Distinct Pathologies Research Articles

Exposure to High-Fat Style Diet Induced Renal and Liver Structural Changes, Lipid Accumulation and Inflammation in Intact and Ovariectomized Female Rats

PurposeWe hypothesized that low estrogen levels aggravate obesity-related complications. Diet-induced obesity can cause distinct pathologies, including impaired glucose tolerance, inflammation, and organ injury that leads to fatty liver and chronic kidney diseases. To test this hypothesis, ovariectomized (OVX) rats were fed a high-fat style diet (HFSD), and we examined structural changes and inflammatory response in the kidney and liver.MethodsSprague-Dawley female rats were ovariectomized or sham-operated and divided into four groups: sham-operated rats fed a normal diet (ND); ovariectomized rats fed a normal diet (OVX-ND); sham-operated rats fed a HFSD; ovariectomized rats fed a high-fat style diet (OVX-HFSD). Mean blood pressure and fasting blood glucose were measured on weeks 0 and 10. The rats were sacrificed 10 weeks after initiation of ND or HFSD, the kidney and liver were harvested for histological, immunohistochemical and immunofluorescence studies.ResultsHFSD-fed rats presented a significantly greater adiposity index compared to their ND counterparts. Liver index, fasting blood glucose and mean blood pressure was increased in OVX-HFSD rats compared to HFSD rats at study terminal. Histological and morphometric studies showed focal interstitial mononuclear cell infiltration in the kidney of HFSD rats with mesangial expansion being greater in the OVX-HFSD rats. Both HFSD fed groups showed increased expressions of renal inflammatory markers, namely TNF-alpha, IL-6 and MCP-1, and infiltrating M1 macrophages with some influence of ovarian hormonal status. HFSD-feeding also caused hepatocellular steatosis which was aggravated in ovariectomized rats fed the same diet. Furthermore, hepatocellular ballooning was observed only in the OVX-HFSD rats. Similarly, HFSD-fed rats showed increased expressions of the inflammatory markers and M1 macrophage infiltration in the liver; however, only IL-6 expression was magnified in the OVX-HFSD.ConclusionOur data suggest that some of the structural changes and inflammatory response in the kidney and liver of rats fed a HFSD are exacerbated by ovariectomy.

Visualizing the dynamics of tuberculosis pathology using molecular imaging.

Nearly 140 years after Robert Koch discovered Mycobacterium tuberculosis, tuberculosis (TB) remains a global threat and a deadly human pathogen. M. tuberculosis is notable for complex host-pathogen interactions that lead to poorly understood disease states ranging from latent infection to active disease. Additionally, multiple pathologies with a distinct local milieu (bacterial burden, antibiotic exposure, and host response) can coexist simultaneously within the same subject and change independently over time. Current tools cannot optimally measure these distinct pathologies or the spatiotemporal changes. Next-generation molecular imaging affords unparalleled opportunities to visualize infection by providing holistic, 3D spatial characterization and noninvasive, temporal monitoring within the same subject. This rapidly evolving technology could powerfully augment TB research by advancing fundamental knowledge and accelerating the development of novel diagnostics, biomarkers, and therapeutics.

Adrenocortical Carcinoma: Updates of Clinical and Pathological Features after Renewed World Health Organisation Classification and Pathology Staging.

Adrenocortical carcinoma (ACC) is a heterogenous group of diseases with different clinical behaviour between adult and paediatric patients. In addition, three histological variants, oncocytic, myxoid and sarcomatoid are noted on the recent World Health Organisation (WHO) classification of ACC. A review of recent literature showed that the different types of ACC have distinctive demographic data, clinical presentation, pathology, biological behaviour, genomic and patients’ prognosis. In addition, recent updates of pathology staging for ACC allow refinement of prognostic grouping for planning treatment of the patients with ACC. These advances in genomic, pathology and staging have driven the development of standardisation of pathology reporting. International standardisation of pathological reporting of adrenocortical carcinoma and adaption to local pathology communities provide universal platforms for clinicians and researchers involved in the management of patients with ACC. To conclude, all these advances in the field of pathology will improve development of management strategies including improvement of clinical care, development of prognostic markers and testing of novel therapeutic approaches for patients with adrenocortical carcinoma.

Interplay between tau and α-synuclein liquid-liquid phase separation.

In Parkinson's disease with dementia, up to 50% of patients develop a high number of tau‐containing neurofibrillary tangles. Tau‐based pathologies may thus act synergistically with the α‐synuclein pathology to confer a worse prognosis. A better understanding of the relationship between the two distinct pathologies is therefore required. Liquid–liquid phase separation (LLPS) of proteins has recently been shown to be important for protein aggregation involved in amyotrophic lateral sclerosis, whereas tau phase separation has been linked to Alzheimer's disease. We therefore investigated the interaction of α‐synuclein with tau and its consequences on tau LLPS. We find α‐synuclein to have a low propensity for both, self‐coacervation and RNA‐mediated LLPS at pH 7.4. However, full‐length but not carboxy‐terminally truncated α‐synuclein efficiently partitions into tau/RNA droplets. We further demonstrate that Cdk2‐phosphorylation promotes the concentration of tau into RNA‐induced droplets, but at the same time decreases the amount of α‐synuclein inside the droplets. NMR spectroscopy reveals that the interaction of the carboxy‐terminal domain of α‐synuclein with the proline‐rich region P2 of tau is required for the recruitment of α‐synuclein into tau droplets. The combined data suggest that the concentration of α‐synuclein into tau‐associated condensates can contribute to synergistic aSyn/tau pathologies.

Similarities and dissimilarities between psychiatric cluster disorders

The common molecular mechanisms underlying psychiatric disorders are not well understood. Prior attempts to assess the pathological mechanisms responsible for psychiatric disorders have been limited by biased selection of comparable disorders, datasets/cohort availability, and challenges with data normalization. Here, using DisGeNET, a gene-disease associations database, we sought to expand such investigations in terms of number and types of diseases. In a top-down manner, we analyzed an unbiased cluster of 36 psychiatric disorders and comorbid conditions at biological pathway, cell-type, drug-target, and chromosome levels and deployed density index, a novel metric to quantify similarities (close to 1) and dissimilarities (close to 0) between these disorders at each level. At pathway level, we show that cognition and neurotransmission drive the similarity and are involved across all disorders, whereas immune-system and signal-response coupling (cell surface receptors, signal transduction, gene expression, and metabolic process) drives the dissimilarity and are involved with specific disorders. The analysis at the drug-target level supports the involvement of neurotransmission-related changes across these disorders. At cell-type level, dendrite-targeting interneurons, across all layers, are most involved. Finally, by matching the clustering pattern at each level of analysis, we showed that the similarity between the disorders is influenced most at the chromosomal level and to some extent at the cellular level. Together, these findings provide first insights into distinct cellular and molecular pathologies, druggable mechanisms associated with several psychiatric disorders and comorbid conditions and demonstrate that similarities between these disorders originate at the chromosome level and disperse in a bottom-up manner at cellular and pathway levels.

Mechanistic Implications of Biomass-Derived Particulate Matter for Immunity and Immune Disorders.

Particulate matter (PM) is a major and the most harmful component of urban air pollution, which may adversely affect human health. PM exposure has been associated with several human diseases, notably respiratory and cardiovascular diseases. In particular, recent evidence suggests that exposure to biomass-derived PM associates with airway inflammation and can aggravate asthma and other allergic diseases. Defective or excess responsiveness in the immune system regulates distinct pathologies, such as infections, hypersensitivity, and malignancies. Therefore, PM-induced modulation of the immune system is crucial for understanding how it causes these diseases and highlighting key molecular mechanisms that can mitigate the underlying pathologies. Emerging evidence has revealed that immune responses to biomass-derived PM exposure are closely associated with the risk of diverse hypersensitivity disorders, including asthma, allergic rhinitis, atopic dermatitis, and allergen sensitization. Moreover, immunological alteration by PM accounts for increased susceptibility to infectious diseases, such as tuberculosis and coronavirus disease-2019 (COVID-19). Evidence-based understanding of the immunological effects of PM and the molecular machinery would provide novel insights into clinical interventions or prevention against acute and chronic environmental disorders induced by biomass-derived PM.

Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity

There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5 × 106 pfu) and medium (5 × 104 pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5 × 102 pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5–15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease.

Gene Expression Signatures Identify Biologically and Clinically Distinct Tuberculosis Endotypes

In vitro, animal model and anecdotal clinical evidence suggests that tuberculosis (TB) is not a monomorphic disease, and that host response to TB is protean with multiple distinct molecular pathways and pathologies (endotypes). We used unbiased clustering to identify separate TB endotypes with distinctive gene expression patterns and different clinical outcomes. A discovery cohort that included 443 TB patients and 527 asymptomatic controls identified two TB endotypes exhibiting distinct gene expression in proliferation, metabolism, and immune pathways. Specifically, TB patient endotype A was characterized by increased expression of genes related to inflammation and immunity and decreased metabolism and proliferation; in contrast, endotype B expressed increased pathways related to metabolism and proliferation. The endotype signatures were validated using an independent RNA-seq validation cohort consisting of two studies that included 118 TB patients and 208 controls. A second validation cohort confirmed differential pathway activity between TB endotypes and demonstrated that TB patients in endotype A had slower time to culture conversion, increased risk of death, and increased risk of poor clinical outcomes. These observations suggest that endotypes reflect different functional immunity; this postulate was further supported by the observation that TB patients with the hyperinflammatory endotype showed hyporesponsive cytokine and chemokine responses. Collectively, these findings provide further evidence that metabolic and immune profiling could inform and optimize targeted endotype-specific therapies for TB.

Pathogenesis of autoimmune demyelination: from multiple sclerosis to neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody-associated disease.

Autoimmunity plays a significant role in the pathogenesis of demyelination. Multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) are now recognised as separate disease entities under the amalgam of human central nervous system demyelinating disorders. While these disorders share inherent similarities, investigations into their distinct clinical presentations and lesion pathologies have aided in differential diagnoses and understanding of disease pathogenesis. An interplay of various genetic and environmental factors contributes to each disease, many of which implicate an autoimmune response. The pivotal role of the adaptive immune system has been highlighted by the diagnostic autoantibodies in NMOSD and MOGAD, and the presence of autoreactive lymphocytes in MS lesions. While a number of autoantigens have been proposed in MS, recent emphasis on the contribution of B cells has shed new light on the well‐established understanding of T cell involvement in pathogenesis. This review aims to synthesise the clinical characteristics and pathological findings, discuss existing and emerging hypotheses regarding the aetiology of demyelination and evaluate recent pathogenicity studies involving T cells, B cells, and autoantibodies and their implications in human demyelination.

Severe OCD Exacerbation in a Patient with Autism Spectrum Disorder: A Case Report.

Autism Spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and social interaction, repetitive and stereotyped behaviors, and/or sensory aberrations. On the other hand, obsessive-compulsive disorder (OCD) is characterized by the presence of obsessions and/or compulsions. In consideration of these distinct pathologies, research suggests that anxiety disorders and OCD are highly prevalent in individuals with ASD. This case report will discuss an adolescent patient with ASD and OCD who experiences an exacerbation, most notably, in his symptoms of OCD. We outline the hospital course of a 13 year-old male who ultimately requires nasogastric (NG) tube feeding resulting from an acute worsening in symptoms and refusal of oral intake during the COVID-19 pandemic. The patient demonstrated significant improvement in symptoms following the administration of high-dose selective serotonin reuptake inhibitor (SSRI) and low-dose antipsychotic therapy.

Mitochondrial Membrane Intracellular Communication in Healthy and Diseased Myocardium.

Research efforts in the twenty-first century have been paramount to the discovery and development of novel pharmacological treatments in a variety of diseases resulting in improved life expectancy. Yet, cardiac disease remains a leading cause of morbidity and mortality worldwide. Over time, there has been an expansion in conditions such as atrial fibrillation (AF) and heart failure (HF). Although past research has elucidated specific pathways that participate in the development of distinct cardiac pathologies, the exact mechanisms of action leading to disease remain to be fully characterized. Protein turnover and cellular bioenergetics are integral components of cardiac diseases, highlighting the importance of mitochondria and endoplasmic reticulum (ER) in driving cellular homeostasis. More specifically, the interactions between mitochondria and ER are crucial to calcium signaling, apoptosis induction, autophagy, and lipid biosynthesis. Here, we summarize mitochondrial and ER functions and physical interactions in healthy physiological states. We then transition to perturbations that occur in response to pathophysiological challenges and how this alters mitochondrial–ER and other intracellular organelle interactions. Finally, we discuss lifestyle interventions and innovative therapeutic targets that may be used to restore beneficial mitochondrial and ER interactions, thereby improving cardiac function.

The Role of Bone Scintigraphy with SPECT/CT in the Characterization and Early Diagnosis of Stage 0 Charcot Neuroarthropathy.

We describe the use of Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) in the investigation and diagnosis of Charcot neuroarthropathy (CN) in patients with a hot swollen foot but normal radiographs and clinical suspicion of CN, usually termed Stage 0. This was a retrospective cohort review of 46 diabetes patients who underwent 3 phase bone scintigraphy with “High Resolution” SPECT/CT. The imaging demonstrated that Stage 0 Charcot foot has a distinct bone pathology, which can be classified into three groups: (1) fractures on Computed Tomography (CT) with accompanying focal uptake of tracer on SPECT, (2) bony abnormalities apart from fracture on CT with focal uptake of tracer on SPECT, and (3) normal CT but focal bony uptake of tracer on SPECT. The CT component of SPECT/CT detected bony fractures in 59% of patients. Early treatment with below knee cast and follow-up for 24 months showed only 4 patients who developed Stage 1 Eichenholtz Charcot foot. Our findings support the use of 3 phase bone scintigraphy with SPECT/CT in the characterization and early diagnosis of CN. Stage 0 Charcot foot has a distinct bone pathology which requires urgent treatment to prevent progression to Stage 1 Eichenholtz Charcot foot. If SPECT/CT is unavailable, CT alone will detect bone fracture in 59% patients.

Improvement of results of surgical treatment of giant hernias of inguinofemoral region by choice of method of hernioplasty (clinical case)

Aim. Description of a clinical case pf patient K., 71 years old, as an illustration of the possibility to improve treatment of giant hernias in the inguinofemoral region. The patient was hospitalized with the diagnosis: bilateral giant irreducible inguinoscrotal hernia. The specificity of this case was implementation of the operation of hernioectomy from preperitoneal access with prosthetics of the posterior surface of the anterior abdominal wall with polypropylene (prolene) mesh on both sides. In a month after discharge from hospital the condition remained satisfactory, postoperative scar was normotrophic, testicles painless to palpation with a small amount of fluid in the dartos, skin of scrotum contracted.
 Conclusion. Hernioectomy from preperitoneal access with prosthetics of the posterior surface of the anterior abdominal wall with polypropylene (prolene) mesh in patients with giant, irreducible and recurrent hernias possesses a number of peculiarities in comparison with traditional methods, since it permits: 1) to fix endoprosthesis to permanent anatomical structures with simultaneous repair of all the defects of the transverse fascia; 2) to operate outside the zone of scar tissue in recurrent hernias; 3) to perform an adequate revision of the organs of the hernial sack in irreducible hernias; 4) to perform operations on patients with distinct comorbid pathology and contraindications to general anesthesia.

Phenotyping the shoulder patient based on ultrasound-detected pathologies: a cross-sectional study in general practice.

Shoulder complaints arise from a single pathology or a combination of different underlying pathologies that are hard to differentiate in general practice. Subgroups of pathologies have been identified on the basis of ultrasound imaging that might affect treatment outcomes. Our aim was to validate the existence of different subgroups of patients with shoulder complaints, based on ultrasound-detected pathology, and compare clinical features among them. Profiling shoulder patients into distinct shoulder pathology phenotypes could help designing tailored treatment trials. This was a cross-sectional study in general practice. Data were extracted from 840 first visit patient records at a single diagnostic centre in the Netherlands. Exclusion criteria were age <18 years and previous shoulder surgery. Latent class analysis was used to uncover cross-combinations of ultrasound detected pathologies, yielding subgroups of shoulder patients. The uncovered subgroups were compared for demographic and clinical characteristics. We uncovered four distinct subgroups of patients with shoulder complaints: (i) Frozen shoulder group (11%), (ii) Limited pathology group (44%), (iii) Degenerative pathology group (31%) and (iv) Calcifying tendinopathy group (15%). Group comparisons showed significant differences in demographic and clinical characteristics among subgroups, consistent with the literature. In a general practice population, we uncovered four different phenotypes of shoulder patients on the basis of ultrasound detected pathology. These phenotypes can be used designing tailored treatment trials in patients with shoulder complaints.

Pancreatic neuroendocrine neoplasms: Clinicopathological features and pathological staging.

The nomenclature and classification of pancreatic neuroendocrine neoplasms has evolved in the last 15 years based on the advances in knowledge of the genomics, clinical behaviour and response to therapies. The current 2019 World Health Organization classification of pancreatic neuroendocrine neoplasms categorises them into three groups; pancreatic neuroendocrine tumours (PanNETs)(grade 1 grade 2, grade 3), pancreatic neuroendocrine carcinomas and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) based on the mitotic rate, Ki-67 index, morphological differentiation and/or co-existing tissue subtype. PanNETs are also classified into non-functional NET, insulinoma, gastrinoma, VIPoma, glucagonoma, somatostatinoma, ACTH-producing NET and serotonin producing NET based on hormone production and clinical manifestations. A portion of the cases were associated with genetic syndromes such as multiple neuroendocrine neoplasia 1 (MEN 1), neurofibromatosis and Von Hippel-Lindau syndrome. In view of the distinctive pathology and clinical behaviour of PanNENs, the current 8th AJCC/UICC staging system has separated prognostic staging grouping for PanNETs from the pancreatic neuroendocrine carcinomas or MiNENs. Pancreatic neuroendocrine carcinomas and MiNENs are staged according to the prognostic stage grouping for exocrine pancreatic carcinoma. The new stage grouping of PanNETs was validated to have survival curves separated between different prognostic groups. This refined histological and staging would lead to appropriate selections of treatment strategies for the patients with pancreatic neuroendocrine neoplasms.

Diverticular Disease of the Appendix Is Associated with Complicated Appendicitis

Introduction: Diverticular disease of the vermiform appendix (DDA) has an incidence of 0.004 to 2.1% in appendicectomy specimens. DDA is variably associated with perforation and malignancy. We report a single-center experience of DDA. The primary aim is to validate the association of DDA with complicated appendicitis or malignancy, and the secondary aim is to validate systemic inflammatory response syndrome (SIRS) criteria and quick Sepsis-related Organ Failure Assessment (qSOFA) scores. Methods: The histopathology reports of 2,305 appendicectomy specimens from January 2011 to December 2015 were reviewed. Acute appendicitis was found in 2,164 (93.9%) specimens. Histology of the remaining 141 (6.1%) patients revealed: normal appendix (n = 110), DDA (n = 22), endometriosis of appendix (n = 6), and an absent appendix (n = 3). Patient demographics, clinical profile, operative data, and perioperative outcomes of DDA patients are studied. Modified Alvarado score, Andersson score, SIRS criteria, and qSOFA scores were retrospectively calculated. Results: The incidence of DDA was 0.95%. Ten patients (45.5%) had diverticulitis. The mean age of DDA patients was 39.5 years (range 23–87), with male preponderance (n = 12, 54.5%). The median Modified Alvarado score was 8 (range 4–9), and the median Andersson score was 5 (range 2–8). Fourteen patients (63.6%) had SIRS, and none had a high qSOFA score. Eight patients (36.4%) had complicated appendicitis (perforation [n = 2] or abscess [n = 6]). Eleven (50%) patients underwent laparoscopic appendicectomy. There were three 30-day readmissions and no mortality. Conclusion: DDA is a distinct clinical pathology associated with complicated appendicitis.

Oligodendroglial alterations in FTD caused by C9orf72 expansion

AbstractBackgroundThe most frequent genetic cause of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) is the hexanucleotide repeat expansion in the C9orf72 gene. Until now, three different mechanisms have been proposed to explain its pathogenic effects: i) loss of function of the C9orf72 protein, ii) toxic gain of function from sense and antisense C9orf72 repeat RNA, or iii) toxic gain of function from Dipeptide Repeat Proteins. Another important hallmark associated with C9orf72 mutations is the TDP43 accumulation in neurons and glia. As in other neurodegenerative diseases, neuroinflammation is a common feature in FTD; however, the specific role of the innate immune system in FTD associated to specific subtypes of the disease is unknown.MethodIn this study, we investigated changes in the pattern of different glial markers (GFAP, YKL‐40, Iba‐1 and MBP) using immunohistochemistry in the frontal cortex and hippocampus of a cohort of 23 cases diagnosed with C9‐FTD/ALS with TDP43 pathology (C9‐FTD), 8 cases diagnosed with sporadic‐FTD TDP43 (sFTD) and 9 healthy controls (HC). Different in‐house semi‐automated MATLAB algorithms were developed and were used to quantify the immunoreactivity of these different markers.ResultWe found a significant increase of GFAP, YKL‐40 and Iba1 immunoreactivity in C9‐FTD and in the sporadic group compared with a group of healthy controls both in frontal cortex and hippocampus. We also found a decreased of MBP protein immunoreactivity in the group of C9‐FTD samples, both in grey and white matter from the frontal cortex, compared to control and sporadic group of samples. In C9‐FTD group we found a negative correlation between MBP and TDP43.ConclusionThese results indicate that FTD caused by C9orf72 is associated with myelin loss likely caused by the mutation or its distinct pathology. Understanding these biological processes will help to identify specific pathways associated with this FTLD subtype and help in the development of new therapeutic strategies implicating oligodendroglial cells as a target to reduce the disease progression and improve quality of life of FTD with C9orf72 expansion patients.

Exploring retinal imaging as a novel biomarker of Alzheimer’s disease

AbstractBackgroundAlzheimer disease (AD) and frontotemporal dementias (FTD) exhibit distinct pathologies but are difficult to reliably differentiate on clinical grounds. Detailed neuropsychiatric evaluations, cerebrospinal fluid analysis, and anatomic or molecular imaging may improve diagnostic accuracy. Even so, these modalities are expensive, time‐consuming, and often inaccessible. The retina is a developmental outgrowth of the brain, and visual dysfunction is well documented in dementia subjects. As such, the retina may be a useful surrogate for diagnosing and monitoring the progression of dementias. We explored the potential role of multimodal retinal imaging for identifying ocular biomarkers of dementia and correlated our findings with cerebral amyloid burden.MethodWe recruited 5 participants with mid‐to‐late stage AD, 2 participants with mid‐to‐late stage FTD, as well as 9 age‐matched healthy controls. Each participant underwent comprehensive ophthalmologic examination and ocular imaging (Optical Coherence Tomography (OCT), OCT‐angiography (OCTA), wide‐field fundus photography, near‐infrared imaging, and fundus autofluorescence). Ocular findings were then correlated with cerebral amyloid burden, as detected by [11C]PiB PET.ResultWe did not observe significant differences in retinal layer thicknesses, retinal perfusion, or sizes of the superficial avascular zones between PET‐confirmed AD, clinically diagnosed FTD, and control subjects. AD subjects consistently demonstrated higher autofluorescence signal intensity (18.5 au), as detected by fundus autofluorescence imaging compared to FTD (16.0 au) and age‐matched control subjects (16.3 au). Near‐infrared ocular imaging also revealed a 1.95 fold increase in retinal reflectance in AD subjects compared to FTD and control subjects.ConclusionIdentification of novel dementia biomarkers is essential for accurate diagnosis and monitoring of dementia progression. Recent studies highlighted the potential use of OCT and OCT‐A to identify retinal layer thickness changes in AD and FTD. Our pilot study suggests that autofluorescence and near‐infrared reflectance, but not OCT or OCT‐A, detect retinal imaging changes that correlate with cerebral amyloid burden. These modalities may thus serve as accurate dementia biomarkers to aid in diagnosis, assessing pathologic severity, and gauging response to therapy in AD and FTD.

Simulation of Abnormal Physiological Signals in a Phantom for Bioengineering Education

In clinical practice and in particular in the diagnostic process, the assessment of cardiac and respiratory functions is supported by electrocardiogram and auscultation. These exams are non-invasive, quick and inexpensive to perform and easy to interpret. For these reasons, this type of assessment is a constant in the daily life of a clinician and the information obtained is central to the decision making process. Therefore, it is essential that during their training, students of health-related subjects acquire skills in the acquisition and evaluation of the referred physiological signals. Simulation, considering the technological possibilities of today, is an excellent preparation tool since it exposes trainees to near real contexts but without the associated risks. Hence, the simulation of physiological signals plays an important role in the education of healthcare professionals, bioengineering professionals and also in the development and calibration of medical devices. This paper describes a project to develop synchronized electrocardiogram (ECG), phonocardiogram (PCG) and breathing sounds simulators that aims to improve an existing phantom simulator. The developed system allows, in an integrated way, to generate normal and pathological signals, being contemplated several distinct pathologies. For engineering education, it is also possible to simulate the introduction of signal disturbances or hardware malfunctions.

Human Motor Neurons With SOD1-G93A Mutation Generated From CRISPR/Cas9 Gene-Edited iPSCs Develop Pathological Features of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by gradual degeneration and elimination of motor neurons (MNs) in the motor cortex, brainstem, and spinal cord. Some familial forms of ALS are caused by genetic mutations in superoxide dismutase 1 (SOD1) but the mechanisms driving MN disease are unclear. Identifying the naturally occurring pathology and understanding how this mutant SOD1 can affect MNs in translationally meaningful ways in a valid and reliable human cell model remains to be established. Here, using CRISPR/Cas9 genome editing system and human induced pluripotent stem cells (iPSCs), we generated highly pure, iPSC-derived MNs with a SOD1-G93A missense mutation. With the wild-type cell line serving as an isogenic control and MNs from a patient-derived iPSC line with an SOD1-A4V mutation as a comparator, we identified pathological phenotypes relevant to ALS. The mutant MNs accumulated misfolded and aggregated forms of SOD1 in cell bodies and processes, including axons. They also developed distinctive axonal pathologies. Mutants had axonal swellings with shorter axon length and less numbers of branch points. Moreover, structural and molecular abnormalities in presynaptic and postsynaptic size and density were found in the mutants. Finally, functional studies with microelectrode array demonstrated that the individual mutant MNs exhibited decreased number of spikes and diminished network bursting, but increased burst duration. Taken together, we identified spontaneous disease phenotypes relevant to ALS in mutant SOD1 MNs from genome-edited and patient-derived iPSCs. Our findings demonstrate that SOD1 mutations in human MNs cause cell-autonomous proteinopathy, axonopathy, synaptic pathology, and aberrant neurotransmission.