Disease Pathology Research Articles

Medial temporal lobe gray matter microstructure in preclinical Alzheimer's disease.

Typical MRI measures of neurodegeneration have limited sensitivity in early disease stages. Diffusion MRI (dMRI) microstructural measures may allow for detection in preclinical stages. Participants had dMRI and either beta-amyloid PET or plasma biomarkers of Alzheimer's pathology within 18 months of MRI. Microstructure was measured in portions of the medial temporal lobe (MTL) with high neurofibrillary tangle (NFT) burden based on a previously developed post mortem 3D-map. Regressions examined relationships between microstructure and markers of Alzheimer's pathology in preclinical disease and then across disease stages. There was higher isometric volume fraction in amyloid-positive compared to amyloid-negative cognitively unimpaired individuals in high tangle MTL regions. Similarly, plasma biomarkers and 18F-flortaucipir were associated with microstructural changes in preclinical disease. Additional microstructural effects were seen across disease stages. Combining a post mortem atlas of NFT pathology with microstructural measures allows for detection of neurodegeneration in preclinical Alzheimer's disease. Highlights Typical markers of neurodegeneration are not sensitive in preclinical Alzheimer's. dMRI measured microstructure in regions with high NFT. Microstructural changes occur in medial temporal regions in preclinical disease. Microstructural changes occur in other typical Alzheimer's regions in later stages. Combining post mortem pathology atlases with in vivo MRI is a powerful framework.

Targeting the Plasmodium falciparum UCHL3 ubiquitin hydrolase using chemically constrained peptides

The ubiquitin-proteasome system is essential to all eukaryotes and has been shown to be critical to parasite survival as well, including Plasmodium falciparum, the causative agent of the deadliest form of malarial disease. Despite the central role of the ubiquitin-proteasome pathway to parasite viability across its entire life-cycle, specific inhibitors targeting the individual enzymes mediating ubiquitin attachment and removal do not currently exist. The ability to disrupt P. falciparum growth at multiple developmental stages is particularly attractive as this could potentially prevent both disease pathology, caused by asexually dividing parasites, as well as transmission which is mediated by sexually differentiated parasites. The deubiquitinating enzyme PfUCHL3 is an essential protein, transcribed across both human and mosquito developmental stages. PfUCHL3 is considered hard to drug by conventional methods given the high level of homology of its active site to human UCHL3 as well as to other UCH domain enzymes. Here, we apply the RaPID mRNA display technology and identify constrained peptides capable of binding to PfUCHL3 with nanomolar affinities. The two lead peptides were found to selectively inhibit the deubiquitinase activity of PfUCHL3 versus HsUCHL3. NMR spectroscopy revealed that the peptides do not act by binding to the active site but instead block binding of the ubiquitin substrate. We demonstrate that this approach can be used to target essential protein-protein interactions within the Plasmodium ubiquitin pathway, enabling the application of chemically constrained peptides as a novel class of antimalarial therapeutics.

Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson’s Disease and Aging

Parkinson’s disease (PD), a progressive neurodegenerative disease, has no cure, and current therapies are not effective at halting disease progression. The disease affects mid-brain dopaminergic neurons and, subsequently, the spinal cord, contributing to many debilitating symptoms associated with PD. The GTP-binding protein, Rho, plays a significant role in the cellular pathology of PD. The downstream effector of Rho, Rho-associated kinase (ROCK), plays multiple functions, including microglial activation and induction of inflammatory responses. Activated microglia have been implicated in the pathology of many neurodegenerative diseases, including PD, that initiate inflammatory responses, leading to neuron death. Calpain expression and activity is increased following glial activation, which triggers the Rho-ROCK pathway and induces inflammatory T cell activation and migration as well as mediates toxic α-synuclein (α-syn) aggregation and neuron death, indicating a pivotal role for calpain in the inflammatory and degenerative processes in PD. Increased calpain activity and Rho-ROCK activation may represent a new mechanism for increased oxidative damage in aging. This review will summarize calpain activation and the role of the Rho-ROCK pathway in oxidative stress and α-syn aggregation, their influence on the neurodegenerative process in PD and aging, and possible strategies and research directions for therapeutic intervention.

Kinetic modeling of the monoamine oxidase-B radioligand [18F]SMBT-1 in human brain with positron emission tomography.

This paper describes pharmacokinetic analyses of the monoamine-oxidase-B (MAO-B) radiotracer [18F](S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([18F]SMBT-1) for positron emission tomography (PET) brain imaging. Brain MAO-B expression is widespread, predominantly within astrocytes. Reactive astrogliosis in response to neurodegenerative disease pathology is associated with MAO-B overexpression. Fourteen elderly subjects (8 control, 5 mild cognitive impairment, 1 Alzheimer's disease) with amyloid ([11C]PiB) and tau ([18F]flortaucipir) imaging assessments underwent dynamic [18F]SMBT-1 PET imaging with arterial input function determination. [18F]SMBT-1 showed high brain uptake and a retention pattern consistent with the known MAO-B distribution. A two-tissue compartment (2TC) model where the K1/k2 ratio was fixed to a whole brain value best described [18F]SMBT-1 kinetics. The 2TC total volume of distribution (VT) was well identified and highly correlated (r2∼0.8) with post-mortem MAO-B indices. Cerebellar grey matter (CGM) showed the lowest mean VT of any region and is considered the optimal pseudo-reference region. Simplified analysis methods including reference tissue models, non-compartmental models, and standard uptake value ratios (SUVR) agreed with 2TC outcomes (r2 > 0.9) but with varying bias. We found the CGM-normalized 70-90 min SUVR to be highly correlated (r2 = 0.93) with the 2TC distribution volume ratio (DVR) with acceptable bias (∼10%), representing a practical alternative for [18F]SMBT-1 analyses.

CAIDE Score, Alzheimer's Disease Pathology, and Cognition in Cognitively Normal Adults: The CABLE Study.

Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score serves as a credible predictor of an individual's risk of dementia. However, studies on the link of the CAIDE score to Alzheimer's disease (AD) pathology are scarce. To explore the links of CAIDE score to cerebrospinal fluid (CSF) biomarkers of AD as well as to cognitive performance. In the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, we recruited 600 cognitively normal participants. Correlations between the CAIDE score and CSF biomarkers of AD as well as cognitive performance were probed through multiple linear regression models. Whether the correlation between CAIDE score and cognitive performance was mediated by AD pathology was researched by means of mediation analyses. Linear regression analyses illustrated that CAIDE score was positively associated with tau-related biomarkers, including pTau (p < 0.001), tTau (p < 0.001), as well as tTau/Aβ42 (p = 0.008), while it was in negative association with cognitive scores, consisting of MMSE score (p < 0.001) as well as MoCA score (p < 0.001). The correlation from CAIDE score to cognitive scores was in part mediated by tau pathology, with a mediation rate varying from 3.2% to 13.2% . A higher CAIDE score, as demonstrated in our study, was linked to more severe tau pathology and poorer cognitive performance, and tau pathology mediated the link of CAIDE score to cognitive performance. Increased dementia risk will lead to cognitive decline through aggravating neurodegeneration.

SARS-CoV-2-Induced Type I Interferon Signaling Dysregulation in Olfactory Networks Implications for Alzheimer’s Disease

Type I interferon signaling (IFN-I) perturbations are major drivers of COVID-19. Dysregulated IFN-I in the brain, however, has been linked to both reduced cognitive resilience and neurodegenerative diseases such as Alzheimer’s. Previous works from our group have proposed a model where peripheral induction of IFN-I may be relayed to the CNS, even in the absence of fulminant infection. The aim of our study was to identify significantly enriched IFN-I signatures and genes along the transolfactory route, utilizing published datasets of the nasal mucosa and olfactory bulb amygdala transcriptomes of COVID-19 patients. We furthermore sought to identify these IFN-I signature gene networks associated with Alzheimer’s disease pathology and risk. Gene expression data involving the nasal epithelium, olfactory bulb, and amygdala of COVID-19 patients and transcriptomic data from Alzheimer’s disease patients were scrutinized for enriched Type I interferon pathways. Gene set enrichment analyses and gene–Venn approaches were used to determine genes in IFN-I enriched signatures. The Agora web resource was used to identify genes in IFN-I signatures associated with Alzheimer’s disease risk based on its aggregated multi-omic data. For all analyses, false discovery rates (FDR) &lt;0.05 were considered statistically significant. Pathways associated with type I interferon signaling were found in all samples tested. Each type I interferon signature was enriched by IFITM and OAS family genes. A 14-gene signature was associated with COVID-19 CNS and the response to Alzheimer’s disease pathology, whereas nine genes were associated with increased risk for Alzheimer’s disease based on Agora. Our study provides further support to a type I interferon signaling dysregulation along the extended olfactory network as reconstructed herein, ranging from the nasal epithelium and extending to the amygdala. We furthermore identify the 14 genes implicated in this dysregulated pathway with Alzheimer’s disease pathology, among which HLA-C, HLA-B, HLA-A, PSMB8, IFITM3, HLA-E, IFITM1, OAS2, and MX1 as genes with associated conferring increased risk for the latter. Further research into its druggability by IFNb therapeutics may be warranted.

Akap5 links synaptic dysfunction to neuroinflammatory signaling in a mouse model of infantile neuronal ceroid lipofuscinosis

Palmitoylation and depalmitoylation represent dichotomic processes by which a labile posttranslational lipid modification regulates protein trafficking and degradation. The depalmitoylating enzyme, palmitoyl-protein thioesterase 1 (PPT1), is associated with the devastating pediatric neurodegenerative condition, infantile neuronal ceroid lipofuscinosis (CLN1). CLN1 is characterized by the accumulation of autofluorescent lysosomal storage material (AFSM) in neurons and robust neuroinflammation. Converging lines of evidence suggest that in addition to cellular waste accumulation, the symptomology of CLN1 corresponds with disruption of synaptic processes. Indeed, loss of Ppt1 function in cortical neurons dysregulates the synaptic incorporation of the GluA1 AMPA receptor (AMPAR) subunit during a type of synaptic plasticity called synaptic scaling. However, the mechanisms causing this aberration are unknown. Here, we used the Ppt1−/− mouse model (both sexes) to further investigate how Ppt1 regulates synaptic plasticity and how its disruption affects downstream signaling pathways. To this end, we performed a palmitoyl-proteomic screen, which provoked the discovery that Akap5 is excessively palmitoylated at Ppt1−/− synapses. Extending our previous data, in vivo induction of synaptic scaling, which is regulated by Akap5, caused an excessive upregulation of GluA1 in Ppt1−/− mice. This synaptic change was associated with exacerbated disease pathology. Furthermore, the Akap5- and inflammation-associated transcriptional regulator, nuclear factor of activated T cells (NFAT), was sensitized in Ppt1−/− cortical neurons. Suppressing the upstream regulator of NFAT activation, calcineurin, with the FDA-approved therapeutic FK506 (Tacrolimus) modestly improved neuroinflammation in Ppt1−/− mice. These findings indicate that the absence of depalmitoylation stifles synaptic protein trafficking and contributes to neuroinflammation via an Akap5-associated mechanism.

Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency

Branched chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a recently described inherited neurometabolic disorder of branched chain amino acid (BCAA) metabolism implying increased BCAA catabolism. It has been hypothesized that a severe reduction in systemic BCAA levels underlies the disease pathophysiology, and that BCAA supplementation may ameliorate disease phenotypes. To test this hypothesis, we characterized a recent mouse model of BCKDK deficiency and evaluated the efficacy of enteral BCAA supplementation in this model. Surprisingly, BCAA supplementation exacerbated neurodevelopmental deficits and did not correct biochemical abnormalities despite increasing systemic BCAA levels. These data suggest that aberrant flux through the BCAA catabolic pathway, not just BCAA insufficiency, may contribute to disease pathology. In support of this conclusion, genetic re-regulation of BCAA catabolism, through Dbt haploinsufficiency, partially rescued biochemical and behavioral phenotypes in BCKDK deficient mice. Collectively, these data raise into question assumptions widely made about the pathophysiology of BCKDK insufficiency and suggest a novel approach to develop potential therapies for this disease.

Examining iron-related off-target binding effects of 18F-AV1451 PET in the cortex of Aβ+ individuals.

The presence of neurofibrillary tangles containing hyper-phosphorylated tau is a characteristic of Alzheimer's disease (AD) pathology. The positron emission tomography (PET) radioligand sensitive to tau neurofibrillary tangles (18F-AV1451) also binds with iron. This off-target binding effect may be enhanced in older adults on the AD spectrum, particularly those with amyloid-positive biomarkers. Here, we examined group differences in 18F-AV1451 PET after controlling for iron-sensitive measures from magnetic resonance imaging (MRI) and its relationships to tissue microstructure and cognition in 40 amyloid beta positive (Aβ+) individuals, 20 amyloid beta negative (Aβ-) with MCI and 31 Aβ- control participants. After controlling for iron, increased 18F-AV1451 PET uptake was found in the temporal lobe and hippocampus of Aβ+ participants compared to Aβ- MCI and control participants. Within the Aβ+ group, significant correlations were seen between 18F-AV1451 PET uptake and tissue microstructure and these correlations remained significant after controlling for iron. These findings indicate that off-target binding of iron to the 18F-AV1451 ligand may not affect its sensitivity to Aβ status or cognition in early-stage AD.

Identification of diffusion, kurtosis, and propagator MRI markers of Alzheimer’s disease pathology in post-mortem human tissue

Abstract Alzheimer’s disease (AD) is an irreversible degenerative brain disease affecting 6.7 million Americans and while the hallmark AD pathologies of plaques and tangles follow a stereotyped progression during the course of the disease, clinical markers for early diagnosis are lacking and approximately 20% of all AD cases are ultimately misdiagnosed. Conventional clinical MRI is capable of reporting severe brain atrophy, but fails to recognize earlier biomarkers associated with more subtle cellular and molecular changes. Microstructural Magnetic Resonance Imaging (MRI) techniques are promising to address this challenge and may sensitively detect and distinguish tissue degeneration, tauopathies, and beta amyloid plaques to improve accuracy of diagnosis and enable early detection. The objective of this study was to identify and compare the most promising microstructural markers of AD pathology over a range of diffusion and relaxometry-based MRI techniques from conventional to advanced. To accomplish this, we performed MRI microscopy of post-mortem human temporal lobe specimens (n = 14) at high resolution and image quality and evaluated the relative influence of metrics across multiple microstructural MRI frameworks using principal component analysis (PCA). We performed additional correlation analysis between metrics identified by PCA and clinical neuropathology scores of Braak stage and plaque and tangle load. Hippocampal diffusion and restriction metrics contributed most to the first principal component, and the correlation with Braak score was positive for diffusivity and negative for restriction metrics. Additionally, the MAP-MRI propagator anisotropy (PA) metric of microscale anisotropy was strongly and negatively correlated with AD pathology while the conventional fractional anisotropy (FA) metric showed little or no correspondence and there was not a strong association between FA and PA by PCA. Entorhinal cortex findings were minimal except for reported increases in restriction due to plaque content. Taken together, our findings suggest that microstructural MRI metrics of restriction and diffusion are most prominent and may reflect degenerative processes in AD brain tissue and that microscale anisotropy may be more advantageous than conventional FA for the detection of subtle and earlier cellular changes in AD.

Metabolomics for Clinical Biomarker Discovery and Therapeutic Target Identification

As links between genotype and phenotype, small-molecule metabolites are attractive biomarkers for disease diagnosis, prognosis, classification, drug screening and treatment, insight into understanding disease pathology and identifying potential targets. Metabolomics technology is crucial for discovering targets of small-molecule metabolites involved in disease phenotype. Mass spectrometry-based metabolomics has implemented in applications in various fields including target discovery, explanation of disease mechanisms and compound screening. It is used to analyze the physiological or pathological states of the organism by investigating the changes in endogenous small-molecule metabolites and associated metabolism from complex metabolic pathways in biological samples. The present review provides a critical update of high-throughput functional metabolomics techniques and diverse applications, and recommends the use of mass spectrometry-based metabolomics for discovering small-molecule metabolite signatures that provide valuable insights into metabolic targets. We also recommend using mass spectrometry-based metabolomics as a powerful tool for identifying and understanding metabolic patterns, metabolic targets and for efficacy evaluation of herbal medicine.

Multimorbidity-associated emergency hospital admissions: a “screen and link” strategy to improve outcomes for high-risk patients in sub-Saharan Africa: a prospective multicentre cohort study protocol

Background The prevalence of multimorbidity (the presence of two or more chronic health conditions) is rapidly increasing in sub–Saharan Africa. Hospital care pathways that focus on single presenting complaints do not address this pressing problem. This has the potential to precipitate frequent hospital readmissions, increase health system and out-of-pocket expenses, and may lead to premature disability and death. We aim to present a description of inpatient multimorbidity in a multicentre prospective cohort study in Malawi and Tanzania. Primary objectives Determine prevalence of multimorbid disease among adult medical admissions and measure patient outcomes. Health Economic: Measure economic costs incurred and changes in health-related quality of life (HRQoL) at 90 days post-admission. Situation analysis: Qualitatively describe pathways of patients with multimorbidity through the health system. Secondary objectives Determine hospital readmission free survival and markers of disease control 90 days after admission. Health Economic: Present economic costs from patient and health system perspective, sub-analyse costs and HRQoL according to presence of different diseases. Situation analysis: Understand health literacy related to their own diseases and experience of care for patients with multimorbidity and their caregivers. Methods This is a prospective longitudinal cohort study of adult (≥18 years) acute medical hospital admissions with nested health economic and situation analysis in four hospitals: 1) Queen Elizabeth Central Hospital, Blantyre, Malawi; 2) Chiradzulu District Hospital, Malawi; 3) Hai District Hospital, Boma Ng’ombe, Tanzania; 4) Muhimbili National Hospital, Dar-es-Salaam, Tanzania. Follow-up duration will be 90 days from hospital admission. We will use consecutive recruitment within 24 hours of emergency presentation and stratified recruitment across four sites. We will use point-of-care tests to refine estimates of disease pathology. We will conduct qualitative interviews with patients, caregivers, healthcare providers and policymakers; focus group discussions with patients and caregivers, and observations of hospital care pathways.

Platelet lipidomics and de novo lipogenesis: impact on health and disease.

Lipids play vital roles in platelet structure, signaling, and metabolism. In addition to capturing exogenous lipids, platelets possess the capacity for de novo lipogenesis, regulated by acetyl-coA carboxylase 1 (ACC1). This review aims to cover the critical roles of platelet de novo lipogenesis and lipidome in platelet production, function, and diseases. Upon platelet activation, approximately 20% of the platelet lipidome undergoes significant modifications, primarily affecting arachidonic acid-containing species. Multiple studies emphasize the impact of de novo lipogenesis, with ACC1 as key player, on platelet functions. Mouse models suggest the importance of the AMPK-ACC1 axis in regulating platelet membrane arachidonic acid content, associated with TXA2 secretion, and thrombus formation. In human platelets, ACC1 inhibition leads to reduced platelet reactivity. Remodeling of the platelet lipidome, alongside with de novo lipogenesis, is also crucial for platelet biogenesis. Disruptions in the platelet lipidome are observed in various pathological conditions, including cardiovascular and inflammatory diseases, with associations between these alterations and shifts in platelet reactivity highlighted. The platelet lipidome, partially regulated by ACC-driven de novo lipogenesis, is indispensable for platelet production and function. It is implicated in various pathological conditions involving platelets.

Chlamydia pneumoniae in Alzheimer's disease pathology

While recent advances in diagnostics and therapeutics offer promising new approaches for Alzheimer's disease (AD) diagnosis and treatment, there is still an unmet need for an effective remedy, suggesting new avenues of research are required. Besides many plausible etiologies for AD pathogenesis, mounting evidence supports a possible role for microbial infections. Various microbes have been identified in the postmortem brain tissues of human AD patients. Among bacterial pathogens in AD, Chlamydia pneumoniae (Cp) has been well characterized in human AD brains and is a leading candidate for an infectious involvement. However, no definitive studies have been performed proving or disproving Cp's role as a causative or accelerating agent in AD pathology and cognitive decline. In this review, we discuss recent updates for the role of Cp in human AD brains as well as experimental models of AD. Furthermore, based on the current literature, we have compiled a list of potential mechanistic pathways which may connect Cp with AD pathology.

Effect of Clemizole on Alpha-Synuclein-Preformed Fibrils-Induced Parkinson's Disease Pathology: A Pharmacological Investigation.

Parkinson's disease (PD) is a neurodegenerative disorder associated with mitochondrial dysfunctions and oxidative stress. However, to date, therapeutics targeting these pathological events have not managed to translate from bench to bedside for clinical use. One of the major reasons for the lack of translational success has been the use of classical model systems that do not replicate the disease pathology and progression with the same degree of robustness. Therefore, we employed a more physiologically relevant model involving alpha-synuclein-preformed fibrils (PFF) exposure to SH-SY5Y cells and Sprague Dawley rats. We further explored the possible involvement of transient receptor potential canonical 5 (TRPC5) channels in PD-like pathology induced by these alpha-synuclein-preformed fibrils with emphasis on amelioration of oxidative stress and mitochondrial health. We observed that alpha-synuclein PFF exposure produced neurobehavioural deficits that were positively ameliorated after treatment with the TRPC5 inhibitor clemizole. Furthermore, Clemizole also reduced p-alpha-synuclein and diminished oxidative stress levels which resulted in overall improvements in mitochondrial biogenesis and functions. Finally, the results of the pharmacological modulation were further validated using siRNA-mediated knockdown of TRPC5 channels, which also decreased p-alpha-synuclein expression. Together, the results of this study could be superimposed in the future for exploring the beneficial effects of TRPC5 channel modulation for other neurodegenerative disorders and synucleopathies.

Stem Cell‐Based Therapies and Tissue Engineering Innovations for Tendinopathy: A Comprehensive Review of Current Strategies and Future Directions

AbstractTendon diseases commonly lead to physical disability, exerting a profound impact on the routine of affected patients. These conditions respond poorly to existing treatments, presenting a substantial challenge for orthopedic scientists. Research into clinical translational therapy has yet to yield highly versatile interventions capable of effectively addressing tendon diseases, including tendinopathy. Stem cell‐based therapies have emerged as a promising avenue for modifying the biological milieu through the secretion of regenerative and immunomodulatory factors. The current review provides an overview of the intricate tendon microenvironment, encompassing various tendon stem progenitor cells within distinct tendon sublocations, gene regulation, and pathways pertinent to tendon development, and the pathology of tendon diseases. Subsequently, the advantages of stem cell‐based therapies are discussed that utilize distinct types of autologous and allogeneic stem cells for tendon regeneration at the translational level. Moreover, this review outlines the challenges, gaps, and future innovations to propose a consolidated stem cell‐based therapy to treat tendinopathy. Finally, regenerative soluble therapies, insoluble bio‐active therapies, along with insoluble bio‐active therapies, and implantable 3D scaffolds for tendon tissue engineering are discussed, thereby presenting a pathway toward enhanced tissue regeneration and engineering.

Foot problems in older adults presenting to a Falls and Balance Clinic.

Foot problems, including musculoskeletal problems, peripheral neuropathy, peripheral arterial disease and dermatologic pathology are common in older adults and are associated with increased risk of falling. Multicomponent podiatry interventions have been shown to reduce the incidence of falls. This paper aims to identify older adults requiring podiatry input in a Falls and Balance clinic; to describe the model of foot health care they receive; to explore cross-sectional associations between foot problems and function and ultimately demonstrate the role of podiatry input in the multidisciplinary management of falls risk. Cohort study of patients attending a Falls and Balance Clinic for Comprehensive Geriatric Assessment. Demographic information was collected and functional independence, mobility, foot problems and footwear were assessed in clinic. One-hundred and two patients were included; median age 79.3 [73-84.3] years, 68.6% female, 93.1% residing independently, 62.7% used a gait aid. Podiatry referrals were made in 80.4% of cases, with muscle weakness being the most common problem identified (90.2%); 74.8% were found to be wearing inappropriate footwear. Most patients received footwear education and half were prescribed foot and ankle strengthening exercises. Hallux and lesser toe weakness were associated with lower Short Physical Performance Battery scores (p&lt;0.001). The majority of older adults in the Falls and Balance Clinic required podiatry input, with foot weakness and inappropriate footwear being common reasons for referral. Those with weakness of the hallux and lesser toes had poorer balance and mobility, which is known to be associated with greater falls risk. This highlights the need for podiatry assessment and interventions as part of the multidisciplinary approach to the management of falls risk in older adults.

Abstract PO2-13-10: Predicting outcomes in locally advanced breast cancer through profiling post-neoadjuvant tissue-based minimal residual disease

Abstract Background: Neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can down-stage disease prior to surgery, monitor chemo-sensitivity, and provide key prognostic information via pathologic response that guides adjuvant treatment. Greater residual disease as assessed by the residual cancer burden (RCB) index is associated with inferior outcomes but imperfectly predicts recurrence, particularly in triple negative breast cancer (TNBC) where there is heterogeneity of outcomes across RCB scores. As an alternative to RCB and PCR, blood-based minimal residual disease (MRD) from circulating tumor DNA (ctDNA) has been explored. However, poor sensitivity limits ctDNA, which is typically negative post-NAC when treatment decisions are made in patients who later recur. Methods: To address this lack of sensitivity, we developed tissue-based MRD (t-MRD) to assess molecular disease burden in post-NAC breast and lymph node resection tissue. We performed whole exome sequencing on diagnostic tumor and matched germline tissues from five pilot patients with early-stage TNBC with a range of responses to NAC. For each patient, we designed a personalized assay to track tumor-specific SNVs, combined with limited panel of genes recurrently mutated in breast cancer, to enable MRD detection. We then applied this assay to DNA from individual pathology blocks from the tumor resection via ultra-deep targeted hybrid capture. We assessed each sample for the presence of MRD using a Monte Carlo statistical framework to integrate all tumor mutations as previously described (Newman et al, Nature Biotechnology 2016). We aggregated results across all pathology blocks from each case to define each patient’s t-MRD profile and assessed the performance of t-MRD versus gold standard pathologic assessment. Results: We tracked a mean of 136 MRD reporters per case across 119 post-NAC blocks derived from five patients. Twenty-five samples had pathologic residual disease and 28 had detectable t-MRD. There was strong concordance between t-MRD mean allele frequency (AF) and tumor cellularity as assessed by pathology, defined as percent cellularity within the region containing viable tumor (Spearman r = 0.9052, p&amp;lt; 0.0001), and excellent classification of true positive pathology samples by genomic sequencing (AUC = 0.9675, p &amp;lt; 0.0001). Samples (n = 6) where t-MRD but not pathologic residual disease was detected had a lower mean AF than those where there was also histologic residual disease (p=0.0001). Among the five studied cases, we confirmed a molecular complete response with no t-MRD detected in the RCB-0 case (0/44 t-MRD positive blocks). In the two RCB-III cases, we observed more diffuse t-MRD than that assessed by pathology (n = 4 additional blocks with t-MRD but not pathologic disease detected), and in the RCB-II case, we detected minimal t-MRD in only a single block where pathology did not detect residual disease. Significance: By applying blood-based MRD assessment tools to tumor tissue, we developed t-MRD to profile molecular residual disease at the landmark post-NAC timepoint when disease burden is low and adjuvant treatment decisions are made. We demonstrated high concordance with gold standard pathologic assessment, with increased sensitivity and minimal false positive signal. Further studies assessing the additional prognostic value of t-MRD beyond stage-based prognostication and post-NAC RCB scores are ongoing. Citation Format: Julia Ransohoff, Mia Carleton, Alisha Birk, Gregory Bean, Melinda Telli, Ash Alizadeh, James Ford, George Duran, Michael Khodadoust, David Kurtz. Predicting outcomes in locally advanced breast cancer through profiling post-neoadjuvant tissue-based minimal residual disease [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-10.

Abstract PO3-12-07: Utility of Volumetric Measurement for Clinical Diagnosis of Breast Cancer-Related Lymphedema

Abstract Background: Early detection of Breast cancer-related lymphedema (BCRL) is crucial since it can significantly reduce the negative impact on a patient’s quality of life after breast cancer treatment. Several objective screening methods have been used in prior studies but have not proven accurate due to a lack of standardization. Bioimpedance spectroscopy (BIS), which assesses tissue resistance to an electric current and converts it into a score to measure interstitial fluid content, has proven to be an accurate tool in diagnosing lymphedema. SOZO® is a BIS device that generates quantitative results in real time and provides a Lymphedema Index (L-Dex) score by measuring the patient's extracellular fluid volume. However, there is a paucity of literature highlighting its clinical applicability. Thus, we aimed to evaluate the clinical utility of SOZO® in diagnosing BCRL in patients undergoing breast cancer surgery. Materials &amp; Methods: A retrospective chart review was carried out of patients who underwent axillary surgery from January 2019 to December 2022. Demographic information such as age, body mass index (BMI), gender, ethnicity, disease pathology, cancer stage, type of axillary surgery, neoadjuvant and adjuvant treatment received was recorded. Patients undergoing sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) were assessed for their preoperative L-Dex score, and they were followed up postoperatively with repeated measurements of their L-Dex score to diagnose lymphedema for a year at 3 months intervals. Clinical lymphedema was defined as those having an absolute L-Dex score of more than +10 and an increase in L-Dex score by 6.5 from the baseline. SOZO® scores measured at each follow-up were compared to their preoperative baseline scores. Results: A total of 200 patients’ data was evaluated whose mean age and BMI were 57.5+10.9 years and 29.6+5.6 kg/m2, respectively. Eighty-five percent of the patients belonged to ethnic minority groups. Furthermore, 84.5% (n=169) of the patients had SLNB, and 15.5% (n=31) had ALND. All the patients included in the study had their preoperative and postoperative quarterly L-Dex scores recorded. Pre- and post-operative L-Dex scores had a mean of -0.20+6.6 and 0.61+6.8, respectively. A total of 20 (10%) patients developed lymphedema without symptoms detected by SOZO®, with 19 (9.5%) resolving at their respective 3-month follow-up and 1 (0.5%) patient with persistent lymphedema at the end of the 24-month follow-up. All 20 patients were treated with a compression sleeve. Of the 20 patients with lymphedema, 4 patients underwent ALND, whereas 16 patients had SLNB. When compared to their preoperative baseline scores, all patients' SOZO® measurements had an absolute score of more than 10 and an increase of 6.5 from their baseline score. Additionally, 21 other patients had an increase in score of 6.5 from their baseline measurements but did not meet the cut-off range of an absolute score of +10. Therefore, we excluded them from the diagnosis of BCRL, and none of these patients later developed any signs of BCRL, such as swelling, pain, or discomfort. Conclusion: SOZO® procedure can accurately detect BCRL. In our study, 1 patient developed clinical lymphedema after undergoing SLNB and was diagnosed using SOZO®. Additionally, 19 patients who were initially diagnosed with lymphedema were later categorized as transient due to the resolution of lymphedema on follow-up. Early identification of transient lymphedema using SOZO® resulted in the prevention of a potentially life-long debilitation in our patients. Moreover, our findings underscore that an increase in SOZO® score from the baseline by &amp;gt; 6.5 with an absolute score of more than +10 should be the threshold to clinically diagnose lymphedema. Future studies with larger sample sizes and longer follow-up duration are necessary to understand better the utility of SOZO® in diagnosing BCRL. Table 1: Baseline characteristics and follow-up data of the patients included in the study. Citation Format: Fardeen Bhimani, Sheldon Feldman, Yu Chen, Anjuli Gupta, Jessica Pastoriza, Areej Shihabi, Maureen McEvoy. Utility of Volumetric Measurement for Clinical Diagnosis of Breast Cancer-Related Lymphedema [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-12-07.

Progression subtypes in Parkinson’s disease identified by a data-driven multi cohort analysis

The progression of Parkinson’s disease (PD) is heterogeneous across patients, affecting counseling and inflating the number of patients needed to test potential neuroprotective treatments. Moreover, disease subtypes might require different therapies. This work uses a data-driven approach to investigate how observed heterogeneity in PD can be explained by the existence of distinct PD progression subtypes. To derive stable PD progression subtypes in an unbiased manner, we analyzed multimodal longitudinal data from three large PD cohorts and performed extensive cross-cohort validation. A latent time joint mixed-effects model (LTJMM) was used to align patients on a common disease timescale. Progression subtypes were identified by variational deep embedding with recurrence (VaDER). In each cohort, we identified a fast-progressing and a slow-progressing subtype, reflected by different patterns of motor and non-motor symptoms progression, survival rates, treatment response, features extracted from DaTSCAN imaging and digital gait assessments, education, and Alzheimer’s disease pathology. Progression subtypes could be predicted with ROC-AUC up to 0.79 for individual patients when a one-year observation period was used for model training. Simulations demonstrated that enriching clinical trials with fast-progressing patients based on these predictions can reduce the required cohort size by 43%. Our results show that heterogeneity in PD can be explained by two distinct subtypes of PD progression that are stable across cohorts. These subtypes align with the brain-first vs. body-first concept, which potentially provides a biological explanation for subtype differences. Our predictive models will enable clinical trials with significantly lower sample sizes by enriching fast-progressing patients.