Postmortem Studies Research Articles

Persistence of Hyper-Ramified Microglia in Porcine Cortical Gray Matter after Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major contributor to morbidity and mortality in the United States as several million people visit the emergency department every year due to TBI exposures. Unfortunately, there is still no consensus on the pathology underlying mild TBI, the most common severity sub-type of TBI. Previous preclinical and post-mortem human studies have detailed the presence of diffuse axonal injury following TBI, suggesting that white matter pathology is the predominant pathology of diffuse brain injury. However, the inertial loading produced by TBI results in strain fields in both gray and white matter. In order to further characterize gray matter pathology in mild TBI, our lab used a pig model (n = 25) of closed-head rotational acceleration-induced TBI to evaluate blood-brain barrier disruptions, neurodegeneration, astrogliosis, and microglial reactivity in the cerebral cortex out to 1 year post-injury. Immunohistochemical staining revealed the presence of a hyper-ramified microglial phenotype-more branches, junctions, endpoints, and longer summed process length-at 30 days post injury (DPI) out to 1 year post injury in the cingulate gyrus (p < 0.05), and at acute and subacute timepoints in the inferior temporal gyrus (p < 0.05). Interestingly, we did not find neuronal loss or astroglial reactivity paired with these chronic microglia changes. However, we observed an increase in fibrinogen reactivity-a measure of blood-brain barrier disruption-predominately in the gray matter at 3 DPI (p = 0.0003) which resolved to sham levels by 7 DPI out to chronic timepoints. Future studies should employ gene expression assays, neuroimaging, and behavioral assays to elucidate the effects of these hyper-ramified microglia, particularly related to neuroplasticity and responses to potential subsequent insults. Further understanding of the brain's inflammatory activity after mild TBI will hopefully provide understanding of pathophysiology that translates to clinical treatment for TBI.

Variations of the grid and place cells in the entorhinal cortex and dentate gyrus of 6 individuals aged 56 to 87 years

IntroductionThe relationship between the entorhinal cortex (EC) and the hippocampus has been studied by different authors, who have highlighted the importance of grid cells, place cells, and the trisynaptic circuit in the processes that they regulate: the persistence of spatial, explicit, and recent memory and their possible impairment with ageing. ObjectiveWe aimed to determine whether older age causes changes in the size and number of grid cells contained in layer III of the EC and in the granular layer of the dentate gyrus (DG) of the hippocampus. MethodsWe conducted post-mortem studies of the brains of 6 individuals aged 56–87 years. The brain sections containing the DG and the adjacent EC were stained according to the Klüver-Barrera method, then the ImageJ software was used to measure the individual neuronal area, the total neuronal area, and the number of neurons contained in rectangular areas in layer III of the EC and layer II of the DG. Statistical analysis was subsequently performed. ResultsWe observed an age-related reduction in the cell population of the external pyramidal layer of the EC, and in the number of neurons in the granular layer of the DG. ConclusionOur results indicate that ageing causes a decrease in the size and density of grid cells of the EC and place cells of the DG.

In Situ Pyrolysis of 3D Printed Building Blocks for Functional Nanoscale Metamaterials

AbstractThis study presents a novel approach for investigating the shrinkage dynamics of 3D‐printed nanoarchitectures during isothermal pyrolysis, utilizing in situ electron microscopy. For the first time, the temporal evolution of 3D structures is tracked continuously until a quasi‐stationary state is reached. By subjecting the 3D objects to different temperatures and atmospheric conditions, significant changes in the resulting kinetic parameters and morphological textures of the 3D objects are observed, particularly those possessing varying surface‐to‐volume ratios. Its results reveal that the effective activation energy required for pyrolysis‐induced morphological shrinkage is approximately four times larger under vacuum conditions than in a nitrogen atmosphere (2.6 eV vs. 0.5–0.9 eV, respectively). Additionally, a subtle enrichment of oxygen on the surfaces of the structures for pyrolysis in nitrogen is found through a postmortem electron energy loss spectroscopy study, differentiating the vacuum pyrolysis. These findings are examined in the context of the underlying process parameters, and a mechanistic model is proposed. As a result, understanding and controlling pyrolysis in 3D structures of different geometrical dimensions not only enables precise modification of shrinkage and the creation of tensegrity structures, but also promotes pyrolytic carbon development with custom architectures and properties, especially in the field of carbon micro‐ and nano‐electromechanical systems.

Acute disseminated toxoplasmosis in an immunocompetent adult patient. Case report

Abstract Introduction: Toxoplasmosis is a disease of global distribution caused by the parasite Toxoplasma gondii, which develops differently depending on the immunologic status of the patient. In immunocompetent patients, it is usually asymptomatic and complications such as pneumonitis, encephalitis, or multiple organ dysfunction are rare. The following is the case of an immunocompetent patient with acute disseminated toxoplasmosis. Case report: A 42-year-old man, with no history of immunocompromise, or relevant medical, family or personal history, was transferred to the emergency department of a tertiary care institution in the city of Bogotá D.C. (Colombia) due to a fever that had lasted for a month, headache, and progressive neurological deterioration. Studies looking for other infectious etiologies, as well as for autoimmunity, neoplasms, and metabolic disorders, were negative. Computed tomography (CT) of the skull showed findings of meningoencephalitis. He was considered as a possible case of toxoplasmosis and treatment with trimethoprim/sulfamethoxazole was initiated. During his stay in the intensive care unit (ICU), he developed multiple organ dysfunction syndrome (MODS) and ultimately died. The post-mortem histopathological study of tissues reported the presence of Toxoplasma gondii bradyzoites, which confirmed the diagnosis of acute toxoplasmosis. Conclusions: Acute disseminated toxoplasmosis is a diagnostic challenge because it can mimic other etiologies. A timely diagnosis may prevent medical complications and increase the patient's chances of recovery. Knowledge about this disease in immunocompetent patients is a subject being developed.

Insights into the Neurobiology of Suicidality: Explicating the role of glutamatergic systems through the lens of ketamine.

Suicidality is a prevalent mental health condition, and managing suicidal patients is one of the most challenging tasks for healthcare professionals due to the lack of rapid-acting, effective psychopharmacological treatment options. According to the literature, suicide has neurobiological underpinnings that are not fully understood, and current treatments for suicidal tendencies have considerable limitations. To treat suicidality and prevent suicide, new treatments are required; to achieve this, the neurobiological processes underlying suicidal behaviour must be thoroughly investigated. Although multiple neurotransmitter systems, particularly serotonergic systems, have been studied in the past, less has been reported in relation to disruptions in glutamatergic neurotransmission, neuronal plasticity and neurogenesis that result from stress-related abnormalities of the hypothalamic-pituitary-adrenal (HPA) system. Informed by the literature which reports robust anti-suicidal and anti-depressive properties of subanaesthetic doses of ketamine, this review aims to provide an examination of the neurobiology of suicidality (and relevant mood disorders) with implications of pertinent animal, clinical and post-mortem studies. We discuss dysfunctions in the glutamatergic system, which may play a role in the neuropathology of suicidality and the role of ketamine in restoring synaptic connectivity at the molecular levels. This article is protected by copyright. All rights reserved.

Histopathological Diagnostic Marker for ALS: Phosphorylated Transacting Response DNA-Binding Protein of 43kDa in Intramuscular Nerve Bundles

The discovery of transacting response DNA-binding protein of 43 kDa (TDP-43) led to a deeper understanding of the pathogenesis of amyotrophic lateral sclerosis (ALS). Since this discovery, blood and cerebrospinal fluid biomarkers of ALS have been reported. However, these biomarkers do not exhibit sufficient specificity for ALS. Our case-control postmortem and retrospective muscle biopsy cohort studies revealed phosphorylated TDP-43 in intramuscular nerve bundles, which precedes the clinical fulfillment of the Gold Coast criteria. We attempted to establish a histopathological biomarker for ALS and identify molecular targets for the treatment of lower motor dysfunction in patients with ALS.

Postmortem Diagnostic Imaging to Evaluate Idiopathic Hypertrophic Cardiomyopathy in a Roborovski Hamster

Idiopathic cardiomyopathy in hamsters can cause death due to cardiac failure. The current case study investigated the capability of imaging to reveal possible cardiomyopathy in a dead hamster. To this end, the cadaver of a 6-month-old male Roborovski dwarf hamster, which showed acute respiratory symptoms a few days before its death, was examined by virtopsy to discover the cause of death. Postmortem radiography was not efficient enough to evaluate the heart due to postmortem lung atelectasis that increases lung opacity and diminishes the contrast between lung and heart. Postmortem computed tomography can be helpful for the assessment of cardiac size. Consistent with postmortem echocardiographic studies, an increased thickness of the left ventricular parietal wall and the interventricular septum and dilation of the left atrium were observed. Thus, hypertrophic cardiomyopathy was determined by imaging and confirmed by the conventional necropsy approach. It showed that the cause of death was acute cardiac failure following idiopathic hypertrophic cardiomyopathy.

Postmortem Study of Sudden Death with Special Reference to Cardiovascular Causes

Postmortem Study of Sudden Death with Special Reference to Cardiovascular Causes

ON THE ISSUE OF CHANGING THE MORPHOLOGY OF THE SPLEEN IN NEMATODOSES IN MICE DURING IMMUNOSTIMULATION

Background. The study of the reaction of the immune system organs to the introduction of immunomodulators in nematodes is relevant for the development of treatment regimens. The purpose of the study was to examine the spleen (the organ of immunogenesis that plays an important role in the formation of immunity). In addition, the aim of the study was also to find the morphological changes of nematodes (capsules of trichinella larvae) and the features of siphatiа.&#x0D; Materials and methods. In the experiment, 35 white mice were used, which were divided into 5 groups of 7 animals in each group. The first and second groups were injected with 0.004 mg saline solution subcutaneously, the 3rd and 4th groups were injected with polyoxidonium at a dose of 0.004 mg/mouse, the 1st and 3rd groups were infected with trichinella larvae, the 2nd and 4th were spontaneously affected by syphilis, the 5th group served as control. Evaluation of the protective properties of polyoxidonium in laboratory models with trichinosis was carried out by determining the intensity of invasion during postmortem studies of all muscle groups of the animal and siphations by the number of eggs in perianal scrapings.&#x0D; Results. The study showed protective efficacy with the introduction of polyoxidonium was 99.43%, 57 ± 20 trichinella larvae / per animal were detected in the entire muscle mass, while only 72% with syphaciosis. The parenchyma of the organ of the spleen is a red-white pulp, in healthy animals the area of the red pulp was 70+5% of the area of the organ, and the white pulp was 26.5+ 5% of the mass of the organ. In animals infected with nematodes, the area of the white pulp increased dramatically to 50% of the organ area or more.&#x0D; Conclusion. Significant protective activity of polyoxidonium (99.43%) was established in parasitological studies, which was accompanied by an increase in the area of lymphoid tissue associated with the intestine. When studying histological preparations of the spleen, it was noted that the restructuring of the structure under the action of trichinella and siphacia antigens is of the same type: the ratio of red and white pulp, their cellular composition changes. It was found that in all infected animals, the area of the white pulp increased dramatically by more than 60% with trichinosis and up to 50% with syphacosis of the organ area or more. The final result of this thesis was using polyoxidonium, there was also a decrease in the number of eggs in the control group and changes in the number and actual distribution of trichinella larvae in various muscle groups.

A Comparative Observational Study of Postmortem Computed Tomography and Traditional Forensic Autopsy Findings in Hanging Cases

Background: The use of advanced radiological techniques is rising in the field of forensics to supplement and validate the evidence. Postmortem Computed Tomography (PMCT) is now used as a standard procedure in many institutions to augment traditional autopsy findings. The application of PMCT in hanging cases will greatly reduce the number of invasive traditional autopsies, as hanging is the most common method of suicide in Northern parts of India. Therefore this observational study was conducted to compare PMCT with traditional autopsy in fifty hanging cases. Result: Out of 50 cases, the age of the subjects ranged between 14 years and 70 years. PMCT with the help of 3D reconstruction was able to detect external ligature marks on the neck in 92% (N=46) of cases giving a sensitivity of 92% (CI = 80.77% to 97.78%). Skin and subcutaneous tissue desiccation were identifiable in 96% (N=48) by PMCT, giving a sensitivity of 96% (CI= 86.29% to 99.51%). The muscle hemorrhage was identified in 4% (N=2) of the cases in traditional autopsy while the authors found difficulty in interpreting the muscle hemorrhage in PMCT. In detecting thyroid cartilage fracture, the sensitivity of PMCT was found to be 100% (CI= 15.81% to 100.00%) and specificity of 100% (CI=92.60% to 100.00%). In detecting hyoid bone fracture, the sensitivity was 100% (CI= 2.50% to 100.00%), and specificity of 100% (CI=92.60% to 100.00%). In addition, there was a great degree of agreement between the two observers for these findings suggesting the reproducibility of the result. Conclusions: A consistency in findings of both the PMCT and traditional autopsy was found. However, CT was unable to detect muscle hemmorhages, compared to traditional autopsy. Authors suggest the use of CT angiography to overcome this shortcoming, till then CT can only augment invasive autopsy findings not replace it

#4654 THROMBOEMBOLIC EVENTS AND THEIR RELATIONSHIP WITH COVID-19 IN HEMODIALYSIS PATIENTS: MYTH OR TRUE ?

Abstract Background and Aims Since the beginning of COVID-19 pandemic, there has been more than 668 million of diagnosis and more than 6 million deaths worldwide. This pandemic also has had a dramatic impact on chronic patients, such as those with end stage renal disease (ESRD) on hemodialysis (HD). Many studies have hypothesized that COVID-19 could induce a hypercoagulability state, activating coagulation cascade. Post-mortem studies revealed vascular injuries in more than 60% of lung tissues and many patients diagnosed with COVID-19 have suffered neurological pathologies, as ischemic stroke. Patients with ESRD are also at higher risk of thromboembolic events than healthy subjects. In this study, we analyze thromboembolic events in HD patients with or without COVID-19 diagnosis. Method We performed a retrospective observational study between March 2020 and December 2022 with 4679 HD patients (2635 COVID-19 positive patients (Group 1) and 2044 COVID-19 negative (Group 2)) from 50 Spanish clinics. The baseline dates of the non COVID-19 patients were randomly chosen. Follow-up time was 1 year since COVID-19 diagnosis (Group 1) or since selection (Group 2). We identified patients who has suffered any thromboembolic event during follow-up time. We compared usual clinical parameters between groups using Chi2 and Mann-Whitney U tests. Survival analysis was performed by Kaplan-Meier and Cox regression. Continuous variables were categorized to perform the Cox analysis. Results Small differences between Group 1 and 2 were found in age (70.45 (62-81) vs 68.94 (61-80); p&amp;lt;0.001), proportion of men (63% vs 67.2%; p&amp;lt;0.05), HD vintage (34 (14-71) vs 30 (11-65); p&amp;lt;0.05), preHD systolic blood pressure (SBP) (140.73 (126-155) vs 142.65 (128-157); p&amp;lt;0.05), plasma hemoglobin (Hb) (11.19 (10.40-11.90) vs 11.31 (10.5-12); p&amp;lt;0.05) and proportion of patients with antithrombic medication (604 (22.9%) vs 401 (19.6%); p&amp;lt;0.05). No statistically significant differences were found in time to first thromboembolic event between the two groups (Figure 1). In univariate Cox regression (Table 1) thromboembolic events showed significant relation with gender, Charlson Index above 8, preHD relative overhydration (relOH) above 13.4% and preHD SBP above 155 mmHg. In multivariate analysis (Table 1), Charlson Index and preHD SBP showed hazard ratio above 1.5 for thromboembolic event (p&amp;lt;0.05). COVID-19 diagnosis did not show relationship with thromboembolic events. Conclusion Publications on thromboembolic events in HD patients who have suffered from COVID-19 are scarce and with small size samples. In our large HD sample, thromboembolic events were not related to COVID-19. Only Charlson Index and preHD SBP showed a significant relationship in the multivariate analysis.

Familial Adult Myoclonus Epilepsy: A Non-Coding Repeat Expansion Disorder of Cerebellar-Thalamic-Cortical Loop.

Familial adult myoclonus Epilepsy (FAME) is a non-coding repeat expansion disorder that has been reported under different acronyms and initially linked to four main loci: FAME1 (8q23.3-q24.1), FAME 2 (2p11.1-q12.1), FAME3 (5p15.31-p15.1), and FAME4 (3q26.32-3q28). To date, it is known that the genetic mechanism underlying FAME consists of the expansion of similar non-coding pentanucleotide repeats, TTTCA and TTTTA, in different genes. FAME is characterized by cortical tremor and myoclonus usually manifesting within the second decade of life, and infrequent seizures by the third or fourth decade. Cortical tremor is the core feature of FAME and is considered part of a spectrum of cortical myoclonus. Neurophysiological investigations as jerk-locked back averaging (JLBA) and corticomuscular coherence analysis, giant somatosensory evoked potentials (SEPs), and the presence of long-latency reflex I (or C reflex) at rest support cortical tremor as the result of the sensorimotor cortex hyperexcitability. Furthermore, the application of transcranial magnetic stimulation (TMS) protocols in FAME patients has recently shown that inhibitory circuits are also altered within the primary somatosensory cortex and the concomitant involvement of subcortical networks. Moreover, neuroimaging studies and postmortem autoptic studies indicate cerebellar alterations and abnormal functional connectivity between the cerebellum and cerebrum in FAME. Accordingly, the pathophysiological mechanism underlying FAME has been hypothesized to reside in decreased sensorimotor cortical inhibition through dysfunction of the cerebellar-thalamic-cortical loop, secondary to primary cerebellar pathology. In this context, the non-coding pentameric expansions have been proposed to cause cerebellar damage through an RNA-mediated toxicity mechanism. The elucidation of the underlying pathological mechanisms of FAME paves the way to novel therapeutic possibilities, such as RNA-targeting treatments, possibly applicable to other neurodegenerative non-coding disorders.

Tau deposition in the locus coeruleus and depression in cognitively unimpaired older adults

AbstractBackgroundDepression is a common manifestation of Alzheimer’s disease (AD) and frequently observed at the early phase of the disease. Several postmortem studies demonstrated that tau deposition was found at the brainstem nuclei including the locus coeruleus (LC) and dossal raphe nucleus (DRN) (3, 4), even before early Braak stages of neurofibrillary tangle pathology. Given the disturbance of monoaminergic system is related to depression in general, tau deposition in the LC or DRN may underlie depression in late‐life, as suggested in a couple of postmortem studies. In this context, we tried to examine the hypothetical association between in vivo tau depostion at the brain stem monoaminergic nuclei and depression in cognitively unimpaired older adults.MethodA total of 69 cognitively unimpaired older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent comprehensive clinical assessment including the Hamilton Rating Scale for Depression (HRSD) and [18F] AV‐1451 positron emission tomography. Tau deposition in the LC and DRN was measured using the Harvard Ascending Arousal Network Atlas (AAN). Tau deposition in the pons was also assessed as a non‐monoaminergic control for comparison. Age, education, sex, and apolipoprotein E ε4 positivity were controlled as covariates in the analyses for the association between brain stem tau and HRSD score.ResultTau deposition in the LC was significantly associated with HRSD total score (β = 3.861, P = .009). In contrast, there was no significant association between tau deposition in the DRN and HRSD score (β = 2.229, P = .090). Tau deposition in the pons was also not related to HRSD score (β = 1.632, P = .207).ConclusionThe findings support the possibility that alteration of the noradrenergic neurons in the LC by tau pathology may underlie depressive manifestation in cognitively unimpaired older individuals.

Rightward lateralization of frontal cortex tau pathologies is associated with late‐onset psychosis: A PET study with 18F‐PM‐PBB3

AbstractBackgroundSeveral cohort studies have recently reported associations between late‐life psychosis and dementia, and postmortem studies have demonstrated that most individuals with late‐onset schizophrenia and delusional disorder had tau pathologies. The present study was aimed to assess the prevalence and topology of tau pathologies by positron emission tomography (PET) with a specific probe, 18F‐PM‐PBB3 (18F‐APN‐1607), in patients with late‐onset psychosis (LOP).MethodWe included LOP patients who experienced the first episode of psychosis after 65 years old and excluded those with dementia. Fourteen patients with LOC (74.2 ± 4.0 years old; 7 females and 7 males)and 16 age‐matched healthy controls (HCs) (72.6 ± 5.7 years old; 9 females and 7 males) underwent PET scans with 18F‐PM‐PBB3 and an amyloid‐β probe, 11C‐PiB. The radioprobe retention was calculated as standardized uptake value ratio (SUVR), and the laterality index (LI) of SUVR was estimated as [Left‐Right/(Left+Right)]. We compared 18F‐PM‐PBB3 SUVRs and LIs in the frontal, temporal, parietal, and occipital cortices between patients and HCs using an independent t‐test after Bonferroni correction (p‐value ≤ 0.05/4).ResultAll HCs were negative for 11C‐PiB‐PET. By contrast, unequivocally increased 18F‐PM‐PBB3 retentions were found in 4 out of 4 11C‐PiB‐positive patients (100%) and 7 out of 10 11C‐PiB‐negative patients (70%) with variable localizations. Tau topologies in four 11C‐PiB‐positive cases were characteristic of Alzheimer’s disease and consisted of limbic predominant (N = 2), medial temporal lobe‐sparing (N = 1), and lateral temporal (N = 1) deposition subtypes. Meanwhile, tau topologies in 7 11C‐PiB‐negative cases were composed of lateral‐posterior diffuse (N = 3), posterior mild (N = 2), lateral temporal local (N = 1), and progressive supranuclear palsy‐like (N = 1) accumulations. None of the target regions exhibited significant differences in 18F‐PM‐PBB3 SUVR between patients and HCs, reflecting the heterogeneous distributions of tau deposits in patients. There was significant rightward lateralization of tau pathologies indicated by a reduced LI in the frontal cortex (P = 0.0093) but not the other cortical regions.ConclusionOur findings indicate that LOP is associated with tau topologies of diverse Alzheimer’s and non‐Alzheimer’s disease subtypes. The rightward lateralization of tau pathologies in the frontal cortex might be involved in the development of psychotic manifestations.

Examining later-in-life health risks associated with sport-related concussion and repetitive head impacts: a systematic review of case-control and cohort studies

ObjectiveConcern exists about possible problems with later-in-life brain health, such as cognitive impairment, mental health problems and neurological diseases, in former athletes. We examined the future risk for adverse health...

Causes of stillbirth and death among children younger than 5 years in eastern Hararghe, Ethiopia: a population-based post-mortem study

Child mortality is high in Ethiopia, but reliable data on the causes of death are scarce. We aimed to gather data for the contributory causes of stillbirth and child deaths in eastern Ethiopia. In this population-based post-mortem study, we established a death-notification system in health facilities and in the community in Kersa (rural), Haramaya (rural) and Harar (urban) in eastern Ethiopia, at a new site of the Child Health and Mortality Prevention Surveillance (CHAMPS) network. We collected ante-mortem data, did verbal autopsies, and collected post-mortem samples via minimally invasive tissue sampling from stillbirths (weighing at least 1000 g or with an estimated gestational age of at least 28 weeks) and children who died younger than 5 years. Children-or their mothers, in the case of stillbirths and deaths in children younger than 6 months-had to have lived in the catchment area for the past 6 months to be included. Molecular, microbiological, and histopathological analyses were done in collected samples. Cause of death was established by an expert panel on the basis of these data and classified as underlying, comorbid, or immediate separately for stillbirths, neonatal deaths (deaths aged 0-27 days), and child deaths (aged 28 days to <5 years). Between Feb 4, 2019, and Feb 3, 2021, 312 deaths were eligible for inclusion, and the families gave consent in 195 (63%) cases. Cause of death was established in 193 (99%) cases. Among 114 stillbirths, the underlying cause of death was perinatal asphyxia or hypoxia in 60 (53%) and birth defects in 24 (21%). Among 59 neonatal deaths, the most common underlying cause was perinatal asphyxia or hypoxia (17 [29%]) and the most common immediate cause of death was neonatal sepsis, which occurred in 27 (60%). Among 20 deaths in children aged 28 days to 59 months, malnutrition was the leading underlying cause (15 [75%]) and infections were common immediate and comorbid causes. Pathogens were identified in 19 (95%) child deaths, most commonly Klebsiella pneumoniae and Streptococcus pneumoniae. Perinatal asphyxia or hypoxia, infections, and birth defects accounted for most stillbirths and child deaths. Most deaths could have been prevented with feasible interventions, such as improved maternity services, folate supplementation, and improved vaccine uptake. Bill & Melinda Gates Foundation.

Identification of PLOD3 and LRRN3 as potential biomarkers for Parkinson’s disease based on integrative analysis

Parkinson’s disease (PD) is one of the most prevalent movement disorders and its diagnosis relies heavily on the typical clinical manifestations in the late stages. This study aims to screen and identify biomarkers of PD for earlier intervention. We performed a differential analysis of postmortem brain transcriptome studies. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify biomarkers related to Braak stage. We found 58 genes with significantly different expression in both PD brain tissue and blood samples. PD gene signature and risk score model consisting of nine genes were constructed using least absolute shrinkage and selection operator regression (LASSO) and logistic regression. PLOD3 and LRRN3 in gene signature were identified to serve as key genes as well as potential risk factors in PD. Gene function enrichment analysis and evaluation of immune cell infiltration revealed that PLOD3 was implicated in suppression of cellular metabolic function and inflammatory cell infiltration, whereas LRRN3 exhibited an inverse trend. The cellular subpopulation expression of the PLOD3 and LRRN3 has significant distributional variability. The expression of PLOD3 was more enriched in inflammatory cell subpopulations, such as microglia, whereas LRRN3 was more enriched in neurons and oligodendrocyte progenitor cells clusters (OPC). Additionally, the expression of PLOD3 and LRRN3 in Qilu cohort was verified to be consistent with previous results. Collectively, we screened and identified the functions of PLOD3 and LRRN3 based the integrated study. The combined detection of PLOD3 and LRRN3 expression in blood samples can improve the early detection of PD.

A Role for the Serotonin Transporter in the Largely Unknown Molecular Pathophysiology of Premenstrual Dysphoric Disorder

Despite a prevalence of approximately 5% in females, premenstrual dysphoric disorder (PMDD) suffers from a lack of investigation at the neurochemical level in humans. The preferred fundamental study design in PMDD is to investigate neurobiology across the menstrual cycle, which inherently rules out direct brain tissue assays from postmortem study that are unable to be repeated in the same participant. Therefore, molecular imaging methods applicable for longitudinal designs are highly relevant for creating advances in PMDD. SEE CORRESPONDING ARTICLE ON PAGE 1081 SEE CORRESPONDING ARTICLE ON PAGE 1081 Increase in Serotonin Transporter Binding in Patients With Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand Positron Emission Tomography Imaging StudyBiological PsychiatryVol. 93Issue 12PreviewPremenstrual dysphoric disorder (PMDD) disrupts the lives of millions of people each month. The timing of symptoms suggests that hormonal fluctuations play a role in the pathogenesis. Here, we tested whether a heightened sensitivity of the serotonin system to menstrual cycle phase underlies PMDD, assessing the relationship of serotonin transporter (5-HTT) changes with symptom severity across the menstrual cycle. Full-Text PDF

Beyond the Microbiota: Understanding the Role of the Enteric Nervous System in Parkinson's Disease from Mice to Human.

The enteric nervous system (ENS) is a nerve network composed of neurons and glial cells that regulates the motor and secretory functions of the gastrointestinal (GI) tract. There is abundant evidence of mutual communication between the brain and the GI tract. Dysfunction of these connections appears to be involved in the pathophysiology of Parkinson's disease (PD). Alterations in the ENS have been shown to occur very early in PD, even before central nervous system (CNS) involvement. Post-mortem studies of PD patients have shown aggregation of α-synuclein (αS) in specific subtypes of neurons in the ENS. Subsequently, αS spreads retrogradely in the CNS through preganglionic vagal fibers to this nerve's dorsal motor nucleus (DMV) and other central nervous structures. Here, we highlight the role of the ENS in PD pathogenesis based on evidence observed in animal models and using a translational perspective. While acknowledging the putative role of the microbiome in the gut-brain axis (GBA), this review provides a comprehensive view of the ENS not only as a "second brain", but also as a window into the "first brain", a potentially crucial element in the search for new therapeutic approaches that can delay and even cure the disease.

Microanatomical organization of hepatic venous lymphatic system in humans.

Lymphatic fluid drains from the liver via the periportal lymphatic, hepatic venous lymphatic, and superficial lymphatic systems. We performed a postmortem study to clarify the three-dimensional structure and flow dynamics of the human hepatic venous lymphatic system, as it still remains unclear. Livers were excised whole from three human cadavers, injected with India ink, and sliced into 1-cm sections from which veins were harvested. The distribution of lymphatic vessels was observed in 5 μm sections immunostained for lymphatic and vascular markers (podoplanin and CD31, respectively) using light microscopy. Continuity and density of lymphatic vessel distribution were assessed in en-face whole-mount preparations of veins using stereomicroscopy. The structure of the external hepatic vein wall was assessed with scanning electron microscopy (SEM). The lymphatic dynamics study suggested that lymphatic fluid flows through an extravascular pathway around the central and sublobular veins. A lymphatic vessel network originates in the wall of sublobular veins, with a diameter greater than 110 μm, and the peripheral portions of hepatic veins and continues to the inferior vena cava. The density distribution of lymphatic vessels is smallest in the peripheral portion of the hepatic vein (0.03%) and increases to the proximal portion (0.22%, p = 0.012) and the main trunk (1.01%, p < 0.001), correlating positively with increasing hepatic vein diameter (Rs = 0.67, p < 0.001). We revealed the three-dimensional structure of the human hepatic venous lymphatic system. The results could improve the understanding of lymphatic physiology and liver pathology.