Markers Of Disease Progression Research Articles

Treatment Patterns and Persistent Disease Activity in Patients With Eosinophilic Esophagitis: A Retrospective Cohort Study

Limited real-world nontertiary care evidence on the patient therapeutic journey and disease burden of eosinophilic esophagitis (EoE) exists. The aim was to collect real-world data on the EoE patient journey across different age groups. This retrospective, real-world, cohort study used electronic medical records and claims data provided by a rural integrated US healthcare system. Eligibility criteria included ≥ 2 diagnoses of EoE (2009-2018), ≥ 1 endoscopy, and ≥ 12 months of data before and after the index date (the first endoscopy date during the 180 days before and the 365 days after the first EoE diagnosis). Clinical findings, all-cause healthcare resource utilization, specialists consulted, therapies, and markers of disease progression were analyzed. Overall, 613 patients were enrolled: 0-11 (children, n= 182), 12-17 (adolescents, n= 146), 18-54 (adults, n= 244), and ≥ 55 years old (older adults, n= 41). Post index, the prevalence of signs and symptoms increased. At baseline, most endoscopies were abnormal (80.5%) and most peak eosinophil counts were > 15 eosinophils/high-power field (87.9%); post index, all age groups had endoscopic and histologic improvements. However, 3 years post index, abnormal endoscopic appearance (62.3%) and histologic activity (51.2%) were observed. Patients of all ages exhibited considerable all-cause healthcare resource utilization. During follow-up, 86.3% of patients consulted a specialist. Before and after index, proton pump inhibitors and corticosteroids were the most commonly used pharmacological therapies; 44.0% of patients discontinued their first treatment post index. Disease progression occurred in 13.9% of patients post index. In this setting, patients with EoE irrespective of age face difficult therapeutic journeys with substantial disease burden.

Identification of inflammatory markers as indicators for disease progression in primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is a systemic autoimmune disorder that affects various systems in the body, resulting in symptoms such as dry eyes and mouth, pain, and fatigue. Inflammation plays a critical role in pSS and its associated complications, with chronic inflammation being a common occurrence in patients with pSS. This review of the literature highlights inflammatory markers that could serve as indicators to predict disease progression in pSS. Laboratory markers are frequently and significantly increased in pSS patients, including erythrocyte sedimentation rate, C-reactive protein, complement proteins, S100 proteins, cytokines (IFNs, CD40 ligand, soluble CD25, rheumatoid factors, interleukins, and TNF-α), and chemokines (CXCL13, CXCL10, CCL2, CXCL11, and CCL25). These inflammatory markers can be used as prognostic indicators for disease progression in pSS. In conclusion, the results from the studies reported in this review indicate that high levels of inflammatory markers may serve as markers for disease progression of pSS, which, in turn, may be valuable in predicting disease outcome.

Lung Structure and Risk of Sleep Apnea in SPIROMICS.

The SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) is a prospective cohort study that enrolled 2981 participants with the goal of identifying new chronic obstructive pulmonary disease (COPD) subgroups and intermediate markers of disease progression. Individuals with COPD and obstructive sleep apnea (OSA) experience impaired quality of life and more frequent exacerbations. COPD severity also associates with computed tomography scan-based emphysema and alterations in airway dimensions. The objective was to determine whether the combination of lung function and structure influences the risk of OSA among current and former smokers. Using 2 OSA risk scores, the Berlin Sleep Questionnaire (BSQ), and the DOISNORE50 (Diseases, Observed apnea, Insomnia, Snoring, Neck circumference > 18 inches, Obesity with body mass index [BMI] > 32, R = are you male, Excessive daytime sleepiness, 50 = age ≥ 50) (DIS), 1767 current and former smokers were evaluated for an association of lung structure and function with OSA risk. The study cohort's mean age was 63 years, BMI was 28 kg/m2, and forced expiratory volume in 1 second (FEV1) was 74.8% predicted. The majority were male (55%), White (77%), former smokers (59%), and had COPD (63%). A high-risk OSA score was reported in 36% and 61% using DIS and BSQ respectively. There was a 9% increased odds of a high-risk DIS score (odds ratio [OR]=1.09, 95% confidence interval [CI]:1.03-1.14) and nominally increased odds of a high-risk BSQ score for every 10% decrease in FEV1 %predicted (OR=1.04, 95%CI: 0.998-1.09). Lung function-OSA risk associations persisted after additionally adjusting for lung structure measurements (%emphysema, %air trapping, parametric response mapping for functional small airways disease, , mean segmental wall area, tracheal %wall area, dysanapsis) for DIS (OR=1.12, 95%CI:1.03-1.22) and BSQ (OR=1.09, 95%CI:1.01-1.18). Lower lung function independently associates with having high risk for OSA in current and former smokers. Lung structural elements, especially dysanapsis, functional small airways disease, and tracheal %wall area strengthened the effects on OSA risk.

Temporal and spatial progression of microstructural cerebral degeneration in ALS: A multicentre longitudinal diffusion tensor imaging study

ObjectiveThe corticospinal tract (CST) reveals progressive microstructural alterations in ALS measurable by DTI. The aim of this study was to evaluate fractional anisotropy (FA) along the CST as a longitudinal marker of disease progression in ALS. MethodsThe study cohort consisted of 114 patients with ALS and 110 healthy controls from the second prospective, longitudinal, multicentre study of the Canadian ALS Neuroimaging Consortium (CALSNIC-2). DTI and clinical data from a harmonized protocol across 7 centres were collected. Thirty-nine ALS patients and 61 controls completed baseline and two follow-up visits and were included for longitudinal analyses. Whole brain-based spatial statistics and hypothesis-guided tract-of-interest analyses were performed for cross-sectional and longitudinal analyses. ResultsFA was reduced at baseline and longitudinally in the CST, mid-corpus callosum (CC), frontal lobe, and other ALS-related tracts, with alterations most evident in the CST and mid-CC. CST and pontine FA correlated with functional impairment (ALSFRS-R), upper motor neuron function, and clinical disease progression rate. Reduction in FA was largely located in the upper CST; however, the longitudinal decline was greatest in the lower CST. Effect sizes were dependent on region, resulting in study group sizes between 17 and 31 per group over a 9-month interval. Cross-sectional effect sizes were maximal in the upper CST; whereas, longitudinal effect sizes were maximal in mid-callosal tracts. ConclusionsProgressive microstructural alterations in ALS are most prominent in the CST and CC. DTI can provide a biomarker of cerebral degeneration in ALS, with longitudinal changes in white matter demonstrable over a reasonable observation period, with a feasible number of participants, and within a multicentre framework.

Amyloid PET imaging

Extracellular amyloid deposition in brain tissue is a hallmark of Alzheimer’s disease. Despite being the most common neurodegenerative disorder, it poses a major diagnostic challenge due to the lack of disease-specific biomarkers. Additionally, plaque-forming amyloid deposits are not unique to Alzheimer’s disease, but are also present in a high proportion of the elderly, as well as in patients with other neurodegenerative conditions such as dementia with Lewy bodies. Histopathological examination is the only reliable method for diagnosing the disease, but it is practically impossible to perform in vivo. Since Alzheimer’s disease is a disorder that develops asymptomatically over many years and eventually leads to severe dementia, new insights into the risk factors and markers of disease progression in the preclinical stage of the disease are needed. A better understanding of the underlying pathology is essential for the development of new therapies. In the past, this understanding came mainly from pathological studies. Positron emission tomography (PET) imaging detects the presence and activity of pathophysiological processes in vivo. By targeting different biological pathways, PET elucidates the metabolic activity of the processes that drive disease progression. Ongoing studies aim to clarify whether amyloid PET imaging can also be useful in assessing treatment response. In this review, recent advances in amyloid PET imaging that have significantly improved our understanding of the pathological basis of this disease are discussed.

Markers of end-stage renal disease progression: beyond the GFR

Chronic kidney disease may progress to end-stage renal disease (ESRD) with a high risk of morbidity and mortality. ESRD requires immediate initiation of therapy or a decision on dialysis or kidney transplantation. Therefore, timely diagnosis of pathology progression is critical for many patients. ESRD is associated with pathological changes, including inflammation, fibrosis, endocrine disorders and following epigenetic changes in various cells, all these alterations could serve as markers for ESRD identification. This review summarizes conventional and promising biomarkers of ESRD, which can be evaluated in kidney tissue, blood, or urine. Some of them are narrowly specific to a particular pathology, while others are more versatile. We suggested several universal inflammatory, fibrotic, hormonal, and epigenetic markers indicative of severe deterioration of renal function and progression of ESRD for improvement of ESRD diagnostics.

Understanding the Impact of HIV-Associated Bone Marrow Alterations on Erythropoiesis

Human Immunodeficiency Virus (HIV) infection presents a multifaceted challenge, extending beyond its primary impact on the immune system to affect various organ systems. Among these, the bone marrow, the primary site for hematopoiesis, undergoes substantial alterations during HIV infection, profoundly influencing erythropoiesis—the process of red blood cell production. Anemia, a prevalent hematologic complication in HIV-infected individuals, often serves as a marker of disease progression and impacts overall health outcomes. This paper aims to delve into the intricate relationship between HIV-associated bone marrow alterations and their consequential effects on erythropoiesis. The mechanisms underlying bone marrow changes in HIV infection, including direct viral effects, dysregulation of cytokine networks, and inflammatory processes, significantly disrupt the delicate balance necessary for efficient erythropoiesis. The impact of these alterations on erythropoiesis manifests through ineffective red blood cell production, decreased erythropoietin responsiveness, and shortened red blood cell lifespan. Chronic inflammation further complicates erythropoietic processes, contributing to the development and perpetuation of anemia in HIV-infected individuals. Therapeutic interventions encompass a multifaceted approach, including antiretroviral therapy (ART) to control viral replication, erythropoiesis-stimulating agents, and adjunctive nutritional support to manage anemia. However, emerging research targeting bone marrow microenvironmental factors and novel agents stimulating erythropoiesis offer promising avenues for future therapeutic development. Keywords: HIV, bone marrow, erythropoiesis, erythropoietin, antiretroviral therapy

Anemia as a Prognostic Marker for Disease Progression in HIV Infection

Anemia, a prevalent hematologic manifestation in individuals living with Human Immunodeficiency Virus (HIV) infection, has garnered considerable attention as a prognostic indicator for disease progression and adverse clinical outcomes. This abstract presents a comprehensive review elucidating the intricate relationship between anemia and the progression of HIV infection, incorporating epidemiological trends, underlying pathophysiological mechanisms, clinical implications, and prognostic significance. Despite advances in antiretroviral therapy (ART), anemia remains a frequent complication in HIVinfected individuals, posing substantial challenges to patient management. This paper aims to provide a nuanced understanding of anemia's role as a prognostic marker, surpassing its conventional characterization as a hematologic abnormality in the context of HIV infection. Anemia's role as a predictive marker for adverse clinical outcomes in HIV patients is explored, encompassing increased mortality rates, heightened risk of opportunistic infections, accelerated disease progression, and compromised quality of life. The review delves into its prognostic significance, shaping therapeutic decisions and prognostic assessments. This paper encapsulates the criticality of anemia as a prognostic marker for disease progression in HIV infection. Understanding its epidemiology, pathophysiological mechanisms, clinical implications, and prognostic significance is pivotal for informed clinical decision-making, prognostic assessments, and optimizing care paradigms in HIV management. Keywords: Anemia, Prognostic Marker, Disease Progression and HIV

KL-6 in adult polymyositis and dermatomyositis patients and its correlation with interstitial lung disease

BackgroundPulmonary involvement is still regarded as a common cause of morbidity in Polymyositis/Dermatomyositis. Interstitial lung disease can result in potentially fatal consequences such as ventilatory failure, secondary pulmonary arterial hypertension, or cor pulmonale. Early diagnosis of interstitial lung disease is hence a top priority in Polymyositis/Dermatomyositis patients. Krebs von den Lungen-6 is a transmembrane mucoprotein that has recently been identified as a promising marker for interstitial lung disease diagnosis and progression. As a result, it is regarded as a powerful predictor of interstitial lung disease severity. Thirty polymyositis/dermatomyocitis patients were enrolled in this study. Thirty age and sex matched healthy individuals were selected as control group. Cutaneous Dermatomyositis Disease Area Severity index(CDASI) was used for evaluation of skin severity, KL6 was measured using Elisa kit, High-resolution computed tomography, pulmonary function tests were made.ResultsSixteen female and 14 male patients had a mean age of 41.64–8.02 and amedian of the disease duration of 4 years. Fifteen patients (50%) had normal readings on High-resolution computed tomography of the chest HRCT chest, while the other half had significant HRCT chest findings. KL-6 concentrations were seen to be higher in Polymyositis/Dermatomyositis patients mainly those with ILD (mean ± SD 38.66 ± 22.98), compared to the control group (Mean ± S 589.04 ± 409) and in patients without ILD (Mean ± SD 86.70 ± 8.99), (p < 0.001). KL-6 serum concentrations were shown to have a significant connection with the HRCT score (r = 0.803, P < 0.001). Forced vital capacity (FVC%) (r = − 0.910, P < 0.001), forced expiratory volume in 1 s (FEV1%) (r = − 0.767, P < 0.001), and FEV1/FVC% (r = − 0.228, P = 0.112) were all inversely related to KL-6 concentrations.ConclusionIndividuals with PM and DM with concomitant ILD have increased KL-6 serum concentrations in comparison to myositis individuals without ILD, denoting its potential role in diagnosis and follow up of PM/DM with ILD. Further studies are needed to discuss the role of KL6 in large sample of the patient's population, and its correlation with other organ affection rather than ILD. Also to clarify the potentiality of adding the KL6 biomarker to the guidelines of treat to target for Rheumatic diseases with lung affection and to see the effect of treatment on KL6 serum level.

Matrix Metalloproteinase-7 in Urinary Extracellular Vesicles Identifies Rapid Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

There is an unmet need for biomarkers of disease progression in autosomal dominant polycystic kidney disease (ADPKD). This study investigated urinary extracellular vesicles (uEVs) as a source of such biomarkers. Proteomic analysis of uEVs identified matrix metalloproteinase 7 (MMP-7) as a biomarker predictive of rapid disease progression. In validation studies, MMP-7 was predictive in uEVs but not in whole urine, possibly because uEVs are primarily secreted by tubular epithelial cells. Indeed, single-nucleus RNA sequencing showed that MMP-7 was especially increased in proximal tubule and thick ascending limb cells, which were further characterized by a profibrotic phenotype. Together, these data suggest that MMP-7 is a biologically plausible and promising uEV biomarker for rapid disease progression in ADPKD. In ADPKD, there is an unmet need for early markers of rapid disease progression to facilitate counseling and selection for kidney-protective therapy. Our aim was to identify markers for rapid disease progression in uEVs. Six paired case-control groups ( n =10-59/group) of cases with rapid disease progression and controls with stable disease were formed from two independent ADPKD cohorts, with matching by age, sex, total kidney volume, and genetic variant. Candidate uEV biomarkers were identified by mass spectrometry and further analyzed using immunoblotting and an ELISA. Single-nucleus RNA sequencing of healthy and ADPKD tissue was used to identify the cellular origin of the uEV biomarker. In the discovery proteomics experiments, the protein abundance of MMP-7 was significantly higher in uEVs of patients with rapid disease progression compared with stable disease. In the validation groups, a significant >2-fold increase in uEV-MMP-7 in patients with rapid disease progression was confirmed using immunoblotting. By contrast, no significant difference in MMP-7 was found in whole urine using ELISA. Compared with healthy kidney tissue, ADPKD tissue had significantly higher MMP-7 expression in proximal tubule and thick ascending limb cells with a profibrotic phenotype. Among patients with ADPKD, rapid disease progressors have higher uEV-associated MMP-7. Our findings also suggest that MMP-7 is a biologically plausible biomarker for more rapid disease progression.

Challenges and advances in serological and molecular tests to aid leprosy diagnosis.

Leprosy is a neglected chronic infectious disease caused by obligate intracellular bacilli, Mycobacterium leprae and Mycobacterium lepromatosis. Despite multidrug therapy (MDT) success, leprosy accounts for more than 200,000 new cases yearly. Leprosy diagnosis remains based on the dermato-neurologic examination, but histopathology of skin biopsy and bacilloscopy of intradermal scraping are subsidiary diagnostic tests that require expertise and laboratory infrastructure. This minireview summarizes the state of the art of serologic tests to aid leprosy diagnosis, highlighting enzyme-linked immunosorbent assay (ELISA) and point-of-care tests (POCT) biotechnologies. Also, the impact of the postgenomic era on the description of new recombinantly expressed M. leprae-specific protein antigens, such as leprosy Infectious Disease Research Institute (IDRI) diagnostic (LID)-1 is summarized. Highly specific and sensitive molecular techniques to detect M. leprae DNA as the quantitative polymerase chain reaction (qPCR) and the loop-mediated isothermal amplification (LAMP) are briefly reviewed. Serology studies using phenolic glycolipid-I (PGL-I) semi-synthetic antigens, LID-1 fusion antigen, and the single fusion complex natural disaccharide-octyl (NDO)-LID show high sensitivity in multibacillary (MB) patients. However, serology is not applicable to paucibacillary patients, as they have weak humoral response and robust cell-mediated response, requiring tests for cellular biomarkers. Unlike ELISA-based tests, leprosy-specific POCT based on semi-synthetic PGL-I antigens and NDO-LID 1 antigen is easy to perform, cheaper, equipment-free, and can contribute to early diagnosis avoiding permanent incapacities and helping to interrupt M. leprae transmission. Besides its use to help diagnosis of household contacts or at-risk populations in endemic areas, potential applications of leprosy serology include monitoring MDT efficacy, identification of recent infection, especially in young children, as surrogate markers of disease progression to orient adult chemoprophylaxis and as a predictor of type 2 leprosy reactions. Advances in molecular biology techniques have reduced the complexity and execution time of qPCR confirming its utility to help diagnosis while leprosy-specific LAMP holds promise as an adjunct test to detect M. leprae DNA.

Clinical and morphological forms of chronic pancreatitis: features of development, diagnosis and treatment

Introduction. Chronic pancreatitis (CP) is a common disease with a complex pathogenesis, characterized by difficulties in its diagnosis and treatment. Purpose of the study. To determine the main pathogenetic links of clinical and morphological forms of CP, markers of disease progression, to develop a diagnostic algorithm and principles of treatment of patients. Material and methods. 210 patients with CP were examined, who were divided into 4 groups: I - obstructive, II - calcifying, III - fibrous-parenchymal, IV – CP, complicated by pseudocyst. Instrumental, functional, morphological, biochemical, immunological, microbiological methods were used. To study the main morphological and biological changes in the pancreas during the development of CP and to study the effectiveness of the proposed treatment, we conducted experimental studies on 45 laboratory white Wistar male rats weighing 180-230 g. Results. Imbalance of the immune system, oxidative stress, toxic-metabolic disorders, and diseases of the biliary system are important in the development of various forms of CP. However, there are differences in the severity of these changes. The most pronounced activity of fibrotic processes in the pancreas is typical for patients with a long course of the disease and in the presence of complications (pseudocyst). The most unfavorable course and prognosis are seen in the calcifying form of CP. The markers of CP progression are the value of the calcification coefficient of 0.5-1.0, the translocation of DNase I from the cytoplasm to the nucleus of the acinar cell, the activation of collagen formation, the increase in the level of fibrosis activators (TGF-β1, TNF-a), and the intensification of lipid peroxidation processes. An early marker of apoptosis is the translocation of DNase I from the cytoplasm to the nucleus of an acinar cell. Conclusions. The developed diagnostic algorithm allows assessing the pathophysiological features of functional and organic disorders of the pancreas, predicting the course of the disease and choosing the optimal treatment. The proposed treatment of patients with CP effectively reduces the severity of pain and oxidative stress, normalizes the cytokine profile, improves the general condition and quality of life of patients.

Association of plasma biomarkers with imaging markers of brain atrophy and white matter disease across three neurodegenerative diseases and cerebrovascular disease

AbstractBackgroundIt is necessary to better understand the value of plasma biomarkers in reflecting ongoing neurodegenerative processes before widespread use as diagnostic and prognostic tools in specialized clinics and as markers of disease progression in trials. Herein, we investigate their association with imaging markers of brain atrophy and white matter disease across three common neurodegenerative diseases and cerebrovascular disease.MethodPatients from the curated multi‐site Ontario Neurodegenerative Disease Research Initiative (ONDRI) were included in this study, classified by diagnostic group: Alzheimer’s disease/Mild cognitive impairment (AD/MCI, n = 126, age = 71.0±8.2, 55%M), frontotemporal dementia (FTD, n = 53, age = 67.8±7.1, 64%M), Parkinson’s disease (PD, n = 140, age = 67.9±6.3, 78%M) and cerebrovascular disease (CVD, n = 161, age = 69.2±7.4, 68%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using high‐sensitivity Simoa assays. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted using the semi‐automated SABRE pipeline on 3T structural MRI sequences harmonized across sites. Fractions of supratentorial total intracranial volume were used when appropriate. Linear regression models controlling for age and sex were used to test the association between plasma biomarkers and MRI variables in each group separately.ResultIn AD/MCI, higher levels of GFAP, NfL and p‐tau181 were all associated with extensive grey matter atrophy, ventricular expansion and, excluding p‐tau181, with increased white matter hyperintensities. In FTD, increased Aβ42/40 ratio was associated with frontal grey matter atrophy, and higher levels of NfL were associated with ventricular expansion. In PD, higher levels of NfL were associated with frontal, temporal and hippocampal grey matter atrophy. In CVD, higher levels of GFAP and NfL were associated with temporal and subcortical grey matter atrophy and ventricular expansion. Higher levels of GFAP were also associated with enlarged perivascular spaces, while higher levels of NfL were associated with increased lacunes. Finally, still in CVD, higher levels of GFAP and p‐tau181 were associated with increased stroke volumes.ConclusionExcluding Aβ42/40, plasma biomarkers appear to reflect various levels of brain atrophy in all neurodegenerative diseases studied, but reflect markers of white matter disease only in AD/MCI and CVD.

Longitudinal retinal changes in mild cognitive impairment and Alzheimer’s Disease

AbstractBackgroundPrevious studies have shown retinal thickness and vascular alterations in Alzheimer’s disease (AD), even in patients with mild cognitive impairment (MCI), suggesting that retinal parameters are potential biomarkers for AD. However, the prospective observation of retinal markers is still insufficient. In this study, we aimed to observe longitudinal retinal thickness and vascular changes in patients with AD and MCI, and to identify critical retinal markers that significantly change over time.MethodPatients with AD (N = 22) and MCI (N = 21) were recruited from the Shanghai Memory Study. Age‐ and gender‐matched cognitively normal (NC) participants (N = 26) were included from the Shanghai Aging Study. Optical coherence tomography (OCT) and OCT angiography were performed in all participants at baseline and after an average 19.2 months follow‐up to assess changes in peripapillary retinal nerve fiber layer thickness (p‐RNFL), ganglion cell layer thickness (GCC), macular thickness and volume divided by the Early Treatment Diabetic Retinopathy Study grid, retinal vessel density, and fovea avascular zone (FAZ). Differences of monthly variation rate of retinal parameters between NC, MCI, and AD individuals were evaluated.ResultThe monthly variation rates among groups showed significant differences in thickness and volume of full temporal para‐fovea sector, inner temporal peri‐fovea sector, outer temporal para‐fovea sector, and thickness of outer superior hemisphere para‐fovea sector (all P&lt;0.05). There was no difference in the rate of change of p‐RNFL, GCC, retinal vessel density, and FAZ among all groups. Post hoc analysis revealed that the monthly change in thickness and volume of the full‐temporal and outer sectors were significantly faster in AD than in NC, whereas the inner‐temporal sectors changed faster in MCI than in NC groups (all P&lt;0.05). Furthermore, the monthly changes in inner temporal peri‐fovea thickness were faster in MCI than in NC and AD participants (all P&lt;0.05).ConclusionDuring follow‐up, retinal temporal thinning was faster in patients with AD, whilst inner retina‐temporal sector thinning was faster in participants with MCI. Accelerated thinning of temporal sectors of the retina, especially the inner‐temporal sector may be an early marker of AD disease progression.

Evaluating brain age as a marker of autosomal dominant Alzheimer disease progression

AbstractBackgroundEstimates of “brain‐predicted age” quantify apparent brain age compared to normative trajectories of neuroimaging features. Brain‐predicted age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD). We used a previously‐trained model (DeepBrainNet [DBN], Bashyam et al., 2020), which requires minimal MRI pre‐processing, to predict brain age in the Dominantly Inherited Alzheimer Network (DIAN) and evaluated brain age as a marker of ADAD progression.MethodWe used DBN to predict brain age from minimally‐processed, whole‐brain T1 structural MRI scans in 265 ADAD mutation‐carriers (MCs) and 183 non‐carrier controls (NCs). We then tested whether the brain age gap (BAG; difference between predicted and true age) differed as a function of mutation and cognitive status, or estimated years until symptom onset (EYO), and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid‐ß‐42/40), phosphorylated tau (CSF and plasma pTau‐181), neurodegeneration (CSF and plasma neurofilament light [NFL]), and cognition (global neuropsychological composite and CDR‐sum of boxes). Finally, we compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of mutation variants (APP vs. PSEN1 before or after codon 200), APOE E4 carrier status, sex, and education.ResultDBN accurately predicted age in DIAN (Figure 1A). BAG was elevated in symptomatic and asymptomatic MCs, compared to NCs, beginning around ‐10 EYO (Figure 1B,C). BAG, hippocampal volume, and a cortical thickness summary followed similar trajectories across EYO (Figure 1D). BAG was positively associated with PiB PET, CSF and plasma pTau, and CSF and plasma NFL, and was associated with worse cognitive scores, especially in symptomatic MCs (Figure 2). BAG was most elevated in MCs with a PSEN1 mutation before codon 200, but did not differ as a function of APOE, sex, or education (Figure 3).ConclusionWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG tracks well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, DBN‐based BAG offers unique benefits in simplicity of data processing and interpretation.

Association of plasma biomarkers with cognitive domains across three neurodegenerative diseases and cerebrovascular disease

AbstractBackgroundIt is critical to better understand the value of plasma biomarkers in predicting cognitive deficits before widespread use as diagnostic and prognostic tools in specialized clinics and as markers of neurodegenerative disease progression in trials. Herein, we investigate their association with five cognitive domains across three common neurodegenerative diseases and cerebrovascular disease.MethodPatients from the curated multi‐site Ontario Neurodegenerative Disease Research Initiative (ONDRI) were included in this study, classified by diagnostic group: Alzheimer’s disease/Mild cognitive impairment (AD/MCI, n = 126, age = 71.0±8.2, 55%M), frontotemporal dementia spectrum disorders (FTD, n = 53, age = 67.8±7.1, 64%M), Parkinson’s disease (PD, n = 140, age = 67.9±6.3, 78%M) and cerebrovascular disease (CVD, n = 161, age = 69.2±7.4, 68%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using high‐sensitivity Simoa assays. Scores from a 26‐test comprehensive neuropsychological assessment were used to compute composite z‐scores for five cognitive domains: attention &amp; working memory, executive function, language, memory, and visuospatial function. Linear regression models controlling for age, sex, education and APOE E4 allele were used to test the association between plasma biomarkers and cognitive domains in each group separately.ResultIn AD/MCI, higher levels of GFAP, NfL and p‐tau181 were all associated with worse attention &amp; working memory, executive function, and memory. In PD, higher levels of NfL were associated with worse attention &amp; working memory, executive function, and visuospatial function; higher levels of GFAP were also associated with worse executive function. In CVD, higher levels of GFAP were associated with worse executive function, memory and visuospatial function; higher levels of p‐tau181 were also associated with worse memory. In FTD, no associations were found.ConclusionPlasma biomarkers indicative of neuronal and glial pathology are useful to predict the severity of widespread cognitive deficits in AD/MCI, PD, and CVD. Interestingly, p‐tau181 predicted memory deficits in both AD/MCI and CVD, suggesting potential mixed disease or pathological overlap. Plasma Aβ42/40 does not appear to predict any cognitive deficits in any of the neurodegenerative diseases studied. As FTD is highly heterogeneous and had the least number of patients, we are possibly lacking power to detect effects in this group.

Total and posterior cerebral blood flow is associated with white matter hyperintensity volume and Alzheimer’s‐like patterns of brain atrophy in older adults

AbstractBackgroundSmall vessel cerebrovascular disease, often visualized as white matter hyperintensities (WMH) on T2‐weighted MRI scans, contributes to risk, progression, and, possibly, pathogenesis of Alzheimer’s disease (AD). When considered in the context of previous neuroimaging biomarker work in AD, WMH appear to colocalize with other markers of disease risk and progression, including metabolic changes, atrophy, and tau pathology, in areas perfused by the posterior circulation. In the current study, we used a novel MR‐based method, termed phase contrast, to quantitate total cerebral blood flow in anterior and posterior circulations and test its relationship with WMH volume and an AD‐like pattern of brain atrophy in older, community‐dwelling adults.MethodTwo hundred forty‐five older adult participants (77±5.6 mean±SD age, 66% women, 42% Latinx, 30% Black, and 28% White individuals) in the Washington Heights Inwood Columbia Aging Project (WHICAP) received T1‐weighted, T2‐weighted (FLAIR), and phase contrast MR imaging. 2D phase contrast imaging can be used to quantify absolute blood flow rates with cross‐sectional velocity‐encoding of major vasculature leading into the brain. Blood flow rates in the anterior circulation (carotid arteries) and posterior circulation (vertebral arteries) were derived with Medis QFlow 4.0. WMH volume and cortical thickness in AD‐signature regions were derived with in‐house software and FreeSurfer v6.0, respectively. Separate general linear models tested the association of total, anterior, and posterior blood flow rates with WMH volumes and AD‐signature cortical thickness.ResultLower total cerebral blood flow was associated with increased total WMH volume (β = ‐0.14, p&lt;0.05, 95%CI [‐1.37E‐2, ‐7.32E‐4]), an effect that was stronger for posterior flow (β_posterior = ‐0.17, 95%CI [‐3.7E‐2, 2.5E3], β_anterior = ‐0.11, 95%CI [‐1.9E‐2, 5.4E3]). Lower posterior blood flow specifically was associated with lower AD‐signature cortical thickness, but only in older participants (age interaction term: β = ‐3.14, p&lt;0.01, 95%CI [‐2.0E‐4, ‐3.5E‐5]).ConclusionLower total cerebral blood flow, particularly in the posterior circulation, is associated with increased WMH volume and decreased cortical thickness, two neuroimaging markers that are implicated in risk and progression of AD. Future work that examines whether or how diminished total cerebral blood flow accounts for the colocalization of AD biomarkers across modalities will provide insight into the vascular contributions to AD.

Investing Peripheral Monocytes, Targeted Therapy and Treatment Outcomes in Erdheim Chester Disease

Introduction Erdheim Chester Disease (ECD) is a rare, non-Langerhans cell histiocytic disease, characterized as a clonal hematopoietic malignancy in 2016. MAP Kinase and PI3-AKT pathway somatic mutations and/or fusion genes play a significant role in disease pathogenesis, and now shape the landscape of targetable treatment options for this patient population. Additionally, previous research has shown that patients with ECD have a higher frequency of concomitant myeloid neoplasms, with clonal hematopoietic mutations detected in peripheral monocytes in such patients. Methods A retrospective analysis of 19 patients diagnosed with ECD at a single institution over a twenty-year period (2002-2022) was conducted. Inclusion criteria included patients age ≥18, histopathologic diagnosis of ECD, and clinical correlation of disease. The following clinical information was collected for each patient: demographics, molecular diagnostics (if utilized), imaging, treatments rendered and best treatment outcomes. Clinical treatments were divided into ‘conventional’ treatments including chemotherapy, immunotherapy, systemic corticosteroids, surgery or radiation, or targeted therapy including all small molecular inhibitors. Information was translated into binary data for comparison of outcomes by treatment type, time to diagnosis and use of targeted agents. Statistical analysis was performed by unpaired-T tests. Variation in treatment response assessment depended on several factors including the anatomic site(s) of disease, extent of disease burden at diagnosis and imaging modality used to assess disease. Determination of stable, progressive, or complete response was made using RECIST assessments (if CT or MR imaging used) or PERCIST assessments (if PET utilized), in addition to overall clinical response. Results In this analysis, 47% of the patients were females; average age at diagnosis was 51.2 years. 36% of patients were diagnosed within 12 months of symptoms onset. Molecular diagnostics were utilized in 100% of patients, (immunohistochemistry 94%, and sequencing 26%). The most common mutations identified were BRAFV600E (7 of 19) and CD68 (7), followed by CD163 (6), S100+ (5) and specific MAP Kinase pathway mutations (3). Most common primary disease site was extranodal (94% of patients), followed by osseous (63%), dermal (52%) and the central nervous system (36%). 57% of patients were treated with targeted therapy, followed by myelosuppressive therapy and steroids (42%), immunotherapy and radiation (10% each). Partial response or better was observed in 83% of patients. Stable disease was seen more often in patients treated with conventional therapy (33%) as compared to patients treated with targeted molecular therapy (11%) and partial response more often in patients treated with targeted therapy (55%). Complete response was more common with conventional therapy than molecular (66 % versus 33%). Lastly, an evaluation of peripheral blood absolute monocytes in all patients who had progressed on therapy identified a decrease in pre-progression absolute monocytes compared to post-progression monocytes after re-initiation of therapy by a mean value of 0.2 K/µL, although results were imprecise (p = 0.3125, 95% CI -0.2373 to 0.6373) (Figure 1A). A decrease in pre-therapy absolute monocytes compared to post-therapy monocytes was observed as well (averages of.0.49 and 0.33 respectively; p = 0.0988, 95% CI -0.0302 to 0.3408) (Figure 1B). Conclusions Peripheral monocytes have been discovered to play a role in histiocytic disease, but to our knowledge, we are the first to look at progression and activity in ECD, as ECD is not commonly known to have overt blood or marrow disease. We theorize that an increase in circulating monocytes may exist as a direct response to disease progression as monocytes may differentiate into dendritic cells and upregulate major histocompatibility class II expression, although this mechanism remains poorly understood. This observation may further explain the high frequency of concomitant myeloid malignancies seen in patients with ECD who have also been found tp harbor clonal hematopoietic mutations in peripheral blood monocytes. Based on our findings, we advocate for the use of absolute monocyte count as an early marker for disease activity or progression. Further studies to explore this trend are in progress.

Elevated serum neurofilament light chain protein in patients with essential tremor.

Quantification of neurofilament light chain protein in serum (sNfL) enables the neuro-axonal damage in peripheral blood to be reliably assessed and monitored. There is a long-standing debate whether essential tremor represents a 'benign' tremor syndrome or whether it is linked to neurodegeneration. This study aims to investigate sNfL concentrations in essential tremor compared to healthy controls (cross-sectionally and longitudinally) and to assess whether sNfL is associated with motor and nonmotor markers of disease progression. Data of patients with essential tremor from our prospective registry on movement disorders (PROMOVE) were retrospectively analysed. Age-, sex- and body-mass-index-matched healthy controls were recruited from an ongoing community-dwelling aging cohort. sNfL was quantified by an ultra-sensitive single molecule array (Simoa). All participants underwent detailed clinical examination at baseline and after approximately 5 years of follow-up. Thirty-seven patients with clinically diagnosed essential tremor were included and 37 controls. The essential tremor group showed significantly higher sNfL levels compared to healthy controls at baseline and follow-up. sNfL levels increased over time in both groups, and the slope of sNfL increase was similar in the essential tremor and healthy control groups. Comparing patients with a disease duration under 5 years to those with a longer disease duration, the former group had a significantly greater increase of sNfL over time, which strongly correlated to worsening of tremor and cognition. Our findings indicate that neurodegeneration, possibly happening at an early disease stage, might play a role in the pathophysiology of essential tremor.

High cell-free DNA is associated with disease progression, inflammasome activation and elevated levels of inflammasome-related cytokine IL-18 in patients with myelofibrosis.

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder classified among chronic myeloproliferative neoplasms, characterized by exacerbated myeloid and megakaryocytic proliferation and bone marrow fibrosis. It is induced by driver (JAK2/CALR/MPL) and high molecular risk mutations coupled to a sustained inflammatory state that contributes to disease pathogenesis. Patient outcome is determined by stratification into risk groups and refinement of current prognostic systems may help individualize treatment decisions. Circulating cell-free (cf)DNA comprises short fragments of double-stranded DNA, which promotes inflammation by stimulating several pathways, including inflammasome activation, which is responsible for IL-1β and IL-18 maturation and release. In this work, we assessed the contribution of cfDNA as a marker of disease progression and mediator of inflammation in MF. cfDNA was increased in MF patients and higher levels were associated with adverse clinical outcome, a high-risk molecular profile, advanced disease stages and inferior overall survival, indicating its potential value as a prognostic marker. Cell-free DNA levels correlated with tumor burden parameters and markers of systemic inflammation. To mimic the effects of cfDNA, monocytes were stimulated with poly(dA:dT), a synthetic double-stranded DNA. Following stimulation, patient monocytes released higher amounts of inflammasome-processed cytokine, IL-18 to the culture supernatant, reflecting enhanced inflammasome function. Despite overexpression of cytosolic DNA inflammasome sensor AIM2, IL-18 release from MF monocytes was shown to rely mainly on the NLRP3 inflammasome, as it was prevented by NLRP3-specific inhibitor MCC950. Circulating IL-18 levels were increased in MF plasma, reflecting in vivo inflammasome activation, and highlighting the previously unrecognized involvement of this cytokine in MF cytokine network. Monocyte counts were higher in patients and showed a trend towards correlation with IL-18 levels, suggesting monocytes represent a source of circulating IL-18. The close correlation shown between IL-18 and cfDNA levels, together with the finding of enhanced DNA-triggered IL-18 release from monocytes, suggest that cfDNA promotes inflammation, at least in part, through inflammasome activation. This work highlights cfDNA, the inflammasome and IL-18 as additional players in the complex inflammatory circuit that fosters MF progression, potentially providing new therapeutic targets.