Early Pathological Changes Research Articles

Lipid-related protein NECTIN2 is an important marker in the progression of carotid atherosclerosis: An intersection of clinical and basic studies.

ABSTRACTBackground:The nectin cell adhesion molecule 2 (NECTIN2) protein is a cell adhesion molecule involved in lipid metabolism. We aimed to explore the potential role of NECTIN2 in carotid atherosclerosis (CA).Materials and Methods:Patients who underwent carotid endarterectomy (CEA) at the First Affiliated Hospital of Zhengzhou University were enrolled in this study. APOE-/- rats fed western or normal diet were used to model early pathological changes in CA. The relationship between patients’ lipid indices and plaque severity was assessed using ordinal regression analysis. Mendelian randomisation (MR) analysis was used to determine the causal links between low-density lipoprotein cholesterol (LDL-C) and atherosclerosis. After matching analysis of the single-cell transcriptome and microarray data of carotid plaques, NECTIN2 was identified as a key factor affecting CA. The importance of NECTIN2 was further verified by immunofluorescence staining of CEA and APOE-/- rat specimens.Results:A total of 108 patients were included. The traditional lipid indices did not correlate significantly with the plaque severity (P > 0.05). NECTIN2 provided a strong causal link between LDL-C level and CA (MR effect size >0). Deep-sequencing data illustrated that NECTIN2 expression was cell specific. In early-stage CA, NECTIN2 expression was increased in endothelial cells; however, in advanced-stage CA, NECTIN2 was overexpressed in macrophages located in fibrous caps. APOE-/- rat carotid artery and human carotid plaques modelled the entire atherosclerotic process, showing an upregulation of NECTIN2 expression in CA.Conclusions:Lipid-related protein NECTIN2 is a potential marker in CA progression and can potentially be a new therapeutic target for clinical prevention.

Analysis of brain structural connectivity networks and white matter integrity in patients with mild cognitive impairment

AbstractBackgroundMild cognitive impairment (MCI) is considered a prodromal phase of Alzheimer’s disease (AD) and patients with MCI convert to AD at a rate of about 10–15% per year. Because of this high conversion rate to AD, studies of MCI may yield insight into early pathological changes in AD. Here, we used a novel approach to analyze structural connectivity and white matter (WM) integrity using fractional anisotropy (FA), intra‐cellular (IC), extra‐cellular (EC), and isotropic (ISO) maps between patients with MCI and healthy controls (HC).MethodThirty‐two HC (age mean ± S.D. = 69 ± 6 years; 22 females) and 20 MCI (71 ± 9 years; 7 females) were included in this study. All subjects completed the Mini‐Mental State Exam (MMSE) and the Montreal Cognitive Assessment (MoCA). Multi‐shell DTI were download from ADNI (http://adni.loni.usc.edu/). Pre‐processing was performed by Mrtrix3, FSL, and ANTs. Tractography was performed with 5 million seeds using the iFOD2 algorithm. Connectome was generated from the Desikan‐Killiany parcellation file and was subsequently filtered using the COMMIT2 algorithm. A three‐compartment Stick‐Zeppelin‐Ball model was used to create the IC, the EC, and the ISO compartments, respectively. Statistical analyses (ANCOVA) were performed by connectomestats (Mrtrix3), randomise (FLS), and by an in‐house Matlab script for Spearman’s correlations.ResultThe two groups did differ in MMSE and MoCA (Mann–Whitney U test: Z=2.031; p=0.021; Z=1.683; p=0.046, respectively). Differences between HC and MCI were found principally in the fornix for FA and in several WM areas for IC and ISO (Figure 1, Table 1). Connectometry analysis found differences between groups in two distinct tracts: Tract#1 between the left‐lateraloccipital and the left‐insula (t=4.25, p=0.023) and Tract#2 between the left‐middletemporal and the left‐parsopercularis (t=3.34, p=0.013) (Figure 2). Figure 3 and Table 2 show the results for the correlations between DTI metrics and the neurological scores.ConclusionIn this study, by using a multi‐shell diffusion MRI acquisition and robust processing of DTI data, we detected alterations in WM integrity and structural connectivity in MCI subjects. Our results demonstrate the potential of these advanced diffusion MRI methods as biomarkers to distinguish MCI and HC.

Neural correlates and predictors of subjective cognitive decline in patients with Parkinson\u2019s disease

BackgroundSubjective cognitive decline (SCD) may occur very early in the course of Parkinson’s disease (PD) before the onset of objective cognitive decline. Data on neural correlates and determinants of SCD in PD are rare.ObjectiveThe aim of the present study was to identify neural correlates as well as sociodemographic, clinical, and neuropsychological predictors of SCD in patients with PD.MethodsWe retrospectively analyzed 30 patients with PD without cognitive impairment (23% female, 66.90 ± 7.20 years, UPDRS-III: 19.83 ± 9.29), of which n = 12 patients were classified as having no SCD (control group, PD-CG) and n = 18 as having SCD (PD-SCD). Neuropsychological testing and 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) were conducted. SCD was assessed using a questionnaire covering multiple cognitive domains.ResultsSCD subscores differed significantly between PD-CG and PD-SCD and correlated significantly with other scales measuring related concepts. FDG-PET whole-brain voxel-wise regression analysis revealed hypometabolism in middle frontal, middle temporal, and occipital areas, and the angular gyrus as neural correlates of SCD in PD. Next to this hypometabolism, depressive symptoms were an independent significant determinant of SCD in a stepwise regression analysis (adjusted R2 = 50.3%).ConclusionThis study strengthens the hypothesis of SCD being an early manifestation of future cognitive decline in PD and, more generally, early pathological changes in PD. The early identification of the vulnerability for future cognitive decline constitutes the basis for successful prevention and delay of this non-motor symptom.

HR-MS Based Untargeted Lipidomics Reveals Characteristic Lipid Signatures of Wilson's Disease.

Background and Aims: The diagnosis of Wilson’s disease (WD) is challenging by clinical or genetic criteria. A typical early pathological change of WD is the increased liver lipid deposition and lowered serum triglyceride (TG). Therefore, the contents of serum lipids may provide evidence for screening of biomarkers for WD. Methods: 34 WD patients, 31 WD relatives, and 65 normal controls were enrolled in this study. Serum lipidomics data was acquired by an ultra-high-performance liquid chromatography high-resolution mass spectrometry system, and the data were analyzed by multivariate statistical methods. Results: Of all 510 identified lipids, there are 297 differential lipids between the WD and controls, 378 differential lipids between the relatives and controls, and 119 differential lipids between the patients and relatives. In WD, the abundances of most saturated TG were increased, whereas other unsaturated lipids decreased, including phosphatidylcholine (PC), sphingomyelin (SM), lysophosphatidylcholine (LPC), ceramide (Cer), and phosphatidylserine (PS). We also found many serum lipid species may be used as biomarkers for WD. The areas under the receiver operating characteristic curve (AUC) of PS (35:0), PS (38:5), and PS (34:0) were 0.919, 0.843, and 0.907. The AUCs of TG (38:0) and CerG1 (d42:2) were 0.948 and 0.915 and the AUCs of LPC (17:0) and LPC (15:0) were 0.980 and 0.960, respectively. The lipid biomarker panel exhibits good diagnostic performance for WD. The correlation networks were built among the different groups and the potential mechanisms of differential lipids were discussed. Interestingly, similar lipid profile of WD is also found in their relatives, which indicated the changes may also related to the mutation of the ATP7B gene. Conclusions: Lipid deregulation is another important hallmark of WD besides the deposition of copper. Our lipidomic results provide new insights into the diagnostic and therapeutic targets of WD.

AICAR upregulates ABCA1/ABCG1 expression in the retinal pigment epithelium and reduces Bruch's membrane lipid deposit in ApoE deficient mice

The etiology of age-related macular degeneration (AMD) is diverse; however, recent evidence suggests that the lipid metabolism-cholesterol pathway might be associated with the pathophysiology of AMD. The ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1, are essential for the formation of high-density lipoprotein (HDL) and the regulation of macrophage cholesterol efflux. The failure of retinal or retinal pigment epithelium (RPE) cholesterol efflux to remove excess intracellular lipids causes morphological and functional damage to the retina. In this study, we investigated whether treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMP-activated protein kinase (AMPK) activator, improves RPE cholesterol efflux and Bruch's membrane (BM) lipid deposits. The protein and mRNA levels of ABCA1 and ABCG1 in ARPE-19 cells and retinal and RPE/choroid tissue from apolipoprotein E-deficient (ApoE-/-) mice were evaluated after 24 weeks of AICAR treatment. The cholesterol efflux capacity of ARPE-19 cells and the cholesterol-accepting capacity of apoB-depleted serum from mice were measured. The thickness of the BM and the degree of lipid deposition were evaluated using electron microscopy. AICAR treatment increased the phosphorylation of AMPK and the protein and mRNA expression of ABCA1 and ABCG1 in vitro. It promoted cholesterol efflux from ARPE-19 cells and upregulated the protein and mRNA levels of ABCA1 and ABCG1 in the retina and RPE in vivo. ApoB-depleted serum from the AICAR-treated group showed enhanced cholesterol-accepting capacity. Long-term treatment with AICAR reduced BM thickening and lipid deposition in ApoE-/- mice. In conclusion, AICAR treatment increased the expression of lipid transporters in the retina and RPE in vivo, facilitated intracellular cholesterol efflux from the RPE in vitro, and improved the functionality of HDL to accept cholesterol effluxed from the cell, possibly via AMPK activation. Collectively, these effects might contribute to the improvement of early age-related pathologic changes in the BM. Pharmacological improvement of RPE cholesterol efflux via AMPK activation may be a potential treatment strategy for AMD.

Abstract 13462: Assessment of the Physiological and Pathological Structural Differences Along the Aorta in a Rat Model of Metabolic Syndrome

Introduction: Vascular geometry may vary along the aortic length in normal and chronic disease conditions such as metabolic syndrome. Aim: This study investigated regional structural changes in the aorta in a rodent model of metabolic syndrome, the high-fat diet streptozotocin-induced diabetes mellitus (HFD-D). Methods: Four-week-old male Wistar albino rats received a control diet (CD) or high fat diet (HFD) for 10 weeks. On week 6, 40 mg/kg streptozotocin and its buffer were injected intraperitoneally into the HFD and CD groups, respectively. Glucose and insulin tolerance tests (GTT and ITT) and tail-cuff systolic blood pressure (SBP) were measured. At the end of the study, rats were euthanized, and the thoracic and abdominal aortic segments collected for histomorphometric analysis of aortic media thickness, medial cross-sectional area (CSA), elastic lamellae number, interlamellar spacing, collagen density and lipid deposit density. Results: HFD-D rats showed elevated GTT, ITT and SBP. Abdominal aortic segments of both CD and HFD-D rats showed smaller media thickness and CSA, lower elastin lamellae number and higher collagen density compared with the thoracic segments, suggestive of physiological rather than pathological structural differences in both groups. Elastin interlamellar spacing and lipid plaque deposits were higher in the abdominal aorta of the HFD-D relative to controls, indicating that early vascular pathological changes favor the abdominal aorta in HFD-D rats. Conclusions: In this disease model of metabolic syndrome, vascular structural changes are differentially expressed along the aorta, with pathological features limited to the abdominal rather than the thoracic aorta. These structural abnormalities may underlie the elevated blood pressure seen in this model and potential progression to hypertensive cardiovascular disease.

P‐tau235: a novel biomarker for staging preclinical Alzheimer’s disease

Alzheimer’s disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p‐tau) species such as p‐tau217 and p‐tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p‐tau235 is a prominent feature of AD pathology. In addition, p‐tau235 seemed to be preceded by p‐tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p‐tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p‐235 increases early in AD continuum, and (ii) changes in CSF p‐tau235 and p‐tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p‐tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment.

Ex vivo MRI atlas of the human medial temporal lobe: characterizing neurodegeneration due to tau pathology

Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages.

Tau Post-Translational Modifications: Potentiators of Selective Vulnerability in Sporadic Alzheimer's Disease.

Sporadic Alzheimer's Disease (AD) is the most common form of dementia, and its severity is characterized by the progressive formation of tau neurofibrillary tangles along a well-described path through the brain. This spatial progression provides the basis for Braak staging of the pathological progression for AD. Tau protein is a necessary component of AD pathology, and recent studies have found that soluble tau species with selectively, but not extensively, modified epitopes accumulate along the path of disease progression before AD-associated insoluble aggregates form. As such, modified tau may represent a key cellular stressing agent that potentiates selective vulnerability in susceptible neurons during AD progression. Specifically, studies have found that tau phosphorylated at sites such as T181, T231, and S396 may initiate early pathological changes in tau by disrupting proper tau localization, initiating tau oligomerization, and facilitating tau accumulation and extracellular export. Thus, this review elucidates potential mechanisms through which tau post-translational modifications (PTMs) may simultaneously serve as key modulators of the spatial progression observed in AD development and as key instigators of early pathology related to neurodegeneration-relevant cellular dysfunctions.

Prediction of abnormal left ventricular geometry on the ECG through machine learning with a focus on obesity

Abstract Background Cardiac remodeling, an important aspect of cardiovascular disease (CVD) progression, is emerging as a significant therapeutic target. However, the ECG is not a sensitive method of detecting left ventricular hypertrophy (LVH), and as far as we know, it cannot detect changes in left ventricular geometry (LVG) at early stages, especially before LVH is present. Its sensitivity is particularly low for obese patients. Purpose To use a machine learning (ML) classifier to detect abnormal LVG from EKG parameters/markers, even before it becomes LVH, and to propose some indicative markers useful for practitioners. We also looked at the results of our model for obese patients to test the markers in this population. Methods We enrolled 594 consecutive subjects, aged 30 years or older (mean age: 61.6±12 years old) with and without essential hypertension and no indications of CVD. We tried to build a “clean” dataset through which we can target the clinical, anthropometric, and electrocardiogram measurements indicative of abnormal LVG. All patients underwent a full echocardiographic evaluation and were classified into 2 groups; those with normal geometry (NG) vs. those with concentric remodeling (CR) or LVH. Abnormal LVG was identified as increased relative wall thickness (RWT) and/or left ventricular mass index (LVMi). We analyzed the EKG waveforms deduced to single beat averages for each lead using custom software and extracted 70 markers. We then trained a Random Forest machine learning model to classify subjects with abnormal LVG and calculated SHAP values to perform feature importance and interaction. Results The percentage of women was 56.5%, while 71.3% of all patients were hypertensive. Hypertension, age, body mass index divided by the Sokolow-Lyon voltage (BMI/S-L), QRS-T angle, and QTc duration were among the most important parameters (Figure, left panel) identified by the model as being predictive of abnormal LVG (AUC/ROC = 0.84, sensitivity = 0.94, specificity 0.61). Specifically for obese patients, whose prevalence in our population was 60.3%, our model performed well (sensitivity = 0.71, specificity = 0.92. When we tried our model without the the BMI/S-L parameter, the specificity dropped to 0.88. We also found that a cut-off point of 18 for the BMI/S-L marker predicted the patients who were more probable to have developed abnormal LVG (Figure 1). Conclusions This study is the first to demonstrate the promising potential of ML modeling for the efficient and cost-effective diagnostic screening of abnormal LVG through ECG. We found specific clinical and ECG parameters that can predict early pathological changes of LVG in patients without established CVD and detect the population who will benefit from a detailed echocardiographic evaluation. Our model contributes to the development of human-centered and autonomous technologies and can optimize patient-management and treatment. Funding Acknowledgement Type of funding sources: None. Figure 1

The favorable prognosis of cystic biliary atresia may be related to early surgery and mild liver pathological changes.

The objectives of this study is to compare the prognostic differences between cystic biliary atresia (CBA) and non-CBA, analyze the clinical and liver pathological differences between the two groups, and explore the possible factors that affect the native liver survival of infants with CBA after Kasai portoenterostomy (KPE). From 2013 to 2020, 131 infants with BA were admitted to Tianjin Children's Hospital. A total of 108 infants with BA were included after excluding those who did not undergo surgery after diagnosis (n = 23), including 12 cases of CBA and 96 cases of non-CBA. The clinical data, native liver survival and liver pathology, including liver fibrosis, bile ductular proliferation (BDP), bile plug, and portal area inflammation infiltration of the two study groups were compared. CBA accounts for 9.16% (12/131) and type I CBA accounts for 6.87% (9/131) of all types of BA. 16.7% (2/12) of CBA were detected prenatally with diagnosis of choledochal cyst (CC). The age at KPE, total bilirubin, direct bilirubin, and total bile acid levels of CBA were significantly lower than those of non-CBA (P = 0.047, P = 0.013, P = 0.009, P = 0.010, respectively). The long and wide diameters of the gallbladder were significantly larger than those of non-CBA (both P < 0.001). The 1-, 3-, and 5-year survival rates of CBA were 83.3%, 71.4%, and 71.4%, respectively, and 56.5%, 32.5%, and 29.8%, respectively, in non-CBA. The difference between the two groups was statistically significant (P = 0.031). The degree of liver fibrosis and bile plug in non-CBA was higher than that of CBA (P = 0.004, P < 0.001, respectively). There was no difference of BDP and inflammation infiltration between the two groups (P = 0.285, P = 0.243, respectively). CBA is a distinct type different from non-CBA, with different pathological processes, pathological manifestations, and clinical prognosis. The favorable prognosis of CBA may be derived from the early diagnosis, early operation, and mild pathological changes.

Recent advances in airway imaging using micro-computed tomography and computed tomography for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a complex lung disease characterized by a combination of airway disease and emphysema. Emphysema is classified as centrilobular emphysema (CLE), paraseptal emphysema (PSE), or panlobular emphysema (PLE), and airway disease extends from the respiratory, terminal, and preterminal bronchioles to the central segmental airways. Although clinical computed tomography (CT) cannot be used to visualize the small airways, micro-CT has shown that terminal bronchiole disease is more severe in CLE than in PSE and PLE, and micro-CT findings suggest that the loss and luminal narrowing of terminal bronchioles is an early pathological change in CLE. Furthermore, the introduction of ultra-high-resolution CT has enabled direct evaluation of the proximal small (1 to 2-mm diameter) airways, and new CT analytical methods have enabled estimation of small airway disease and prediction of future COPD onset and lung function decline in smokers with and without COPD. This review discusses the literature on micro-CT and the technical advancements in clinical CT analysis for COPD. Hopefully, novel micro-CT findings will improve our understanding of the distinct pathogeneses of the emphysema subtypes to enable exploration of new therapeutic targets, and sophisticated CT imaging methods will be integrated into clinical practice to achieve more personalized management.

Association of Amyloid-β Pathology with Decision Making and Scam Susceptibility.

Recent findings suggest that poor decision making and increased scam susceptibility are harbingers of Alzheimer's disease (AD) dementia and may be among the earliest behavioral manifestations of pathologic cognitive aging. However, the degree to which poor decision making and scam susceptibility reflect accumulating Alzheimer's disease (AD) pathology remains unclear. To investigate the associations of AD pathology with decision making and scam susceptibility in older adults without dementia. Data came from 198 deceased participants without clinical dementia (mean age at death = 90 years; 69%women) from two ongoing studies of aging. All underwent annual clinical evaluations, completed assessments of healthcare and financial decision making and scam susceptibility, and brain donation. Neuropathologic evaluations quantified pathologic hallmarks of AD, amyloid-β and tau-tangles, Lewy body pathology, and TDP-43 proteinopathy. In linear regression models adjusted for demographics, amyloid-β pathology was associated with lower decision making (estimate = -0.35; SE = 0.16, p = 0.03), particularly healthcare decision making (estimate = -0.20; SE = 0.09, p = 0.03), as well as greater scam susceptibility (estimate = 0.12; SE = 0.04, p = 0.003); tau-tangle pathology was not related. Further, TDP-43 pathology was associated with greater scam susceptibility (estimate = 0.10; SE = 0.04; p = 0.02). Accumulating AD pathology, particularly amyloid-β, is associated with poor decision making and increased scam susceptibility among older persons without overt cognitive impairment. These findings provide compelling evidence that decision making and scam susceptibility are sensitive to the earliest pathological changes of AD.

Histological Tracking into the Third Dimension: Evolution of Early Tumorigenesis in VHL Kidney.

Using a novel three-dimensional (3D) approach, we tracked histological changes to elucidate the earliest stages of renal clear cell neoplasia in normal kidney tissue of patients with von Hippel-Lindau (VHL) disease. Tissue blocks of interest were procured, serially sectioned, and 3D reconstruction of the entirety of pathologic events was performed. The results reveal an abundance of foci with aberrant clear cell proliferation that initially develop along the tubular lining, but have the potential to aggregate within individual tubules. This stage is followed by the extension of clear cell aggregates beyond the tubular basement membrane, which allows for the recruitment of angiogenesis derived from interstitial vasculature. The results suggest that the most frequent pathologic event in VHL kidneys is the presence of isolated or aggregated clear cells within the tubular epithelium, potentially developing further into a protracted process of neoplasia. The abundance of independent pathologic events in VHL kidneys confirms developmental mechanisms to precede tumor initiation. To our knowledge, this is the first report demonstrating that tracking of histologic changes in the 3rd dimension enables the confirmation of the sequence of events from the earliest pathologic change in the VHL kidney to the neoplastic stage. This approach is not only useful for visualization and quantification of pathologic changes but also for targeted sampling allowing selective analysis of the earliest stages of clear cell carcinogenesis.

Cognitive Decline in Parkinson's Disease: A Subgroup of Extreme Decliners Revealed by a Data-Driven Analysis of Longitudinal Progression.

Cognitive impairment is an important symptom of Parkinson’s disease (PD) and predicting future cognitive decline is crucial for clinical practice. Here, we aim to identify latent sub-groups of longitudinal trajectories of cognitive change in PD patients, and explore predictors of differences in cognitive change. Longitudinal cognitive performance data from 349 newly diagnosed PD patients and 145 healthy controls from the Parkinson Progression Marker Initiative were modeled using a multivariate latent class linear mixed model. Resultant latent classes were compared on a number of baseline demographics and clinical variables, as well as cerebrospinal fluid (CSF) biomarkers and striatal dopamine transporter (DAT) density markers of neuropathology. Trajectories of cognitive change in PD were best described by two latent classes. A large subgroup (90%), which showed a subtle impairment in cognitive performance compared to controls but remained stable over the course of the study, and a small subgroup (10%) which rapidly declined in all cognitive performance measures. Rapid decliners did not differ significantly from the larger group in terms of disease duration, severity, or motor symptoms at baseline. However, rapid decliners had lower CSF amyloidß42 levels, a higher prevalence of sleep disorder and pronounced loss of caudate DAT density at baseline. These data suggest the existence of a distinct minority sub-type of PD in which rapid cognitive change in PD can occur uncoupled from motor symptoms or disease severity, likely reflecting early pathological change that extends from motor areas of the striatum into associative compartments and cortex.

Antemortem vs Postmortem Histopathologic and Ultrastructural Findings in Paired Transbronchial Biopsy Specimens and Lung Autopsy Samples From Three Patients With Confirmed SARS-CoV-2.

ObjectivesRespiratory failure is the major cause of death in coronavirus disease 2019 (COVID-19). Autopsy-based reports describe diffuse alveolar damage (DAD), organizing pneumonia, and fibrotic change, but data on early pathologic changes and during progression of the disease are rare.MethodsWe prospectively enrolled three patients with COVID-19 and performed full clinical evaluation, including high-resolution computed tomography. We took transbronchial biopsy (TBB) specimens at different time points and autopsy tissue samples for histopathologic and ultrastructural evaluation after the patients’ death.ResultsSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed by reverse transcription polymerase chain reaction and/or fluorescence in situ hybridization in all TBBs. Lung histology showed reactive pneumocytes and capillary congestion in one patient who died shortly after hospital admission with detectable virus in one of two lung autopsy samples. SARS-CoV-2 was detected in two of two autopsy samples from another patient with a fulminant course and very short latency between biopsy and autopsy, showing widespread organizing DAD. In a third patient with a prolonged course, autopsy samples showed extensive fibrosis without detectable virus.ConclusionsWe report the course of COVID-19 in paired biopsy specimens and autopsies, illustrating vascular, organizing, and fibrotic patterns of COVID-19–induced lung injury. Our results suggest an early spread of SARS-CoV-2 from the upper airways to the lung periphery with diminishing viral load during disease.

A-6 Cognitive Impairment and SES-Related Differences in Affective Traits

Abstract Objective Recent research has suggested that positive affect (PA) and negative affect (NA) may be sensitive markers of early pathological changes in Alzheimer’s disease and mild cognitive impairment (MCI). However, mechanisms underlying this relationship are poorly understood and likely reflect diverse etiological factors. Method The present study aimed to determine whether individual differences in NA and PA were related to group differences in global cognition and socioeconomic status (SES). We collected data from a group of adult participants aged 57–87 (N = 120). Participants were categorized as cognitively normal (CN) or MCI based on Montreal Cognitive Assessment (MoCA) scores. The Positive and Negative Affect Schedule (PANAS) measured PA and NA. Information on SES including education level and household income were collected via interview. Results Results indicated that those with psychometrically-defined MCI statistically differed in PA but not in NA compared to CN adults. Additionally, economically insecure older adults were higher in NA than economically secure older adults. Further, examination of this effect suggested that this economically-related group difference was significantly greater in those with evidence of cognitive impairments than CN. Older age was associated with greater positive affect (r = 0.170, p &amp;lt; 0.050) and lower negative affect (r = −0.296, p = 0.001). Conclusions Results highlight the combined effect of economic insecurity and cognitive impairment on NA, suggesting that economically insecure adults with cognitive impairments may benefit from additional support to reduce its harmful effects on mood. Future research is needed to examine whether heightened NA is a sensitive predictor of depression and MCI.

A\u03b2 misfolding in blood plasma is inversely associated with body mass index even in middle adulthood

BackgroundTo understand the potential for early intervention and prevention measures in Alzheimer’s disease, the association between risk factors and early pathological change needs to be assessed. Hence, the aim of this study was to determine whether risk factors of Alzheimer’s clinical syndrome (clinical AD), such as body mass index (BMI), are associated with Aβ misfolding in blood, a strong risk marker for AD among older adults.MethodsInformation on risk factors and blood samples were collected at baseline in the ESTHER study, a population-based cohort study of older adults (age 50–75 years) in Germany. Aβ misfolding in blood plasma was analyzed using an immuno-infrared-sensor in a total of 872 participants in a nested case-control design among incident dementia cases and matched controls. Associations between risk factors and Aβ misfolding were assessed by multiple logistic regression. For comparison, the association between the risk factors and AD incidence during 17 years of follow-up was investigated in parallel among 5987 cohort participants.ResultsAn inverse association with Aβ misfolding was seen for BMI at age 50 based on reported weight history (aOR 0.64, 95% CI 0.43–0.96, p = 0.03). Similar but not statistically significant associations were seen for BMI at baseline (i.e., mean age 68) and at age 40. No statistically significant associations with Aβ misfolding were found for other risk factors, such as diabetes, smoking, and physical activity. On the other hand, low physical activity was associated with a significantly reduced risk of developing clinical AD compared to physical inactivity.ConclusionsOur results support that AD pathology may be detectable and associated with reduced weight even in middle adulthood, many years before clinical diagnosis of AD. Physical activity might reduce the risk of onset of AD symptoms.

Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy.

Cardiac immune-related adverse events (irAEs) from immune checkpoint inhibition (ICI) targeting programmed death 1 (PD1) are of growing concern. Once cardiac irAEs become clinically manifest, fatality rates are high. Cardio-oncology aims to prevent detrimental effects before manifestation of severe complications by targeting early pathological changes. We therefore aimed to investigate early consequences of PD1 inhibition for cardiac integrity to prevent the development of overt cardiac disease. We investigated cardiac-specific consequences from anti-PD1 therapy in a combined biochemical and in vivo phenotyping approach. Mouse hearts showed broad expression of the ligand PDL1 on cardiac endothelial cells as a main mediator of immune-crosstalk. Using a novel melanoma mouse model, we assessed that anti-PD1 therapy promoted myocardial infiltration with CD4+ and CD8+ T cells, the latter being markedly activated. Left ventricular (LV) function was impaired during pharmacological stress, as shown by pressure-volume catheterization. This was associated with a dysregulated myocardial metabolism, including the proteome and the lipidome. Analogous to the experimental approach, in patients with metastatic melanoma (n = 7) receiving anti-PD1 therapy, LV function in response to stress was impaired under therapy. Finally, we identified that blockade of tumour necrosis factor alpha (TNFα) preserved LV function without attenuating the anti-cancer efficacy of anti-PD1 therapy. Anti-PD1 therapy induces a disruption of cardiac immune homeostasis leading to early impairment of myocardial functional integrity, with potential prognostic effects on the growing number of treated patients. Blockade of TNFα may serve as an approach to prevent the manifestation of ICI-related cardiotoxicity.

Alterations in Circulating MicroRNAs and the Relation of MicroRNAs to Maximal Oxygen Consumption and Intima-Media Thickness in Ultra-Marathon Runners.

The impact of long-term training on cardiovascular disease (CVD) is not clear. Carotid intima–media thickness (CIMT) test is recommended as a useful measure to diagnose the early stages of atherosclerosis. MicroRNAs (miRNAs) are altered due to endurance exercise and can be promising biomarkers of pathophysiological changes. We aimed to evaluate the association of circulating miRNAs with physical fitness and markers of atherosclerosis in ultra-marathon runners. Ultra-marathon runners had 28-fold upregulation of miR-125a-5p expressions compared to control individuals (p = 0.002), whereas let-7e and miR-126 did not differ statistically between ultra-marathon runners and controls. In the ultra-marathon runners’ group, negative correlations were observed between VO2max/kg and relative expression of miR-125a-5p and miR-126 (r = −0.402, p = 0.028; r = −0.438, p = 0.032, respectively). Positive correlations were observed between CIMT and miR-125a-5p and miR-126 (r = 0.388, p = 0.050; r = 0.504, p = 0.023, respectively) in ultra-marathon runners. Individuals with the highest quartile of VO2max/kg had 23-fold lower miR-126 expression in comparison to subgroups with lower VO2max/kg (p = 0.017). Our results may indicate that both miRNAs may serve as a biomarker for early pathological changes leading to atherosclerosis burden in athletes. Furthermore, the association between miRNAs and traditional risk factors for CVD indicate a possible use of these molecules as early biomarkers of future cardiovascular health.