Assessing interstitial fluid dynamics in type 2 diabetes mellitus and prediabetes cases through diffusion tensor imaging analysis along the perivascular space.

Background and purpose: Glymphatic system in type 2 diabetes mellitus (T2DM) but not in the prodrome, prediabetes (Pre-DM) was investigated using diffusion tensor image analysis along the perivascular space (DTI-ALPS). Association between glymphatic system and insulin resistance of prominent characteristic in T2DM and Pre-DM between is yet elucidated. Therefore, this study delves into the interstitial fluid dynamics using the DTI-ALPS in both Pre-DM and T2DM and association with insulin resistance. Materials and methods: In our cross-sectional study, we assessed 70 elderly individuals from the Bunkyo Health Study, which included 22 with Pre-DM, 18 with T2DM, and 33 healthy controls with normal glucose metabolism (NGM). We utilized the general linear model (GLM) to evaluate the ALPS index based on DTI-ALPS across these groups, considering variables like sex, age, intracranial volume, years of education, anamnesis of hypertension and hyperlipidemia, and the total Fazekas scale. Furthermore, we have explored the relationship between the ALPS index and insulin resistance, as measured by the homeostasis model assessment of insulin resistance (HOMA-IR) using GLM and the same set of covariates. Results: In the T2DM group, the ALPS index demonstrated a reduction compared with the NGM group [family-wise error (FWE)-corrected p < 0.001; Cohen's d = -1.32]. Similarly, the Pre-DM group had a lower ALPS index than the NGM group (FWE-corrected p < 0.001; Cohen's d = -1.04). However, there was no significant disparity between the T2DM and Pre-DM groups (FWE-corrected p = 1.00; Cohen's d = -0.63). A negative correlation was observed between the ALPS index and HOMA-IR in the combined T2DM and Pre-DM groups (partial correlation coefficient r = -0.35, p < 0.005). Conclusion: The ALPS index significantly decreased in both the pre-DM and T2DM groups and showed a correlated with insulin resistance. This indicated that changes in interstitial fluid dynamics are associated with insulin resistance.

Cross-vendor multiparametric mapping of the human brain using 3D-QALAS: A multicenter and multivendor study.

PURPOSE: To evaluate a vendor-agnostic multiparametric mapping scheme based on 3D quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS) for whole-brain T1, T2, and proton density (PD) mapping. METHODS: This prospective, multi-institutional study was conducted between September 2021 and February 2022 using five different 3T systems from four prominent MRI vendors. The accuracy of this technique was evaluated using a standardized MRI system phantom. Intra-scanner repeatability and inter-vendor reproducibility of T1, T2, and PD values were evaluated in 10 healthy volunteers (6 men; mean age ± SD, 28.0 ± 5.6 y) who underwent scan-rescan sessions on each scanner (total scans = 100). To evaluate the feasibility of 3D-QALAS, nine patients with multiple sclerosis (nine women; mean age ± SD, 48.2 ± 11.5 y) underwent imaging examination on two 3T MRI systems from different manufacturers. RESULTS: Quantitative maps obtained with 3D-QALAS showed high linearity (R2 = 0.998 and 0.998 for T1 and T2, respectively) with respect to reference measurements. The mean intra-scanner coefficients of variation for each scanner and structure ranged from 0.4% to 2.6%. The mean structure-wise test-retest repeatabilities were 1.6%, 1.1%, and 0.7% for T1, T2, and PD, respectively. Overall, high inter-vendor reproducibility was observed for all parameter maps and all structure measurements, including white matter lesions in patients with multiple sclerosis. CONCLUSION: The vendor-agnostic multiparametric mapping technique 3D-QALAS provided reproducible measurements of T1, T2, and PD for human tissues within a typical physiological range using 3T scanners from four different MRI manufacturers.

Noninvasive Magnetic Resonance Imaging Measures of Glymphatic System Activity.

The comprehension of the glymphatic system, a postulated mechanism responsible for the removal of interstitial solutes within the central nervous system (CNS), has witnessed substantial progress recently. While direct measurement techniques involving fluorescence and contrast agent tracers have demonstrated success in animal studies, their application in humans is invasive and presents challenges. Hence, exploring alternative noninvasive approaches that enable glymphatic research in humans is imperative. This review primarily focuses on several noninvasive magnetic resonance imaging (MRI) techniques, encompassing perivascular space (PVS) imaging, diffusion tensor image analysis along the PVS, arterial spin labeling, chemical exchange saturation transfer, and intravoxel incoherent motion. These methodologies provide valuable insights into the dynamics of interstitial fluid, water permeability across the blood-brain barrier, and cerebrospinal fluid flow within the cerebral parenchyma. Furthermore, the review elucidates the underlying concept and clinical applications of these noninvasive MRI techniques, highlighting their strengths and limitations. It addresses concerns about the relationship between glymphatic system activity and pathological alterations, emphasizing the necessity for further studies to establish correlations between noninvasive MRI measurements and pathological findings. Additionally, the challenges associated with conducting multisite studies, such as variability in MRI systems and acquisition parameters, are addressed, with a suggestion for the use of harmonization methods, such as the combined association test (COMBAT), to enhance standardization and statistical power. Current research gaps and future directions in noninvasive MRI techniques for assessing the glymphatic system are discussed, emphasizing the need for larger sample sizes, harmonization studies, and combined approaches. In conclusion, this review provides invaluable insights into the application of noninvasive MRI methods for monitoring glymphatic system activity in the CNS. It highlights their potential in advancing our understanding of the glymphatic system, facilitating clinical applications, and paving the way for future research endeavors in this field. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 5.

Advancements in Diffusion MRI Tractography for Neurosurgery.

ABSTRACT: Diffusion magnetic resonance imaging tractography is a noninvasive technique that enables the visualization and quantification of white matter tracts within the brain. It is extensively used in preoperative planning for brain tumors, epilepsy, and functional neurosurgical procedures such as deep brain stimulation. Over the past 25 years, significant advancements have been made in imaging acquisition, fiber direction estimation, and tracking methods, resulting in considerable improvements in tractography accuracy. The technique enables the mapping of functionally critical pathways around surgical sites to avoid permanent functional disability. When the limitations are adequately acknowledged and considered, tractography can serve as a valuable tool to safeguard critical white matter tracts and provides insight regarding changes in normal white matter and structural connectivity of the whole brain beyond local lesions. In functional neurosurgical procedures such as deep brain stimulation, it plays a significant role in optimizing stimulation sites and parameters to maximize therapeutic efficacy and can be used as a direct target for therapy. These insights can aid in patient risk stratification and prognosis. This article aims to discuss state-of-the-art tractography methodologies and their applications in preoperative planning and highlight the challenges and new prospects for the use of tractography in daily clinical practice.

Traveling Subject-Informed Harmonization Increases Reliability of Brain Diffusion Tensor and Neurite Mapping.

Diffusion-weighted magnetic resonance imaging (dMRI) of brain has helped elucidate the microstructural changes of psychiatric and neurodegenerative disorders. Inconsistency between MRI models has hampered clinical application of dMRI-based metrics. Using harmonized dMRI data of 300 scans from 69 traveling subjects (TS) scanning the same individuals at multiple conditions with 13 MRI models and 2 protocols, the widely-used metrics such as diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) were evaluated before and after harmonization with a combined association test (ComBat) or TS-based general linear model (TS-GLM). Results showed that both ComBat and TS-GLM significantly reduced the effects of the MRI site, model, and protocol for diffusion metrics while maintaining the intersubject biological effects. The harmonization power of TS-GLM based on TS data model is more powerful than that of ComBat. In conclusion, our research demonstrated that although ComBat and TS-GLM harmonization approaches were effective at reducing the scanner effects of the site, model, and protocol for DTI and NODDI metrics in WM, they exhibited high retainability of biological effects. Therefore, we suggest that, after harmonizing DTI and NODDI metrics, a multisite study with large cohorts can accurately detect small pathological changes by retaining pathological effects.

Noise reduction by multiple path neural network using Attention mechanisms with an emphasis on robustness against Errors: A pilot study on brain Diffusion-Weighted images.

PURPOSE: In deep learning-based noise reduction, larger networks offer advanced and complex functionality by utilizing its greater degree of freedom, but come with increased unpredictability, raising the potential risk of unforeseen errors. Here, we introduce a novel denoising model for diffusion-weighted images that intentionally limits the network output freedom by incorporating multiple pathways with varying degrees of freedom, with the aim of minimizing the chance of unintended alterations to the input. The purpose of this pilot study is to assess the model's ability to perform effective denoising under the constraints. METHODS: Images from 10 healthy volunteers were used. Key innovations in our model development include: (1) neural network architecture that separated the function for calculating the specific output values from the function for adjusting the calculation for each pixel and (2) training that optimised the network based on both image and secondary obtained diffusion tensor. The generated images were compared with the original ones by measuring the deviation from ground truth images (averaged across eight acquisitions). RESULTS: The generated images demonstrated closer alignment with the ground truth images, both visually and statistically (Q < 0.05), compared to the original images. Furthermore, the advantage of the generated images over the original images was also found in the secondary obtained quantitative parameter maps with significance (Q < 0.05). CONCLUSION: The usefulness of the proposed method was suggested because it was successful in improving both the quality of the generated images and accuracy of the major diffusion parameter maps under the given restrictions.

Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter.

Antenatal steroid therapy is the standard of care for women at imminent risk of preterm delivery. Current dosing regimens use suprapharmacological doses to achieve extended fetal steroid exposures. We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation. Ewes with single fetuses underwent surgery to install a fetal jugular catheter. Adopting a stepwise design, ewes were randomized to either a saline-only group (negative control group; n = 9) or one of four betamethasone treatment groups. Each betamethasone group fetus received a fetal intravenous infusion to target a constant plasma betamethasone level of either 1) 2 ng/mL (2 ng/mL positive control group, n = 9); 2) 1 ng/mL, (1 ng/mL group, n = 10); 3) 0.5 ng/mL (0.5 ng/mL group, n = 10); or 4) 0.25 ng/mL (0.25 ng/mL group, n = 10). Fetuses were infused for 48 h, delivered, and ventilated. The positive control group, negative control group, and mid-point 0.5 ng/mL group animals were tested first. An interim analysis informed the final betamethasone group tested. Positive control group animals had large, statistically significant improvements in respiratory function. Based on an interim analysis, the 1.0 ng/mL group was studied in favor of the 0.25 ng/mL group. Treatment efficacy was progressively lost at plasma betamethasone concentrations lower than 2 ng/mL. We demonstrated that the acute respiratory benefit conveyed by antenatal steroid exposure in the fetal sheep is progressively lost when constant fetal plasma betamethasone concentrations are reduced below a targeted value of 2 ng/mL.NEW & NOTEWORTHY Lung maturation benefits in preterm lambs were progressively lost when fetal plasma betamethasone concentrations fell below 2 ng/mL. The effective floor threshold for a robust, lung-maturing exposure likely lies between 1 and 2 ng betamethasone per milliliter of plasma. Hypothalamic pituitary adrenal axis signaling and immunocyte populations remained materially disrupted at subtherapeutic steroid concentrations. These data demonstrate the potential to improve antenatal steroid therapy using reduced dose regimens informed by glucocorticoid pharmacokinetics and pharmacodynamics.

Artificial placenta support of extremely preterm ovine fetuses at the border of viability for up to 336 hours with maintenance of systemic circulation but reduced somatic and organ growth.

Introduction: Artificial placenta therapy (APT) is an experimental life support system to improve outcomes for extremely preterm infants (EPI) less than 1,000 g by obviating the need for pulmonary gas exchange. There are presently no long-term survival data for EPI supported with APT. To address this, we aimed to maintain 95d-GA (GA; term-150d) sheep fetuses for up to 2 weeks using our APT system. Methods: Pregnant ewes (n = 6) carrying singleton fetuses underwent surgical delivery at 95d GA. Fetuses were adapted to APT and maintained for up to 2 weeks with constant monitoring of key physiological parameters and extensive time-course blood and urine sampling, and ultrasound assessments. Six age-matched in-utero fetuses served as controls. Data were tested for group differences with ANOVA. Results: Six APT Group fetuses (100%) were adapted to APT successfully. The mean BW at the initiation of APT was 656 ± 42 g. Mean survival was 250 ± 72 h (Max 336 h) with systemic circulation and key physiological parameters maintained mostly within normal ranges. APT fetuses had active movements and urine output constantly exceeded infusion volume over the experiment. At delivery, there were no differences in BW (with edema in three APT group animals), brain weight, or femur length between APT and in-utero Control animals. Organ weights and humerus lengths were significantly reduced in the APT group (p < 0.05). Albumin, IGF-1, and phosphorus were significantly decreased in the APT group (p < 0.05). No cases of positive blood culture were detected. Conclusion: We report the longest use of APT to maintain extremely preterm fetuses to date. Fetal systemic circulation was maintained without infection, but growth was abnormal. This achievement suggests a need to focus not only on cardiovascular stability and health but also on the optimization of fetal growth and organ development. This new challenge will need to be overcome prior to the clinical translation of this technology.

Reduced neurite density index in the prefrontal cortex of adults with autism assessed using neurite orientation dispersion and density imaging.

Background: Core symptoms of autism-spectrum disorder (ASD) have been associated with prefrontal cortex abnormalities. However, the mechanisms behind the observation remain incomplete, partially due to the challenges of modeling complex gray matter (GM) structures. This study aimed to identify GM microstructural alterations in adults with ASD using neurite orientation dispersion and density imaging (NODDI) and voxel-wise GM-based spatial statistics (GBSS) to reduce the partial volume effects from the white matter and cerebrospinal fluid. Materials and methods: A total of 48 right-handed participants were included, of which 22 had ASD (17 men; mean age, 34.42 ± 8.27 years) and 26 were typically developing (TD) individuals (14 men; mean age, 32.57 ± 9.62 years). The metrics of NODDI (neurite density index [NDI], orientation dispersion index [ODI], and isotropic volume fraction [ISOVF]) were compared between groups using GBSS. Diffusion tensor imaging (DTI) metrics and surface-based cortical thickness were also compared. The associations between magnetic resonance imaging-based measures and ASD-related scores, including ASD-spectrum quotient, empathizing quotient, and systemizing quotient were also assessed in the region of interest (ROI) analysis. Results: After controlling for age, sex, and intracranial volume, GBSS demonstrated significantly lower NDI in the ASD group than in the TD group in the left prefrontal cortex (caudal middle frontal, lateral orbitofrontal, pars orbitalis, pars triangularis, rostral middle frontal, and superior frontal region). In the ROI analysis of individuals with ASD, a significantly positive correlation was observed between the NDI in the left rostral middle frontal, superior frontal, and left frontal pole and empathizing quotient score. No significant between-group differences were observed in all DTI metrics, other NODDI (i.e., ODI and ISOVF) metrics, and cortical thickness. Conclusion: GBSS analysis was used to demonstrate the ability of NODDI metrics to detect GM microstructural alterations in adults with ASD, while no changes were detected using DTI and cortical thickness evaluation. Specifically, we observed a reduced neurite density index in the left prefrontal cortices associated with reduced empathic abilities.

Fiber-Specific White Matter Alterations in Parkinson's Disease Patients with GBA Gene Mutations.

BACKGROUND: Patients with Parkinson's disease (PD) carrying GBA gene mutations (GBA-PD) have a more aggressive disease course than those with idiopathic PD (iPD). OBJECTIVE: The objective of this study was to investigate fiber-specific white matter (WM) differences in nonmedicated patients with early-stage GBA-PD and iPD using fixel-based analysis, a novel technique to assess tract-specific WM microstructural and macrostructural features comprehensively. METHODS: Fixel-based metrics, including microstructural fiber density (FD), macrostructural fiber-bundle cross section (FC), and a combination of FD and FC (FDC), were compared among 30 healthy control subjects, 16 patients with GBA-PD, and 35 patients with iPD. Associations between FDC and clinical evaluations were also explored using multiple linear regression analyses. RESULTS: Patients with GBA-PD showed significantly lower FD in the fornix and superior longitudinal fasciculus than healthy control subjects, and lower FC in the corticospinal tract (CST) and lower FDC in the CST, middle cerebellar peduncle, and striatal-thalamo-cortical pathways than patients with iPD. Contrarily, patients with iPD showed significantly higher FC and FDC in the CST and striatal-thalamo-cortical pathways than healthy control subjects. In addition, lower FDC in patients with GBA-PD was associated with reduced glucocerebrosidase enzyme activity, lower cerebrospinal fluid total α-synuclein levels, lower Montreal Cognitive Assessment scores, lower striatal binding ratio, and higher Unified Parkinson's Disease Rating Scale Part III scores. CONCLUSIONS: We report reduced fiber-specific WM density and bundle cross-sectional size in patients with GBA-PD, suggesting neurodegeneration linked to glucocerebrosidase deficiency, α-synuclein accumulation, and poorer cognition and motor functions. Conversely, patients with iPD showed increased fiber bundle size, likely because of WM reorganization. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Fiber-specific micro- and macroscopic white matter alterations in progressive supranuclear palsy and corticobasal syndrome.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are characterized by progressive white matter (WM) alterations associated with the prion-like spreading of four-repeat tau, which has been pathologically confirmed. It has been challenging to monitor the WM degeneration patterns underlying the clinical deficits in vivo. Here, a fiber-specific fiber density and fiber cross-section, and their combined measure estimated using fixel-based analysis (FBA), were cross-sectionally and longitudinally assessed in PSP (n = 20), CBS (n = 17), and healthy controls (n = 20). FBA indicated disease-specific progression patterns of fiber density loss and subsequent bundle atrophy consistent with the tau propagation patterns previously suggested in a histopathological study. This consistency suggests the new insight that FBA can monitor the progressive tau-related WM changes in vivo. Furthermore, fixel-wise metrics indicated strong correlations with motor and cognitive dysfunction and the classifiability of highly overlapping diseases. Our findings might also provide a tool to monitor clinical decline and classify both diseases.

High Expression of Adrenal Cortisol Synthases Is Acquired After Intrauterine Inflammation in Periviable Sheep Fetuses.

Context: Intrauterine inflammation, a representative stressor for the fetus, has been shown to alter the hypothalamus-pituitary-adrenal (HPA) axis reactivity in preterm fetuses and increase postnatal cortisol production. However, the mechanism of this alteration has not yet been elucidated. Objective: We aimed to clarify the effects of endotoxin-induced intrauterine inflammation on the HPA axis of periviable sheep fetuses. Methods: Fetal sheep (0.63 term) were divided into 2 groups: (1) the endotoxin group, in which the endotoxin was injected into the amniotic fluid; and (2) the control group, in which the saline solution was injected instead. A corticotropin-releasing hormone (CRH) challenge test was performed on the third day after injection to evaluate the cortisol-producing capacity of each group. Gene expression levels in the fetal adrenal glands of each group were analyzed by RNA-seq. Results: The cortisol levels were significantly higher in the endotoxin group than in the control group after CRH challenge (P = .02). There were no significant differences in the responsiveness of adrenocorticotropin and cortisone between the 2 groups. Gene expression levels of the following enzymes involved in cortisol synthesis were significantly elevated in the endotoxin group: cytochrome P450 family (CYP) 11 subfamily A member 1 (log2FC 1.75), CYP 17 subfamily A member 1 (log2FC 3.41), 3ß-hydroxysteroid dehydrogenase type I (log2FC 1.13), steroidogenic acute regulatory protein (log2FC 1.09), and CYP 21 (log2FC 0.89). Conclusion: Periviable fetuses exposed to inflammation in utero have altered the responsiveness of the HPA axis with increased expression of enzymes involved in cortisol synthesis in the adrenal gland.

Glymphatic system impairment in corticobasal syndrome: diffusion tensor image analysis along the perivascular space (DTI-ALPS).

PURPOSE: This study aimed to evaluate the along the perivascular space (ALPS) index based on the diffusion tensor image ALPS (DTI-ALPS) in corticobasal degeneration with corticobasal syndrome (CBD-CBS) and investigate its correlation with motor and cognitive functions. MATERIALS AND METHODS: The data of 21 patients with CBD-CBS and 17 healthy controls (HCs) were obtained from the 4-Repeat Tauopathy Neuroimaging Initiative and the Frontotemporal Lobar Degeneration Neuroimaging Initiative databases. Diffusion magnetic resonance imaging was performed using a 3-Tesla MRI scanner. The ALPS index based on DTI-ALPS was automatically calculated after preprocessing. The ALPS index was compared between the CBD-CBS and HC groups via a general linear model analysis, with covariates such as age, sex, years of education, and intracranial volume (ICV). Furthermore, to confirm the relation between the ALPS index and the motor and cognitive score in CBD-CBS, the partial Spearman's rank correlation coefficient was calculated with covariates such as age, sex, years of education, and ICV. A p value of < 0.05 was considered as statistically significant in all statistical analyses. RESULTS: The ALPS index of CBD-CBS was significantly lower than that of HC (Cohen's d = - 1.53, p < 0.005). Moreover, the ALPS index had a significant positive correlation with the mini mental state evaluation score (rs = 0.65, p < 0.005) and a significant negative correlation with the unified Parkinson's Disease Rating Scale III score (rs = - 0.75, p < 0.001). CONCLUSION: The ALPS index of patients with CBD-CBS, which is significantly lower than that of HCs, is significantly associated with motor and cognitive functions.

Glymphatic system impairment in sleep disruption: diffusion tensor image analysis along the perivascular space (DTI-ALPS).

PURPOSE: This study aimed to evaluate the relationship between sleep quality as assessed using the Pittsburgh Sleep Quality Index (PSQI) and the index of diffusivity along the perivascular space (ALPS index), a possible indirect indicator of glymphatic system activity. MATERIALS AND METHODS: This study included the diffusion magnetic resonance imaging (MRI) data of 317 people with sleep disruption and 515 healthy controls (HCs) from the Human Connectome Project (WU-MINN HCP 1200). The ALPS index was calculated automatically based on diffusion tensor image analysis (DTI)-ALPS of diffusion MRI. The ALPS index of the sleep disruption and HC groups was compared using general linear model (GLM) analysis with covariates, such as age, sex, level of education, and intracranial volume. In addition, to confirm the relationship between sleep quality and the ALPS index in the sleep disruption group as well as evaluate the effect of each PSQI component on the ALPS index, correlation analyses between the ALPS indices and PSQI scores of all the components and between the ALPS index and each PSQI component was performed using GLM analysis with the abovementioned covariates, respectively. RESULTS: The ALPS index was significantly lower in the sleep disruption group than in the HC group (p = 0.001). Moreover, the ALPS indices showed significant negative correlations with the PSQI scores of all the components (false discovery rate [FDR]-corrected p < 0.001). Two significant negative correlations were also found between the ALPS index and PSQI component 2 (sleep latency, FDR-corrected p < 0.001) and 6 (the use of sleep medication, FDR-corrected p < 0.001). CONCLUSION: Our findings suggest that glymphatic system impairment contributes to sleep disruption in young adults.

Reproducibility of automated calculation technique for diffusion tensor image analysis along the perivascular space.

PURPOSE: The method of diffusion tensor image analysis along the perivascular space (DTI-ALPS) was gathering attention to evaluate the brain's glymphatic function or interstitial fluid dynamics. However, to the best knowledge, no study was conducted on the reproducibility of these automated methods for ALPS index values. Therefore, the current study evaluated the ALPS index reproducibility based on DTI-ALPS using two major automated calculation techniques in scan and rescan of the same subject on the same day. MATERIALS AND METHODS: This study included 23 participants, including 2 with Alzheimer's disease, 15 with mild cognitive impairment, and 6 with cognitive normals. Scan and rescan data of diffusion magnetic resonance images were obtained, as well as automatically index for ALPS (ALPS index) and ALPS index maintaining tensor vector orientation information (vALPS index) with region of interest on the template fractional anisotropy map calculated by FSL software.These ALPS indices were compared in terms of scan and rescan reproducibility. RESULTS: The absolute difference in ALPS-index values between scan and rescan was larger in the ALPS index than in the vALPS index by approximately 0.6% as the relative difference. Cohen's d for the left and right ALPS indices between methods were 0.121 and 0.159, respectively. CONCLUSION: The vALPS index based on DTI-ALPS maintaining tensor vector orientation information has higher reproducibility than the ALPS index. This result encourages a multisite study on the ALPS index with a large sample size and helps detect a subtle pathological change in the ALPS index.