C9orf72 repeat expansions modify risk for secondary motor and cognitive-behavioral symptoms in behavioral-variant frontotemporal degeneration and amyotrophic lateral sclerosis.

In behavioral-variant frontotemporal degeneration (bvFTD) and amyotrophic lateral sclerosis (ALS), the presence of secondary motor or cognitive-behavioral symptoms, respectively, is associated with shorter survival. However, factors influencing the risk and hazard of secondary symptom development remain largely unexplored. We performed a retrospective evaluation of the entire disease course of individuals with amyotrophic lateral sclerosis (n=172) and behavioral-variant frontotemporal degeneration (n=69). Only individuals who had neuropathological confirmation of a TDP-43 proteinopathy at autopsy or had a C9orf72 repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether they were modified by the presence of a C9orf72 repeat expansion or initial clinical syndrome. Binary logistic regression and Cox proportional hazard analyses revealed increased odds (OR=4.25 [1.97-9.14]; p<0.001) and an increased hazard (HR= 4.77 [2.33-9.79], p<0.001) for developing secondary symptoms in C9orf72 expansion carriers compared to noncarriers. Initial clinical syndrome (bvFTD or ALS), age at symptom onset, and sex were not associated with development of secondary motor or cognitive-behavioral symptoms. These findings highlight the need for clinician vigilance to detect the onset of secondary motor symptoms and cognitive-behavioral in patients carrying a C9orf72 repeat expansion, regardless of initial clinical syndrome, and may warrant dual referrals between cognitive and neuromuscular clinics in these cases.

Large-scale Deep Proteomic Analysis in Alzheimer's Disease Brain Regions Across Race and Ethnicity.

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups. Methods: Dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS). Results: As a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals. Discussion: This comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies.

Spread and aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed "strains" for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain ( e.g., in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear. Here, we developed assays using monoclonal antibodies selective for two different aSyn species generated in vitro - termed Strain A and Strain B - and used them to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma, through immunohistochemistry, enzyme-linked immunoassay, and immunoblotting. Surprisingly, we found that plasma aSyn species detected by these antibodies differentiated individuals with PD vs. DLB in a discovery cohort (UPenn, n=235, AUC 0.83) and a multi-site replication cohort (Parkinson's Disease Biomarker Program, or PDBP, n=200, AUC 0.72). aSyn plasma species detected by the Strain A antibody also predicted rate of cognitive decline in PD. We found no evidence for aSyn strains in CSF, and ability to template aSyn fibrillization differed for species isolated from plasma vs. brain, and in PD vs. DLB. Taken together, our findings suggest that aSyn conformational differences may impact clinical presentation and cortical spread of pathological aSyn. Moreover, the enrichment of these aSyn strains in plasma implicates a non-central nervous system source.

A modern way to teach and practice manual therapy.

BACKGROUND: Musculoskeletal conditions are the leading contributor to global disability and health burden. Manual therapy (MT) interventions are commonly recommended in clinical guidelines and used in the management of musculoskeletal conditions. Traditional systems of manual therapy (TMT), including physiotherapy, osteopathy, chiropractic, and soft tissue therapy have been built on principles such as clinician-centred assessment, patho-anatomical reasoning, and technique specificity. These historical principles are not supported by current evidence. However, data from clinical trials support the clinical and cost effectiveness of manual therapy as an intervention for musculoskeletal conditions, when used as part of a package of care. PURPOSE: The purpose of this paper is to propose a modern evidence-guided framework for the teaching and practice of MT which avoids reference to and reliance on the outdated principles of TMT. This framework is based on three fundamental humanistic dimensions common in all aspects of healthcare: safety, comfort, and efficiency. These practical elements are contextualised by positive communication, a collaborative context, and person-centred care. The framework facilitates best-practice, reasoning, and communication and is exemplified here with two case studies. METHODS: A literature review stimulated by a new method of teaching manual therapy, reflecting contemporary evidence, being trialled at a United Kingdom education institute. A group of experienced, internationally-based academics, clinicians, and researchers from across the spectrum of manual therapy was convened. Perspectives were elicited through reviews of contemporary literature and discussions in an iterative process. Public presentations were made to multidisciplinary groups and feedback was incorporated. Consensus was achieved through repeated discussion of relevant elements. CONCLUSIONS: Manual therapy interventions should include both passive and active, person-empowering interventions such as exercise, education, and lifestyle adaptations. These should be delivered in a contextualised healing environment with a well-developed person-practitioner therapeutic alliance. Teaching manual therapy should follow this model.

A cross-sectional study of α-synuclein seed amplification assay in Alzheimer's disease neuroimaging initiative: Prevalence and associations with Alzheimer's disease biomarkers and cognitive function.

INTRODUCTION: Alzheimer's disease (AD) pathology is defined by ß-amyloid (Aß) plaques and neurofibrillary tau, but Lewy bodies (LBs; 𝛼-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed. METHODS: A validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aß and tau biomarkers, risk-factors, genetics, and cognitive trajectories. RESULTS: SAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aß burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive. DISCUSSION: SAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression. HIGHLIGHTS: SAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aß burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment.

Proteomic changes in the human cerebrovasculature in Alzheimer's disease and related tauopathies linked to peripheral biomarkers in plasma and cerebrospinal fluid.

INTRODUCTION: Cerebrovascular dysfunction is a pathological hallmark of Alzheimer's disease (AD). Nevertheless, detecting cerebrovascular changes within bulk tissues has limited our ability to characterize proteomic alterations from less abundant cell types. METHODS: We conducted quantitative proteomics on bulk brain tissues and isolated cerebrovasculature from the same individuals, encompassing control (N = 28), progressive supranuclear palsy (PSP) (N = 18), and AD (N = 21) cases. RESULTS: Protein co-expression network analysis identified unique cerebrovascular modules significantly correlated with amyloid plaques, cerebrovascular amyloid angiopathy (CAA), and/or tau pathology. The protein products within AD genetic risk loci were concentrated within cerebrovascular modules. The overlap between differentially abundant proteins in AD cerebrospinal fluid (CSF) and plasma with cerebrovascular network highlighted a significant increase of matrisome proteins, SMOC1 and SMOC2, in CSF, plasma, and brain. DISCUSSION: These findings enhance our understanding of cerebrovascular deficits in AD, shedding light on potential biomarkers associated with CAA and vascular dysfunction in neurodegenerative diseases.

Super-Resolution Imaging Uncovers Nanoscale Tau Aggregate Hyperphosphorylation Patterns in Human Alzheimer's Disease Brain Tissue.

Tau aggregation plays a critical role in Alzheimer's Disease (AD), where tau neurofibrillary tangles (NFTs) are a key pathological hallmark. While much attention has been given to NFTs, emerging evidence underscores nano-sized pre-NFT tau aggregates as potentially toxic entities in AD. By leveraging DNA-PAINT super-resolution microscopy, we visualized and quantified nanoscale tau aggregates (nano-aggregates) in human postmortem brain tissues from intermediate and advanced AD, and Primary Age-Related Tauopathy (PART). Nano-aggregates were predominant across cases, with AD exhibiting a higher burden compared to PART. Hyperphosphorylated tau residues (p-T231, p-T181, and p-S202/T205) were present within nano-aggregates across all AD Braak stages and PART. Moreover, nano-aggregates displayed morphological differences between PART and AD, and exhibited distinct hyperphosphorylation patterns in advanced AD. These findings suggest that changes in nano-aggregate morphology and hyperphosphorylation patterns may exacerbate tau aggregation and AD progression. The ability to detect and profile nanoscale tau aggregates in human brain tissue opens new avenues for studying the molecular underpinnings of tauopathies.

Characterization of Microwave Generator Energy and Ablation Volumes Following Transarterial Embolization in an In Vivo Porcine Liver Model.

PURPOSE: This study aims to characterize the relationship between ablation zone volume (AZV) and microwave ablation (MWA) energy in an in vivo porcine liver model following arterial embolization. MATERIALS AND METHODS: With animal IRB approval, eleven female swine underwent either right (n= 5) or left (n= 6) hepatic artery embolization under fluoroscopic guidance. Subsequently, ultrasound guided MWA was performed in each liver segment (left lateral, left medial, right medial, right lateral) at either 30 Watts (W) (n=4 lobes), 60W (n=4), 65W (n=20), 90W (n=8), 120W (n=4), or 140W (n=4) continuously for 5 minutes. Post-procedural volumetric segmentation was performed on standardized multiphase T1 MRI sequences. RESULTS: AZVs in embolized lobes (15.8 ± 10.6 mL) were significantly larger than non-embolized lobes (11.2 ± 6.5 mL, P <0.01). MWA energy demonstrated significant positive linear correlation with both embolized (R2=0.66, P <0.01) and non-embolized lobes (R2=0.64, P < 0.01). The slope of the linear models corresponded to a 0.95 ± 0.16 and 0.54 ± 0.09 mL/kJ increase in ablation volume per applied kJ of energy (E) in embolized and non-embolized lobes, respectively. In the multivariate model, embolization status significantly modified the relationship between E and AZV as described by the interaction term: 0.42*E*(Embolization Status), (P = 0.031). CONCLUSION: Linear models demonstrate a near 1.8 fold increase in ratio of AZV per unit E, R(AZV:E), when applied to embolized lobes relative to non-embolized lobes. Absolute AZV differences between embolized and non-embolized lobes were greater at higher power MWA.

Malnutrition in Head and Neck Free Flap Reconstruction as a Predictor of Adverse Outcomes.

INTRODUCTION: Malnutrition is associated with increased mortality in patients with head and neck (H&N) cancer. Because albumin levels are used as a surrogate for nutritional status, the purpose of this study is to assess whether malnutrition is associated with adverse postoperative outcomes in H&N free flap reconstruction. MATERIALS AND METHODS: The 2006-2018 National Surgical Quality Improvement Program Database was queried for patients undergoing flap procedures of the H&N based on Current Procedure Terminology codes. Patients were included if they were operated on by an otolaryngologist or when the primary surgical site was H&N. Nutritional status was categorized as malnourished (preoperative albumin level <3.5 g/dL) or normal (preoperative albumin level ≥3.5 g/dL). Major complications included pulmonary complications, cardiac complications, deep vein thrombosis/pulmonary embolism, and sepsis/septic shock. Minor complications included surgical infection, urinary tract infection, bleeding, and dehiscence. Data were analyzed via univariate chi-square and multivariate regression analyses. RESULTS: Of the patients, 2532 (83.3%) had normal albumin and 506 (16.7%) had hypoalbuminemia. Patients with hypoalbuminemia were more likely to have smoking history (P = 0.008), pulmonary comorbidity (P < 0.001), renal comorbidity (P = 0.018), disseminated cancer (P < 0.001), steroid use (P < 0.001), recent weight loss (P < 0.001), bleeding disorder (P = 0.023), and preoperative transfusion (P < 0.001). After adjustment for preoperative variance, malnourished patients were more likely to experience death (P < 0.001), return to operating room (P < 0.001), free flap failure (P = 0.008), pulmonary complication (P < 0.001), deep vein thrombosis/pulmonary embolism (P = 0.019), wound disruption (P = 0.042), intraoperative transfusion (P < 0.001), minor complication (P < 0.001), major complication (P < 0.001), and extended length of stay (P < 0.001). Of the patients with normal albumin, 2.1% experienced flap failure compared with 6.3% of patients with hypoalbuminemia. It should be noted that malnourished patients were 3.370 times more likely to experience flap failure (95% confidence interval, 1.383-8.212; P = 0.008) and 3.975 times more likely to experience death (95% confidence interval, 1.700-9.626; P = 0.001) than those with normal albumin. CONCLUSION: Malnutrition is associated with death, flap failure, minor complications, and other major complications following H&N free flap surgery, even after controlling for preoperative variance. Optimizing preoperative nutrition status before free flap procedures may ameliorate morbidity and mortality in H&N patients.

Utilization of the gastrocnemius flap for post-traumatic knee reconstruction: a systematic review.

PURPOSE: High-energy injuries to the knee may lead to extensive soft tissue loss, fractures, and potential loss of extensor function. The gastrocnemius flap is a prominent reconstructive option for patients with injuries involving the knee and proximal third of the lower extremity. To the best of our knowledge, there has not been an informative review that has evaluated outcomes of patients who have undergone post-traumatic knee reconstruction with a pedicled medial or lateral gastrocnemius flap. The goal of this study is to assess outcomes in patients who have undergone gastrocnemius flap reconstruction after traumatic injuries to the knee. METHODS: The review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) methodology. Four databases were utilized including PubMed, Cochrane Reviews, Embase, and CINAHL. Our search criteria consisted of the following keywords: gastrocnemius, flap, knee, and traum*. RESULTS: A total of 204 studies were imported for screening, from which five papers met our final inclusion/exclusion criteria. The most common studies utilized in this review were case series followed by retrospective chart reviews. In total, 43 patients with traumatic soft tissue knee defects were included with an average patient age of 27.28 years. All patients had successful and clinical viable flaps post-operatively, and there were a total of five patients who had complications. CONCLUSION: The gastrocnemius flap has demonstrated to be an effective option for individuals undergoing post-traumatic knee reconstruction. Infection rates, loss of mobility, and scarring represent a minority of complications that may be seen when this reconstructive technique is utilized. Still, additional randomized controlled trials and retrospective studies are required in order to further evaluate for other potential complications that may occur in this patient population.

Psychiatric Diagnoses Are Associated With Postoperative Disparities in Patients Undergoing Major Colorectal Operations.

BACKGROUND: Over 50% of hospitalized patients have comorbid psychiatric diagnoses, resulting in increased risk of morbidity such as longer lengths of stay, worse health-related quality of life, and increased mortality. However, data regarding colorectal surgery postoperative outcomes in patients with psychiatric diagnoses (PD) are limited. METHODS: We queried a single institution's National Surgical Quality Improvement Program from 2013-2019 for major colorectal procedures. Postsurgical outcomes for patients with and without PD were compared. Primary outcomes were prolonged length of stay (pLOS) and 30-day readmission. RESULTS: From a total of 1447 patients, 402 (27.8%) had PD. PD had more smokers (20.9% vs 15%) and higher mean body mass index (29.1 kg/m2 vs 28.2 kg/m2). Bivariate outcomes showed more surgical site infections (SSI) (10.2% vs 6.12%), reoperation (9.45% vs 6.35%), and pLOS (34.8% vs 29.0%) (all P values <.05) in the PD group. On multivariate analysis, PD had higher likelihood of reoperation (OR 1.53, 95% CI: [1.02-2.80]) and SSI (OR 1.82, 95% CI: [1.25-2.66]). DISCUSSION: Psychiatric diagnoses are a risk factor for adverse outcomes after colorectal procedures. Further studies are needed to evaluate the benefit of perioperative mental health support services for these patients.

Cytoarchitectonic gradients of laminar degeneration in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) is a clinical syndrome primarily caused by either tau (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. We previously found lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD is understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topologic order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation. Here, we tested this hypothesis in a frontal cortical gradient consisting of five cytoarchitectonic types (i.e., periallocortex, agranular mesocortex, dysgranular mesocortex, eulaminate-I isocortex, eulaminate-II isocortex) spanning anterior cingulate, paracingulate, orbitofrontal, and mid-frontal gyri in bvFTD-tau (n=27), bvFTD-TDP (n=47), and healthy controls (HC; n=32). We immunostained all tissue for total neurons (NeuN; neuronal-nuclear protein) and pyramidal neurons (SMI32; non-phosphorylated neurofilament) and digitally quantified NeuN-immunoreactivity (ir) and SMI32-ir in supragranular II-III, infragranular V-VI, and all I-VI layers in each cytoarchitectonic type. We used linear mixed-effects models adjusted for demographic and biologic variables to compare SMI32-ir between groups and examine relationships with the cortical gradient, long-range pathways, and clinical symptoms. We found regional and laminar distributions of SMI32-ir expected for HC, validating our measures within the cortical gradient framework. While SMI32-ir loss was not related to the cortical gradient in bvFTD-TDP, SMI32-ir progressively decreased along the cortical gradient of bvFTD-tau and included greater SMI32-ir loss in supragranular eulaminate-II isocortex in bvFTD-tau vs bvFTD-TDP ( p =0.039). In a structural model for long-range laminar connectivity between infragranular mesocortex and supragranular isocortex, we found a larger laminar ratio of mesocortex-to-isocortex SMI32-ir in bvFTD-tau vs bvFTD-TDP ( p =0.019), suggesting select long-projecting pathways may contribute to isocortical-predominant degeneration in bvFTD-tau. In cytoarchitectonic types with the highest NeuN-ir, we found lower SMI32-ir in bvFTD-tau vs bvFTD-TDP ( p =0.047), suggesting pyramidal neurodegeneration may occur earlier in bvFTD-tau. Lastly, we found that reduced SMI32-ir related to behavioral severity and frontal-mediated letter fluency, not temporal-mediated confrontation naming, demonstrating the clinical relevance and specificity of frontal pyramidal neurodegeneration to bvFTD-related symptoms. Our data suggest loss of neurofilament-rich pyramidal neurons is a clinically relevant feature of bvFTD that selectively worsens along a frontal cortical gradient in bvFTD-tau, not bvFTD-TDP. Therefore, tau-mediated degeneration may preferentially involve pyramidal-rich layers that connect more distant cytoarchitectonic types. Moreover, the hierarchical arrangement of cytoarchitecture along cortical gradients may be an important neuroanatomical framework for identifying which types of cells and pathways are differentially involved between proteinopathies.

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.

MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations.

INTRODUCTION: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS: To bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTS: We generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION: Inclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

Pathologic and cognitive correlates of plasma biomarkers in neurodegenerative disease.

INTRODUCTION: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog). METHODS: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed ß-amyloid (Aß+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aß+ from Aß-. Survival analyses tested time to clinical dementia rating (global CDR) progression. RESULTS: Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aß+ in NormCog (ROCAUC = 0.87) and ImpCog (ROCAUC = 0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aß+ (hazard ratio [HR] = 2.94; p = 8.1e-06) and Aß- individuals (HR = 3.11; p = 2.6e-09). DISCUSSION: Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease. HIGHLIGHTS: Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aß. Combining plasma p-tau181, GFAP, and NfL improved diagnostic accuracy for Aß status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aß/tau. Plasma NfL predicted longitudinal cognitive decline in both Aß+ and Aß- individuals.

A Comparison of Plastic Surgery Authorship Trends Under Single Versus Double-Blinded Review.

INTRODUCTION: Research is key to academic advancement in plastic surgery. However, access to publication opportunities may be inequitable as seen in other fields. We compared authorship trends of plastic surgery manuscripts that underwent single-blinded review (SBR) versus double-blinded review (DBR) to identify potential disparities in publication opportunities. METHODS: Publications from two plastic surgery journals using SBR and two using DBR from September 2019 to September 2021 were evaluated. Name and institution of the article's first and senior author and journal's editor-in-chief (EIC) were recorded. Chi-squared and Fisher's exact analyses were used to compare author characteristics between SBR and DBR articles. RESULTS: Of 2500 manuscripts, 65.7% underwent SBR and 34.3% underwent DBR. SBR articles had higher percentages of women as first authors (31.9% versus 24.3%, P < 0.001) but lower percentages of first (50.7% versus 71.2%, P < 0.001) and senior (49.6% versus 70.3%, P < 0.001) authors from international institutions. First (26.0% versus 12.9%, P < 0.001) and senior (27.9% versus 18.0%, P = 0.007) authors of SBR articles tended to have more plastic surgery National Institutes of Health funding. Journals using SBR tended to have higher rates of authorship by EICs or authors sharing institutions with the EIC (P ≤ 0.005). CONCLUSIONS: While associated with greater female first authorship suggesting potential efforts toward gender equity in academia, SBR of plastic surgery articles tends to favor authors from institutions with higher National Institutes of Health funding and disadvantage authors from international or lower-resourced programs. Careful consideration of current peer-review proceedings may make publication opportunities more equitable.

MSUT2 regulates tau spreading via adenosinergic signaling mediated ASAP1 pathway in neurons.

Inclusions comprised of microtubule-associated protein tau (tau) are implicated in a group of neurodegenerative diseases, collectively known as tauopathies, that include Alzheimer's disease (AD). The spreading of misfolded tau "seeds" along neuronal networks is thought to play a crucial role in the progression of tau pathology. Consequently, restricting the release or uptake of tau seeds may inhibit the spread of tau pathology and potentially halt the advancement of the disease. Previous studies have demonstrated that the Mammalian Suppressor of Tauopathy 2 (MSUT2), an RNA binding protein, modulates tau pathogenesis in a transgenic mouse model. In this study, we investigated the impact of MSUT2 on tau pathogenesis using tau seeding models. Our findings indicate that the loss of MSUT2 mitigates human tau seed-induced pathology in neuron cultures and mouse models. In addition, MSUT2 regulates many gene transcripts, including the Adenosine Receptor 1 (A1AR), and we show that down regulation or inhibition of A1AR modulates the activity of the "ArfGAP with SH3 Domain, Ankyrin Repeat, and PH Domain 1 protein" (ASAP1), thereby influencing the internalization of pathogenic tau seeds into neurons resulting in reduction of tau pathology.

Ultrastructure of human brain tissue vitrified from autopsy revealed by cryo-ET with cryo-plasma FIB milling.

Ultrastructure of human brain tissue has traditionally been examined using electron microscopy (EM) following fixation, staining, and sectioning, which limit resolution and introduce artifacts. Alternatively, cryo-electron tomography (cryo-ET) allows higher resolution imaging of unfixed cellular samples while preserving architecture, but it requires samples to be vitreous and thin enough for transmission EM. Due to these requirements, cryo-ET has yet to be employed to investigate unfixed, never previously frozen human brain tissue. Here we present a method for generating lamellae in human brain tissue obtained at time of autopsy that can be imaged via cryo-ET. We vitrify the tissue via plunge-freezing and use xenon plasma focused ion beam (FIB) milling to generate lamellae directly on-grid at variable depth inside the tissue. Lamellae generated in Alzheimer's disease brain tissue reveal intact subcellular structures including components of autophagy and potential pathologic tau fibrils. Furthermore, we reveal intact compact myelin and functional cytoplasmic expansions. These images indicate that plasma FIB milling with cryo-ET may be used to elucidate nanoscale structures within the human brain.