Marker Of Progression Research Articles

Associations of Multimorbidity with Cerebrospinal Fluid Biomarkers for Neurodegenerative Disorders in Early Parkinson's Disease: A Crosssectional and Longitudinal Study.

The study aims to determine whether multimorbidity status is associated with cerebrospinal fluid (CSF) biomarkers for neurodegenerative disorders. A total of 827 patients were enrolled from the Parkinson's Progression Markers Initiative (PPMI) database, including 638 patients with early-stage Parkinson's disease (PD) and 189 healthy controls (HCs). Multimorbidity status was evaluated based on the count of long-term conditions (LTCs) and the multimorbidity pattern. Using linear regression models, cross-sectional and longitudinal analyses were conducted to assess the associations of multimorbidity status with CSF biomarkers for neurodegenerative disorders, including α-synuclein (αSyn), amyloid-β42 (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL). At baseline, the CSF t-tau (p = 0.010), p-tau (p = 0.034), and NfL (p = 0.049) levels showed significant differences across the three categories of LTC counts. In the longitudinal analysis, the presence of LTCs was associated with lower Aβ42 (β < -0.001, p = 0.020), and higher t-tau (β = 0.007, p = 0.026), GFAP (β = 0.013, p = 0.022) and NfL (β = 0.020, p = 0.012); Participants with tumor/musculoskeletal/mental disorders showed higher CSF levels of t-tau (β = 0.016, p = 0.011) and p-tau (β = 0.032, p = 0.044) than those without multimorbidity. Multimorbidity, especially severe multimorbidity and the pattern of mental/musculoskeletal/ tumor disorders, was associated with CSF biomarkers for neurodegenerative disorders in early-stage PD patients, suggesting that multimorbidity might play a crucial role in aggravating neuronal damage in neurodegenerative diseases.

PRIM2: A Marker of MYC-driven Hyper-proliferation, Disease Progression, Tumor Aggressiveness and Poor Survival in Glioma Patients.

Gliomas are the most prevalent brain tumors with metabolic alterations playing a pivotal role in disease progression. However, the precise coordination of metabolic alterations with tumor-promoting cellular mechanisms, leading to tumor initiation, progression, and aggressiveness, resulting in poor outcomes, remains poorly understood in gliomas. We conducted a metabolism-targeted differential gene expression analysis using glioma patients' expression profiling data from The Cancer Genome Atlas (TCGA) database. In addition, pathway enrichment analysis, gene set enrichment analysis (GSEA), transcription factor prediction, network construction, and correlation analyses were performed. Survival analyses were performed in R. All results were validated using independent GEO expression datasets. Metabolism-targeted analysis identified 5 hits involved in diverse metabolic processes linking them to disease aggressiveness in gliomas. Subsequently, we established that cell cycle progression and hyper-proliferation are key drivers of tumor progression and aggressiveness in gliomas. One of the identified metabolic hits, DNA primase 2 (PRIM2), a gene involved in DNA replication was found directly associated with cell cycle progression in gliomas. Furthermore, our analysis indicated that PRIM2, along with other cell cycle-related genes, is under the control of and regulated by the oncogenic MYC transcription factor in gliomas. In addition, PRIM2 expression alone is enough to predict MYC-driven cell cycle progression and is associated with tumor progression, aggressive disease state, and poor survival in glioma patients. Our findings highlight PRIM2 as a marker of MYC-driven cell cycle progression and hyper-proliferation, disease onset and progression, tumor aggressiveness, and poor survival in glioma patients.

Systematic muscle and nerve ultrasound as an early detection and progression marker in the diagnosis of hereditary polyneuropathies

Systematic muscle and nerve ultrasound as an early detection and progression marker in the diagnosis of hereditary polyneuropathies

Analysis of white matter tract integrity using diffusion kurtosis imaging reveals the correlation of white matter microstructural abnormalities with cognitive impairment in type 2 diabetes mellitus.

This study aimed to identify disruptions in white matter integrity in type 2 diabetes mellitus (T2DM) patients by utilizing the white matter tract integrity (WMTI) model, which describes compartment-specific diffusivities in the intra- and extra-axonal spaces, and to investigate the relationship between WMTI metrics and clinical and cognitive measurements. A total of 73 patients with T2DM and 57 healthy controls (HCs) matched for age, sex, and education level were enrolled and underwent diffusional kurtosis imaging and cognitive assessments. Tract-based spatial statistics (TBSS) and atlas-based region of interest (ROI) analysis were performed to compare group differences in diffusional metrics, including fractional anisotropy (FA), mean diffusivity (MD), axonal water fraction (AWF), intra-axonal diffusivity (Daxon), axial extra-axonal space diffusivity (De,//), and radial extra-axonal space diffusivity (De,⊥) in multiple white matter (WM) regions. Relationships between diffusional metrics and clinical and cognitive functions were characterized. In the TBSS analysis, the T2DM group exhibited decreased FA and AWF and increased MD, De,∥, and De,⊥ in widespread WM regions in comparison with the HC group, which involved 56.28%, 32.07%, 73.77%, 50.47%, and 75.96% of the mean WM skeleton, respectively (P < 0.05, TFCE-corrected). De,⊥ detected most of the WM changes, which were mainly located in the corpus callosum, internal capsule, external capsule, corona radiata, posterior thalamic radiations, sagittal stratum, cingulum (cingulate gyrus), fornix (stria terminalis), superior longitudinal fasciculus, and uniform fasciculus. Additionally, De,⊥ in the genu of the corpus callosum was significantly correlated with worse performance in TMT-A (β = 0.433, P < 0.001) and a longer disease duration (β = 0.438, P < 0.001). WMTI is more sensitive than diffusion tensor imaging in detecting T2DM-related WM microstructure abnormalities and can provide novel insights into the possible pathological changes underlying WM degeneration in T2DM. De,⊥ could be a potential imaging marker in monitoring disease progression in the brain and early intervention treatment for the cognitive impairment in T2DM.

Anatomical correlates of apathy and impulsivity co-occurrence in early Parkinson’s disease

BackgroundAlthough apathy and impulse control disorders (ICDs) are considered to represent opposite extremes of a continuum of motivated behavior (i.e., hypo- and hyperdopaminergic behaviors), they may also co-occur in Parkinson’s disease (PD).ObjectivesWe aimed to explore the co-occurrence of ICDs and apathy and its neural correlates analyzing gray matter (GM) changes in early untreated PD patients. Moreover, we aimed to investigate the possible longitudinal relationship between ICDs and apathy and their putative impact on cognition during the first five years of PD.MethodsWe used the Parkinson’s Progression Markers Initiative (PPMI) database to identify the co-occurrence of apathy and ICDs in 423 early drug-naïve PD patients at baseline and at 5-year follow-up. Baseline MRI volumes and gray matter changes were analyzed between groups using voxel-based morphometry. Multi-level models assessed the longitudinal relationship (across five years) between apathy and ICDs and cognitive functioning.ResultsAt baseline, co-occurrence of apathy and ICDs was observed in 23 patients (5.4%). This finding was related to anatomical GM reduction along the cortical regions involved in the limbic circuit and cognitive control systems. Longitudinal analyses indicated that apathy and ICDs were related to each other as well as to the combined use of levodopa and dopamine agonists. Worse apathetic and ICDs states were associated with poorer executive functions.ConclusionsApathy and ICDs are joint non-exclusive neuropsychiatric disorders also in the early stages of PD and their co-occurrence was associated with GM decrease in several cortical regions of the limbic circuit and cognitive control systems.

Evaluation of ATNPD Framework and Biofluid Markers to Predict Cognitive Decline in Early Parkinson Disease.

In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-β-amyloid 1-42 (Aβ42), phosphorylated tau 181 (p-tau181), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau181 and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ42. First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD β-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATNPD) using CSF Aβ42 (A), p-tau181 (T), and serum NfL (N) and tested ATNPD prediction of longitudinal cognitive decline in PD. Participants were selected from the Parkinson's Progression Markers Initiative cohort, clinically diagnosed with sporadic PD or as controls, and followed up annually for 5 years. Linear mixed-effects models (LMEMs) tested the interaction of diagnosis with longitudinal trajectories of analytes (log transformed, false discovery rate [FDR] corrected). In patients with PD, LMEMs tested how baseline ATNPD status (AD [A+T+N±] vs not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank transformed, FDR corrected). Participants were 364 patients with PD and 168 controls, with comparable baseline mean (±SD) age (patients with PD = 62 ± 10 years; controls = 61 ± 11 years]; Mann-Whitney Wilcoxon: p = 0.4) and sex distribution (patients with PD = 231 male individuals [63%]; controls = 107 male individuals [64%]; χ2: p = 1). Patients with PD had overall lower CSF p-tau181 (β = -0.16, 95% CI -0.23 to -0.092, p = 2.2e-05) and t-tau than controls (β = -0.13, 95% CI -0.19 to -0.065, p = 4e-04), but not Aβ42 (p = 0.061) or NfL (p = 0.32). Over time, patients with PD had greater increases in serum NfL than controls (β = 0.035, 95% CI 0.022 to 0.048, p = 9.8e-07); slopes of patients with PD did not differ from those of controls for CSF Aβ42 (p = 0.18), p-tau181 (p = 1), or t-tau (p = 0.96). Using ATNPD, PD classified as A+T+N± (n = 32; 9%) had worse cognitive decline on global MoCA (β = -73, 95% CI -110 to -37, p = 0.00077) than all other ATNPD statuses including A+ alone (A+T-N-; n = 75; 21%). In patients with early PD, CSF p-tau181 and t-tau were low compared with those in controls and did not increase over 5 years of follow-up. Our study shows that classification using modified ATNPD (incorporating CSF Aβ42, CSF p-tau181, and serum NfL) can identify biologically relevant subgroups of PD to improve prediction of cognitive decline in early PD.

Longitudinal brain changes in Parkinson's disease with severe olfactory deficit

IntroductionOlfactory dysfunction and REM sleep behavior disorder (RBD) are associated with distinct cognitive trajectories in the course of Parkinson's disease (PD). The underlying neurobiology for this relationship remains unclear but may involve distinct patterns of neurodegeneration. This study aimed to examine longitudinal cortical atrophy and thinning in early-stage PD with severe olfactory deficit (anosmia) without and with concurrent probable RBD. MethodsLongitudinal MRI data over four years of 134 de novo PD and 49 healthy controls (HC) from the Parkinson Progression Marker Initiative (PPMI) cohort were analyzed using a linear mixed-effects model. Patients were categorized into those with anosmia by the University of Pennsylvania Smell Identification Test (UPSIT) score ≤ 18 (AO+) and those without (UPSIT score > 18, AO-). The AO+ group was further subdivided into AO+ with probable RBD (AO+RBD+) and without (AO+RBD-) for subanalysis. ResultsCompared to subjects without baseline anosmia, the AO+ group exhibited greater longitudinal declines in both volume and thickness in the bilateral parahippocampal gyri and right transverse temporal gyrus. Patients with concurrent anosmia and RBD showed more extensive longitudinal declines in cortical volume and thickness, involving additional brain regions including the bilateral precuneus, left inferior temporal gyrus, right paracentral gyrus, and right precentral gyrus. ConclusionsThe atrophy/thinning patterns in early-stage PD with severe olfactory dysfunction include regions that are critical for cognitive function and could provide a structural basis for previously reported associations between severe olfactory deficit and cognitive decline in PD. Concurrent RBD might enhance the dynamics of cortical changes.

Can motor decline be a modifiable marker of clinical progression in subjective cognitive decline? A national prospective cohort study

ObjectivesSubjective cognitive decline represents a critical stage for preventing mild cognitive impairment and dementia, but the links between clinical progression in the subjective cognitive decline stage and various motor functions remain inconclusive. This cohort study aimed to elucidate the independent and joint associations between the clinical progression of subjective cognitive decline and motor functions. MethodsWe enrolled 4880 community-dwelling elderly participants from a national cohort and used Cox proportional hazard regression model and restricted cubic spline models to explore the longitudinal associations between motor functions (gait, strength, balance, and endurance) and the clinical progression of subjective cognitive decline. ResultsDuring 5-years follow-up, 1239 participants experienced clinical progression. After adjusting for demographics, vascular burden, body components, and polypharmacy, gait speed [hazard ratios (HRs)= 0.96, 95% confidence interval (CI) 0.94–0.99], chair stand test (HRs=1.02, 95%CI 1.01–1.03), and endurance limitation in jogging 1 kilometer (HRs=1.18, 95%CI 1.04–1.34) were significantly associated with clinical progression. Among all participants, individuals characterized by poor upper- and lower-body strength, as well as those with slow pace and reduced endurance, faced the highest risk of cognitive impairment. ConclusionsThis study emphasizes the potential of gait speed, muscle strength, and endurance as non-cognitive indicators of clinical progression in subjective cognitive decline. Understanding their combined effectiveness may reveal primary physiological mechanisms contributing to the dual decline of motor and cognition.

Associations between Verbal Fluency and Asymmetry of White Matter Integrity in the Superior Longitudinal Fasciculus in At-Risk Mental States for Psychosis.

Verbal fluency is one of the most severely impaired components of cognitive function in schizophrenia and is also impaired in at-risk mental states (ARMSs) for psychosis. The aim of this study was to explore the markers of disease progression in subjects with ARMSs by comparing the association between the white matter integrity of the superior longitudinal fasciculus (SLF) and verbal fluency in subjects with ARMSs and healthy control (HC) subjects. The correlations of the fractional anisotropy (FA) values on diffusion tensor imaging (DTI) and the laterality index (LI) values of SLF branches I, II, and III with the verbal fluency performance were analyzed in right-handed subjects with ARMSs (ARMS group; n = 18) and HC subjects (HC group; n = 34) aged 18 to 40 years old. In the HC group compared with the ARMS group, the LI values suggested right lateralization of the SLF II and III. Letter fluency was significantly correlated with the LI of the SLF III in both the ARMS and HC groups. The regression coefficient (β) of this correlation was calculated using the least squares method and yielded a positive number (73.857) in the ARMS group and a negative number (-125.304) in the HC group. The association of the rightward asymmetry of the SLF III with the verbal fluency performance observed in the HC group appeared to be lost in the ARMS group, and this could serve as one of the markers of the pathological progression to psychosis in patients with schizophrenia.

From Theory to Action: A Saudi Arabian Case Study of Feminist Academic Activism against State Oppression

This article explores the intricate landscape of women’s rights in Saudi Arabia, an authoritarian state within the Gulf Cooperation Council countries (GCC), where the pursuit of modernization strategically utilizes women’s issues as symbols of national identity and markers of progress. The article focuses on the transformative potential of academic activism, exemplified by the work of Hatoon Ajwad al-Fassi, in countering oppression against women. It demonstrates how women navigate the realms of academia and activism to reshape gender dynamics and shape their nation’s modernization trajectory. By emphasizing the critical intersection between academic inquiry and activism, this article dispels the misconception that academia and activism are mutually exclusive. In contexts such as Saudi Arabia, where women’s rights face suppression, this intersection emerges as imperative for informed research and frontline advocacy, effectively addressing state-sponsored violence. Furthermore, this article critically evaluates the persistent challenge of feminist neo-Orientalist scholarship, which often distorts the depiction of Saudi women’s experiences. It offers a contribution to a nuanced understanding of women’s theorization that includes the ethico-political context within which women operate.

Correlation of Procalcitonin with Acid Fast Bacilli and Gene Xpert MTB/RIF as a Marker of Treatment Progress in Pulmonary Tuberculosis patients

There are several limitations in using AFB and GeneXpert to evaluate the treatment of TB patients, one of which is influenced by sputum quality. Therefore, an alternative method is needed to help evaluate the treatment of TB patients. This study aimed to analyze the correlation of the Procalcitonin test with AFB and GeneXpert for evaluating the treatment of TB patients and the performance of Procalcitonin as a marker of TB patient treatment progress. A prospective cohort study was conducted from May to September 2022 at the West Nusa Tenggara General Hospital, Indonesia. Sputum and blood samples were collected from 36 patients who were confirmed positive for TB by GeneXpert MTB/RIF examination, then examined for procalcitonin and AFB before being given treatment and after the intensive phase of treatment. Procalcitonin tested with VIDAS Biomerieux and VIDAS BRAHMS PCT kit. Procalcitonin did not correlate with AFB (p=0.064, r= 0.327) and GeneXpert before treatment (p=0.169, r=0.245), but correlated with AFB (p=0.013, r=0.427) and GeneXpert MTB/RIF (p=0.020, r=0.405) after the intensive phase of treatment. Procalcitonin test with a cut-off value of 0.07 detected negative AFB cases after treatment with a sensitivity of 28.6 and a specificity of 96.2%. The procalcitonin cut-off value of 0.07 also detected negative Xpert MTB/RIF after treatment with a sensitivity of 16.7% and a specificity of 100%. The performance of Procalcitonin for detecting negative smear and negative Xpert MTB/RIF after the intensive phase of treatment is classified as having high specificity, but its sensitivity is still low. Future studies are needed to evaluate the performance of Procalcitonin compared to bacterial cultures.

Osimertinib Plasma Trough Concentration in Relation to Brain Metastases Development in Patients With Advanced EGFR-Mutated NSCLC

IntroductionBrain metastases (BM) are common in patients with advanced EGFR-mutated (EGFRm+) NSCLC. Despite good BM-related outcomes of osimertinib, several patients still experience intracranial progression. A possible explanation is pharmacologic failure due to low plasma trough levels (Cmin,SS) and consequently limited intracranial osimertinib exposure. We investigated the relation between osimertinib Cmin,SS and BM development or progression. MethodsA prospective multicenter cohort study, including patients receiving osimertinib for advanced EGFRm+ NSCLC. At osimertinib start, patients were allocated to the BM or no or unknown BM cohort and were further divided into subgroups based on osimertinib Cmin,SS (low, middle, and high exposure). Cumulative incidence of BM progression or development and overall survival were determined for each group. ResultsA total of 173 patients were included, with 49 (28.3%) had baseline BM. Of these patients, 36.7% experienced BM progression, of which 16.7% in the low (<159.3 ng/mL), 40.0% in the middle, and 47.1% in the high (>270.7 ng/mL) Cmin,SS subgroups. After 12 months, the cumulative incidence of BM progression for the BM cohort was 20% (95% confidence interval [CI] 2.6–49.0), 31% (95% CI:10.6–53.9), and 31% (95% CI:10.8–54.5) per Cmin,SS subgroup, respectively. After 20 months, this was 20% (95% CI:2.6–49.0), 52% (95% CI:23.8–74.2), and 57% (95% CI:24.9–79.7), respectively. For the no or unknown BM cohort, 4.0% developed BM without differences within Cmin,SS subgroups. ConclusionsNo relation was found between osimertinib Cmin,SS and BM development or progression in patients with advanced EGFRm+ NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development or progression.

Integrative transcriptomic and genomic analyses unveil the IFI16 variants and expression as MASLD progression markers.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a broad and continuous spectrum of liver diseases ranging from fatty liver to steatohepatitis. The intricate interactions of genetic, epigenetic, and environmental factors in the development and progression of MASLD remain elusive. Here, we aimed to achieve an integrative understanding of the genomic and transcriptomic alterations throughout the progression of MASLD. RNA-Seq profiling (n = 146) and whole-exome sequencing (n = 132) of MASLD liver tissue samples identified 3 transcriptomic subtypes (G1-G3) of MASLD, which were characterized by stepwise pathological and molecular progression of the disease. Macrophage-driven inflammatory activities were identified as a key feature for differentiating these subtypes. This subtype-discriminating macrophage interplay was significantly associated with both the expression and genetic variation of the dsDNA sensor IFI16 (rs6940, A>T, T779S), establishing it as a fundamental molecular factor in MASLD progression. The in vitro dsDNA-IFI16 binding experiments and structural modeling revealed that the IFI16 variant exhibited increased stability and stronger dsDNA binding affinity compared to the wild-type. Further downstream investigation suggested that the IFI16 variant exacerbated DNA sensing-mediated inflammatory signals through mitochondrial dysfunction-related signaling of the IFI16-PYCARD-CASP1 pathway. This study unveils a comprehensive understanding of MASLD progression through transcriptomic classification, highlighting the crucial roles of IFI16 variants. Targeting the IFI16-PYCARD-CASP1 pathway may pave the way for the development of novel diagnostics and therapeutics for MASLD.

Data-driven disease progression model of Parkinson's disease and effect of sex and genetic variants.

As Parkinson's disease (PD) progresses, there are multiple biomarker changes, and sex and genetic variants may influence the rate of progression. Data-driven, long-term disease progression model analysis may provide precise knowledge of the relationships between these risk factors and progression and would allow for the selection of appropriate diagnosis and treatment according to disease progression. To construct a long-term disease progression model of PD based on multiple biomarkers and evaluate the effects of sex and leucine-rich repeat kinase 2 (LRRK2) mutations, a technique derived from the nonlinear mixed-effects model (Statistical Restoration of Fragmented Time course [SReFT]) was applied to datasets of patients provided by the Parkinson's Progression Markers Initiative. Four biomarkers, including the Unified PD Rating Scale, were used, and a covariate analysis was performed to investigate the effects of sex and LRRK2-related mutations. A model of disease progression over ~30 years was successfully developed using patient data with a median of 6 years. Covariate analysis suggested that female sex and LRRK2 G2019S mutations were associated with 21.6% and 25.4% significantly slower progression, respectively. LRRK2 rs76904798 mutation also tended to delay disease progression by 10.4% but the difference was not significant. In conclusion, a long-term PD progression model was successfully constructed using SReFT from relatively short-term individual patient observations and depicted nonlinear changes in relevant biomarkers and their covariates, including sex and genetic variants.

Differences in brain aging between sexes in Parkinson’s disease

Parkinson’s disease (PD) is linked to faster brain aging. Male sex is associated with higher prevalence, severe symptoms, and a faster progression rate in PD. There remains a significant gap in understanding the function of sex in the process of brain aging in PD. The structural T1-weighted MRI-driven brain-predicted age difference (i.e., Brain-PAD: the actual age subtracted from the brain-predicted age) was computed in a group of 373 people with PD (mean age ± SD: 61.37 ± 9.81, age range: 33–85, 34% female) from the Parkinson’s Progression Marker Initiative database using a robust brain-age estimation framework that was trained on 949 healthy subjects. Linear regression models were used to investigate the association between Brain-PAD and clinical variables in PD, stratified by sex. Males with Parkinson’s disease (PD-M) exhibited a significantly higher mean Brain-PAD than their female counterparts (PD-F) (t(256) = 2.50, p = 0.012). In the propensity score-matched PD-M group (PD-M*), Brain-PAD was found to be associated with a decline in general cognition, a worse degree of sleep behavior disorder, reduced visuospatial acuity, and caudate atrophy. Conversely, no significant links were observed between these factors and Brain-PAD in the PD-F group. Having ‘older’ looking brains in PD-M than PD-F supports the idea that sex plays a vital function in PD, such that the PD mechanism may be different in males and females. This study has the potential to broaden our understanding of dissimilarities in brain aging between sexes in the context of PD.

Metabolites of intestinal fora can be used as diagnostic and progressive markers for mild cognitive impairment.

The aim of the work was to analyze the metabolites of the intestinal microbiota from the patients with mild cognitive impairment (MCI) and progressive MCI due to Alzheimer's disease (AD). Two cohorts were established. The first one included 87 subjects with 30 healthy controls (NC), 22 patients with MCI due to AD, and 35 patients with AD. The second cohort included 87 patients with MCI due to AD, who were followed up for 2 years and finally were divided into progressive MCI due to AD group (P-G) and unprogressive MCI due to AD group (U-G) according their cognitive levels. Fecal samples were collected to all patients at the baseline time point. Differential metabolites were subjected to pathway analysis by MetaboAnalyst. In the first cohort, we found 21 different metabolites among the three groups (AD, MCI, and NC). In the second cohort, we identified 19 differential metabolites between the P-G and U-G groups. By machine learning analysis, we found that seven characteristic metabolites [Erythrodiol, alpha-Curcumene, Synephrine, o-Hydroxylaminobenzoate, 3-Amino-4-hydroxybenzoic acid, 2-Deoxystreptamine, and 9(S] were of characteristic significance for the diagnosis of MCI due to AD, and six metabolites (Indolelactate, Indole-3-acetaldehyde, L-Proline, Perillyl, Mesaconate, and Sphingosine) were the characteristic metabolites of early warning for the progression of MCI due to AD. D-Glucuronic acid was negatively correlated with Apolipoprotein E4 (APOE4). Perillyl alcohol was negatively correlated with all of the five biomarkers [P-tau181, Neurofilament light chain (NF-light), Aβ1-42, Aβ1-40, and glial fibrillary acidic protein (GFAP)], but Indoleacetaldehyde was positively correlated with three biomarkers (P-tau181, Aβ1-42, and GFAP). Three characteristic metabolites (3-Amino-4-hydroxybenzoate, 2-Deoxystreptamine, and p-Synephrine) were positively correlated with Aβ1-42. 2-Deoxystreptamine, 9(S)-HPOT, and Indoleacetaldehyde were positively correlated with GFAP. L-Proline and Indoleacetaldehyde were positively correlated with NF-light. Specific metabolites of intestinal fora can be used as diagnostic and progressive markers for MCI.

Associations between Sleep Disorders and Impulsive-Compulsive Behaviors in Parkinson’s Disease: A Prospective Cohort Study

Objective: To examine the associations of excessive daytime sleepiness (EDS) and probable rapid eye movement sleep behavior disorder (pRBD), respectively, with impulsive-compulsive behaviors (ICBs) over a 5-year follow-up in patients with early Parkinson’s disease (PD). Methods: The Parkinson’s Progression Markers Initiative is a multicenter cohort study based on an ongoing and open-ended registry. Longitudinal associations of sleep disorders with ICB over 5-year follow-up visits were estimated using generalized linear mixed-effects models among PD participants. Results: A total of 825 PD participants were enrolled at baseline. The study sample had a median baseline age of 63.1 (interquartile range: 55.6–69.3) years and comprised 496 (61.5%) men. Among them, 201 (24.9%) had ICB at baseline. In the generalized mixed-effects models, EDS (odds ratio [OR] = 1.09, 95% confidence interval [CI] 1.05, 1.12) and RBD (OR = 1.07, 95% CI 1.03, 1.12) were substantially associated with higher odds of developing ICB over time in PD patients, after multivariate adjustment including age, gender, family history, GDS score, STAI-Y score, MDS-UPDRS part III score, LEDD, and disease duration. Consistent results were observed when stratifying by age at baseline, gender, and PD family history. Conclusions: The study findings suggest a longitudinal association between EDS and pRBD with an increased risk of developing ICB in patients with PD. The findings emphasize the significance of evaluating and addressing sleep disorders in PD patients as a potential approach to managing ICB.

Body mass index and altered lipid profile as major risk markers for breast cancer progression: a cross-sectional study of postmenopausal women in Pakistan

BackgroundIn Pakistan, the death rate for post-menopausal women with breast cancer is significant due to late detection and delayed referral to proper facilities. There are a few reports on Pakistan’s epidemiology and breast cancer risk factors. There are modifiable and non-modifiable risk factors associated with the development of breast carcinoma; of which body mass index (BMI), central obesity, and lipid profile are considered as major risk markers.MethodsThis was a cross-sectional analytical study. A total of 384 women constituted the present study sample. Purposive sampling was used to collect 192 confirmed new breast cancer cases throughout the study. By using basic random sampling, an equal number of controls were chosen. Studied parameters included age, fasting blood sugar, cholesterol, triglyceride, serum high-density lipoprotein, cholesterol, serum low-density lipoprotein cholesterol, weight, height, BMI, waist circumference, and waist-to-hip ratio. The inclusion criteria of this study were post-menopausal women (45–65 years) in Pakistan. The confirmation of breast carcinoma was done through histopathology. Breast cancer occurrence was taken as a dependent variable, whereas BMI, central obesity, and lipid profile were taken as independent variables.ResultsStudied risk factors (cholesterol, BMI, and central obesity) significantly correlated with breast cancer. Cholesterol has a significantly high positive correlation (0.646) with breast cancer. BMI has a positive significant correlation (0.491) with breast cancer, and central obesity has a low but positive significant correlation (0.266) with breast cancer. Moreover, the binary logistic regression model also showed a significant association between biochemical factors and breast cancer occurrence. Regression analysis depicted a linear relationship between a dependent variable (breast cancer occurrence) and independent variables (central obesity, cholesterol, BMI).ConclusionPostmenopausal overweight (central obesity), increased BMI and high cholesterol levels are major risk factors for breast cancer. Moreover, high total cholesterol proved to be the most significant risk marker for the occurrence of breast cancer in post-menopausal women of Pakistan.

ARHGAP29 Is Involved in Increased Invasiveness of Tamoxifen-resistant Breast Cancer Cells and its Expression Levels Correlate With Clinical Tumor Parameters of Breast Cancer Patients.

Aggressive breast cancer (BC) cells show high expression of Rho GTPase activating protein 29 (ARHGAP29), a negative regulator of RhoA. In breast cancer cells in which mesenchymal transformation was induced, ARHGAP29 was the only one of 32 GTPase-activating enzymes whose expression increased significantly. Therefore, we investigated whether there is a correlation between expression of ARHGAP29 and tumor progression in BC. Since tamoxifen-resistant BC cells exhibit increased mesenchymal properties and invasiveness, we additionally investigated the relationship between ARHGAP29 and increased invasion rate in tamoxifen resistance. The question arises as to whether ARHGAP29 is a suitable prognostic marker for the progression of BC. Tissue microarrays were used to investigate expression of ARHGAP29 in BC and adjacent normal breast tissues. Knockdown experiments using siRNA were performed to investigate the influence of ARHGAP29 and the possible downstream actors RhoC and pAKT1 on invasive growth of tamoxifen-resistant BC spheroids in vitro. Expression of ARHGAP29 was frequently increased in BC tissues compared to adjacent normal breast tissues. In addition, there was evidence of a correlation between high ARHGAP29 expression and advanced clinical tumor stage. Tamoxifen-resistant BC cells show a significantly higher expression of ARHGAP29 compared to their parental wild-type cells. After knockdown of ARHGAP29 in tamoxifen-resistant BC cells, expression of RhoC was significantly reduced. Further, expression of pAKT1 decreased significantly. Invasive growth of three-dimensional tamoxifen-resistant BC spheroids was reduced after knockdown of ARHGAP29. This could be partially reversed by AKT1 activator SC79. Expression of ARHGAP29 correlates with the clinical tumor parameters of BC patients. In addition, ARHGAP29 is involved in increased invasiveness of tamoxifen-resistant BC cells. ARHGAP29 alone or in combination with its downstream partners RhoC and pAKT1 could be suitable prognostic markers for BC progression.

NCAPH drives breast cancer progression and identifies a gene signature that predicts luminal a tumour recurrence.

Luminal A tumours generally have a favourable prognosis but possess the highest 10-year recurrence risk among breast cancers. Additionally, a quarter of the recurrence cases occur within 5 years post-diagnosis. Identifying such patients is crucial as long-term relapsers could benefit from extended hormone therapy, while early relapsers might require more aggressive treatment. We conducted a study to explore non-structural chromosome maintenance condensin I complex subunit H's (NCAPH) role in luminal A breast cancer pathogenesis, both in vitro and in vivo, aiming to identify an intratumoural gene expression signature, with a focus on elevated NCAPH levels, as a potential marker for unfavourable progression. Our analysis included transgenic mouse models overexpressing NCAPH and a genetically diverse mouse cohort generated by backcrossing. A least absolute shrinkage and selection operator (LASSO) multivariate regression analysis was performed on transcripts associated with elevated intratumoural NCAPH levels. We found that NCAPH contributes to adverse luminal A breast cancer progression. The intratumoural gene expression signature associated with elevated NCAPH levels emerged as a potential risk identifier. Transgenic mice overexpressing NCAPH developed breast tumours with extended latency, and in Mouse Mammary Tumor Virus (MMTV)-NCAPHErbB2 double-transgenic mice, luminal tumours showed increased aggressiveness. High intratumoural Ncaph levels correlated with worse breast cancer outcome and subpar chemotherapy response. A 10-gene risk score, termed Gene Signature for Luminal A 10 (GSLA10), was derived from the LASSO analysis, correlating with adverse luminal A breast cancer progression. The GSLA10 signature outperformed the Oncotype DX signature in discerning tumours with unfavourable outcomes, previously categorised as luminal A by Prediction Analysis of Microarray 50 (PAM50) across three independent human cohorts. This new signature holds promise for identifying luminal A tumour patients with adverse prognosis, aiding in the development of personalised treatment strategies to significantly improve patient outcomes.