Pathological Patterns Research Articles

Tau accumulation and its spatial progression across the Alzheimer's disease spectrum.

The accumulation of tau abnormality in sporadic Alzheimer's disease is believed typically to follow neuropathologically defined Braak staging. Recent in-vivo PET evidence challenges this belief, however, as accumulation patterns for tau appear heterogeneous among individuals with varying clinical expressions of Alzheimer's disease. We, therefore, sought a better understanding of the spatial distribution of tau in the preclinical and clinical phases of sporadic Alzheimer's disease and its association with cognitive decline. Longitudinal tau-PET data (1370 scans) from 832 participants (463 cognitively unimpaired, 277 with mild cognitive impairment and 92 with Alzheimer's disease dementia) were obtained from the Alzheimer's Disease Neuroimaging Initiative. Among these, we defined thresholds of abnormal tau deposition in 70 brain regions from the Desikan atlas, and for each group of regions characteristic of Braak staging. We summed each scan's number of regions with abnormal tau deposition to form a spatial extent index. We then examined patterns of tau pathology cross-sectionally and longitudinally and assessed their heterogeneity. Finally, we compared our spatial extent index of tau uptake with a temporal meta-region of interest-a commonly used proxy of tau burden-assessing their association with cognitive scores and clinical progression. More than 80% of amyloid-beta positive participants across diagnostic groups followed typical Braak staging, both cross-sectionally and longitudinally. Within each Braak stage, however, the pattern of abnormality demonstrated significant heterogeneity such that the overlap of abnormal regions across participants averaged less than 50%, particularly in persons with mild cognitive impairment. Accumulation of tau progressed more rapidly among cognitively unimpaired and participants with mild cognitive impairment (1.2 newly abnormal regions per year) compared to participants with Alzheimer's disease dementia (less than 1 newly abnormal region per year). Comparing the association of tau pathology and cognitive performance our spatial extent index was superior to the temporal meta-region of interest for identifying associations with memory in cognitively unimpaired individuals and explained more variance for measures of executive function in patients with mild cognitive impairments and Alzheimer's disease dementia. Thus, while participants broadly followed Braak stages, significant individual regional heterogeneity of tau binding was observed at each clinical stage. Progression of the spatial extent of tau pathology appears to be fastest in cognitively unimpaired and persons with mild cognitive impairment. Exploring the spatial distribution of tau deposits throughout the entire brain may uncover further pathological variations and their correlation with cognitive impairments.

Trends in keratoplasty from central and Northern India. Part I: Indications for keratoplasty.

To report the indications for keratoplasty and analyze trends in two decades in India. This was a retrospective review of eye bank registries of six tertiary eye care centers located in central and northern India from 2005 to 2021. The patterns of corneal pathology and changes in trends were analyzed. Between 2005 and 2021, 13223 corneal grafts were performed in the six collaborating tertiary eye care centers. The most common indication for keratoplasty in both decades was corneal ulcer (41.1%), followed by corneal scar (25.5%), failed graft (12.0%), post-cataract surgery corneal edema (11.7%), corneal dystrophies (3.1%), corneal ectasia (1.8%), corneal trauma (0.3%), congenital corneal opacity (0.3%), and others (4.1%). An increasing trend was seen in corneal ulcers, failed grafts, and keratoconus. A reducing trend was seen in corneal scar and aphakic bullous keratopathy. There was no change in pseudophakic bullous keratopathy and Fuchs endothelial corneal dystrophy. Corneal ulcers, corneal scars, failed grafts, and post-cataract surgery corneal edema remained the foremost indications for keratoplasty in two decades in India. An increasing trend was seen in corneal ulcers and failed grafts which are of concern as these indications carry a poorer outcome. Capacity building in lamellar keratoplasty techniques is the need of the hour as pseudophakic bullous keratopathy was an important indication, and an increasing trend was noticed in keratoconus.

An Overview of Mathematical Methods Applied in the Biomechanics of Foot and Ankle–Foot Orthosis Models

Ankle–foot orthoses (AFOs) constitute medical instruments designed for patients exhibiting pathological gait patterns, notably stemming from conditions such as stroke, with the primary objective of providing support and facilitating rehabilitation. The present research endeavors to conduct a comprehensive review of extant scholarly literature focusing on mathematical techniques employed for the examination of AFO models. The overarching aim is to gain deeper insights into the biomechanical intricacies underlying these ankle–foot orthosis models from a mathematical perspective, while concurrently aiming to advance novel models within the domain. Utilizing a specified set of keywords and their configurations, a systematic search was conducted across notable academic databases, including ISI Web of Knowledge, Google Scholar, Scopus, and PubMed. Subsequently, a total of 23 articles were meticulously selected for in-depth review. These scholarly contributions collectively shed light on the utilization of nonlinear optimization techniques within the context of ankle–foot orthoses (AFOs), specifically within the framework of fully Cartesian coordinates, encompassing both kinematic and dynamic dimensions. Furthermore, an exploration of a two-degree-of-freedom AFO design tailored for robotic rehabilitation, which takes into account the interplay between foot and orthosis models, is delineated. Notably, the review article underscores the incorporation of shape memory alloy (SMA) elements in AFOs and overviews the constitutive elastic, viscoelastic, and hyperelastic models. This comprehensive synthesis of research findings stands to provide valuable insights for orthotists and engineers, enabling them to gain a mathematical understanding of the biomechanical principles underpinning AFO models and fostering the development of innovative AFO designs.

The diagnosis and treatment of Criss-Cross injury of the forearm: A retrospective analysis

BackgroundDue to the paucity of ‘Criss-Cross’ injury, the pathological changes and injury patterns have not been clearly described; as well as the treatment and prognosis. This retrospective study aimed to investigate the treatment and clinical outcomes of ‘Criss-Cross’ injury of the forearm. MethodsAll patients diagnosed with Criss-Cross injury meeting the inclusion and exclusion criteria in our Level 3 hospital (most advanced level) from 2010 to 2022, were enrolled in the study. A total of 12 patients were enrolled in our retrospective analysis. Closed reduction was successful in 3 patients, open reduction performed in the remaining patients. 6 patients associated with a fracture, while 2 cases had a concomitant convergent elbow dislocation. The follow-up time in conservative patients was 23.0 months on average (3–51 months), while 38.4 months in surgery group on average (3–108 months). The forearm function was evaluated with the Anderson's forearm function score. The range of motion (ROM) of the elbow and wrist and forearm rotation including any complications was also documented during the follow-up. ResultsOn final follow-up, ROM of the elbow, wrist, and forearm rotation significantly improved after conservative treatment (50.0 ± 24.5° to 128.3 ± 2.9°, 55.0 ± 7.1° to 166.7 ± 5.8°, 83.3 ± 20.8° to 165.0 ± 15.0°, respectively, p < 0.001) and surgical treatment (41.7 ± 22.4° to 102.8 ± 21.1°, 42.2 ± 16.4° to 125.6 ± 25.1°, 34.4 ± 26.5° to 138.3 ± 22.6°, respectively, p < 0.001). However, compared with the contralateral side, there were still significant difference regarding the ROM of the elbow (102.8 ± 21.1° to 143.9 ± 4.9°), wrist (125.6 ± 25.1° to 167.8 ± 5.1°), and forearm rotation (138.3 ± 22.6° to 163.3 ± 3.5°) after surgical treatment (P < 0.01). Anderson's Forearm Function Score was excellent in all conservative cases and 2 of 9 patients treated with operation. 2 patients complained about occasional elbow locking, wrist pain and reduced power after conservative treatment. 2 patients reported ulnar neuritis after the operation, one of which was treated with anterior transposition of the ulnar nerve. ConclusionThe Criss-Cross injury could be associated with different fractures and/or simultaneous convergent elbow dislocation. The basic principle of treatment is to reduce both PRUJ and DRUJ by closed reduction or surgery, with early rehabilitation. Most of the patients regained good forearm function after receiving either conservative or surgical treatment.

Chinese expert consensus on multidisciplinary discussion of interstitial lung disease

Interstitial lung disease (ILD) is a group of heterogeneous diseases characterized by interstitial lung inflammation and fibrosis. Its causes are diverse, symptoms can be non-specific, and the associated imaging and pathologic patterns can vary widely. The diagnosis and management of these conditions often require input from multiple medical disciplines. Over the past few decades, the importance of multidisciplinary discussion (MDD) in the management of ILD has grown internationally, and MDD has gradually become a part of the gold standard for ILD diagnosis and an essential reference for disease management. Recognizing this, the Chinese Medical Association-Chinese Thoracic Society and the Chinese Association of Chest Physicians have collaborated with experts to standardize the ILD-MDD process in China.Key recommendations:1. Formation of teams: ILD centers should establish multidisciplinary teams (MDT) and integrate MDD into the ILD patient care process. (strong recommendation)2. Patient preparation: Prior to ILD-MDD, patients should undergo as thorough an ILD assessment as possible, including medical history, diagnostic tests, and functional evaluations. (strong recommendation)3. MDD frequency & logistics:(1) The frequency, duration and number of cases to be discussed in ILD-MDD should be based on the clinical needs of each center, but should be held at least monthly. (2) Consistent timing and location of ILD-MDD is recommended to improve attendance. (medium recommendation)4. Team composition: The MDT should include experts from a range of disciplines with experience of ILD. These should include specialists in Pulmonary and Critical Care Medicine, Radiology, and Pathology. Where appropriate, experts in Rheumatology, Hematology, Thoracic Surgery, and Respiratory Care and Rehabilitation should also be involved. (strong recommendation)5. Case presentation & goals:(1) The physician in charge should present clinical information, preferably using standardized slides. Real-time imaging and pathology data are encouraged. (2) The primary goals of ILD-MDD discussions should be disease diagnosis and management. (strong recommendation)6. Operational leadership: Assign a dedicated professional to manage the ILD-MDD operations and maintain the information discussed. (strong recommendation)7. Specific conditions:(1) Suspected idiopathic pulmonary fibrosis should be diagnosed by a standardized MDD process. (2) Suspected idiopathic interstitial pneumonia (IIP) should be classified by MDD. If IIP is indicated by imaging or pathology, prioritize identifying potential underlying causes such as connective tissue diseases (CTDs), certain medications, or aspiration.(3) Suspected hypersensitivity pneumonitis should also be diagnosed by MDD. (4) If an ILD patient shows signs suggestive of CTDs, the diagnosis should be made by ILD-MDD with the involvement of rheumatologists. (strong recommendation)8. Unclassifiable ILD: For ILD patients who cannot be clearly classified, create a tailored management plan based on the patient's specific disease features. (strong recommendation)9. Progressive pulmonary fibrosis: Use ILD-MDD to determine whether an ILD patient meets the criteria for progressive pulmonary fibrosis and to discuss a personalized care plan. (strong recommendation).

Childhood Obesity: Insight into Kidney Involvement.

This review examines the impact of childhood obesity on the kidney from an epidemiological, pathogenetic, clinical, and pathological perspective, with the aim of providing pediatricians and nephrologists with the most current data on this topic. The prevalence of childhood obesity and chronic kidney disease (CKD) is steadily increasing worldwide, reaching epidemic proportions. While the impact of obesity in children with CKD is less pronounced than in adults, recent studies suggest a similar trend in the child population. This is likely due to the significant association between obesity and the two leading causes of end-stage renal disease (ESRD): diabetes mellitus (DM) and hypertension. Obesity is a complex, systemic disease that reflects interactions between environmental and genetic factors. A key mechanism of kidney damage is related to metabolic syndrome and insulin resistance. Therefore, we can speculate about an adipose tissue-kidney axis in which neurohormonal and immunological mechanisms exacerbate complications resulting from obesity. Adipose tissue, now recognized as an endocrine organ, secretes cytokines called adipokines that may induce adaptive or maladaptive responses in renal cells, leading to kidney fibrosis. The impact of obesity on kidney transplant-related outcomes for both donors and recipients is also significant, making stringent preventive measures critical in the pre- and post-transplant phases. The challenge lies in identifying renal involvement as early as possible, as it is often completely asymptomatic and not detectable through common markers of kidney function. Ongoing research into innovative technologies, such as proteomics and metabolomics, aims to identify new biomarkers and is constantly evolving. Many aspects of pediatric disease progression in the population of children with obesity still require clarification. However, the latest scientific evidence in the field of nephrology offers glimpses into various new perspectives, such as genetic factors, comorbidities, and novel biomarkers. Investigating these aspects early could potentially improve the prognosis of these young patients through new diagnostic and therapeutic strategies. Hence, the aim of this review is to provide a comprehensive exploration of the pathogenetic mechanisms and prevalent pathological patterns of kidney damage observed in children with obesity.

DrasCLR: A self-supervised framework of learning disease-related and anatomy-specific representation for 3D lung CT images

Large-scale volumetric medical images with annotation are rare, costly, and time prohibitive to acquire. Self-supervised learning (SSL) offers a promising pre-training and feature extraction solution for many downstream tasks, as it only uses unlabeled data. Recently, SSL methods based on instance discrimination have gained popularity in the medical imaging domain. However, SSL pre-trained encoders may use many clues in the image to discriminate an instance that are not necessarily disease-related. Moreover, pathological patterns are often subtle and heterogeneous, requiring the ability of the desired method to represent anatomy-specific features that are sensitive to abnormal changes in different body parts. In this work, we present a novel SSL framework, named DrasCLR, for 3D lung CT images to overcome these challenges. We propose two domain-specific contrastive learning strategies: one aims to capture subtle disease patterns inside a local anatomical region, and the other aims to represent severe disease patterns that span larger regions. We formulate the encoder using conditional hyper-parameterized network, in which the parameters are dependant on the anatomical location, to extract anatomically sensitive features. Extensive experiments on large-scale datasets of lung CT scans show that our method improves the performance of many downstream prediction and segmentation tasks. The patient-level representation improves the performance of the patient survival prediction task. We show how our method can detect emphysema subtypes via dense prediction. We demonstrate that fine-tuning the pre-trained model can significantly reduce annotation efforts without sacrificing emphysema detection accuracy. Our ablation study highlights the importance of incorporating anatomical context into the SSL framework. Our codes are available at https://github.com/batmanlab/DrasCLR.

Affection of Motor Network Regions by Tau Pathology Across the Alzheimer's Disease Spectrum.

Stereotypical isocortical tau protein pathology along the Braak stages has been described as an instigator of neurodegeneration in Alzheimer's disease (AD). Less is known about tau pathology in motor regions, although higher-order motor deficits such as praxis dysfunction are part of the clinical description. Here, we examined how tau pathology in cytoarchitectonically mapped regions of the primary and higher-order motor network in comparison to primary visual and sensory regions varies across the clinical spectrum of AD. We analyzed tau PET scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort in patients with mild cognitive impairment (MCI; N = 84) and dementia of the Alzheimer's disease type (DAD; N = 25). Additionally, an amyloid-negative sample of healthy older individuals (HC; N = 26) were included. Standard uptake ratio values (SUVRs) were extracted in native space from the left and the right hemispheres. A repeated measurement analysis of variance was conducted to assess the effect of diagnostic disease category on tau pathology in the individual motor regions, controlling for age. We observed that tau pathology varies as a function of diagnostic category in predominantly higher motor regions (i.e., supplementary motor area, superior parietal lobe, angular gyrus, and dorsal premotor cortex) compared to primary visual, sensory and motor regions. Indeed, tau in higher-order motor regions was significantly associated with decline in cognitive function. Together, these results expand our knowledge on the in vivo pattern of tau pathology in AD and suggest that higher motor regions are not spared from tau aggregation in the course of disease, potentially contributing to the symptomatic appearance of the disease.

Subtypes of exercise are differentially associated with baseline eating disorder pathology and treatment outcome among individuals with bulimia nervosa.

Individuals with bulimia nervosa (BN) engage in both maladaptive (i.e., compulsive and/or compensatory) and adaptive exercise (e.g., for enjoyment). No research has examined whether those who engage in adaptive, compulsive, and/or compensatory exercise exhibit differences in BN pathology or treatment outcome compared to those not engaging in exercise, limiting intervention efficacy. We examined associations of baseline exercise engagement with baseline and posttreatment BN pathology among 106 treatment-seeking adults (Mage = 37.4, SDage = 12.95, 87.74% female, 68.87% White) enrolled across four clinical trials of outpatient enhanced cognitive behavioral therapy for BN (range: 12-16 sessions). Analysis of covariances examined associations between baseline exercise type and baseline/posttreatment global eating pathology, dietary restraint, loss-of-control (LOC) eating, and purging frequency. Those engaging in only adaptive exercise reported lower global eating pathology compared to those engaging in compulsive-only exercise (Est = -1.493, p = .014, Mdiff = -.97) while those engaging in baseline compulsive exercise reported less LOC eating compared to those not engaging in exercise (Est = -22.42, p = .012, Mdiff = -12.50). Baseline engagement in compulsive-only exercise was associated with lower posttreatment global eating pathology compared to baseline engagement in no exercise (Est = -.856, p = .023, Mdiff = -.64) and both compulsive and compensatory exercise (Est = .895, p = .026, Mdiff = -1.08). Those engaging in compulsive, compensatory, adaptive, and no exercise exhibit different patterns and severity of BN pathology. Future research is needed to position treatments to intervene on maladaptive, while still promoting adaptive, exercise. No research to date has examined whether those who engage in adaptive, compulsive, and/or compensatory exercise exhibit differences in BN pathology or treatment outcome compared to those not engaging in exercise, limiting targeted intervention efforts. We found that those engaging in compulsive, compensatory, and adaptive exercise exhibit different patterns of BN pathology and that adaptive exercise engagement was related to lower cognitive eating disorder symptoms at baseline.

Novel data-driven subtypes and stages of brain atrophy in the ALS–FTD spectrum

BackgroundTDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS–FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS–FTD spectrum.MethodsWe used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS–FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS–FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease.ResultsSuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS–FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King’s stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology.ConclusionsOur findings suggest distinct neurodegenerative subtypes of disease along the ALS–FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.

Uniform granular pigmentation as a novel dermoscopic feature of drug reaction

Objective: In clinical practice, black-brown-gray pigment granules are common under dermoscopy. However, little is known about their clinical significance. We conducted this study to investigate the dermoscopy features of drug reaction. Methods: We searched the clinical database in Xiangya Hospital, Central South University from August 2017 to August 2022. Patients with full information on pigment granules and demographic and pathological findings were entered into the final analysis. Cases were reviewed for information regarding pathological and dermoscopic patterns. Fisher’s exact test was used to examine the correlation between individual histologic variables and established diagnoses. The depth of pigment granules showed a non-normal distribution and was analyzed using a nonparametric test. Results: In total, 83 patients were included in this analysis. The presence of pigment granules under dermoscopy significantly indicated destruction of basal cells or pigment incontinence (91.5%, 76/83). The pigment granules within lesions were divided into uniform and nonuniform patterns with respect to their size, color, and distribution. Uniform granular pigmentation was more likely to be associated with eosinophils (numerous or in aggregates, P&lt;0.001) or perifollicular inflammatory infiltration in the dermis (P=0.008). Notably, uniform granular pigmentation was more likely to be induced by medications. Conclusion: Uniform granular pigmentation under dermoscopy is a novel indicator of a drug reaction and necessitates a detailed inquiry.

A CLINICOPATHOLOGICAL STUDY OF LESIONS OF BONE

Objective: The objective is to study the clinico-pathological diagnosis of bone lesions. Methods: The present study was a prospective and observational (non-interventional) type of study. A total of 100 patients from March 2012 to April 2013 were recruited. All excised bone specimens received in the Department of Pathology, SBKS MI and RC, Pipariya, constituted the study material. The specimens were subjected to a detailed histopathological examination. In each case, the pathological reaction pattern was studied carefully and documented. Results: The total number of cases studied was one hundred, of which 63 were males and 37 were females in the age group of 3 years–65 years. The most common presenting symptoms were pain and swelling in all bone lesions. Out of 100 cases, non-neoplastic cases were 54% and neoplastic cases were 46%. Among 46% of neoplastic lesions, we found that 30% were benign and 16% were malignant. Among non-neoplastic lesions, 14% were tumor-like lesions, 13% were non-specific osteomyelitis, 12% were tuberculosis inflammation, and 15% were avascular necrosis. The most common benign lesion was a giant cell tumor (17%). The most common malignant lesion was osteosarcoma (6%). The most common tumor-like lesion was fibrous dysplasia (9%). The majority of bone tumors were located in the epiphysis of long bones. Conclusion: Light microscopy or histopathological examination is the gold standard in the diagnosis of bone lesions and is invariably accurate when correlated with clinico-radiological features.

Examining the overlap between patterns of tau deposition and cortical neurite microstructure in preclinical Alzheimer’s disease

AbstractBackgroundIncreased Amyloid‐beta (Aβ) is associated with the neuropathological features of Alzheimer’s disease (AD), and it has been suggested to amplify tau spreading in the brain that leads to neurodegeneration. However, little is known about how the pattern of tau spreading overlaps with that of cortical microstructural neurodegeneration in the preclinical stages of the disease. Here, we utilized molecular imaging and neurite orientation dispersion and density imaging (NODDI) to identify the spreading pattern of tau pathology with the disease progression in cross‐sectional data and interaction with the degradation of cortical neurite microstructures.MethodsThe study consisted of normal controls (CN) and patients with mild cognitive impairments (MCI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Table 1). All participants had structural and multi‐shell diffusion magnetic resonance imaging (MRI), and positron emission tomography (PET) scans using 18F‐florbetapir (AV45) for and 18F‐flortaucipir (AV1451) for tau. The preprocessed PET images were used to generate the standardized uptake value ratio (SUVR) values in each hemisphere consisting of 180 cerebral cortical brain regions defined by the Glasser atlas. The preprocessed dMRI data were used to compute cortical NODDI coefficients (neurite density (intracellular volume fraction; ICVF), orientation dispersion index (ODI), and isotropic volume fraction (FISO)). The tau and NODDI microstructural values are then normalized compared to the Aβ− CN group by adjusting the values for age and sex. The tau spreading order was defined based on the frequencies of the normalized tau values that exceeded the given threshold and compared the patterns with the neurite microstructures.ResultsWe found a sharp increase of tau deposition in patients with Aβ+ MCI, and the medial temporal regions were identified as the earliest region to become tau positive and continue to spread to inferior temporal and inferior parietal regions. Most importantly, we found significant patterns of cortical ODI degradation with the tau spreading in the right entorhinal cortex (p = 0.004) and the right hippocampus (p = 0.02).ConclusionThe findings of this cross‐sectional study provide that regional cortical neurite imaging could provide higher sensitivity to changes in the pathological process of tau spreading in tau epicenters in AD.

Anatomical characterization of pT217‐tau in aged rhesus macaque association cortices: Relevance for trans‐synaptic propagation in sporadic Alzheimer’s Disease

AbstractBackgroundTau pathology in Alzheimer’s Disease (AD) targets higher cortical circuits, with evidence that phosphorylated tau propagates from the entorhinal cortex (ERC) to “seed” pathology throughout the neuronal network affecting the dorsolateral prefrontal cortex (dlPFC) with advanced neurodegeneration. Recent discoveries indicate that phosphorylated tau (pT217‐tau) can be captured in CSF and plasma as an early biomarker of ensuing disease. However, the role of pT217‐tau in brain tau pathology is unknown, especially as soluble tau species are dephosphorylated postmortem in humans. Rhesus macaques naturally develop the same qualitative pattern and sequence of tau and amyloid pathology, with neurofibrillary tangles comprised of paired helical filaments, identical to human AD. Perfusion fixed monkey tissue preserves phosphorylation state and allows imaging of molecular location and interactions with nanometer resolution not possible in humans due to postmortem degradation. The current study examined the ultrastructural localization of pT217‐tau in ERC and dlPFC of the aged rhesus macaques, focusing on potential evidence of propagation between neurons, and exposure to the extracellular space.MethodWe used immunohistochemistry paired with high spatial‐resolution immunoelectron microscopy (immunoEM) in aged rhesus macaques (18‐33 years) to localize pT217‐tau in ERC layer II, which show the earliest signatures of tau pathology in AD and dlPFC layer III critical for working memory.ResultpT217‐tau immunolabeling was predominantly observed in postsynaptic compartments and accumulated on the calcium‐storing smooth endoplasmic reticulum spine apparatus near axospinous asymmetric glutamatergic synapses in dendritic spines. We observed extensive, trans‐synaptic pT217‐tau trafficking between interconnected neurons within omega‐shaped bodies and endosomes, specifically near excitatory, but not inhibitory synapses. Within dendritic shafts, pT217‐tau aggregated on microtubules often in concordance with autophagic vacuoles indicative of neurite dystrophy.ConclusionpT217‐tau accumulates in ERC and dlPFC subcompartments known to be the earliest to show pathology in humans. The data provide the first evidence of pT217‐tau trafficking between neurons to “seed” tau pathology in higher brain circuits, potentially interfacing with the extracellular space to become readily accessible and captured in CSF and blood as a robust AD biomarker. Illuminating patterns of neurodegeneration with pT217‐tau could potentially guide earlier intervention of therapeutics that might mitigate tau hyperphosphorylation in AD.

Domain‐specific cognitive decline associates with differential regional tau burden in the Alzheimer’s disease spectrum

AbstractBackgroundPatients presenting with distinct clinical variants of Alzheimer’s disease (AD) present differential patterns of tau pathology measured with positron emission tomography (PET). Yet, a single set of brain regions like a temporal meta‐ROI is often chosen to study the association between cognition and tau. Instead, we aimed to map the associations between regional tau and multiple cognitive domains, and to test whether using whole brain information yields stronger associations with cognition compared to a singular composite region.MethodWe included 372 amyloid‐positive ADNI participants that had at least one tau‐PET scan (163 cognitively unimpaired [CU], 132 with mild cognitive impairment [MCI], 77 with AD dementia). Composite cognitive scores for memory, executive functioning, visuospatial and language were used for cross‐sectional (closest score to tau‐PET) and longitudinal analyses. Individual rate of cognitive decline was computed using linear mixed effect models, leveraging all visits available for each participant. We did region‐wise analyses, relating tau in the 64 regions of the Desikan‐Killiany atlas plus the amygdalae with cognitive performance and rate of cognitive decline. We also derived a “spatial extent index” where we computed the number of abnormal tau regions and compared the performance of this index to detect cognitive impairment to what would have been found with a classical temporal meta‐ROI SUVR value.ResultNo regional association between tau and cognition survived FDR correction in CU participants. Cross‐sectionally and longitudinally, participants with MCI and with AD dementia, associations between tau and memory were predominant in the temporal lobe, associations with language were restricted mostly to the left hemisphere and associations with executive functioning spanned the entire cortex. (Fig 1) Comparing the sum of tau positive regions (spatial extent index) to tau SUVR in the temporal meta‐ROI, both measures were similarly associated with cognition, except for executive functioning at baseline where the spatial extent index was more strongly associated with cognition than the meta‐ROI. (Fig 2)ConclusionWhile temporal meta‐ROI tau SUVR may be sufficient to track non‐executive cognitive performance in individual with cognitive impairments, a whole brain measure may provide additional information regarding executive impairment occurring in AD.

Domain‐specific cognitive decline associates with differential regional tau burden in the Alzheimer’s disease spectrum

AbstractBackgroundPatients presenting with distinct clinical variants of Alzheimer’s disease (AD) present differential patterns of tau pathology measured with positron emission tomography (PET). Yet, a single set of brain regions like a temporal meta‐ROI is often chosen to study the association between cognition and tau. Instead, we aimed to map the associations between regional tau and multiple cognitive domains, and to test whether using whole brain information yields stronger associations with cognition compared to a singular composite region.MethodWe included 372 amyloid‐positive ADNI participants that had at least one tau‐PET scan (163 cognitively unimpaired [CU], 132 with mild cognitive impairment [MCI], 77 with AD dementia). Composite cognitive scores for memory, executive functioning, visuospatial and language were used for cross‐sectional (closest score to tau‐PET) and longitudinal analyses. Individual rate of cognitive decline was computed using linear mixed effect models, leveraging all visits available for each participant. We did region‐wise analyses, relating tau in the 64 regions of the Desikan‐Killiany atlas plus the amygdalae with cognitive performance and rate of cognitive decline. We also derived a “spatial extent index” where we computed the number of abnormal tau regions and compared the performance of this index to detect cognitive impairment to what would have been found with a classical temporal meta‐ROI SUVR value.ResultNo regional association between tau and cognition survived FDR correction in CU participants. Cross‐sectionally and longitudinally, participants with MCI and with AD dementia, associations between tau and memory were predominant in the temporal lobe, associations with language were restricted mostly to the left hemisphere and associations with executive functioning spanned the entire cortex. (Fig 1) Comparing the sum of tau positive regions (spatial extent index) to tau SUVR in the temporal meta‐ROI, both measures were similarly associated with cognition, except for executive functioning at baseline where the spatial extent index was more strongly associated with cognition than the meta‐ROI. (Fig 2)ConclusionWhile temporal meta‐ROI tau SUVR may be sufficient to track non‐executive cognitive performance in individual with cognitive impairments, a whole brain measure may provide additional information regarding executive impairment occurring in AD.

Fibrosis in burns: an overview of mechanisms and therapies.

Scar development remains a common occurrence and a major healthcare challenge affecting the lives of millions of patients annually. Severe injuries to the skin, such as burns can lead to pathological wound healing patterns, often characterized by dermal fibrosis or excessive scarring, and chronic inflammation. The two most common forms of fibrotic diseases following burn trauma are hypertrophic scars (HSCs) and keloids, which severely impact the patient's quality of life. Although the cellular and molecular mechanisms are similar, HSC and keloids have several distinct differences. In this review, we discuss the different forms of fibrosis that occur postburn injury, emphasizing how the extent of burn influences scar development. Moreover, we highlight how a systemic response induced by a burn injury drives wound fibrosis, including both the role of the inflammatory response, as well as the fate of fibroblast during skin healing. Finally, we list potential therapeutics aimed at alleviating pathological scar formation. An understanding of the mechanisms of postburn fibrosis will allow us to effectively move studies from bench to bedside.

Survival impact of pathological shrinkage patterns of pancreatic ductal adenocarcinoma after neoadjuvant chemotherapy.

Survival impact of pathological shrinkage patterns of pancreatic ductal adenocarcinoma after neoadjuvant chemotherapy.

Outbreak of tauopathy in the olfactory system of PS19 mice: an early marker for Alzheimer’s disease diagnosis?

AbstractBackgroundClinical data indicate that impairment of olfactory function is an early indicator of neurodegenerative diseases, including Alzheimer’s disease (AD)(Attems et al., 2014). Our hypothesis is that typical AD lesions could appear in olfactory neurons from the olfactory epithelium (OE). The olfactory epithelium can be easily collected in human individuals (e.g., by nasal brushing), which provides an important tool to investigate the pathology in patients. Here, we address the question of the occurrence of tauopathy in the OE of transgenic mice and its correlation with pathology in the central nervous system (CNS). We use Tau P301S mice (PS19 mice), a tauopathy mouse model. These mice express human tau protein (1N4R) carrying the P301S mutation. They develop neurofibrillary tangle‐like inclusions in the cortex and hippocampus, leading to progressive neurodegeneration at eight months (Yoshiyama et al., 2007).MethodMouse samples were collected from heterozygous PS19 and wild‐type (WT) mice. Immunohistochemical staining (DAB) was used to demonstrate the presence of hyperphosphorylated human tau protein (hTau). We investigated regions of the olfactory system to correlate with data obtained in CNS regions (e.g., hippocampal formation, entorhinal cortex). Mouse heads decalcification was also implemented to preserve the olfactory epithelium structure. Western blots were performed to monitor tau levels and tau phosphorylation pattern.ResultThe hyperphosphorylated human tau protein (Ser202, Thr205) is only detected in PS19 mice sections while the endogenous murine tau protein is expressed both in WT and PS19 mice. The localization and expression of these proteins vary according to the region (OE or CNS subregions), the age (3, 6 or 9 months), and the genotype of the mice (WT or heterozygous PS19). It also seems that tau lesions may spread between brain regions that are directly connected, notably through the olfactory pathway.ConclusionIn PS19 mice, a pathological phosphorylation pattern peaked in the OE prior to vulnerable CNS regions or olfactory bulbs. We hypothesize that tau lesions appearing early in the OE may spread in the olfactory bulb and finally reach the entorhinal cortex and piriform cortex, highlighting the significance of the olfactory system investigation as an early diagnosis tool.

AD Biological Domains—an evolving computational resource for big data classification in AD from the TREAT‐AD Consortium

AbstractBackgroundAlzheimer’s disease (AD) is a highly heterogenous disease with a multitude of subtypes and interacting biological systems emerging in a complex pattern of pathology, neurodegeneration and cognitive decline. In order to help organize large scale data analysis in AD in an unbiased manner, we developed a computational model of endophenotypes associated with AD. We call these models the AD Biological Domains.MethodThe Common Alzheimer’s Disease Research Ontology (CADRO) was leveraged in association with literature mining to identify 19 parent endophenotypes that are largely sufficient to cover AD related pathology. These endophenotypes are instantiated as large sets of manually curated gene ontology (GO) terms and linked genes. This framework enables researchers to unambiguously move from an identified gene to a larger disease‐associated biological phenotype.ResultWe defined 19 biological domains in terms of constitutive sets of GO terms. A gene‐set enrichment analysis has confirmed that these 19 biological domains cover almost all AD‐enriched GO terms, barring those that fall outside the reach of the biological domains due to lack of specificity in biological implication. The size of the biological domains ranges from over a thousand GO terms for ‘Proteostasis’ and ‘Synapse’, and just over a dozen for the terms ‘APP Metabolism’ and ‘Tau homeostasis’. There is a low level of cross‐domain utilization of common GO terms, as the biological domains are effectively siloed in their definition, however, at the level of gene annotation we see high levels of promiscuity across domains, potentially providing a molecular trail to find interdependencies between domains. These biological domains are currently being used across several NIA‐funded consortia, including TREAT‐AD, AMP‐AD, MODEL‐AD, and have been adopted by partnered resources such as the AD‐Atlas and Agora. The full list of biological domains and associated GO terms and genes are openly accessible through the AD Knowledge Portal.ConclusionThe biological domains are an open resource designed to provide a community driven definition of discrete areas of AD biology, allowing AD investigators to utilize a standard set of computationally accessible resources to define emerging transcriptomic and proteomic datasets in a unified manner, making cross study comparisons more informative.