific loci, including those that are directly relevant to current therapeutic deployment, underlines the importance of understanding the basis of disease in all populations.

Background: Quantitative genome wide association studies (GWAS) primarily rely on additive linear models that compare average phenotypic differences between genotype groups. While effective for detecting common variants of moderate effect in large sample sizes, such approaches inherently reduce high resolution phenotypic data to summary statistics (group averages), potentially limiting the detection of subtle genotype phenotype relationships. Genomic Informational Field Theory (GIFT) is a recently developed methodology that preserves the fine-grained informational structure of quantitative traits by analysing ranked phenotypic configurations rather than relying solely on mean differences. Methods: We applied GIFT to genetic and neuropathological data from the Brains for Dementia Research cohort, a well characterised dataset of 563 individuals, and compared its performance with conventional GWAS. Principal component analysis (PCA) derived matrix was used to derive independent quantitative traits linked to from Alzheimer disease (AD) neuropathology measures (CERAD, Thal, Braak staging), with and without inclusion of age at death. Principal component analyses were performed using GWAS and GIFT frameworks on the same filtered genotype dataset. Results: Both GWAS and GIFT identified genome-wide significant associations (pvalue<0.000001) within the APOE locus (NECTIN2/TOMM40/APOE/APOC1), demonstrating concordance with established AD genetic variants. However, GIFT detected additional significant 19 SNPs beyond those identified by GWAS. Variants associated with AD pathology implicated genes involved in amyloid processing, neuronal apoptosis, synaptic function, neuroinflammation, and metabolic regulation. Notably, GIFT identified 29 loci associated with age at death related variation that were not detected by GWAS, highlighting genes linked to lipophagy, mitochondrial quality control, sphingolipid metabolism, frailty, and aging-related processes. Conclusions: GIFT recapitulates canonical GWAS findings while uncovering additional biologically relevant associations. By preserving the fine-grained structure of phenotypic data distributions and detecting non random genotype segregation across ranked trait values, GIFT enables the identification of associations that remained undetected by traditional average based GWAS approaches. These results demonstrate that rethinking analytical representation, rather than solely increasing sample size, can expand discovery potential of genetic association studies, offering a transparent and complementary framework for quantitative genomics in deeply phenotyped datasets.

Gait impairment (GI) and freezing of gait (FOG) affect 80% of patients with advanced Parkinsons disease. Continuous deep brain stimulation (cDBS) provides limited adaptability to address the episodic nature of FOG due to fixed parameters. Neural biomarkers for adaptive DBS are limited by signal artifacts and poor FOG classification. Wearable inertial measurement units (IMUs) offer a promising alternative by directly measuring signatures of GI&FOG. We developed Kinematic adaptive DBS (KaDBS), the first intelligent system to dynamically modulate stimulation in response to real-time gait metrics. KaDBS integrates bilateral shank-mounted IMUs with an investigational neurostimulator through a wireless architecture enabling step-detection, arrhythmicity calculation, and probabilistic FOG classification. Two control algorithms were implemented: an arrhythmicity model based on stride variability, and a P(FOG) classifier implementing tri-state control based on stepwise freezing probabilities. In the largest KaDBS cohort to date (n=8), we compared OFF, cDBS, KaDBS, and intermittent DBS during harnessed stepping and free walking. KaDBS was safe and well tolerated with no serious adverse events; symptom-free reports were 87.5% and 71.4% for arrhythmicity and P(FOG) models respectively, compared to 50.0% for cDBS. All symptoms were mild, transient, and resolved without intervention. KaDBS significantly reduced percent time freezing versus OFF during stepping-in-place (35.8%, P= 4.80 x 10-3) and free walking (33.4%, p = 9.00 x 10-). Therapeutic effects concentrated in baseline freezers: two participants with 100% time freezing during OFF achieved complete resolution with KaDBS, while non-freezers maintained stable gait. These findings establish KaDBS as a safe, effective approach to personalized neuromodulation for PD.

BackgroundMultiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system affecting 2.8 million people worldwide. Both genetic and environmental factors contribute to MS risk, with Epstein-Barr virus (EBV) infection being an important environmental factor. To better clarify the role of EBV in MS, we examined its impact on gene expression, chromatin accessibility, and transcription factor binding in primary B cells and EBV-transformed B cells derived from patients with MS and healthy controls. ResultsRNA-seq and ATAC-seq analyses revealed extensive MS-dependent gene expression and chromatin accessibility differences in EBV-transformed, but not in primary B cells. These changes are largely accounted for by the expression levels of EBNA2, an EBV-encoded transcriptional regulator previously implicated in MS. ChIP-seq analysis revealed that EBNA2 binding with its interacting human partners RBPJ, EBF1, and PU.1 is highly enriched at MS genetic risk loci, with extensive EBNA2 allelic binding and increased enrichment at MS genetic risk loci in MS-derived cells. ConclusionsOur findings demonstrate that enhanced EBNA2 activity in MS alters human gene expression, chromatin accessibility, and transcription factor binding in an MS-dependent manner. Collectively, this study provides new insights into the molecular mechanisms through which EBV, particularly EBNA2, interacts with host genetic risk to contribute to MS pathogenesis.

BackgroundPostoperative delirium is a common complication in surgical patients, and is associated with a multitude of negative outcomes, including mortality, dementia, and increased healthcare costs. Therefore, a better understanding of what factors contribute to postoperative delirium, especially those that can be easily obtained, is important. MethodsWe conducted a retrospective cohort study using patients from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Adult patients undergoing procedures in abdominal surgery who did not have pre-existing delirium were included in the study. Overall, we included 8022 procedures across 7212 patients. For each admission, we extracted values obtained from common blood tests, the Charlson and Elixhauser comorbidity score, and patient demographic information. We used stepwise logistic regression to identify predictive factors of postoperative delirium in this cohort. ResultsThe model isolated factors well known to be associated with postoperative delirium, such as age, comorbidity (as represented by the Elixhauser comorbidity score), and Parkinsons disease. The model also selected variables that are less studied, such as minimum preoperative platelets and maximum preoperative sodium levels. We hypothesize that the former is associated with postoperative delirium as a surrogate marker for inflammation as an acute phase reactant, and the second due to it being a marker for cerebral edema and altered neurotransmission. ConclusionPreoperative blood tests contain valuable information that can be used alongside patient demographics and past medical history to better predict the risk of postoperative delirium.

Lysosomal dysfunction is central to Parkinsons disease pathogenesis, with GBA1 as the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid and ceramide metabolism have been proposed as contributors to Parkinsons disease, underscoring the need for comprehensive genetic analyses across these pathways. We analysed rare variants (minor allele frequency < 0.01) across 36 lysosomal genes (excluding GBA1) in 8,267 individuals with Parkinsons disease and 68,208 controls, including a subset of 793 early-onset Parkinsons disease ([&le;]50 years) cases. Targeted sequencing was performed in four cohorts at McGill University (3,456 Parkinsons disease patients and 2,664 controls) and results were combined with whole-genome sequencing data from the UK Biobank (2,848 cases, 62,451 controls), and from the Accelerating Medicines Partnership - Parkinsons Disease (1,963 cases, 3,093 controls). We analysed the association of rare variants in these genes with Parkinsons disease using Sequence Kernel Association Test-Optimal (SKAT-O) across variant classes (all rare variants, nonsynonymous, loss-of-function and predicted damaging variants with a Combined Annotation Dependent Depletion (CADD) score >20), with meta-analysis across cohorts. We additionally performed per-domain analyses for variants in gene segments encoding functional domains. False discovery rate correction was applied. Meta-analysis identified a significant association between rare variants in ST3GAL3 and Parkinsons disease (Pfdr=0.04). Several additional lysosomal genes showed nominal associations (P<0.05), including HGSNAT, ASAH1, CTSD, HEXA, ST3GAL4 and SGPP1. Domain-based analyses identified a strong enrichment of nonsynonymous variants within the beta-acetyl-hexosaminidase-like domain of HEXA (P = 8.0 x 10), although this signal did not survive correction for multiple testing (Pfdr=0.154). In early-onset Parkinsons disease, domain-based analyses revealed significant associations in NAGLU (Pfdr=7.3x10) and ST3GAL5 (Pfdr=0.03). Together, these results provide genetic evidence that rare variants across multiple lysosomal pathways, particularly those related to sialylation, ganglioside metabolism, ceramide biology, and lysosomal proteolysis, may contribute to Parkinsons disease susceptibility beyond GBA1, highlighting biologically coherent pathways for future replication and functional investigation.

Parkinsons disease (PD) is a disabling neurodegenerative disorder with a substantial heritable component. Despite major advances in genome-wide association studies (GWAS), polygenic risk scores (PRS) show reduced predictive performance outside European populations, limiting equitable translation. Latin American populations represent a particularly difficult case because of their characteristic three-way admixture. We evaluated the cross-ancestry transferability of PD PRS in 1,872 PD cases and 1,443 controls of Latin American ancestry using data from the Global Parkinsons Genetics Program (GP2). PRS were constructed using summary statistics from a large European-ancestry GWAS, a moderately sized mixed-ancestry GWAS meta-analysis, and a small ancestry-matched Latin American GWAS. We benchmarked two single-ancestry approaches (PRSice-2 and SBayesRC) against two multi-ancestry methods (PRS-CSx and BridgePRS) that explicitly model cross-population genetic architecture. Across all performance metrics, SBayesRC performed best. PRS derived from large European GWAS achieved the highest effect size (odds ratio = 2.02; pseudo-R{superscript 2} = 0.031) while PRS derived from mixed ancestry GWAS meta-analysis yielded the highest discriminative ability (AUC=0.67). Our findings demonstrate that, under current sample size imbalances, well-powered European discovery GWAS outperform ancestry-matched but underpowered datasets in three-way admixed populations. Incorporating functional annotations, as implemented in SBayesRC, improves portability across ancestries. However, the full potential of multi-ancestry PRS methods will require substantially larger ancestry-matched discovery GWAS, underscoring the urgent need to expand genetic studies in underrepresented populations.

Importance: Dementia is common in Parkinson's disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised. Objective: To investigate whether visual deficits and genetic factors predict PD dementia. Design: Large prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months. Setting: Cases were recruited between 2017-2020 at 35 UK PD clinics. Participants: People with PD without dementia at baseline were included. Main outcomes and measures: Visual function was measured using a web-based platform. The main outcome measure was global cognition, measured as the Montreal Cognitive Assessment (MoCA). Blood samples were collected for genetics. Results: 450 patients with PD were included. Mean age of PD patients was 71.7 (SD=7.8), 68% male. Mean baseline MoCA was 27.7 (SD=1.7). 263 patients with PD were classed as poor-vision based on baseline visual tests: mean age 74.4 (SD=6.8) compared to 69.7 (SD=7.5) with good-vision. Poor-vision PD patients had higher rates of progression to mild cognitive impairment (PD-MCI) (HR=2.34, CI=1.58-3.48, pFDR=0.00062, age- and sex-corrected). The combination of genetic factors together with vision influenced outcomes. In good-vision PD patients, high-risk GBA1 gene variants were linked with greater progression to PD-MCI (HR=4.61, CI=1.73-12.28, pFDR=0.0068). Polygenic Risk Score (PRS) for both PD and Alzheimer's disease (AD) also modified cognitive survival when combined with vision status. High PD-PRS was associated with greater progression to PD-MCI in good-vision patients (HR=2.66, CI=1.21-5.81, pFDR=0.0381); and high AD-PRS with greater progression to PD-MCI in poor-vision PD patients (HR=1.91, CI=1.10-3.32, pFDR=0.04999). Combining high PD- and AD-PRS, compared to low PD- and AD-PRS in good-vision PD showed even higher progression to PD-MCI (HR=6.14, CI=1.36-27.83, pFDR=0.046). Simulations showed that adding visual and genetic stratification reduced sample size from n=705 to n=160 for clinical trials. Conclusions and relevance: Poor vision in PD predicts progression to PD-MCI and dementia. This combines with the effects of genetic factors including GBA risk variants and PD- and AD-PRS. These findings can enable enrichment of clinical trials for patients at higher risk of PD dementia, for more efficient trial design for interventions to slow progression.

BackgroundEarly laparoscopic cholecystectomy (ELC) is the standard treatment for acute calculous cholecystitis (ACC), but difficult laparoscopic cholecystectomy (DLC) remains a challenge. Predicting DLC and ACC severity is crucial for clinical decision-making. MethodsThis retrospective single-center study included 198 ACC patients who underwent ELC. Preoperative clinical, laboratory, and imaging data were analyzed. DLC was defined by operative time >90 min, conversion, or subtotal cholecystectomy. ACC severity was graded using TG18. Multivariate logistic regression identified independent predictors. ResultsDLC occurred in 81 (40.9%) patients; 102 (51.5%) had severe ACC. Serum cholinesterase (ChE) and CRP were independent predictors of DLC. CRP and male sex independently predicted ACC severity. Other markers (e.g., NLR, PCT) were not independently associated. ConclusionPreoperative ChE and CRP levels are reliable predictors of DLC, while CRP and male sex predict ACC severity. These findings support their use in risk stratification and surgical planning.

While 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is an established biomarker in amyotrophic lateral sclerosis (ALS), the metabolic correlates of motor neuron disease motor variants remain poorly defined. This is why we investigated patterns of cerebral glucose metabolism across the spectrum of motor neuron disorders (MND), including progressive muscular atrophy (PMA), primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS). We retrospectively included 18 PMA, 25 PLS and 43 matched non-hereditary ALS patients according to most recent diagnostic criteria. FDG-PET imaging revealed similar widespread hypometabolism in PMA, as in ALS, whereas PLS showed a more focal motor cortical pattern of hypometabolism. Despite clinical differences between MND subtypes, PMA and ALS showed similar FDG-PET metabolic patterns, whereas PLS exhibited a more restricted cortical signature in this retrospective study.

Background & AimsThe increasing global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) including metabolic dysfunction-associated steatohepatitis (MASH) creates an urgent need for objective methods of histopathological assessment. Conventional histological approaches are time-consuming and rely on interpreters experience. Therefore, the results obtained may suffer from high variability and only offer coarse categorisation. In this study, we propose a fully automated, deep-learning-based pipeline for the segmentation and characterisation of histological liver features for MASH/MASLD assessment. MethodsSegmentation was applied to H&E sections from 45 mice and 44 humans with MASH/MASLD. The method, which we named qHisto (quantitative histology), utilises the nnU-Net framework and quantifies key histological components of the MASH score, including macro- and microvesicular steatosis, fibrosis, inflammation, hepatocellular ballooning and glycogenated nuclei. Additionally, we characterized the tissue using novel features that are inaccessible through manual histology, such as the distribution of fat droplet sizes, aspect ratio of nuclei and heatmaps. ResultsqHisto parameters showed strong positive correlations with conventional histology scores (fat area R=0.91, inflammation density R=0.7, ballooning density R=0.49) and also with quantitative magnetic resonance imaging (fat area vs. hepatic fat fraction R=0.87). Our novel scores showed that deformation of nuclei is driven by large fat droplets rather than the overall amount of fat. ConclusionsA key advantage of our method is spatially resolved, precise histological quantification. These features provide a finely resolved assessment of disease severity than conventional categorical scoring. By automating time-consuming and repetitive readouts, qHisto improves standardisation and reproducibility of MASH/MASLD feature quantification and provides scalable, slide-wide readouts that can support histopathologists and enhance clinical assessment and therapeutic development. Impact and ImplicationsThe proposed method provides an objective, automatic tool for comprehensive, histological liver analysis of MASH/MASLD, which can be extended to other diseases and organs. By offering classic and novel quantitative parameters and scores, our method could support histologists in their daily routines and provide researchers with further insight into steatotic liver diseases.

Type 1 narcolepsy (NT1), a disorder caused by the loss of hypocretin/orexin transmission, is characterized by daytime sleepiness and symptoms where Rapid Eye Movement (REM) sleep, a state normally occurring from middle to late in the night, can intermingle with wakefulness. This results in cataplexy and sleep paralysis, episodes of muscle paralysis when awake, or in the generation of dream-like hallucinations and vivid dreaming, periods of visual imagery or sensory experiences that occur while awake, notably when falling asleep (hypnagogic hallucinations) or lingering dreams with over-realistic recall. Using deep learning of nocturnal sleep polysomnography (PSG) signals (EEG, EMG and EOG) applied to sleep stage scoring, we found that NT1 shows abnormally short wake to REM sleep transitions and occurrences of abnormal sleep stages probabilities of wake, REM sleep and N1 (very light NREM) sleep abnormally co-occurs (sleep stage mixing). Interestingly, although presence of these during sleep enables NT1 diagnosis with performances similar to gold standard diagnostic procedure, the multiple sleep latency test (MSLT), the cortical localization of these dissociations remains unclear. In this work, we used electrode specific predictions of sleep stages to explore if these are global or observed at the local cortical level. Surprisingly, although sleep stage mixing was preeminent between REM sleep, N1 and wake across all electrodes, it was found to fluctuate across locations, with stronger fluctuations found in frontal and central locations, notably in the dominant (left) hemisphere. The strongest single discriminator for NT1 was N1-REM stage mixing across central electrodes (C3-C4), showing 4.3-fold higher dissociation in NT1 patients (Cohens d = 0.61). Analysis of sleep stage dissociations across varying time scales revealed that windows lasting several minutes were most predictive of NT1 status, aligning with the duration of clinically reported symptoms of dissociated REM sleep in narcolepsy. Local N1-W-REM sleep dissociations correlated with CSF orexin/hypocretin levels and severity as measured using MSLT. The predominance of stage mixing in frontal and central regions, areas typically associated with executive and motor control, may contribute to the partial preservation of awareness during dissociated REM phenomena. Further, self-reports of hypnagogic hallucinations correlated best with dissociations involving occipital locations, in agreement with its usual visual content. Coherence analysis was also conducted but did not reveal additional insight. These results suggest that orexin deficiency destabilizes REM sleep organization across cortical projection area contributing both to REM sleep dissociation and to abnormal state transitions observed in NT1.

BackgroundOscillations underpin a large spectrum of brain function. Brain oscillations are altered by neuromodulation approaches including deep brain stimulation (DBS), but a mechanistic understanding of the brain oscillation - DBS interaction is missing. DBS is predominantly used in the treatment of Parkinsons disease. DBS can induce or alter pre-existing narrow frequency band gamma oscillations at half the stimulation frequency. Such half-harmonic responses have been interpreted as entrainment of endogenous oscillations by an exogenous oscillator with an associated Arnold tongue structure. However, half-harmonic responses are not exhibited by all patients. MethodsHere, a Wilson-Cowan model of subcortical neuronal populations is used to set out a broad theoretical framework explaining the heterogeneity of observed responses. ResultsIn the absence of stimulation, the model exhibited either damped oscillations or self-sustained oscillations, depending on parameter values. Off-stimulation behaviour determined observed stimulation response. When oscillations were strongly damped, the only observed response was a driven oscillation at the stimulation frequency. When off-stimulation oscillations were weakly damped, additional half-harmonic responses occurred for sufficiently large amplitude stimulation. When self-sustained oscillations were present they were entrained by the stimulation frequency leading to harmonic, half-harmonic and many other subharmonic responses. Varying stimulation amplitude highlighted hysteresis with the onset and offset of half-harmonic responses appearing at different thresholds. Such two-threshold systems present challenges for adaptive control systems. ConclusionsThis framework captures observed heterogeneity and will help guide future therapeutic practices and the development of adaptive neuromodulation techniques for more effective promotion of physiological rhythms and suppression of abnormal rhythms.

The molecular basis of cognitive resilience in Alzheimers disease (AD), wherein individuals harbor substantial neuropathology yet maintain cognition, remains poorly understood. To systematically decode the regulatory logic underlying divergent cognitive outcomes, we constructed the largest cell-type-resolved gene regulatory network (GRN) atlas of AD to date, profiling 1.7 million nuclei from 687 individuals classified as Controls, cognitively Resilient, or AD dementia across 27 cell types in the human dorsolateral prefrontal cortex. From 223 high-confidence transcription factor regulons, we identify a three-state framework of transcriptional dysregulation: homeostatic erosion of IRF8/STAT1 interferon programs in microglia (State I), compensatory NF-{kappa}B suppression via BCL6 in glial populations that distinguishes resilient from demented individuals despite equivalent neuropathological burden (State II), and pathogenic escalation through FLI1/IKZF1 network expansion driving vascular-immune remodeling in AD (State III). NF-{kappa}B emerges as the central regulatory hub, with BCL6-mediated repression and FLI1/RELA-driven activation constituting opposing molecular switches that determine cognitive trajectory. These findings, replicated across independent cohorts, reframe resilience as an active regulatory state rather than attenuated disease, and nominate BCL6, IRF8, and FLI1 as priority targets for interventions aimed at extending the compensatory window before dementia onset.

BackgroundThe FACE-Q Skin Cancer Module is a condition-specific patient-reported outcome measure for facial skin cancer. While its psychometric properties have been established, normative reference values that enable score interpretation in clinical practice and research are lacking. ObjectiveTo establish normative reference values for the FACE-Q Skin Cancer Module using preoperative patient data and to validate these values by comparison with a demographically matched cohort of healthy partners. MethodsTwo cohorts were analyzed: 287 patients with facial skin cancer (preoperative scores) and 82 healthy partners of skin cancer patients (same-age population without facial skin cancer). Both cohorts completed the Appearance (9 items) and Psychosocial Distress (8 items) scales. Patients additionally completed the Cancer Worry scale (10 items) and Sun Protection scale (5 items). Scores were transformed to a 0-100 scale. Normative values were expressed as percentiles overall and stratified by sex and age group. Group comparisons used independent t-tests, Mann-Whitney U tests, and Cohens d. Internal consistency was assessed with Cronbachs alpha. ResultsPatient and partner cohorts were well matched for age (68.6{+/-}11.9 vs 68.4{+/-}13.0, p=0.902) and sex (46.7% vs 41.5% female, p=0.476). Surprisingly, preoperative facial appearance scores were virtually identical between patients and partners (55.6{+/-}14.0 vs 56.6{+/-}13.6, p=0.590, d=-0.08), as were psychosocial distress scores (14.3{+/-}12.0 vs 14.4{+/-}13.3, p=0.942, d=-0.01). This equivalence held across age groups. A significant sex interaction was identified: female patients scored lower on appearance than female partners (54.3 vs 59.9, p=0.048, d=-0.40), whereas no difference existed among males (56.9 vs 53.1, p=0.168). Internal consistency was excellent in both cohorts (Cronbachs 0.82-0.93). Patients reported marginally higher sun protection behaviors than partners (38.0 vs 33.6, p=0.050). ConclusionsPreoperative FACE-Q Skin Cancer scores in patients are equivalent to those of demographically matched healthy individuals, confirming that these scores serve as valid normative references. The established percentile norms enable clinicians and researchers to interpret individual patient scores in context. The sex-specific difference in appearance scores warrants further investigation.