Disease Subjects Research Articles

Muscle spindle receptors and their impact on Parkinson´s disease and Cerebral Palsy subjects.

In some neurological conditions, like Parkinson's disease (PD) and Cerebral Palsy (CP), as well as with ageing, muscle spindles have been mentioned as participating in the pathological response of observed muscles. The aim of this review has therefore been to examine what is known about muscle spindle receptors, their function and how they are involved in regulating precise muscle movement in relation to these two conditions. Data from acoustic myography (AMG) studies with healthy controls (HC), CP and PD subjects have been re-examined with a view to identifying possible effects of changes in muscle movement which could be related to muscle spindle receptor function. Studies of muscle spindles have shown that during shortening and lengthening contractions the fusimotor system is activated differently with different discharge frequencies and sensitivities. With increasing age comes a loss of precise proprioception, something that coincides with a change in the AMG E-score towards lower values, indicating a reduced level of coordination and efficiency of muscle use. With PD and CP there is likewise a documented decrease in proprioception, also showing lower E-values than age-matched HC subjects. We conclude that the decrease in proprioception observed in these subjects must be partly due to a change in the muscle spindle / C-centre feedback system.

Identification of extracellular matrix proteins in plasma as a potential biomarker for intervertebral disc degeneration.

Recently, there has been significant focus on extracellular matrix proteolysis due to its importance in the pathological progression of intervertebral disc degeneration (IVDD). The present study investigates the circulating levels of extracellular matrix proteins in the plasma of IVDD and determines their potential relevance as biomarkers in disc degeneration. Global proteomic analysis was performed in the plasma samples of 10 healthy volunteers (HV) and 10 diseased subjects (DS) after depletion of highly abundant proteins such as albumin and IgG. We identified 144 and 135 matrix-associated proteins in plasma samples from healthy volunteers (HV) and patients with disc degeneration (DS), respectively. Among these, 49 of the matrix-associated proteins were identical to the proteins found in intervertebral disc (IVD) tissues retrieved from the in-house library. Applying stringent parameters, we selected 28 proteins, with 26 present in DS and 21 in HV. 19 proteins were found common between the groups, two of which-aggrecan (ACAN) and fibulin 1 (FBLN1) - showed statistically significant differences. Specifically, ACAN was up-regulated and FBLN1 was down-regulated in the DS-plasma. In particular, DS-plasma exhibited specific expression of collagen type 2a1 (COL2A1), native to the nucleus pulposus. The distinct presence of collagen type 2a1 and the elevated expression of aggrecan in IVDD plasma may serve as the basis for the development of a potential biomarker for monitoring the progression of disc degeneration.

Beat-to-beat analysis of hemodynamic response to mental and psychological stress in sickle cell anemia

Abstract Vaso-occlusive crises are a hallmark symptom of sickle cell disease. Physical stressors can trigger decreased microvascular blood flow and increase the risk for vaso-occlusive crises. However, the effect of mental and psychological stressors on vascular physiology in sickle cell disease is not well-established. We hereby examined fluctuations in continuous blood pressure to evaluate hemodynamic changes in sickle cell disease patients during mental and psychological stress. Thirteen sickle cell disease subjects from the Children’s Hospital Los Angeles and 11 healthy volunteers were recruited. Continuous blood pressure was recorded during two mental tasks and one psychological stress task. Systolic beat-to-beat blood pressure variability measurements were calculated for each subject. Three very short-term blood pressure variability metrics served as outcome measures: standard deviation, coefficient of variation, and average real variability. Peripheral augmentation index was calculated from arterial waveforms. Linear mixed effects models evaluated associations between patient factors and outcome measures. Sickle cell disease patients exhibit increased systolic blood pressure variability in response to psychological stress. All subjects exhibited a decrease in systolic blood pressure variability in response to mental stress tasks. During mental stress, both groups displayed increased augmentation index, reflective of stress-induced vasoconstriction, while psychological stress in sickle cell disease patients led to both decreased mean arterial pressure and increased augementation index, suggestive of uncompensated vasoconstriction. These findings emphasize the impact of mental and psychological stressors on vascular function in sickle cell disease and the potential for monitoring physiological signals to predict vaso-occlusive crisis events.

Early Diagnosis of Huntington Disease: Insights from Magnetic Resonance Spectroscopy-A Systematic Review.

Background/Objectives: Huntington's disease (HD) is a fully penetrant neurodegenerative disease with a profound effect on quality of life. In recent years, there has been rapid growth in the description of its pathogenesis and diagnosis. Magnetic resonance spectroscopy (MRS) measurements can aid in the discrimination between premanifest Huntington's disease (Pre-HD) and healthy control (HC) subjects to establish early supportive and symptomatic management. Our objective was to evaluate metabolic changes using MRS to shed light on its potential as a biomarker through a systematic review. Methods: We followed the PRISMA guidelines, extracting articles from PubMed, Scopus, and the Virtual Health Library. We included patients with pre-HD, HD, and HC subjected to MRS, reporting the concentration of metabolites in at least one brain region. Results: In the putamen, N-acetyl Aspartate (NAA) was significantly decreased in 77.9% and total NAA (tNAA) was decreased in 72.4% of cases; no significant difference was found in 27.5% (n = 19) of cases. Furthermore, when looking into HD vs. pre-HD in the putamen, tNAA and NAA were decreased in 100% of participants. In the caudate nucleus, NAA and creatine were significantly decreased in 100% of HD in comparison to pre-HD participants, whereas tNAA showed a significant decrease in only 50%. Conclusions: MRS can be a relevant tool for the early diagnosis of HD; potential objective biomarkers related to its onset and pathogenesis exist and show differences between controls, pre-HD and HD patients. However, an effort should be made to standardize MRS methodology and reporting in subsequent studies.

Synaptic and extrasynaptic distribution of NMDA receptors in the cortex of Alzheimer's disease patients.

Synaptic and extrasynaptic distribution of N-methyl-D-aspartate receptors (NMDARs) has not been addressed in the brain from Alzheimer´s disease (AD) subjects, despite theircontribution to neurodegeneration. We have developed a protocol to isolate synaptic and extrasynaptic membranes from controls and AD frontal cortex. We characterized the distribution of the NMDAR subunits GluN2B, GluN2A, GluN1, and GluN3A, as well aspost-translational modifications, such as phosphorylation and glycosylation. Lower levels of synaptic GluN2B and GluN2A were found in AD fractions, while extrasynaptic GluN2B and GluN1 levels were significantly higher; GluN3A distribution remained unaffected in AD. We also identified different glycoforms of GluN2B and GluN2A in extrasynaptic membranes. Synaptic Tyr1472 GluN2B phosphorylation was significantly lower in AD fractions. Reduction of synaptic NMDAR subunits, particularly for GluN2B, is likely to contribute to synaptic transmission failure in AD. Additionally, the increment of extrasynaptic NMDAR subunits could favor the activation of excitotoxicity in AD. New protocol to isolate synaptic and extrasynaptic membranes from the human cortex. Low GluN2B and GluN2A levels in Alzheimer´s disease (AD) synaptic membranes. High GluN2B and GluN1 levels in AD extrasynaptic membranes. Specific glycoforms of extrasynaptic GluN2B and GluN2A. Low phosphorylation at Tyr1472 in synaptic GluN2B in AD.

Reductions in the white-gray functional connectome in preclinical Alzheimer's disease and their associations with amyloid and cognition.

The magnitudes and patterns of alterations of the white-gray matter (WM-GM) functional connectome in preclinical Alzheimer's disease (AD), and their associations with amyloid and cognition, remain unclear. We compared regional WM-GM functional connectivity (FC) and network properties in subjects with preclinical AD (or AD dementia) and controls (total n=344). Their associations with positron emission tomography AV45-measured amyloid beta (Aβ) load and modified Preclinical Alzheimer Cognitive Composite (mPACC) scores were examined. Preclinical AD subjects showed lower FC in specific WM-GM pairs and reduced segregation of control, dorsal attention, and somatomotor networks. A major portion of the reduced FC and network segregations were linked to elevated Aβ. Reduced FC of one WM-GM pair correlated with impaired mPACC. AD dementia exhibited broader reductions and stronger associations. The WM-GM functional connectome undergoes regional and systemic dysfunctions as early as in the preclinical stage, correlating with amyloid deposition and predicting cognitive impairment. Preclinical Alzheimer's disease (AD) subjects showed lower functional connectivity in specific white-gray matter (WM-GM) pairs and reduced segregations of control, dorsal attention, and somatomotor networks. A major portion of the reduced connectivity and network segregations were linked to elevated amyloid beta load. Only one WM-GM pair's reduced connectivity was linearly correlated with impaired cognitive composite scores. AD dementia showed more extensive reductions in connectivity, network integration, and segregation, with stronger associations with amyloid elevation and cognitive impairment. The WM-GM functional connectome offers a distinct perspective for understanding changes in brain functional architecture throughout the AD continuum.

Performance of newly developed add-on devices on aerosol delivery in noninvasive ventilated subjects

Background: Several techniques had been developed to generate aerosolized medications during noninvasive ventilation (NIV) using variable inhalation methods. This study hypothesized that large spacers were more efficient significantly than small spacers and adapters during NIV. Objective: The main objective of this study was to compare the performance of newly developed spacers with standard T-piece in NIV chronic obstructive pulmonary disease (COPD) subjects. Methods: Sixty COPD subjects requiring NIV were included in this study. A dual-limb circuit was used, and the mode of ventilator was set in spontaneous volume-controlled mode. Dual-limb ventilation circuit, consists of inspiratory-limb and expiratory-limb, is pressure and volume controlled in response to subject expiration providing relatively high resistance to expiratory flow. Two experimental sets were evaluated: the first was introducing two preliminary pressurized metered-dose inhalers (pMDI) puffs before the nebulization of 1 ml of a respirable solution of salbutamol by vibrating mesh nebulizer (VMN) using Minimhal and Combihaler. The second was to only nebulize 1 ml of salbutamol respirable solution by VMN using Combihaler, Minimhal, and standard T-piece. Two urine samples were collected after aerosol delivery: urine sample after 30 min. (USAL0.5) as an indicator of lung deposition and all urine pooled 24 h (USAL24) post-inhalation as an indicator of systemic absorption. The amount of salbutamol extracted from urine samples was assayed by high-performance liquid chromatography. Results: Minimhal + pMDI + VMN delivered a higher percentage of salbutamol 30 min post-inhalation than Minimhal + VMN (p < 0.001). Also, Combihaler + pMDI + VMN delivered a higher percentage of salbutamol 30 min post-inhalation than Combihaler + VMN (p < 0.001). Combihaler + VMN delivered a higher percentage of salbutamol 30 min and 24 h post-inhalation than both Minimhal + VMN and T-piece + VMN (p < 0.001). Standard T-piece delivered the lowest aerosol amount delivered to the lung compared to both spacers (p < 0.05). Conclusions: Introducing two pMDI puffs significantly improved aerosol delivery by both spacers. Combihaler significantly improves aerosol delivery more than Minimhal.

B-348 Performance of the Atellica IM Analyzer’s HighSensitivity PSA Assay as an Aid for Monitoring Prostate Cancer Recurrence

Abstract Background Prostate specific antigen (PSA) is a suitable marker for monitoring men with prostate cancer (PC), and for detecting recurrence after therapy in conjunction with other diagnostic measures. Studies were performed to evaluate performance of the Atellica® IM High-Sensitivity PSA assay (hsPSA)* versus the Atellica® IM PSA assay in patients undergoing management (monitoring) of PC. Methods A total of 868 serum samples from 170 subjects with PC (92 [54%] subjects had a radical prostatectomy (RP) before enrollment) were collected at 7 sites across the United States. Subjects had baseline and &amp;gt;2 follow-up visits during treatment (average 5.106 visits, SD=1.414). Samples were tested using the Atellica IM hsPSA assay and the commercially available Atellica IM PSA assay (comparative method). For RP and non-RP combined, 644 paired samples for each assay were tested. Subjects were designated “No Progression” (responding, stable, and no evidence of disease subjects) or “Progression” at each visit based on clinical classification. Results In this study the Atellica IM hsPSA assay demonstrated equivalent performance as commercial Atellica IM PSA in predicting disease status (table). The PPA between the assays was 95.5% and the NPA was 98.9%. Concordance to clinician classification was similar for both assays (∼80% PPA and 90% NPA). Conclusions Preliminary results demonstrated equivalent performance of the Atellica IM hsPSA assay as the commercially available Atellica IM PSA assay in terms of predicting disease status. This hsPSA assay can detect very low levels of PSA, which is particularly important for the monitoring of RP patients. *CAUTION: Investigational Device. Not available for sale. Future availability cannot be guaranteed. The results are preliminary and were achieved in unique setting with no expected timeline for completion.

18F]FDG PET integrated with structural MRI for accurate brain age prediction.

Brain aging is a complex and heterogeneous process characterized by both structural and functional decline. This study aimed to establish a novel deep learning (DL) method for predicting brain age by utilizing structural and metabolic imaging data. The dataset comprised participants from both the Universal Medical Imaging Diagnostic Center (UMIDC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). The former recruited 395 normal control (NC) subjects, while the latter included 438 NC subjects, 51 mild cognitive impairment (MCI) subjects, and 56 Alzheimer's disease (AD) subjects. We developed a novel dual-pathway, 3D simple fully convolutional network (Dual-SFCNeXt) to estimate brain age using [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) and structural magnetic resonance imaging (sMRI) images of NC subjects as input. Several prevailing DL models were trained and tested using either MRI or PET data for comparison. Model accuracies were evaluated using mean absolute error (MAE) and Pearson's correlation coefficient (r). Brain age gap (BAG), deviations of brain age from chronologic age, was correlated with cognitive assessments in MCI and AD subjects. Both PET- and MRI-based models achieved high prediction accuracy. The leading model was the SFCNeXt (the single-pathway version) for PET (MAE = 2.92, r = 0.96) and MRI (MAE = 3.23, r = 0.95) on all samples. By integrating both PET and MRI images, the Dual-SFCNeXt demonstrated significantly improved accuracy (MAE = 2.37, r = 0.97) compared to all single-modality models. Significantly higher BAG was observed in both the AD (P < 0.0001) and MCI (P < 0.0001) groups compared to the NC group. BAG correlated significantly with Mini-Mental State Examination (MMSE) scores (r=-0.390 for AD, r=-0.436 for MCI) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores (r = 0.333 for AD, r = 0.372 for MCI). The integration of [18F]FDG PET with structural MRI enhances the accuracy of brain age prediction, potentially introducing a new avenue for related multimodal brain age prediction studies.

A Study to Analyse the Relation between Consanguineous Marriage and Type of Dialysis in Chronic Kidney Disease Subjects

A Study to Analyse the Relation between Consanguineous Marriage and Type of Dialysis in Chronic Kidney Disease Subjects

Investigation of the utility of smartphone-based gait analyses in discrimination between patients with Alzheimer’s disease and Parkinson’s disease

Objective To reveal the discriminative value of gait parameters between Alzheimer’s disease (AD) and Parkinson’s disease (PD) subjects. Methods We included all consecutive patients with newly diagnosed AD and those with a diagnosis of PD who applied to our polyclinic between March 2022 and June 2022. The demographic and clinical features were evaluated during interviews. The gait analyses were performed using a quantitative, smartphone-based gait analyses program. Using this program, the step time (ST), step length (SL), step number (SN), gait velocity (GV), and cadence were measured in all individuals. Results Overall, 31 patients with AD and 45 with PD were enrolled in the analyses. The mean age of the AD group was higher according to those with PD. As expected, the Mini-Mental State Examination (MMSE) values were lower in the AD group. The comparative analyses of the gait parameters between groups did not reveal differences in any of the measures. The correlation analyses to investigate the possible association between the disease severity and gait parameters revealed that the MDS-UPDRS showed low negative correlations with SL and GV. Conclusion Our findings suggest that the evaluation of gait using the gait analyses program does not contribute to the discrimination between AD and PD in clinical practice.

Temporal gamma tACS and auditory stimulation affect verbal memory in healthy adults.

Research suggests a potential of gamma oscillation entrainment for enhancing memory in Alzheimer's disease and healthy subjects. Gamma entrainment can be accomplished with oscillatory electrical, but also sensory stimulation. However, comparative studies between sensory stimulation and transcranial alternating current stimulation (tACS) effects on memory processes are lacking. This study examined the effects of rhythmic gamma auditory stimulation (rAS) and temporal gamma-tACS on verbal long-term memory (LTM) and working memory (WM) in 74 healthy individuals. Participants were assigned to two groups according to the stimulation techniques (rAS or tACS). Memory was assessed in three experimental blocks, in which each participant was administered with control, 40, and 60 Hz stimulation in counterbalanced order. All interventions were well-tolerated, and participants reported mostly comparable side effects between real stimulation (40 and 60 Hz) and the control condition. LTM immediate and delayed recall remained unaffected by stimulations, while immediate recall intrusions decreased during 60 Hz stimulation. Notably, 40 Hz interventions improved WM compared to control stimulations. These results highlight the potential of 60 and 40 Hz temporal cortex stimulation for reducing immediate LTM recall intrusions and improving WM performance, respectively, probably due to the entrainment of specific gamma oscillations in the auditory cortex. The results also shed light on the comparative effects of these neuromodulation tools on memory functions, and their potential applications for cognitive enhancement and in clinical trials.

A Comprehensive Physiologically Based Pharmacokinetic Model for Predicting Vildagliptin Pharmacokinetics: Insights into Dosing in Renal Impairment.

Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly a review of the literature was thoroughly conducted and the PK information of vildagliptin was collected. PBPK modeling software, PK-Sim®, was then used to build and assess the IV, oral, and drug-specific models. Next, the average fold error, visual predictive checks, and predicted/observed ratios were used for the assessment of the robustness of the model for all the essential PK parameters. This evaluation demonstrated that all PK parameters were within an acceptable limit of error, i.e., 2 fold. Also to display the influence of CKD on the total and unbound AUC (the area under the plasma concentration-time curve) and to make modifications in dose, the analysis results of the model on this aspect were further examined. This PBPK model has successfully depicted the variations of PK of vildagliptin in healthy subjects and patients with CKD, which can be useful for medical practitioners in dosage optimization in renal disease patients.

Western diet reduces small intestinal intraepithelial lymphocytes via FXR-Interferon pathway

The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar “Western” diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity.

Prediction of left ventricle ejection fraction from HRV in diabetics and cardiac diseased subjects: A mathematical model approach

Heart Rate variability (HRV) is the variation between beat-to-beat intervals in a consecutive heartbeat. HRV provides enormous information about cardiac health. Electrocardiogram and echocardiography (2D echo) are the two major techniques used by medical practitioners to diagnose cardiac health. The 2D echo provides more accurate results as compared to electrocardiography but costs ten times more. This research provides low-cost solution for cardiac health diagnosis to the level of 2D echo derived from the electrocardiogram. ECG and the 2D echo data of the same cohort are collected from 15 diabetics and 15 cardiac-diseased subjects. In this research, we found a correlation between significant HRV parameters and 2D Echo parameters. Maximum correlation is obtained between LF/HF (low-frequency power to high-frequency power ratio), the HRV parameter, and LVEF (left ventricle ejection fraction), the 2D echo parameter. We derived various mathematical models, to predict the LVEF, from LF/HF for both cardiac diseased and diabetics separately. The combined best-fit model is obtained using nonlinear regression with the goodness of fit, R2 ​= ​94.54 %.

Multispectral label-free in vivo cellular imaging of human retinal pigment epithelium using adaptive optics fluorescence lifetime ophthalmoscopy improves feasibility for low emission analysis and increases sensitivity for detecting changes with age and eccentricity.

Adaptive optics fluorescence lifetime ophthalmoscopy (AOFLIO) provides a label-free approach to observe functional and molecular changes at cellular scale in vivo. Adding multispectral capabilities improves interpretation of lifetime fluctuations due to individual fluorophores in the retinal pigment epithelium (RPE). To quantify the cellular-scale changes in autofluorescence with age and eccentricity due to variations in lipofuscin, melanin, and melanolipofuscin in RPE using multispectral AOFLIO. AOFLIO was performed on six subjects at seven eccentricities. Four imaging channels ( ) were used: 473/SSC, 473/LSC, 532/LSC, and 765/NIR. Cells were segmented and the timing signals of each pixel in a cell were combined into a single histogram, which were then used to compute the lifetime and phasor parameters. An ANOVA was performed to investigate eccentricity and spectral effects on each parameter. A repeatability analysis revealed change in lifetime parameters in repeat visits for 532/LSC. The 765/NIR and 532/LSC had eccentricity and age effects similar to previous reports. The 473/LSC had a change in eccentricity with mean lifetime and a phasor component. Both the 473/LSC and 473/SSC had changes in eccentricity in the short lifetime component and its relative contribution. The 473/SSC had no trend in eccentricity in phasor. The comparison across the four channels showed differences in lifetime and phasor parameters. Multispectral AOFLIO can provide a more comprehensive picture of changes with age and eccentricity. These results indicate that cell segmentation has the potential to allow investigations in low-photon scenarios such as in older or diseased subjects with the co-capture of an NIR channel (such as 765/NIR) with the desired spectral channel. This work represents the first multispectral, cellular-scale fluorescence lifetime comparison in vivo in the human RPE and may be a useful method for tracking diseases.

Differential Responses to Low- and High-Frequency Subthalamic Nucleus Deep Brain Stimulation on Sensor-Measured Components of Bradykinesia in Parkinson's Disease.

The current approach to assessing bradykinesia in Parkinson's Disease relies on the Unified Parkinson's Disease Rating Scale (UPDRS), which is a numeric scale. Inertial sensors offer the ability to probe subcomponents of bradykinesia: motor speed, amplitude, and rhythm. Thus, we sought to investigate the differential effects of high-frequency compared to low-frequency subthalamic nucleus (STN) deep brain stimulation (DBS) on these quantified facets of bradykinesia. We recruited advanced Parkinson's Disease subjects with a chronic bilateral subthalamic nucleus (STN) DBS implantation to a single-blind stimulation trial where each combination of medication state (OFF/ON), electrode contacts, and stimulation frequency (60 Hz/180 Hz) was assessed. The Kinesia One sensor system was used to measure upper limb bradykinesia. For each stimulation trial, subjects performed extremity motor tasks. Sensor data were recorded continuously. We identified STN DBS parameters that were associated with improved upper extremity bradykinesia symptoms using a mixed linear regression model. We recruited 22 subjects (6 females) for this study. The 180 Hz STN DBS (compared to the 60 Hz STN DBS) and dopaminergic medications improved all subcomponents of upper extremity bradykinesia (motor speed, amplitude, and rhythm). For the motor rhythm subcomponent of bradykinesia, ventral contacts yielded improved symptom improvement compared to dorsal contacts. The differential impact of high- and low-frequency STN DBS on the symptoms of bradykinesia may advise programming for these patients but warrants further investigation. Wearable sensors represent a valuable addition to the armamentarium that furthers our ability to conduct objective, quantitative clinical assessments.

Evaluation of the Possible Pathophysiological Role of Redox Status in Patients with Sickle Cell Anemia

Abstract BACKGROUND: The disease of sickle cell anemia (SCA) is an inherited blood disease that causes several complications, and oxidative stress (OS) may play a very important role in its complications and pathophysiology. OBJECTIVE: The aims of the study is to evaluate the possible pathophysiological role of some antioxidant and oxidant biomarkers within SCA patients and to evaluate the correlation of OS and atherogenic index of plasma (AIP) to predict the cardiovascular risk in SCA subjects. MATERIALS AND METHODS: A case–control research includes three study groups: SCA patients, sickle cell trait (SCT) subjects, and healthy controls (HCs). All study groups were evaluated for their serum catalase (CAT), serum superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) as well as plasma triglycerides and high-density lipoprotein cholesterol. Data were collected, tabulated, and statistically analyzed using (SPSS) version 31 program. The frequencies, relative frequencies, and means were obtained as descriptive methods. The associations among parameters were obtained using the Chi-square statistical method. RESULTS: The results revealed significantly lower levels of serum SOD and GPx among sickle cell disease (SCD) and SCT subjects than the HCs, whereas the inverse findings were reported for CAT and AIP. However, the MDA results revealed a significantly higher level in SCD patients compared to SCT and HC. Furthermore, the levels of SOD and MDA were positively associated in all study groups, and the levels of GPx and MDA were negatively correlated in SCD and SCT groups. The AIP was positively correlated with MDA in the SCT group and negatively correlated with CAT in the SCD group. CONCLUSIONS: The conclusion of the study indicated the presence of an OS and antioxidant compensatory status in patients with SCD and the SCT subjects. The altered biomarkers in SCA patients made it clear that the impairment and generation of OS in this disease, as well as antioxidant biomarkers, are contributory factors toward cellular redox homeostasis. This addressed the aim of the study.

APOLLOE4 Phase 3 study of oral ALZ-801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics.

The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid-related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. This Phase 3 randomized, double-blind, placebo-controlled, 78-week study of ALZ-801 administered as 265mg twice per day tablets, enrolled 50- to 80-year-old homozygotes with Mini-Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating-Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug-placebo difference on the Alzheimer's Disease Assessment Scale 13-item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating-Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population. The APOLLOE4 Phase 3, placebo-controlled, 78-week study is designed to evaluate the efficacy and safety of ALZ-801 265mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N=325) has 51% females, a mean age = 69 years, and a mean Mini-Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13-item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating-Sum of Boxes, Amsterdam-Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ-801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.

Prediction of motor and non-motor Parkinson’s disease symptoms using serum lipidomics and machine learning: a 2-year study

Identifying biological factors which contribute to the clinical progression of heterogeneous motor and non-motor phenotypes in Parkinson’s disease may help to better understand the disease process. Several lipid-related genetic risk factors for Parkinson’s disease have been identified, and the serum lipid signature of Parkinson’s disease patients is significantly distinguishable from controls. However, the extent to which lipid profiles are associated with clinical outcomes remains unclear. Untargeted high-performance liquid chromatography-tandem mass spectrometry identified >900 serum lipids in Parkinson’s disease subjects at baseline (n = 122), and the potential for machine learning models using these lipids to predict motor and non-motor clinical scores after 2 years (n = 67) was assessed. Machine learning models performed best when baseline serum lipids were used to predict the 2-year future Unified Parkinson’s disease rating scale part three (UPDRS III) and Geriatric Depression Scale scores (both normalised root mean square error = 0.7). Feature analysis of machine learning models indicated that species of lysophosphatidylethanolamine, phosphatidylcholine, platelet-activating factor, sphingomyelin, diacylglycerol and triacylglycerol were top predictors of both motor and non-motor scores. Serum lipids were overall more important predictors of clinical outcomes than subject sex, age and mutation status of the Parkinson’s disease risk gene LRRK2. Furthermore, lipids were found to better predict clinical scales than a panel of 27 serum cytokines previously measured in this cohort (The Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium). These results suggest that lipid changes may be associated with clinical phenotypes in Parkinson’s disease.