Monitoring Disease Progression Research Articles

Metabolic dysfunction-associated steatotic liver disease: a narrative review of pathophysiology, diagnosis, and management

Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD) poses a significant healthcare burden, affecting approximately 38% of the global population. The rising prevalence of MASLD, particularly among younger individuals, increases the risk of severe liver complications such as cirrhosis and hepatocellular carcinoma. In this narrative review, we present a detailed examination of MASLD, previously referred to as Non-alcoholic Fatty Liver Disease(NAFLD), which is distinguished by the accumulation of excess fat in hepatocytes without the involvement of alcohol intake. We examine the multifaceted pathophysiology of MASLD, showing the interplay of metabolic, genetic, and environmental factors contributing to its development and progression. Diagnostic approaches are discussed, which show the role of non-invasive imaging techniques such as ultrasound, CT, and MRI, alongside histopathological evaluation when necessary. The review also explores the potential of biomarkers related to inflammation, fibrosis, and oxidative stress in improving diagnostic accuracy and monitoring disease progression. Management strategies for MASLD focus mainly on lifestyle adjustments, such as changes in diet, enhanced physical activity, and weight reduction, which are vital for improving liver steatosis and preventing the progression of the disease. Additionally, pharmacological treatments targeting various pathophysiological pathways, such as insulin resistance and lipid metabolism, are reviewed. Promising agents include pioglitazone, GLP-1 receptor agonists, SGLT2 inhibitors, resmetirom, FGF21 analogues, and lanifibranor. This review highlights the need for continued research into the factors influencing MASLD to develop individualized prevention and treatment strategies. By summarizing current knowledge and identifying future research directions, this narrative review aims to contribute to the better understanding and management of MASLD, ultimately reducing its global health burden.

Modified rat pup cerebrospinal fluid collection method

BackgroundCerebrospinal fluid (CSF) reflects biochemical changes in the brain due to its direct contact with brain interstitial fluid, making it a valuable tool for diagnosing and monitoring disease progression and therapeutic effectiveness in clinical practice. However, collecting CSF in animal studies, particularly from small animals like rat pups or mice, poses significant challenges. New methodAfter attempting various reported protocols, we encountered difficulties in consistently obtaining sufficient CSF from rat pups (P7-P42). Consequently, we modified these methods and developed a protocol with controllable and precise parameters for each step, enhancing reproducibility across different researchers. ResultsThe newly developed method enables rapid, single-operator, and reproducible CSF extraction while ensuring high-quality (the absorbance of the “quality control solution” at 415 nm < 0.05 AU, an indicator of oxyhemoglobin contamination for the collected CSF samples) and high-yield samples (33 ± 2.128 μL for P7 pups, 34.10 ± 2.747 μL for P8 pups, 36.67 ± 3.997 μL for P9 pups, 36.90 ± 1.946 μL for P10 pups, 35.11 ± 3.285 μL for P10 hypoxic-ischemic brain damage (HIBD) pups and 51.70 ± 5.256 μL for P42 pups, respectively). Comparison with existing methodsUnlike existing methods of CSF extraction in rat pups, our protocol has reproducible capillary pipette pulling parameters, controllable CSF quality indexes, and can be operated by a single person with high yield in a short time. ConclusionsThis paper provides a step-by-step comparison and discussion of the CSF collection process, establishing a method that enables a single operator to collect CSF rapidly, consistently, sufficiently, and with controlled quality.

TGF-β-mediated crosstalk between TIGIT+ Tregs and CD226+CD8+ T cells in the progression and remission of type 1 diabetes

Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by hyperglycemia resulting from the destruction of insulin-producing β-cells that is traditionally deemed irreversible, but partial remission (PR) with temporary reversal of hyperglycemia is sometimes observed. Here we use single-cell RNA sequencing to delineate the immune cell landscape across patients in different T1D stages. Together with cohort validation and functional assays, we observe dynamic changes in TIGIT+CCR7− Tregs and CD226+CCR7−CD8+ cytotoxic T cells during the peri-remission phase. Machine learning algorithms further identify TIGIT+CCR7− Tregs and CD226+CD8+ T cells as biomarkers for β-cell function decline in a predictive model, while cell communication analysis and in vitro assays suggest that TIGIT+CCR7− Tregs may inhibit CD226+CCR7−CD8+ T cells via TGF-β signaling. Lastly, in both cyclophosphamide-induced and streptozotocin (STZ)-induced mouse diabetes models, CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity. Our results thus identify two interrelated immune cell subsets that may serve as biomarkers for monitoring disease progression and targets for therapeutic intervention of T1D.

Alzheimer's Disease: Exploring the Landscape of Cognitive Decline.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD is marked by the accumulation of amyloid beta plaques and tau protein tangles in the brain, along with neuroinflammation and synaptic dysfunction. Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, contribute to increased risk of acquiring AD. Currently available treatments provide symptomatic relief but do not halt disease progression. Research efforts are focused on developing disease-modifying therapies that target the underlying pathological mechanisms of AD. Advances in identification and validation of reliable biomarkers for AD hold great promise for enhancing early diagnosis, monitoring disease progression, and assessing treatment response in clinical practice in effort to alleviate the burden of this devastating disease. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in Alzheimer's disease. We examine the publication landscape in effort to provide insights into current knowledge advances and developments. We also review the most discussed and emerging concepts and assess the strategies to combat the disease. We explore the genetic risk factors, pharmacological targets, and comorbid diseases. Finally, we inspect clinical applications of products against AD with their development pipelines and efforts for drug repurposing. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding AD, to outline challenges, and to evaluate growth opportunities to further efforts in combating the disease.

Quantification of the fungal pathogen Didymella segeticola in Camellia sinensis using a DNA-based qRT-PCR assay.

The fungal pathogen Didymella segeticola causes leaf spot and leaf blight on tea plant (Camellia sinensis), leading to production losses and affecting tea quality and flavor. Accurate detection and quantification of D. segeticola growth in tea plant leaves are crucial for diagnosing disease severity or evaluating host resistance. In this study, we monitored disease progression and D. segeticola development in tea plant leaves inoculated with a GFP-expressing strain. By contrast, a DNA-based qRT-PCR analysis was employed for a more convenient and maneuverable detection of D. segeticola growth in tea leaves. This method was based on the comparison of D. segeticola-specific DNA encoding a Cys2His2-zinc-finger protein (NCBI accession number: OR987684) in relation to tea plant Cs18S rDNA1. Unlike ITS and TUB2 sequences, this specific DNA was only amplified in D. segeticola isolates, not in other tea plant pathogens. This assay is also applicable for detecting D. segeticola during interactions with various tea cultivars. Among the five cultivars tested, 'Zhongcha102' (ZC102) and 'Fuding-dabaicha' (FDDB) were more susceptible to D. segeticola compared with 'Longjing43' (LJ43), 'Zhongcha108' (ZC108), and 'Zhongcha302' (ZC302). Different D. segeticola isolates also exhibited varying levels of aggressiveness towards LJ43. In conclusion, the DNA-based qRT-PCR analysis is highly sensitive, convenient, and effective method for quantifying D. segeticola growth in tea plant. This technique can be used to diagnose the severity of tea leaf spot and blight or to evaluate tea plant resistance to this pathogen.

F.sh: A 3D Recurrent Residual Attention U-Net for Automated Multiple Sclerosis Lesion Segmentation

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system, characterized by lesions in the brain and spinal cord. Accurate detection and localization of these lesions on MRI scans is crucial for diagnosis and monitoring disease progression. Manual segmentation is time-consuming and prone to inter-rater variability. This study proposes F.sh (3DR2AUNet), a novel deep learning architecture for automated MS lesion segmentation. F.sh combines 3D recurrent residual blocks, attention gates, and the U-Net structure to effectively capture lesion features. The model was trained and evaluated using a comprehensive approach, including patch-based preprocessing, data augmentation, and a composite loss function combining Binary Cross-Entropy and 3D Dice Loss. Experimental results demonstrate the superior performance of F.sh compared to baseline methods, achieving a Dice score of 0.92. The proposed approach has the potential to assist radiologists in the accurate and efficient assessment of MS lesion burden.

Neuropsychological Correlates of Clinical Progression in Subjective Cognitive Decline.

Subjective cognitive decline (SCD) refers to self-reported cognitive decline in individuals with normal performance on standardized cognitive tests. Understanding the factors predicting progression from SCD to mild cognitive impairment (MCI) is crucial, as approximately 14% of SCD cases progress to dementia and about 27% develop MCI over four years. This study aims to identify neuropsychological predictors of progression from SCD to MCI, focusing on cognitive domains assessed through neuropsychological tests. This retrospective study at Seoul National University Bundang Hospital analyzed a cohort of 107 patients diagnosed with SCD through comprehensive assessment. Patients underwent annual neuropsychological testing, including the Digit Span Test, Boston Naming Test, Rey Complex Figure Test, Seoul Verbal Learning Test, and Stroop Test. Annually, these patients underwent neuropsychological tests over a 5-year period; 24 progressed to MCI per NIA-AA criteria. Key predictors of MCI progression included age, ischemic heart disease, and scores from the forward digit span, delayed recall, and Boston naming tests. Lower scores in delayed recall and Boston naming tests significantly correlated with a higher risk of MCI (p < 0.001). These findings suggest a need for targeted management of memory and language functions to monitor disease progression effectively.

ANALYZING THE RELATIONSHIP AMONG CLINICAL SYMPTOMS, X-RAY RESULTS, AND CARTILAGE WEAR PATTERNS IN KNEE OSTEOARTHRITIS USING T2 MAPPING MRI

Objectives: Osteoarthritis (OA) is a condition that causes joint pain, varying degrees of functional limitations, and a decrease in overall quality of life. The purpose of this study was to examine the progression of cartilage degeneration in knees affected by symptomatic OA and determine its relationship with X-ray and T2 map MRI findings. Methods: This study was conducted at a Tertiary Care Teaching Institute in India and involved 40 patients. It was an observational type of study. For our assessment, we utilized the Western Ontario and McMaster University (WOMAC) osteoarthrosis index to evaluate function, quality of life, and joint pain. Medical imaging technique A standing AP view of the affected knee joint was taken using plain radiographs. Once the X-rays were obtained, they were graded using the Kellgren–Lawrence Classification, which ranges from 0 to 4 grades. Results: Out of the total patients, 6.0% were &lt;40 years old, 21.2% were between 41 and 50 years old, 27.2% were between 51 and 60 years old, 39.3% were between 61 and 70 years old, and 6.0% were above 70 years old. In this study, there were 21 females (63.6%) and 12 males (36.4%). In this study, the researchers found that there was no distinction between the sides of the limb affected. Both the left and right sides were involved in 13 cases each, accounting for 39.39% of the total cases. In addition, 7 cases, or 21.21%, reported experiencing bilateral knee pain. Merchant grade reported that out of the knees examined, 17.5% had Grade 0, 45% had Grade 1, 27.5% had Grade 2, 10% had Grade 3, and none had Grade 4. Conclusion: The findings of this study suggest that T2 map MRI has the ability to accurately measure abnormal cartilage changes in conditions that affect the mechanical properties of the knee joint. It is crucial to have non-invasive methods that can assess early cartilage matrix changes. These methods are important for initiating early treatment, monitoring disease progression, planning operative procedures, and following up on operative cartilage repair.

Seeding Aggregation Assays in Lewy Bodies Disorders: A Narrative State-of-the-Art Review

Multiple system atrophy and Lewy body diseases (LBDs) such as Parkinson’s disease, dementia with Lewy bodies, and Parkinson’s disease with dementia, known as synucleinopathies, are defined neuropathologically by the accumulation and deposition of aberrant protein aggregates, primarily in neuronal cells. Seeding aggregation assays (SAA) have significant potential as biomarkers for early diagnosis, monitoring disease progression, and evaluating treatment efficacy for these diseases. Real-time quaking-induced conversion (RT-QuIC) and Protein Misfolding Cyclic Amplification (PMCA) assays represent two ultrasensitive protein amplification techniques that were initially tested for the field of prion disorders. Although the fundamental idea behind the creation of these two methods is very similar, their technical differences resulted in different levels of diagnostic accuracy for the identification of prion proteins, making the RT-QuIC assay the most trustworthy and effective instrument for the detection of suspected cases of LBDs and prion-like diseases.

7708 Navigating Thyroid Cancer With Differences in Thyroglobulin Assessment Techniques

Abstract Disclosure: M.S. Shah: None. S. Humayon: None. N.A. Mungo: None. This case report delves into the diagnostic journey of a patient with papillary thyroid carcinoma, emphasizing the importance of precise thyroglobulin measurement methods. The case highlights the differences between immunoassay and mass spectrometry in monitoring disease progression and treatment response.A 42-year-old female with a family history of thyroid-related issues, was found to have a thyroid nodule on physical exam. She underwent fine-needle aspiration (FNA) revealing papillary thyroid carcinoma, Bethesda category VI. Lymphatic invasion was present necessitating total thyroidectomy and lymph node dissection. Left level 3 and 4 lymph node excision showing 2 of 15 positive for metastatic papillary thyroid carcinoma without extranodal extension. Left superficial jugular lymph node excision showing 1 of 3 lymph node being positive for metastatic thyroid carcinoma without extranodal extension. RAI therapy and post-ablative scan showed focal moderate increased activity adjacent to the left hyoid bone. CT scan of the neck later showed stable appearance of the thyroidectomy bed with no new suspicious soft tissue mass. A small crescentic focus of enhancing soft tissue medial to the left common carotid artery is favored to represent residual thyroid tissue. Multiple small enhancing lymph node in the left neck at level llB and junction of levels ll and lll. Several of these are new or increased in size from prior examination and somewhat acidly enhanced. Although these are within normal limits by size criteria, recurrent diseases cannot be excluded. She underwent another surgical neck dissection with no cancer found. Given the negative findings, a shift from checking thyroglobulin (TG) from immunoassay to mass spectrometry was ideal.Patient was found to have persistent thyroglobulin elevation with Immunoassay, thyroglobulin level (60.5 ng/mL, n&amp;lt;35 ng/ml), without the presence of TG antibodies, whereas liquid chromatography-tandem mass spectrometry (LC-MS/MS) showing (&amp;lt;0.5 ng/mL), highlighting the methodological divergence. To date she has no imaging concerns and repeat testing from different labs similarly demonstrated undetectably Tg by LC-MS/MS and varying levels when tested by Immunoassay. Her levels by Immunoassay have trended down to her most recent level of (38 ng/ml).This case emphasizes the critical role of accurate thyroglobulin assessment in thyroid carcinoma follow-up. Immunoassay and mass spectrometry present divergent results, with LC-MS/MS proving more reliable in monitoring disease progression but more expensive and time consuming. Clinicians should consider the implications of methodological choices on patient management, particularly in cases of persistent elevation despite treatment. The potential discrepancies between these methods should be emphasized considering the impact on treatment decisions. Presentation: 6/1/2024

Visual Field Patterns in Optic Neuropathy

The optic nerve is susceptible to a wide variety of pathological processes. In optic neuropathy, quantitative visual field analysis using standard automated perimetry is critical in initial diagnosis, monitoring disease progression, and guiding treatment plans. While acquired visual field defects may progress rapidly, congenital visual field defects may not progress or may progress slowly. Although the most common defect in congenital or acquired optic neuropathy is the central defect, many defect types that are not pathognomonic to the disease can be seen. In ischemic optic neuropathy, which is common among optic neuropathies, arcuate defect and central defect are usually seen. In disc disorders with localized nerve damage, such as optic disc coloboma or optic pit, localized defects such as arcuate scotoma or cecocentral scotoma in which the fixation point is preserved may be observed. Papilledema causes peripapillary fluid accumulation and an enlarged blind spot in the perimetry. In compressive optic neuropathies, non-specific defects such as central and subtudinal defects may be observed, as well as quadrant defects such as hemianopsia and quadrionopsia. Studies show that the combined use of optical coherence tomography and standard automated perimetry to determine structure-function relationships improves clinical care in neuro-ophthalmic disorders.

7908 GPNMB Promotes Tumor Growth And Is A Biomarker For Lymphangioleiomyomatosis (LAM)

Abstract Disclosure: E. Gibbons: None. M. Taya: None. H. Wu: None. S. Lopa: None. J. Moss: None. E.P. Henske: None. F.X. McCormack: None. S.R. Hammes: None. Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here we establish that GPNMB regulates TSC2-null tumor cell invasion as well as TSC2-null xenograft tumor growth, and that GPNMB expression is dependent on mTORC1 signaling. Further, we show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by ADAM10 and 17 proteases, and we identify the protease target sequence on GPNMB. In fact, mutating this cleavage sequence so that the GPNMB ectodomain can no longer be shed results in cessation of TSC2-null tumor growth. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls, and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker. Presentation: 6/3/2024

7908 GPNMB Promotes Tumor Growth and is a Biomarker for Lymphangioleiomyomatosis (LAM)

Abstract Disclosure: E. Gibbons: None. M. Taya: None. H. Wu: None. S. Lopa: None. J. Moss: None. E.P. Henske: None. F.X. McCormack: None. S.R. Hammes: None. Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here we establish that GPNMB regulates TSC2-null tumor cell invasion as well as TSC2-null xenograft tumor growth, and that GPNMB expression is dependent on mTORC1 signaling. Further, we show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by ADAM10 and 17 proteases, and we identify the protease target sequence on GPNMB. In fact, mutating this cleavage sequence so that the GPNMB ectodomain can no longer be shed results in cessation of TSC2-null tumor growth. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls, and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker. Presentation: 6/3/2024

9308 GPNMB Promotes Tumor Growth And Is A Biomarker For Lymphangioleiomyomatosis (LAM)

Abstract Disclosure: E. Gibbons: None. M. Taya: None. H. Wu: None. S. Lopa: None. J. Moss: None. E.P. Henske: None. F.X. McCormack: None. S.R. Hammes: None. Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here we establish that GPNMB regulates TSC2-null tumor cell invasion as well as TSC2-null xenograft tumor growth, and that GPNMB expression is dependent on mTORC1 signaling. Further, we show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by ADAM10 and 17 proteases, and we identify the protease target sequence on GPNMB. In fact, mutating this cleavage sequence so that the GPNMB ectodomain can no longer be shed results in cessation of TSC2-null tumor growth. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls, and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker. Presentation: 6/3/2024

12573 Management Challenges In A Young Male With Bilateral Macronodular Adrenal Hyperplasia

Abstract Disclosure: C. Nguyen: None. V. Ghernautan: None. L.Y. Melendez-Ramirez: None. M.C. Chiang: None. D. Lovre: None. Bilateral adrenal hyperplasia (BAH) may present in isolation or as part of a syndrome. It is classified according to nodule size as Macronodular: primary bilateral macronodular adrenal hyperplasia (PBMAH), or Micronodular: primary pigmented micronodular adrenal hyperplasia (PPNAD) and isolated micronodular adrenal hyperplasia (iMAD). High variability in cortisol secretion and disease progression is seen in both forms subclinical and overt Cushing’s Syndrome (CS). In PBMAH, bilateral adrenalectomy is advised for remission of CS, but benefits must be weighed against risks of lifelong adrenal insufficiency. A 45-year-old male with hypertension, depression, prediabetes, obesity presented to clinic for second opinion regarding incidentally discovered adrenal nodules five years prior with negative initial hormonal workup. Over the previous year he had gained 20 lbs. and developed proximal muscle weakness and sleep apnea. Physical exam showed uncontrolled hypertension and increased abdominal and supraclavicular fat. Hormonal testing revealed hypercortisolism. Adrenal CT confirmed bilateral adrenal nodules up to 4.9 cm with absolute washout ≥60% consistent with benign etiology. CS secondary to PBMAH was diagnosed. Prior to surgical evaluation. Ketoconazole 200 mg twice daily was started and titrated to 400 mg twice daily over the next three months. ACTH became detectable and symptoms of hypercortisolism improved. Right adrenalectomy was performed. Surgical pathology showed golden yellow-orange nodules with minimal grey adrenal parenchyma without necrosis or hemorrhage. The gland was 9.5 x 5.8 x 2.6 cm and weighed 85 g. Microscopic examination showed macronodular hyperplasia. Following surgery, he experienced a 17-pounds weight loss, improvement in blood pressure and quality of life. Three months later, hypercortisolism recurred. He elected to be monitored clinically and contemplating option of left adrenalectomy.Our case highlights the challenges in the care of patients with PBMAH. Bilateral adrenalectomy (BA) is the classical treatment. Its disadvantages include life-long hormone replacement with risk for adrenal crisis, increased morbidity, and mortality. Surgical alternatives, such as unilateral adrenalectomy (UA) and UA with subtotal contralateral adrenal resection, have shown promising results with up to 90% remission rates. The role of adjuvant novel medical therapy is unknown. Studies to compare cost, quality of life, cardiovascular risk, comorbidities, and life span between BA and UA are lacking. New biomarkers are needed to allow closer monitoring of disease progression. Additional research is necessary on medical management of hypercortisolism recurrence after UA and its long-term safety. Finally, given the presence of germline defects associated with adrenal hyperplasia, genetic testing should be offered to all patients with BAH. Presentation: 6/1/2024

12362 Pathophysiology From Oxidative Stress Effectively Monitored In A Pre-clinical Model Of Type 2 Diabetes (T2D) With Point-of-care Microscale Magnetic Resonance (µNMR)

Abstract Disclosure: A.T. Alves: ; Co-Founder. ; Self. ; LarmorBio. S.S. Thamarath: ; Co-Founder. ; Self. ; LarmorBio. S. Fjordside: Employee; Self; Novo Nordisk. S. Sassower, MS.EE: ; Co-Founder. ; Self. ; LarmorBio. J. Han: None. L. Bouchard: Advisory Board Member; Self; LarmorBio. R. Rohr, BS.EE: ; Co-Founder, CEO. ; Self. ; LarmorBio. A.P. Chambers: Employee; Self; Novo Nordisk. The declining age of onset of T2D is a vital factor influencing its prospective burden. An early manifestation of the disease leads to an extended duration, which amplifies and accelerates the risk of micro and macrovascular complications. Oxidative stress is a major driver in the pathogenesis of T2D. Early detection and prevention of oxidative stress overload can improve and potentially modify the long-term harmful outcomes of metabolic diseases, including chronic hyperglycaemia.A novel µNMR assay was developed to monitor oxidative stress from minimally invasive plasma samples at the point of care. This approach is highly sensitive to redox changes in the blood microenvironment, including increased ferric iron (Fe3+), protein oxidation, and lipid peroxidation[1]. We hypothesized that oxidative stress would increase significantly faster in the disease group, enabling disease progression monitoring throughout the study and near real-time subject risk stratification based on the core pathophysiology of the diabetic phenotype.This 15-week longitudinal study (6th - 21st week of age) quantified oxidative stress in db/db and db/+ mice (n = 15 per group), accompanied by HbA1c, blood glucose (BG), and body weight (BW). The assay detailed separation (P ≤ 0.01) between the db/db and db/+ mice from the onset of the diabetic phenotype of db/db at 10 weeks of age (mean HbA1c = 6.5%). The oxidative stress monitored continued to increase in the subsequent weeks, where the HbA1c of db/db mice reached maximum (mean HbA1c = 8.8%). The definition of good (HbA1c ≤ 8) and poor (HbA1c &amp;gt; 8) glycaemic control was defined where sub-stratification (P ≤ 0.05) was achieved. Furthermore, the assay highlights a positive correlation with BW (ρ+/db = 0.52, P ≤ 0.0001, ρdb/db = 0.57, P ≤ 0.0001). In the two groups of mice, a positive correlation of oxidative stress with HbA1c (ρ = 0.58, P ≤ 0.0001) and BG (ρ = 0.47, P ≤ 0.0001) was reported. During the 15-week study, the control db/+ group exhibited a 13% mean increase in oxidative stress. In contrast, the db/db group demonstrated a cumulative 20% increase. Notably, considering the diabetic phenotype of the db/db mice, we quantified oxidative stress attributed to aging at 13%.In view of changing diabetes demographics, a multimodal approach of targeted sub-phenotype treatment combined with advanced metabolic monitoring may provide holistic, clinically relevant information to reduce the micro and macrovascular burden of diabetes. In summary, the µNMR assay is an effective method for real-time monitoring of oxidative stress assessment in metabolic disease research and opens new possibilities for cardiometabolic risk assessment and targeted interventions.(1) Peng, W.K. et.al., npj Aging Mech Dis 2020, 6, 11 Presentation: 6/1/2024

Mobile Spatiotemporal Gait Segmentation Using an Ear-Worn Motion Sensor and Deep Learning.

Mobile health technologies enable continuous, quantitative assessment of mobility and gait in real-world environments, facilitating early diagnoses of gait disorders, disease progression monitoring, and prediction of adverse events like falls. Traditionally, mobile gait assessment predominantly relied on body-fixed sensors positioned at the feet or lower trunk. Here, we investigate the potential of an algorithm utilizing an ear-worn motion sensor for spatiotemporal segmentation of gait patterns. We collected 3D acceleration profiles from the ear-worn sensor during varied walking speeds in 53 healthy adults. Temporal convolutional networks were trained to detect stepping sequences and predict spatial relations between steps. The resulting algorithm, mEar, accurately detects initial and final ground contacts (F1 score of 99% and 91%, respectively). It enables the determination of temporal and spatial gait cycle characteristics (among others, stride time and stride length) with good to excellent validity at a precision sufficient to monitor clinically relevant changes in walking speed, stride-to-stride variability, and side asymmetry. This study highlights the ear as a viable site for monitoring gait and proposes its potential integration with in-ear vital-sign monitoring. Such integration offers a practical approach to comprehensive health monitoring and telemedical applications, by integrating multiple sensors in a single anatomical location.

High-affinity antibodies specific to the core region of the tau protein exhibit diagnostic and therapeutic potential for Alzheimer’s disease

BackgroundRecent advances in blood-based biomarker discovery are paving the way for simpler, more accessible diagnostic tools that can detect early signs of Alzheimer’s disease (AD). Recent successes in the development of amyloid-targeting immunotherapy approaches mark an important advancement in providing new options for the treatment of AD. We have developed a set of high-affinity monoclonal antibodies (mAbs) to tau protein that have the potential as tools for diagnosis and treatment of AD.MethodsSheep were immunised with either full-length tau (1-441) or truncated paired helical filament (PHF)-core tau (297–391). A stringent bio-panning and epitope selection strategy, with a particular focus directed to epitopes within the disease-relevant PHF-core tau, was used to identify single-chain antibodies (scAbs). These scAbs were ranked by affinity for each epitope class, with leads converted to high-affinity mAbs. These antibodies and their potential utility were assessed by their performance in tau immunoassays, as well as their ability to prevent tau aggregation and propagation. Further characterisation of these antibodies was performed by immunohistochemical staining of brain sections and immuno-gold electronmicroscopy of isolated PHFs.ResultsOur work resulted in a set of high-affinity antibodies reacting with multiple epitopes spanning the entire tau protein molecule. The tau antibodies directed against the core tau unit of the PHF inhibited pathological aggregation and seeding using several biochemical and cell assay systems. Through staining of brain sections and PHFs, the panel of antibodies revealed which tau epitopes were available, truncated, or occluded. In addition, highly sensitive immunoassays were developed with the ability to distinguish between and quantify various tau fragments.ConclusionThis article introduces an alternative immunodiagnostic approach based on the concept of a “tauosome” – the diverse set of tau fragments present within biological fluids. The development of an antibody panel that can distinguish a range of different tau fragments provides the basis for a novel approach to potential diagnosis and monitoring of disease progression. Our results further support the notion that tau immunotherapy targeting the PHF-core needs to combine appropriate selection of both the target epitope and antibody affinity to optimise therapeutic potential.

A-120 Analytical and Clinical Verification of the Elecsys® Alzheimer’s Disease Cerebrospinal Fluid Biomarkers pTau/Abeta42 and Total-Tau/Abeta42

Abstract Background Alzheimer’s disease (AD) is the most common form of dementia characterized by amyloid beta (Abeta) plaques and neurofibrillary tau tangles in the brain. Cerebrospinal fluid (CSF) biomarkers Abeta42, total tau (tTau), and phosphorylated tau (pTau181) offer a high degree of sensitivity and specificity in the diagnosis of AD and have utility in monitoring disease progression. AD biomarker ratios, pTau181/Abeta42 and tTau/Abeta42, correlate with amyloid positron emission tomography (PET) imaging, and several assays have received FDA clearance. This study was designed to evaluate the analytical performance and clinical utility of AD-related Abeta and tau biomarkers on the Roche cobas e601. Methods Precision studies were performed using Roche PreciControl kits. Intra- and inter-precision samples were tested ten times in a single day or twice a day for ten days, respectively. Five levels of Roche Calcheck material were measured in triplicate for linearity. Method comparison was carried out using 39 samples from the Elecsys CSF Correlation Sample Panel from Roche. Qualitative comparisons to amyloid PET Centiloid scores were performed using 35 CSF samples (n=11 PET negative, n=24 PET positive). CSF samples and PET interpretation were obtained from the Cleveland Clinic Institutional Review Board approved Cleveland Alzheimer's Disease Research Center (CADRC) and Cleveland Clinic Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank (LRCBH-Biobank). Results Conclusions Evaluation of AD biomarkers on the Roche cobas e601 revealed reliable precision and analytical accuracy. The pTau181/Abeta42 and tTau/Abeta42 ratios demonstrated excellent positive agreement when compared to amyloid PET, but poor negative agreement. This may be due to the small sample size of PET-negative patients. Alternatively, as amyloid PET detects neuritic plaque accumulation, the CSF biomarker-positive/PET-negative patients may have early non-neuritic amyloid plaque pathology not detectable by imaging. Overall, this assay is suitable for use and may serve as a valuable tool in AD diagnosis.

Ganglion Cell Complex Thickness and Visual Function in Chronic Leber Hereditary Optic Neuropathy.

To evaluate the correlation between the macular ganglion cell complex (GCC) thickness measured with manually corrected segmentation and visual function in individuals with chronic Leber hereditary optic neuropathy (LHON). Twenty-six chronic LHON subjects (60% treated with idebenone or Q10) from the Swedish LHON registry were enrolled. Best-corrected visual acuity (BCVA), visual field tests, and optical coherence tomography (OCT) were performed. Visual field was evaluated with the Haag-Streit Octopus 900 with the Esterman test and a custom 30° test. Canon OCT-HS100 scans were exported to the Iowa Reference Algorithm. GCC thickness was obtained after the segmentation was corrected manually in nine macular sectors. The GCC thickness was overestimated by 16 to 30 µm in different macular sectors with the automated segmentation compared with the corrected (P < 0.001). GCC thickness in all sectors showed significant correlation with all functional parameters. The strongest correlation was seen for the external temporal sector (BCVA: r = 0.604, P < 0.001; mean defect: r = 0.457, P = 0.001; Esterman score: r = 0.421, P = 0.003). No differences were seen between treated and untreated subjects with regard to GCC and visual field scores (P > 0.05), but BCVA was better among treated subjects (P = 0.017). The corrected GCC thickness showed correlation with visual function in chronic LHON subjects. The frequently occurring segmentation errors in OCT measurements related to chronic LHON can potentially be misleading in monitoring of disease progression and in evaluating the treatment effects. Precise measurements of GCC could serve as a sensitive tool to monitor structural changes in LHON. We therefore emphasize the importance of careful evaluation of the accuracy of OCT segmentation.