Automated deep learning segmentation of high-resolution 7 Tesla postmortem MRI for quantitative analysis of structure-pathology correlations in neurodegenerative diseases.

Postmortem MRI allows brain anatomy to be examined at high resolution and to link pathology measures with morphometric measurements. However, automated segmentation methods for brain mapping in postmortem MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this work, we present a high-resolution dataset of 135 postmortem human brain tissue specimens imaged at 0.3 mm3 isotropic using a T2w sequence on a 7T whole-body MRI scanner. We developed a deep learning pipeline to segment the cortical mantle by benchmarking the performance of nine deep neural architectures, followed by post-hoc topological correction. We evaluate the reliability of this pipeline via overlap metrics with manual segmentation in 6 specimens, and intra-class correlation between cortical thickness measures extracted from the automatic segmentation and expert-generated reference measures in 36 specimens. We also segment four subcortical structures (caudate, putamen, globus pallidus, and thalamus), white matter hyperintensities, and the normal appearing white matter, providing a limited evaluation of accuracy. We show generalizing capabilities across whole-brain hemispheres in different specimens, and also on unseen images acquired at 0.28 mm3 and 0.16 mm3 isotropic T2*w fast low angle shot (FLASH) sequence at 7T. We report associations between localized cortical thickness and volumetric measurements across key regions, and semi-quantitative neuropathological ratings in a subset of 82 individuals with Alzheimer's disease (AD) continuum diagnoses. Our code, Jupyter notebooks, and the containerized executables are publicly available at the project webpage (https://pulkit-khandelwal.github.io/exvivo-brain-upenn/).

Genomic Data Characterize Reproductive Ecology Patterns in Michigan Invasive Red Swamp Crayfish (Procambarus clarkii).

The establishment and spread of invasive species are directly related to intersexual interactions as dispersal and reproductive success are related to distribution, effective population size, and population growth. Accordingly, populations established by r-selected species are particularly difficult to suppress or eradicate. One such species, the red swamp crayfish (Procambarus clarkii) is established globally at considerable ecological and financial costs to natural and human communities. Here, we develop a single nucleotide polymorphism (SNP) loci panel for P. clarkii using restriction-associated DNA-sequencing data. We use the SNP panel to successfully genotype 1800 individuals at 930 SNPs in southeastern Michigan, USA. Genotypic data were used to reconstruct pedigrees, which enabled the characterization of P. clarkii's mating system and statistical tests for associations among environmental, demographic, and phenotypic predictors and adult reproductive success estimates. We identified juvenile cohorts using genotype-based pedigrees, body size, and sampling timing, which elucidated the breeding phenology of multiple introduced populations. We report a high prevalence of multiple paternity in each surveyed waterbody, indicating polyandry in this species. We highlight the use of newly developed rapid genomic assessment tools for monitoring population reproductive responses, effective population sizes, and dispersal during ongoing control efforts.

Association of quantitative histopathology measurements with antemortem medial temporal lobe cortical thickness in the Alzheimer's disease continuum.

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer's disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies.

Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics.

The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNA-seq and ATAC-seq in Alzheimer's disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), analyzing 41 participants and ∼1 million cells (RNA + ATAC) from three brain regions varying in vulnerability and pathological burden. We identify 32 shared, disease-associated cell types and 14 that are disease specific. Disease-specific cell states represent glial-immune mechanisms and selective neuronal vulnerability impacting layer 5 intratelencephalic neurons in AD, layer 2/3 intratelencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We identify disease-associated gene regulatory networks and cells impacted by causal genetic risk, which differ by disorder. These data illustrate the heterogeneous spectrum of glial and neuronal compositional and gene expression alterations in different dementias and identify therapeutic targets by revealing shared and disease-specific cell states.

A Non-Randomized Comparison of Online and In-Person Formats of the Canadian Androgen Deprivation Therapy Educational Program: Impacts on Side Effects, Bother, and Self-Efficacy.

Although Androgen Deprivation Therapy (ADT) is effective in controlling prostate cancer (PCa) and increasing survival, it is associated with a myriad of side effects that cause significant morbidity. Previous research has shown that PCa patients starting on ADT are neither fully informed nor well-equipped to manage the breadth of ADT's side effects. The ADT Educational Program (a 1.5 h interactive class plus a book) was developed as an evidence-based resource for patients dealing with ADT. Our aim here was to compare the efficacy of an online version of the class with a previously assessed in-person version of the class. Using mixed MANOVAs within a non-randomized comparison design, we assessed: (1) changes in patients' experiences of self-efficacy to manage and bother associated with side effects approximately 10 weeks after attending a class, and (2) potential differences in these variables between online and in-person class formats. Side effect bother decreased from pre- to post-class but did not differ between in-person (n = 94) and online (n = 137) class cohorts. While self-efficacy to manage side effects was slightly higher post-class in both cohorts, the increase was not statistically significant. Average self-efficacy ratings were significantly higher among in-person versus online class participants (p < 0.05; ηp2 = 0.128). Both online and in-person classes are associated with a significant reduction in the severity of side effect bother reported by PCa patients, suggesting non-inferiority of online versus in-person formats. Online classes offer greater accessibility to the program for patients outside the reach of in-person classes, increasing the availability of the program to more PCa patients and family members across Canada.

Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer's disease.

Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer's Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.

Enhancing care: evaluating the impact of True North Sexual Health and Rehabilitation eTraining for healthcare providers working with prostate cancer patients and partners.

Background: Educational programs that enhance healthcare providers' competence in managing the care of patients with sexual dysfunction following prostate cancer treatments are needed to facilitate comprehensive sexual health treatments for patients and their partners. Aim: In this study we evaluated the impact of a real-world online sexual health educational intervention called the True North Sexual Health and Rehabilitation eTraining Program. This program is designed to increase healthcare providers' knowledge and self-efficacy in providing sexual healthcare to prostate cancer patients and their partners. Methods: Healthcare providers were invited to join a 12-week virtual training program. Participants completed precourse surveys (n = 89), retrospective prepost surveys (n = 58), and a 3-month follow-up survey (subset n = 18) to assess retention of relevant outcomes. Additionally, a course satisfaction survey was administered to participants (n = 57) at the end of the course. Outcomes: The main outcomes focused on participants' perceived knowledge and self-efficacy in conducting assessments and providing interventions for various relevant physical, functional, psychological, and relational domains of sexual dysfunction in prostate cancer patients and their partners. Results: According to the retrospective analysis of post-then-pre-survey results, graduates perceived that their knowledge of and self-efficacy in providing sexual health counseling improved after completing the course. The 3-month follow-up survey indicated that the course graduate self-efficacy remained high 3 months after the course. Furthermore, the satisfaction survey indicated that a vast majority (98.2%) of participants were satisfied with the educational intervention. Clinical Implications: This real-world sexual health educational intervention can increase self-efficacy and knowledge in healthcare providers who are supporting prostate cancer patients dealing with sexual dysfunction. Strengths and Limitations: The use of a retrospective post-then-pre-survey helped to mitigate response shift bias while minimizing data gaps. However, it is important to note that this investigation was not a traditional research study and lacked a control group, thus limiting causal attributions. Conclusion: The True North Sexual Health and Rehabilitation eTraining program acts as an accessible and effective resource for healthcare providers seeking specialized training in providing sexual healthcare for prostate cancer patients and their partners.

Solvent Exchange Dynamics in M2(dobdc): An Interplay among Binding Strength, Exchange Kinetics, and Cooperativity.

Solvent exchange is a crucial step in ensuring the complete activation of metal-organic frameworks (MOFs); however, the conditions for solvent exchange vary among MOFs, even within the isostructural variants. This study examines the factors contributing to solvent exchange by investigating the isostructural M2(dobdc) (M═Mg, Co, Zn) series. Common solvents N,N-dimethylformamide (DMF), ethanol (EtOH), and methanol (MeOH) are employed to assess the solvent exchange at coordinatively unsaturated sites (CUS) of M2(dobdc). By monitoring both solvents released from the MOF during solvent exchange and the coordination environment of metals within the MOF, a picture is constructed of exchange rates during early stages of solvent exchange as well as expulsion of the last traces of bound solvents. This differentiation is achieved by a combination of bulk monitoring of solvent phase composition and microscopic application of Raman spectroscopy on the single-crystal level. The kinetics of solvent replacement is revealed to have a substantial contribution from cooperativity; this phenomenon is observed in both the forward and reverse directions. Thermogravimetric analysis coupled with IR spectroscopy and density functional theory (DFT) calculations are employed to elucidate the relationship between solvent exchange rates and solvent binding energy. The solvent exchange rates are determined by the kinetic barriers of solvent exchange that do not follow the order of the solvent binding affinity. This work contributes to understanding the solvent exchange of MOFs by examining the interplay among the binding strength, exchange kinetics, and cooperativity. It further provides valuable insights for scrutinizing MOF activation protocols.

In-Plane Compressive Responses of Non-Homogenous Re-Entrant Honeycombs Fabricated by Fused Deposition Modelling.

Auxetic structures, with re-entrant (inverted hexagonal or bow tie) unit cells, have received considerable interest due to their negative Poisson's ratio property that results in superior mechanical properties. This study proposes a simple method to create non-homogeneous re-entrant honeycombs by modifying the size of chevron crosslinks. The various structural designs were conceived by changing the geometrical dimensions of the crosslinks, namely the length (lcl) and the thickness (tcl), while maintaining the parameters of the re-entrant cell walls. The influence of the design parameters of chevron crosslinks on the mechanical behaviour of additively manufactured re-entrant honeycombs was investigated experimentally and numerically. The structures were fabricated using the Fused Deposition Modelling (FDM) technique from polylactic acid (PLA) plastic. In-plane quasi-static compression tests were conducted to extract the elastic, plastic, and densification properties of the structures. Furthermore, a Finite Element (FE) model was developed via LS-DYNA R11.0 software, validated experimentally, and was then used to obtain a deeper insight into the deformation behaviour and auxetic performance of various designs. The obtained results revealed that the mechanical performance of re-entrant honeycombs can only be tuned by controlling the geometrical configuration of chevron crosslinks.

Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies.

TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD-TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD-TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3-6%) of sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD-TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.

Scaling up area-based conservation to implement the Global Biodiversity Framework's 30x30 target: The role of Nature's Strongholds.

The Global Biodiversity Framework (GBF), signed in 2022 by Parties to the Convention on Biological Diversity, recognized the importance of area-based conservation, and its goals and targets specify the characteristics of protected and conserved areas (PCAs) that disproportionately contribute to biodiversity conservation. To achieve the GBF's target of conserving a global area of 30% by 2030, this Essay argues for recognizing these characteristics and scaling them up through the conservation of areas that are: extensive (typically larger than 5,000 km2); have interconnected PCAs (either physically or as part of a jurisdictional network, and frequently embedded in larger conservation landscapes); have high ecological integrity; and are effectively managed and equitably governed. These areas are presented as "Nature's Strongholds," illustrated by examples from the Congo and Amazon basins. Conserving Nature's Strongholds offers an approach to scale up initiatives to address global threats to biodiversity.

Kidney stone growth through the lens of Raman mapping.

Bulk composition of kidney stones, often analyzed with infrared spectroscopy, plays an essential role in determining the course of treatment for kidney stone disease. Though bulk analysis of kidney stones can hint at the general causes of stone formation, it is necessary to understand kidney stone microstructure to further advance potential treatments that rely on in vivo dissolution of stones rather than surgery. The utility of Raman microscopy is demonstrated for the purpose of studying kidney stone microstructure with chemical maps at ≤ 1 µm scales collected for calcium oxalate, calcium phosphate, uric acid, and struvite stones. Observed microstructures are discussed with respect to kidney stone growth and dissolution with emphasis placed on < 5 µm features that would be difficult to identify using alternative techniques including micro computed tomography. These features include thin concentric rings of calcium oxalate monohydrate within uric acid stones and increased frequency of calcium oxalate crystals within regions of elongated crystal growth in a brushite stone. We relate these observations to potential concerns of clinical significance including dissolution of uric acid by raising urine pH and the higher rates of brushite stone recurrence compared to other non-infectious kidney stones.

Non-invasive suppression of the human nucleus accumbens (NAc) with transcranial focused ultrasound (tFUS) modulates the reward network: a pilot study.

Background: The nucleus accumbens (NAc) is a key node of the brain reward circuit driving reward-related behavior. Dysregulation of NAc has been demonstrated to contribute to pathological markers of addiction in substance use disorder (SUD) making it a potential therapeutic target for brain stimulation. Transcranial focused ultrasound (tFUS) is an emerging non-invasive brain stimulation approach that can modulate deep brain regions with a high spatial resolution. However, there is currently no evidence showing how the brain activity of NAc and brain functional connectivity within the reward network neuromodulated by tFUS on the NAc. Methods: In this pilot study, we carried out a single-blind, sham-controlled clinical trial using functional magnetic resonance imaging (fMRI) to investigate the underlying mechanism of tFUS neuromodulating the reward network through NAc in ten healthy adults. Specifically, the experiment consists of a 20-min concurrent tFUS/fMRI scan and two 24-min resting-state fMRI before and after the tFUS session. Results: Firstly, our results demonstrated the feasibility and safety of 20-min tFUS on NAc. Additionally, our findings demonstrated that bilateral NAc was inhibited during tFUS on the left NAc compared to sham. Lastly, increased functional connectivity between the NAc and medial prefrontal cortex (mPFC) was observed after tFUS on the left NAc, but no changes for the sham group. Conclusion: Delivering tFUS to the NAc can modulate brain activations and functional connectivity within the reward network. These preliminary findings suggest that tFUS could be potentially a promising neuromodulation tool for the direct and non-invasive management of the NAc and shed new light on the treatment for SUD and other brain diseases that involve reward processing.

Exploring software navigation tools for liver tumour angiography: a scoping review.

INTRODUCTION: Liver cancer presents a growing global health concern, necessitating advanced approaches for intervention. This review investigates the use and effectiveness of software navigation in interventional radiology for liver tumour procedures. METHODS: In accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, a scoping review was conducted of the literature published between 2013 and 2023 sourcing articles through MEDLINE, Scopus, CINAHL and Embase. Eligible studies focused on liver cancer, utilised cone-beam computed tomography (CBCT), and employed software for intervention. Twenty-one articles were deemed eligible for data extraction and analysis. RESULTS: Categorised by type, software applications yielded diverse benefits. Feeder detection software significantly enhanced vessel identification, reducing non-target embolisation by up to 43%. Motion correction software demonstrated a 20% enhancement in image quality, effectively mitigating breathing-induced motion artefacts. Liver perfusion software facilitated efficient tumour targeting while simultaneously reducing the occurrence of side effects. Needle guide software enabled precise radiofrequency ablation needle placement. Additionally, these software applications provided detailed anatomical simulations. Overall, software integration resulted in shorter procedures, reduced radiation exposure and decreased contrast media usage. CONCLUSION: This scoping review highlights the innovative yet relatively underexplored role of software navigation for liver tumour procedures. The integration of software applications not only enhances procedural efficiency but also bolsters operator confidence, and contributes to improved patient outcomes. Despite the current lack of uniformity and standardisation, these software-driven advancements hold significant promise for transforming liver tumour interventions. To realise these benefits, further research is needed to explore the clinical impact and optimal utilisation of software navigation tools in interventional radiology.

Calcium Channel Blocker Overdose: What Role Does Extracorporeal Membrane Oxygenation Have in Support? A Systematic Review of the Literature.

Extracorporeal membrane oxygenation (ECMO) has had increasing prevalence and indications in the last decade. Calcium channel blocker overdose (CCBOD) can lead to significant cardiopulmonary dysfunction and has also increased in recent years. CCBOD results in cardiac depression, vasoplegia, and hyperglycemia. Expert consensus recommends treatment with calcium, high-dose insulin, inotropes, and vasopressors. Our systematic review evaluated when to initiate ECMO in the CCBOD population and the mortality rate associated with use. Electronic literature review identified all relevant studies for CCBOD and ECMO. PRISMA guidelines for systematic review were followed. Three independent authors reviewed abstracts and full texts, and only CCB ingestion without polypharmacy was included. Two authors independently collected data, which included demographics, current medical treatments, ECMO type, and survival. From 314 abstracts, 25 papers were included with a median publication year of 2019. Twenty-six patients were included with an average age of 32.7 years and 42%/58% male/female. Average time on ECMO 4.3 days. VA and VV ECMO use were 92.3% and 7.7%, respectively, and 84.6% of patients survived to hospital discharge. Before ECMO, most patients received 4-5 medical treatments (53.8%). Our systematic review demonstrates ECMO is a newly used, yet valuable therapy for CCBOD when medical treatment fails. Survival to discharge after ECMO for CCBOD is substantially higher than standard VV or VA ECMO. Medical management is still the mainstay therapy for CCBOD, but we show that a persistently unstable patient may benefit from prompt evaluation at an ECMO center for treatment.

Deintensification of potentially inappropriate medications amongst older frail people with type 2 diabetes: Protocol for a cluster randomised controlled trial (D-MED study).

AIMS: Amongst elderly people with type 2 diabetes (T2D) over prescribing can result in emergency ambulance call-outs, falls and fractures and increased mortality, particularly in frail patients. Current clinical guidelines, however, remain focused on medication intensification rather than deintensification where appropriate. This study aims to evaluate the effectiveness of an electronic decision-support system and training for the deintensification of potentially inappropriate medications amongst older frail people with T2D, when compared to 'usual' care at 12-months. METHODS: This study is an open-label, multi-site, two-armed pragmatic cluster-randomised trial. GP practices randomised to the 'enhanced care' group have an electronic decision support system installed and receive training on the tool and de-intensification of diabetes medications. The system flags eligible patients for possible deintensification of diabetes medications, linking the health care professional to a clinical algorithm. The primary outcome will be the number of patients at 12-months who have had potentially inappropriate diabetes medications de-intensified. RESULTS: Study recruitment commenced in June 2022. Data collection commenced in January 2023. Baseline data have been extracted from 40 practices (3145 patients). CONCLUSIONS: Digital technology, involving computer decision systems, may have the potential to reduce inappropriate medications and aid the process of de-intensification. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN53221378. Available at: https://www.isrctn.com/ISRCTN53221378.

Everything but the Kitchen Sink: An Analysis of Bacterial and Chemical Contaminants Found in Syringe Residue From People Who Inject Drugs.

Background: People who inject drugs (PWID) are at high risk of severe wounds, invasive infections, and overdoses. To date, there are few data on the bacterial and chemical contaminants PWID are exposed to when using illicitly manufactured fentanyls and stimulants. Methods: Previously used injection drug use equipment was recovered in St Louis, Missouri, by harm reduction organizations over a 12-month period. Syringe residue was analyzed for bacterial contaminants by routine culturing followed by whole genome sequencing of single bacterial isolates. Chemical adulterants in syringe residue were identified by liquid chromatography-mass spectrometry. Results: Bacteria were cultured from 58.75% of 160 syringes analyzed. Polymicrobial growth was common and was observed in 23.75% of samples. Bacillus cereus was the most common pathogen present and was observed in 20.6% of syringe residues, followed closely by Staphylococcus aureus at 18.8%. One hundred syringes underwent mass spectrometry, which demonstrated that chemical adulterants were common and included caffeine, diphenhydramine, lidocaine, quinine, and xylazine. Conclusions: Analysis of syringe residue from discarded drug use equipment demonstrates both chemical and biological contaminants, including medically important pathogens and adulterants.

Polypathologic Associations with Gray Matter Atrophy in Neurodegenerative Disease.

Mixed pathologies are common in neurodegenerative disease; however, antemortem imaging rarely captures copathologic effects on brain atrophy due to a lack of validated biomarkers for non-Alzheimer's pathologies. We leveraged a dataset comprising antemortem MRI and postmortem histopathology to assess polypathologic associations with atrophy in a clinically heterogeneous sample of 125 human dementia patients (41 female, 84 male) with T1-weighted MRI ≤ 5 years before death and postmortem ordinal ratings of amyloid-[Formula: see text], tau, TDP-43, and [Formula: see text]-synuclein. Regional volumes were related to pathology using linear mixed-effects models; approximately 25% of data were held out for testing. We contrasted a polypathologic model comprising independent factors for each proteinopathy with two alternatives: a model that attributed atrophy entirely to the protein(s) associated with the patient's primary diagnosis and a protein-agnostic model based on the sum of ordinal scores for all pathology types. Model fits were evaluated using log-likelihood and correlations between observed and fitted volume scores. Additionally, we performed exploratory analyses relating atrophy to gliosis, neuronal loss, and angiopathy. The polypathologic model provided superior fits in the training and testing datasets. Tau, TDP-43, and [Formula: see text]-synuclein burden were inversely associated with regional volumes, but amyloid-[Formula: see text] was not. Gliosis and neuronal loss explained residual variance in and mediated the effects of tau, TDP-43, and [Formula: see text]-synuclein on atrophy. Regional brain atrophy reflects not only the primary molecular pathology but also co-occurring proteinopathies; inflammatory immune responses may independently contribute to degeneration. Our findings underscore the importance of antemortem biomarkers for detecting mixed pathology.

Tau-neurodegeneration mismatch reveals vulnerability and resilience to comorbidities in Alzheimer's continuum.

INTRODUCTION: Variability in relationship of tau-based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer's disease (AD) arises from non-specific nature of N, modulated by non-AD co-pathologies, age-related changes, and resilience factors. METHODS: We used regional T-N residual patterns to partition 184 patients within the Alzheimer's continuum into data-driven groups. These were compared with groups from 159 non-AD (amyloid "negative") patients partitioned using cortical thickness, and groups in 98 patients with ante mortem MRI and post mortem tissue for measuring N and T, respectively. We applied the initial T-N residual model to classify 71 patients in an independent cohort into predefined groups. RESULTS: AD groups displayed spatial T-N mismatch patterns resembling neurodegeneration patterns in non-AD groups, similarly associated with non-AD factors and diverging cognitive outcomes. In the autopsy cohort, limbic T-N mismatch correlated with TDP-43 co-pathology. DISCUSSION: T-N mismatch may provide a personalized approach for determining non-AD factors associated with resilience/vulnerability in AD.