Proteomic changes in the human cerebrovasculature in Alzheimer's disease and related tauopathies linked to peripheral biomarkers in plasma and cerebrospinal fluid.

INTRODUCTION: Cerebrovascular dysfunction is a pathological hallmark of Alzheimer's disease (AD). Nevertheless, detecting cerebrovascular changes within bulk tissues has limited our ability to characterize proteomic alterations from less abundant cell types. METHODS: We conducted quantitative proteomics on bulk brain tissues and isolated cerebrovasculature from the same individuals, encompassing control (N = 28), progressive supranuclear palsy (PSP) (N = 18), and AD (N = 21) cases. RESULTS: Protein co-expression network analysis identified unique cerebrovascular modules significantly correlated with amyloid plaques, cerebrovascular amyloid angiopathy (CAA), and/or tau pathology. The protein products within AD genetic risk loci were concentrated within cerebrovascular modules. The overlap between differentially abundant proteins in AD cerebrospinal fluid (CSF) and plasma with cerebrovascular network highlighted a significant increase of matrisome proteins, SMOC1 and SMOC2, in CSF, plasma, and brain. DISCUSSION: These findings enhance our understanding of cerebrovascular deficits in AD, shedding light on potential biomarkers associated with CAA and vascular dysfunction in neurodegenerative diseases.

Bridging the gap: Multi-omics profiling of brain tissue in Alzheimer's disease and older controls in multi-ethnic populations.

INTRODUCTION: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS: To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTS: We generated multi-omics data and curated and harmonized phenotypic data from BA (n = 306), LA (n = 326), or BA and LA (n = 4) brain donors plus non-Hispanic White (n = 252) and other (n = 20) ethnic groups, to establish a foundational dataset enriched for BA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION: The inclusion of traditionally underrepresented groups in multi-omics studies is essential to discovering the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD. HIGHLIGHTS: Accelerating Medicines Partnership in Alzheimer's Disease Diversity Initiative led brain tissue profiling in multi-ethnic populations. Brain multi-omics data is generated from Black American, Latin American, and non-Hispanic White donors. RNA, whole genome sequencing and tandem mass tag proteomicsis completed and shared. Multiple brain regions including caudate, temporal and dorsolateral prefrontal cortex were profiled.

Abnormalities of neural stem cells in Lesch-Nyhan disease.

Lesch-Nyhan disease (LND) is a neurodevelopmental disorder caused by variants in the HPRT1 gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGprt). HGprt deficiency provokes numerous metabolic changes which vary among different cell types, making it unclear which changes are most relevant for abnormal neural development. To begin to elucidate the consequences of HGprt deficiency for developing human neurons, neural stem cells (NSCs) were prepared from 6 induced pluripotent stem cell (iPSC) lines from individuals with LND and compared to 6 normal healthy controls. For all 12 lines, gene expression profiles were determined by RNA-seq and protein expression profiles were determined by shotgun proteomics. The LND lines revealed significant changes in expression of multiple genes and proteins. There was little overlap in findings between iPSCs and NSCs, confirming the impact of HGprt deficiency depends on cell type. For NSCs, gene expression studies pointed towards abnormalities in WNT signaling, which is known to play a role in neural development. Protein expression studies pointed to abnormalities in the mitochondrial F0F1 ATPase, which plays a role in maintaining cellular energy. These studies point to some mechanisms that may be responsible for abnormal neural development in LND.

Uric Acid in Parkinson's Disease: What Is the Connection?

Numerous studies have linked Parkinson's disease (PD) with low levels of uric acid (UA). Low UA has been associated with the risk of developing PD, and its progression and severity. The biological mechanisms underlying these relationships have never been firmly established. The most frequently proposed mechanism is that UA is an antioxidant. Low UA is thought to predispose to oxidative stress, which contributes to dopamine neuron degeneration, and leads to initial appearance of symptoms of PD and its worsening over time. Several recent studies have questioned this explanation. In this review, we describe the biology of UA, its many links with PD, evidence regarding UA as an antioxidant, and we question whether UA causes PD or contributes to its progression. We also address the possibility that something about PD causes low UA (reverse causation) or that low UA is a biomarker of some other more relevant mechanism in PD. We hope the evidence provided here will stimulate additional studies to better understand the links between UA and PD. Elucidating these mechanisms remains important, because they may provide new insights into the pathogenesis of PD or novel approaches to treatments. © 2022 International Parkinson and Movement Disorder Society.

α-Lipoic acid, functional fatty acid, as a novel therapeutic alternative for central nervous system diseases: A review.

OBJECTIVES: α-lipoic acid (ALA) is a natural antioxidant which acts as a cofactor of bioenergetic mitochondrial enzymes. Along with its mitochondrial action, ALA and its reduced form have many biological functions resulting in a wide variety of actions such as anti-inflammation and antioxidant protection, scavenging reactive oxygen species, regenerating other antioxidant agents, such as vitamins C and E, and cytosolic glutathione, chelating the transitional metal ions (e.g. iron and copper), and modulating the signal transduction of nuclear factor. METHODS: By selecting papers from PubMed, Science Direct, EBSCO, and databases, this review discusses the biochemical properties of LA, its mechanism of action, pharmacokinetics, and its possible therapeutic role in central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Multiple sclerosis, stroke, and spinal cord injury. RESULTS: ALA as an antioxidant and anti-inflammation agent has therapeutical effects on central nervous system diseases, especially multiple sclerosis and PD. DISCUSSION: ALA can be considered as a potentially useful treatment in central nervous disorders.

The Effect of Females' Reproductive Factors on Pituitary Gland Size in Women at Reproductive Age.

Background and Objectives: The brain imaging of the pituitary gland in females has shown a change in pituitary size and volume in the female's population. It has been proven that the pituitary gland is affected by pregnancy, giving birth, and hormone-related factors. Therefore, this study aimed to evaluate the factors which may have an impact on the pituitary size in females at reproductive age and compare the pituitary size in females with a history of pregnancy, those at the postpartum period, and nullipara females. Materials and Methods: This population-based study was conducted on 208 healthy women aged 12-55 years old. Participants underwent cranial Magnetic resonance imaging (MRI), and pituitary diameters (craniocaudal, anteroposterior, and transverse) and volume were measured for each subject. The correlation of age, gravity, parity, lactation, and intake of oral contraceptives with pituitary size were analyzed. Results: One-hundred and eighty females met the criteria for participation. The pituitary volume correlated negatively with hormone-related factors. The gravity (r = -0.35) and parity (r = -0.35) had significant negative effects on the pituitary volume (p < 0.001). The use of oral contraceptives and lactation were also in negative correlation with the pituitary volume (r = -0.20, p = 0.006, r = -0.56, p < 0.001, respectively). The craniocaudal diameter was also affected by gravity (r = -0.62), parity (r = -0.57), intake of contraceptives (r = -0.32), and lactation (r = -0.70), p < 0.001. The anteroposterior diameter of the pituitary gland associated significantly with gravity (r = -0.19, p = 0.009), parity (r = -0.20, p = 0.007), and lactation (r = -0.25, p = 0.001). The transverse diameter of the pituitary gland also related negatively with reproductive factors such as gravity (r = -0.15, p = 0.04), parity (r = -0.17, p = 0.02), and lactation (r = -0.17, p = 0.02). The pituitary gland of nullipara females was the greatest in size. Recent pregnancy led to increased craniocaudal and anteroposterior diameters. Conclusions: In this study, we found a negative effect of pregnancy and giving birth on pituitary size. Nullipara females were found to have the greatest pituitaries, even greater than the females in the postpartum period.

Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: A double blind randomized clinical trial.

OBJECTIVES: Multiple sclerosis (MS) is the chronic inflammatory and demyelinating disorder of central nervous system which is accompanied with disability and negative life style changes such as fatigue and depression. The aim of this study is to investigate the effect of coenzyme Q10 (CoQ10) supplementation on fatigue and depression in patients with MS. METHODS: We performed a randomized, double-blinded, placebo-controlled trial to determine the effect of CoQ10 supplement (500 mg/day) vs. placebo for 12 weeks. Fatigue symptoms were quantified by means of fatigue severity scale (FSS) and the Beck depression inventory (BDI) was used to assess depressive symptoms. RESULTS: A significant decrease of FSS was observed in CoQ10 group during the intervention (P = 0.001) and significant increase of FSS change was observed within placebo group (P = 0.001). Repeated measure analysis of variance showed a significant time-by-treatment interaction for FSS (baseline 41.5 ± 15.6 vs. endpoint 45 ± 13.6; F1,45 = 55.23, P < 0.001, η(2) = 0.56) and BDI (baseline 17.8 ± 12.2 vs. endpoint 20.4 ± 11.4; F1,45 = 40.3, P < 0.001, η(2) = 0.48), indicating significant decrease of FSS and BDI in CoQ10 group compared to placebo group. CONCLUSION: Our study suggests that CoQ10 supplementation (500 mg/day) can improve fatigue and depression in patients with multiple sclerosis.

Proteomic Changes in the Human Cerebrovasculature in Alzheimer's Disease and Related Tauopathies Linked to Peripheral Biomarkers in Plasma and Cerebrospinal Fluid.

Dysfunction of the neurovascular unit stands as a significant pathological hallmark of Alzheimer's disease (AD) and age-related neurodegenerative diseases. Nevertheless, detecting vascular changes in the brain within bulk tissues has proven challenging, limiting our ability to characterize proteomic alterations from less abundant cell types. To address this challenge, we conducted quantitative proteomic analyses on both bulk brain tissues and cerebrovascular-enriched fractions from the same individuals, encompassing cognitively unimpaired control, progressive supranuclear palsy (PSP), and AD cases. Protein co-expression network analysis identified modules unique to the cerebrovascular fractions, specifically enriched with pericytes, endothelial cells, and smooth muscle cells. Many of these modules also exhibited significant correlations with amyloid plaques, cerebral amyloid angiopathy (CAA), and/or tau pathology in the brain. Notably, the protein products within AD genetic risk loci were found concentrated within modules unique to the vascular fractions, consistent with a role of cerebrovascular deficits in the etiology of AD. To prioritize peripheral AD biomarkers associated with vascular dysfunction, we assessed the overlap between differentially abundant proteins in AD cerebrospinal fluid (CSF) and plasma with a vascular-enriched network modules in the brain. This analysis highlighted matrisome proteins, SMOC1 and SMOC2, as being increased in CSF, plasma, and brain. Immunohistochemical analysis revealed SMOC1 deposition in both parenchymal plaques and CAA in the AD brain, whereas SMOC2 was predominantly localized to CAA. Collectively, these findings significantly enhance our understanding of the involvement of cerebrovascular abnormalities in AD, shedding light on potential biomarkers and molecular pathways associated with CAA and vascular dysfunction in neurodegenerative diseases.

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations.

INTRODUCTION: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS: To bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTS: We generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION: Inclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

Large-scale Deep Proteomic Analysis in Alzheimer's Disease Brain Regions Across Race and Ethnicity.

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups. Methods: Dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS). Results: As a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals. Discussion: This comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

Transplantation of Stem Cells as a Potential Therapeutic Strategy in Neurodegenerative Disorders.

Stem cells are considered to have significant capacity to differentiate into various cell types in humans and animals. Unlike specialized cells, these cells can proliferate several times to produce millions of cells. Nowadays, pluripotent stem cells are important candidates to provide a renewable source for the replacement of cells in tissues of interest. The damage to neurons and glial cells in the brain or spinal cord is present in neurological disorders such as Amyotrophic lateral sclerosis, stroke, Parkinson's disease, multiple sclerosis, Alzheimer's disease, Huntington's disease, spinal cord injury, lysosomal storage disorder, epilepsy, and glioblastoma. Therefore, stem cell transplantation can be used as a novel therapeutic approach in cases of brain and spinal cord damage. Recently, researchers have generated neuron-like cells and glial-like cells from embryonic stem cells, mesenchymal stem cells, and neural stem cells. In addition, several experimental studies have been performed for developing stem cell transplantation in brain tissue. Herein, we focus on stem cell therapy to regenerate injured tissue resulting from neurological diseases and then discuss possible differentiation pathways of stem cells to the renewal of neurons.

Induced pluripotent stem cells from subjects with Lesch-Nyhan disease.

Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers. Gene expression profiling with RNAseq demonstrated significant heterogeneity among the lines. Despite this heterogeneity, several anticipated abnormalities were readily detectable across all LND lines, including reduced HPRT1 mRNA. Several unexpected abnormalities were also consistently detectable across the LND lines, including decreases in FAR2P1 and increases in RNF39. Shotgun proteomics also demonstrated several expected abnormalities in the LND lines, such as absence of HGprt protein. The proteomics study also revealed several unexpected abnormalities across the LND lines, including increases in GNAO1 decreases in NSE4A. There was a good but partial correlation between abnormalities revealed by the RNAseq and proteomics methods. Finally, functional studies demonstrated LND lines had no HGprt enzyme activity and resistance to the toxic pro-drug 6-thioguanine. Intracellular purines in the LND lines were normal, but they did not recycle hypoxanthine. These cells provide a novel resource to reveal insights into the relevance of heterogeneity among iPSC lines and applications for modeling LND.

Diagnostic Value of Elastography, Strain Ratio, and Elasticity to B-Mode Ratio and Color Doppler Ultrasonography in Breast Lesions.

PURPOSE: The aim of this study was to investigate the sensitivity, specificity, and diagnostic accuracy of sonoelastography (SE), strain ratio (SR), elasticity to B-mode (E/B) ratio, and color Doppler ultrasonography (US) in suspected breast lesions. MATERIALS AND METHODS: This prospective study was conducted on women referred to Alzahra university hospital of Tabriz for annual screening of breast cancer between May 2017 and December 2018. B-mode US, SE, and color Doppler imaging were conducted in females with suspected mammography reports. The lesions in B-mode were classified according to the Breast Imaging Reporting and Data System (B-RADS). The results of SE imaging were graded based on five-grade SE score. SR and E/B ratio of each lesion were also analyzed in SE images. Color Doppler findings were categorized from 0 (no visible vessel) to 2 (> two vessels) based on the vascularity of the tumor. Pathology results were used as the gold standard to measure the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and diagnostic accuracy of each modality. RESULTS: One-hundred and ten breast lesions of 104 women aged 42.05±10.33 years were included in the study. Seventy-seven of the lesions were benign and 3 were malignant. Sensitivity and specificity of 97.0% and 77.9% for B-mode US, 93.9% and 87.0% for SE score, 81.8% and 66.2% for color Doppler US, 72.7% and 77.6% for E/B ratio (cutoff: 1.05), and 77.3% and 79.6% for SR (cutoff: 1.90) were obtained, respectively. Addition of SE score to B-mode US increased the sensitivity to 93.9%, specificity to 93.5%, and AUC from 0.95 to 0.97. Cumulative color Doppler US with B-mode US did not enhance the diagnostic accuracy of B-mode US. CONCLUSION: SE was more effective than color Doppler US for distinguishing malignant from benign breast lesion. Among the three different SE features, five-grade SE score was superior to E/B ratio and SR.

The predictive value of red cell distribution width for stroke severity and outcome.

OBJECTIVES: In the present study, we sought to investigate the association between red cell distribution width (RDW) and stroke severity and outcome in patients who underwent anti-thrombolytic therapy with tissue plasminogen activator (tPA). RESULTS: In this prospective study, 282 stroke patients who underwent tPA injection were included. The categorization of RDW to < 12.9% and > 13% values revealed insignificant difference in stroke severity score, accounting for the mean 36-h NIHSS of 8.19 ± 8.2 in normal RDW values and 9.94 ± 8.28in higher RDW group (p = 0.64). In seventh day, NIHSS was 6.46 ± 7.28 in normal RDW group and was 8.52 ± 8.35 in increased RDW group (p = 0.058). Neither the 36-h, nor the seventh day and 3-month mRS demonstrated significant difference between those with normal and higher RDW values.

Diagnostic Accuracy of a 64-Slice Multi-Detector CT Scan in the Preoperative Evaluation of Periampullary Neoplasms.

Periampullary tumors are highly malignant masses with poor prognosis. Surgical resection is the only treatment for patients with this disease. The preoperative evaluation of masses is essential to determine the tumor resectability and vascular invasion. The aim of this study was to determine the diagnostic accuracy of 64-slice multi-detector computed tomography (MDCT) in detecting the resectability of periampullary masses. A cross-sectional study was conducted on patients with a definite diagnosis of periampullary cancer. All the participants underwent an MDCT scan before the surgical pancreaticoduodenectomy. The preoperative results were compared to the intraoperative findings and the diagnostic accuracy was determined based on the sensitivity and specificity of the MDCT. From June 2015 until June 2016, 32 patients with periampullary carcinoma were enrolled in the study. Of 32 masses, one of them considered nonresectable because of the gross vascular invasion in th CT images. After the operation, the overall resectability rate was 81.3%. The sensitivity and specificity of MDCT for tumor resectability was 100% and 16.7%, respectively, with an overall accuracy of 84.4%. To sum up, MDCT had high sensitivity but low specificity in the preoperative evaluation of preampullary carcinomas. The low specificity resulted from the low accuracy of the CT scan in detecting vascular involvement.