Two Novel Variants of the CAPN3 Gene in Chinese Patients with Limb-Girdle Muscular Dystrophy Recessive 1.

INTRODUCTION: Recessive mutations in the CAPN3 gene can lead to limb-girdle muscular dystrophy recessive 1 (LGMD R1). Targeted next-generation sequencing facilitates the discovery of new mutations linked with disease, owing to its ability to selectively enrich specific genomic regions. METHODS: We performed targeted next-generation sequencing of all exons of the CAPN3 gene in 4 patients with sporadic limb-girdle muscular dystrophy (LGMD) and further analyzed the effects of the novel identified variant using various software tools. RESULTS: We found 5 variants in CAPN3 gene in 4 patients, c.82_83insC (insertion mutation) and c.1115+2T>C (splicing mutation) are reported for the first time in CAPN3 (NM_000070.2). The bioinformatics analysis indicated that these two novel variants affected CAPN3 transcription as well as translation. DISCUSSION: Our findings reveal previously unreported splicing mutation and insertion mutation in CAPN3 gene, further expanding the pathogenic gene profile of LGMD.

Regional white matter hyperintensity volume predicts persistent cognitive impairment in acute lacunar infarct patients.

Background: White matter hyperintensity (WMH) is often described in acute lacunar stroke (ALS) patients. However, the specific relationship between regional WMH volume and persistent cognitive impairment remains unclear. Methods: We enrolled patients with ALS who were hospitalized at the First Affiliated Hospital of Soochow University between January 2020 and November 2022. All patients were assessed for global cognitive function using the Montreal Cognitive Assessment (MoCA) scale at 14 ± 2 days and 6 months after the onset of ALS. Manifestations of chronic cerebral small vessel disease (CSVD) were assessed via MRI scan. The distributions of regional WMH were segmented, and their relationship with cognitive impairment was evaluated. Results: A total of 129 patients were enrolled. Baseline frontal WMH volume (OR = 1.18, P = 0.04) was an independent risk factor for long-term cognitive impairment after ALS. Furthermore, the presence of WMH at the genu of the corpus callosum (GCC) at baseline (OR = 3.1, P = 0.033) was strongly associated with persistent cognitive decline. Multivariable logistic regression analysis showed that depression (OR = 6.252, P = 0.029), NIHSS score (OR = 1.24, P = 0.011), and albumin at admission (OR = 0.841, P = 0.032) were also important determinants of long-term cognitive impairment after ALS. Conclusions: Our study found that WMH, especially frontal WMH volume and the presence of WMH at the GCC at baseline, independently contributed to long-term cognitive decline in ALS patients. This study provides new evidence of the clinical relationship between regional WMH volume and cognitive impairment in ALS patients.

MYCT1 attenuates renal fibrosis and tubular injury in diabetic kidney disease.

Tubulointerstitial abnormalities contribute to the progression of diabetic kidney disease (DKD). However, the underlying mechanism of the pathobiology of tubulointerstitial disease is largely unknown. Here, we showed that MYCT1 expression was downregulated in in vitro and in vivo DKD models. Adeno-associated virus (AAV)-Myct1 significantly attenuated renal dysfunction and tubulointerstitial fibrosis in diabetic db/db mice and downregulated Sp1 transcription and TGF-ß1/SMAD3 pathway activation. In human proximal tubular epithelial cells, high glucose-induced high expression of SP1 and TGF-ß1/SMAD3 pathway activation as well as overaccumulation of extracellular matrix (ECM) were abrogated by MYCT1 overexpression. Mechanistically, the binding of VDR to the MYCT1 promoter was predicted and confirmed using dual-luciferase reporter and ChIP analysis. VDR transcriptionally upregulates MYCT1. Our data reveal MYCT1 as a new and potential therapeutic target in treating DKD.

A systematic analysis of genotype-phenotype associations with PLA2G6.

BACKGROUND: PLA2G6-associated neurodegeneration (PLAN) can be categorized into infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (aNAD), neurodegeneration with brain iron accumulation (NBIA), and early-onset parkinsonism (EOP). OBJECTIVES: To determine the genotype-phenotype association in PLAN. METHODS: "PLA2G6" or "PARK14" or "phospholipase A2 group VI" or "iPLA2ß" were searched across MEDLINE from June 23, 1997, to March 1, 2023. A total of 391 patients were identified, and 340 patients of them were finally included in the assessment. RESULTS: The loss of function (LOF) mutation ratios were significantly different (p < 0.001), highest in INAD, followed by NBIA, aNAD, and EOP. Four ensemble scores (i.e., BayesDel, VARITY, ClinPred, and MetaRNN) were assessed to predict the deleteriousness of missense mutations and demonstrated significant differences (p < 0.001). Binary logistic regression analyses demonstrated that LOF mutations were independently associated with brain iron accumulation (p = 0.006) and ataxia (p = 0.025). CONCLUSIONS: LOF or more deleterious missense mutations are more likely to promote the development of serious phenotype of PLAN, and LOF mutations are independently associated with brain iron accumulation and ataxia.

Effects of silent brain infarction on the hemorrhagic transformation and prognosis in patients with acute ischemic stroke after intravenous thrombolysis.

Background: Silent brain infarction (SBI) is a special type of stroke with no definitive time of onset, which can be found on pre-thrombolysis imaging examination in some patients with acute ischemic stroke (AIS). However, the significance of SBI on intracranial hemorrhage transformation (HT) and clinical outcomes after intravenous thrombolysis therapy (IVT) is uncertain. We aimed to explore the effects of SBI on intracranial HT and the 3-month clinical outcome in patients with AIS after IVT. Methods: We consecutive collected patients who were diagnosed with ischemic stroke and received IVT from August 2016 to August 2022, and conducted a retrospective analysis in this study. The clinical and laboratory data were obtained from hospitalization data. Patients were divided into SBI and Non-SBI groups based on clinical and neuroimaging data. We use Cohen's Kappa to assess the interrater reliability between the two evaluators, and multivariate logistic regression analysis was used to further assess the association between SBI, HT and clinical outcomes at 3 months after IVT. Results: Of the 541 patients, 231 (46.1%) had SBI, 49 (9.1%) had HT, 438 (81%) had favorable outcome, 361 (66.7%) had excellent outcome. There was no significant difference in the incidence of HT (8.2 vs. 9.7%, p = 0.560) and favorable outcome (78.4% vs. 82.9%, p = 0.183) between patients with SBI and Non-SBI. However, patients with SBI had a lower incidence of excellent outcome than the patients with Non-SBI (60.2% vs. 71.6%%, p = 0.005). After adjustment for major covariates, multivariate logistic regression analysis disclosed that SBI was independently associated with the increased risk of worse outcome (OR = 1.922, 95%CI: 1.229-3.006, p = 0.004). Conclusion: We found that SBI was no effect for HT after thrombolysis in ischemic stroke patients, and no effect on favorable functional outcome at 3 months. Nevertheless, SBI remained an independent risk factor for non-excellent functional outcomes at 3 months.

Case report: Novel ETFDH compound heterozygous mutations identified in a patient with late-onset glutaric aciduria type II.

Glutaric aciduria type II (GA II) is an autosomal recessive metabolic disorder of fatty acid, amino acid, and choline metabolism. The late-onset form of this disorder is caused by a defect in the mitochondrial electron transfer flavoprotein dehydrogenase or the electron transfer flavoprotein dehydrogenase (ETFDH) gene. Thus far, the high clinical heterogeneity of late-onset GA II has brought a great challenge for its diagnosis. In this study, we reported a 21-year-old Chinese man with muscle weakness, vomiting, and severe pain. Muscle biopsy revealed myopathological patterns of lipid storage myopathy, and urine organic acid analyses showed a slight increase in glycolic acid. All the aforementioned results were consistent with GA II. Whole-exome sequencing (WES), followed by bioinformatics and structural analyses, revealed two compound heterozygous missense mutations: c.1034A > G (p.H345R) on exon 9 and c.1448C>A (p.P483Q) on exon 11, which were classified as "likely pathogenic" according to American College of Medical Genetics and Genomics (ACMG). In conclusion, this study described the phenotype and genotype of a patient with late-onset GA II. The two novel mutations in ETFDH were found in this case, which further expands the list of mutations found in patients with GA II. Because of the treatability of this disease, GA II should be considered in all patients with muscular symptoms and acute metabolism decompensation such as hypoglycemia and acidosis.

MYCT1 alters the glycogen shunt by regulating selective translation of RACK1-mediated enzymes.

MYCT1 has been shown to function as a tumor suppressor in various tumors, but its role in metabolism has never been reported. Here, we showed that global inactivation of Myct1 in mice led to progressive accumulation of glycogen in the liver, which was accompanied by aberrant changes in intermediates of the glycogen metabolic pathway. Mechanistically, MYCT1 appeared to promote translation efficiency of PGM1, UGP2 and GSK3A in hepatic cells in a RACK1-dependent manner. Consequently, upregulation of the three enzymes enhanced the glycogen shunt. Our data reveal a critical role of MYCT1 as a switch for the glycogen shunt in tumor cells.

A Variant in Genes of the NPY System as Modifier Factor of Machado-Joseph Disease in the Chinese Population.

Recently, NPY overexpression has been proposed to alleviate motor deficits and neuropathy in Machado-Joseph disease (MJD) mouse models, indicating its neuroprotective role in the pathogenesis of MJD. We aimed to evaluate the association between SNPs in NPY and its receptors and the susceptibility of MJD in the Chinese population. Moreover, we investigated whether these SNPs modulate the age at onset (AO) of MJD. In total, 527 MJD patients and 487 healthy controls were enrolled in the study, and four specific selected SNPs (rs16139, rs3037354, rs2234759, and rs11100494) in NPY and its receptor genes were genotyped. In this study, the genotypic frequency using the dominant model and the allelic distribution of rs11100494 in NPY5R revealed a significant difference between the MJD and control group during the first-stage analysis (P = 0.048 and P = 0.024, respectively). After we expanded the sample size, significant differences were observed between the two groups using the dominant model in genotypic and allelic distribution (P = 0.034, P = 0.046, and P = 0.016, respectively). No significant differences in genotypic and allelic distribution were found between the MJD and control groups for the other three SNPs. All selected SNPs had no significant effect on the AO of MJD. The association of rs11100494 in the NPY5R gene and susceptibility of MJD suggested that the NPY system might be implicated in the pathogenesis of MJD. Our study demonstrated the existence of other genetic modifiers in MJD, along with CAG expansion and known genetic modifier factors, which might lead to a better understanding of MJD pathogenesis.

Total magnetic resonance imaging of cerebral small vessel disease burden predicts dysphagia in patients with a single recent small subcortical infarct.

BACKGROUND: This study was performed to identify the association between the total magnetic resonance imaging burden of small vessel disease and the occurrence of post-stroke dysphagia in patients with a single recent small subcortical infarct (RSSI). METHODS: We retrospectively identified all patients with a magnetic resonance imaging-confirmed single RSSI. The water-swallowing test and volume-viscosity swallow test were performed within the first 24 h following admission to assess swallowing. Demographic and clinical data were extracted from our stroke database. Based on brain magnetic resonance imaging, we independently rated the presence of cerebral microbleeds, lacunes, white matter hyperintensities and enlarged perivascular spaces. The presence of each small vessel disease feature was summed to determine the total small vessel disease burden, ranging from 0 to 4. RESULTS: In total, 308 patients with a single RSSI were enrolled. Overall, 54 (17.5%) were diagnosed with post-stroke dysphagia. The risk factors related to post-stroke dysphagia included the following: older age, higher National Institute of Health Stroke Scale scores, higher C-reactive protein level and higher fibrinogen level. Based on multiple logistic regression, National Institute of Health Stroke Scale scores and total small vessel disease burden were independent risk factors of post-stroke dysphagia in patients with a single RSSI, after adjusting for age, gender, history of hypertension, C-reactive protein level and fibrinogen level. CONCLUSIONS: Dysphagia in patients with a single RSSI was associated with a more severe total small vessel disease burden as reflected by MRI. Total MRI of cerebral small vessel disease burden may predict dysphagia in these patients. Furthermore, more severe total small vessel disease burden was associated with systemic inflammation.

Impact of glycosylated hemoglobin on early neurological deterioration in acute mild ischemic stroke patients treated with intravenous thrombolysis.

Objective: In patients with acute mild ischemic stroke treated with intravenous thrombolysis, the relationship between chronic hyperglycemic status and their early neurological deterioration (END) and clinical outcomes is unclear. We attempted to analyze the relationship between glycated hemoglobin (HbA1c) levels and END and 90-day functional outcomes. Participants and methods: The research comprised 267 patients with acute mild ischemic stroke. The incidence of END and functional outcomes at 90 days were evaluated between subgroups. END was defined in this study as a rise of at least 1 point in the National Institutes of Health Stroke Scale (NIHSS) score within 72 h of admission, with an excellent outcome of a modified Rankin Scale (mRS) score of 0-1 at 90 days following stroke beginning. The association between HbA1c and END, and clinical outcomes in patients with mild stroke, was assessed by logistic regression after adjusting for confounding factors. In addition, we used receiver operating characteristic (ROC) curves to predict the predictive value of HbA1c for the incidence of END. Results: There were 38 patients who suffered END and 105 patients who had disabled functional outcomes at 90 days. In multivariate analysis, elevated HbA1c levels were associated with END (adjusted OR = 1.476; 95% CI: 1.129-1.928; p = 0.004). With HbA1c greater than 7.75%, the ROC curve predicted a higher risk of END. However, they were not associated with patients' functional outcomes at 90 days. Conclusion: HbA1c levels were an independent predictor of END in patients with mild stroke, while there was no effect on functional outcomes at 90 days. The impact of HbA1c on functional prognosis may be a contributing factor rather than a direct factor.

Predictive Model of Dysphagia and Brain Lesion-Symptom Mapping in Acute Ischemic Stroke.

Background and purpose: Early recognition and management of post-stroke dysphagia (PSD) based on MRI may reduce the incidence of complications. Combining clinical symptoms with applications of MRI, we aimed to identify the risk factors of PSD, develop a prediction scale with high accuracy and map key dysphagia brain areas. Methods: A total of 275 acute ischemic stroke patients were enrolled in this study, and 113 (41.1%) patients were diagnosed with PSD. All patients underwent the water-swallowing test (WST) and volume-viscosity swallow test (V-VST) within first 24 h following admission to assess swallowing. Vascular factors were evaluated and MRI brain scans were obtained within 3 days after symptom onset for each participant admitted to the hospital. T-test, chi-squared test and Fisher's exact test were used to investigate the associations of various patient characteristics with dysphagia, and multivariable logistic regression models were used to construct a prediction scale. Scale accuracy was assessed using receiver operating characteristic (ROC) analysis. We extracted white matter hyperintensities for each patient as potential brain lesions. Voxel-based lesion-symptom mapping (VLSM) was used to identify key brain areas for dysphagia. Results: Risk factors related with PSD were older age, history of atrial fibrillation, higher fasting blood glucose, NIH stroke scale, TOAST classification, progressive stroke, middle cerebral artery lesion and anterior cerebral artery lesion. Three variables with most significant associations, including NIH stroke scale, TOAST classification and progressive stroke, combined with age and gender, were used to construct a dysphagia prediction scale with high accuracy (AUC = 0.86). VLSM identified left inferior parietal gyrus as a key brain region for PSD. Conclusion: Risk factors of PSD were identified and a predictive model of dysphagia was constructed intelligently and automatically. The left inferior parietal gyrus was identified as a key brain area for dysphagia, which provides a new symptom-based treatment target for early rehabilitation in the future.

Primary biliary cirrhosis associated with myasthenia gravis after postpartum: a case report.

BACKGROUND: Autoimmune diseases refers to a class of diseases involving abnormal immune response of human body and tissue damage caused by the dysregulation of autoimmune balance or destruction of immune tolerance. Recent research has revealed that the occurrence of autoimmune diseases is influenced by genetic, hormonal, immunological, and environmental factors. As sex hormone levels change obviously during pregnancy and postpartum, the morbidity and recurrence rate of autoimmune diseases increase during this period. CASE PRESENTATION: A 31-year-old Asian woman was admitted to our hospital for myasthenia gravis and treated with methylprednisolone and pyridostigmine bromide 3 months postpartum. Physical examination and laboratory inspection after admission suggested that the patient had primary biliary cirrhosis. Subsequently, azathioprine was added to the treatment, and the symptoms of both diseases were successfully controlled. CONCLUSIONS: This case exhibits a rare condition of myasthenia gravis combined with primary biliary cirrhosis postpartum. Given the fluctuation of the immune status during the postpartum period, combined autoimmune diseases need to be taken into account when patients develop clinical symptoms of an autoimmune disease. Therefore, detailed physical and laboratory examination can help to prevent the missed diagnosis of these diseases.

Gadolinium enhancement of atherosclerotic plaque in the intracranial artery.

Background: Gadolinium enhancement on high resolution magnetic resonance imaging (HR-MRI) has been considered a sign of instability and inflammation of intracranial atherosclerotic plaques. Our research objective was to explore the relationship between the extent of plaque enhancement (PE), the degree of intracranial artery stenosis, and acute ischemic stroke events.Methods: HR-MRI was performed in 91 patients with intracranial vascular stenosis to determine the existence and intensity of PE.Results: Among 91 patients enrolled in the trial, there were 43 patients in the acute/subacute group (≤1 month from ischemic stroke event), 15 patients in the chronic group (>1 month from ischemic stroke event), and 33 patients in the non-culprit plaques group (no ischemic stroke event). A total of 105 intracranial atherosclerotic plaques were detected in 91 patients. 14 (13.3%) were mild-stenosis plaques, 22 (21.0%) were moderate-stenosis plaques, and 69 (65.7%) were severe-stenosis plaques. There were 12 (11.4%), 18 (17.1%), and 75 (71.4%) plaques in the non-enhanced plaque group, the mild-enhancement group, and the significant-enhancement group, respectively. The degree of PE among the acute/subacute group, the chronic group, and the non-culprit plaque group had a significant difference (P = 0.005). Enhanced plaques were more often observed in culprit plaques (acute/subacute group and chronic group) than non-culprit plaques (96.7% vs 77.3%). Non-enhanced plaques were more often observed in non-culprit plaques than culprit plaques (acute/subacute group and chronic group) (22.7% vs 3.3%). And 36.6% of the enhanced plaques were non-culprit plaques. After performing univariate and multivariate logistic regression analysis, the results showed that strong plaque enhancement (P = 0.025, odds ratio [OR] 3.700, 95% confidence interval [95% CI] 1.182-11.583) and severe stenosis (P = 0.008, OR 4.393, 95%CI 1.481-13.030) were significantly associated with acute ischemic events.Conclusion: Enhanced plaques were more often observed in culprit plaques, and non-enhanced plaques were more often observed in non-culprit plaques. Moreover, significant plaque enhancement and severe ICAS were closely associated with acute ischemic events.

Intravenous Thrombolysis Benefits Mild Stroke Patients With Large-Artery Atherosclerosis but No Tandem Steno-Occlusion.

At present, there is controversy regarding whether thrombolysis is beneficial for patients suffering from a mild stroke. In this study, we therefore sought to determine whether the therapeutic benefit of thrombolysis is dependent upon stroke subtype for those with mild stroke. We conducted a retrospective analysis of data from consecutive mild stroke patients (National Institutes of Health Stroke Scale ≤5) with and without recombinant tissue plasminogen activator (rt-PA) therapy. The TOAST (Trial of Org 10172 in acute stroke treatment) criteria was used to determine stroke subtypes. Patients suffering from large-artery atherosclerosis (LAA) were subdivided based upon whether or not they exhibited tandem steno-occlusion, as defined by the association of a proximal intracranial occlusion and a cervical internal carotid artery lesion (complete occlusion or severe stenosis ≥ 90%). For this study, favorable outcomes at 90 days of onset (modified Rankin Scale Score [mRS] of 0-1) were the primary measured outcome. Three hundred thirty-nine patients were included in the study. For patients with non-LAA, there were not statistically significant improvements in favorable outcomes for rt-PA treatment (p = 0.889, 0.929, 0.708; respectively). For patients with LAA, compared with non-treated group, rt-PA-treated patients had a significant in the rate of favorable outcomes at 90 days (82.8 vs. 64.9%; OR 2.59; 95%CI, 1.13-5.92; P = 0.024). Among LAA patients exhibiting tandem lesions, favorable outcomes were observed in 66.7% of rt-PA-treated patients, with no significant differences to those observed in untreated patients (OR 1.00; 95%CI, 0.23-4.28; p = 1.000). Among LAA patients without tandem lesions, compared with non-treated group, we found that rt-PA treatment was associated with a significant beneficial impact on favorable outcomes after 90 days (64.4 vs. 88.4%; OR 4.20; 95%CI, 1.43-12.30; p = 0.009). Our findings suggest that intravenous rt-PA is only beneficial in mild stroke patients with LAA-type strokes that do not exhibit tandem steno-occlusion.

Highly Efficient and Color-Stable Thermally Activated Delayed Fluorescence White Light-Emitting Diodes Featured with Single-Doped Single Emissive Layers.

Despite their merits of environmental friendliness, low cost, and large-scale production, thermally activated delayed fluorescence (TADF) based white organic light-emitting diodes (WOLEDs) for daily lighting applications still face the formidable challenges of structural simplification and controllable exciton allocation. Here, the state-of-the-art full-TADF WOLEDs with features of the single-doped single emissive layers (EMLs) and ultrasimple trilayer structure are demonstrated. The EMLs are binary systems as yellow TADF emitter (4CzTPNBu) doped blue TADF matrix (ptBCzPO2 TPTZ) with the large steric hindrance and mismatched frontier molecular orbital energy levels to effectively restrain excessive blue-to-yellow triplet exciton transfer and host-dopant interaction induced triplet quenching. Simultaneously, Förster resonance energy transfer is utilized to optimize exciton allocation for the balance of blue and yellow emissions, giving rise to the photoluminescence quantum yield beyond 90%. Consequently, these single-doped EMLs endow their cool white, pure white, and warm white diodes with the high-quality and ultrastable white light and the 100% exciton utilization efficiencies through the extremely simple structures, making them competent for the diverse daily lighting applications.

Polyglutamine-expanded ataxin3 alter specific gene expressions through changing DNA methylation status in SCA3/MJD.

DNA methylation has recently been linked to transcriptional dysregulation and neuronal dysfunction in polyglutamine (polyQ) disease. This study aims to determine whether (CAG)n expansion in ATXN3 perturbs DNA methylation status and affects gene expression. We analyzed DNA methylation throughout the genome using reduced representation bisulfite sequencing (RRBS) and confirmed the results using MethylTarget sequencing. Dynamic changes in DNA methylation, transcriptional and translational levels of specific genes were detected using BSP, qRT-PCR and western blot. In total, 135 differentially methylated regions (DMRs) were identified between SCA3/MJD and WT mouse cerebellum. KEGG analysis revealed differentially methylated genes involved in amino acid metabolism, Hedgehog signaling pathway, thyroid cancer, tumorigenesis and other pathways. We focused on DMRs that were directly associated with gene expression. On this basis, we further assessed 7 genes, including 13 DMRs, for DNA methylation validation and gene expression. We found that the methylation status of the DMRs of En1 and Nkx2-1 was negatively associated with their transcriptional and translational levels and that alteration of the DNA methylation status of DMRs and the corresponding transcription occurred before dyskinesia in SCA3/MJD mice. These results revealed novel DNA methylation-regulated genes, En1 and Nkx2-1, which may be useful for understanding the pathogenesis of SCA3/MJD.

Polymorphisms in DNA methylation-related genes are linked to the phenotype of Machado-Joseph disease.

DNA methylation has been reported as an important regulator of genomic structure stability, including large tandem repeats. To test the modulation effect of variants in DNA methylation-related genes on distribution of expanded (CAG)n alleles and age at onset (AO) of patients with Machado-Joseph disease (MJD), we conducted an association analysis on 23 selected SNPs in these genes in 613 patients with MJD and 581 controls. There were significant differences in the distribution of rs12957023 between patients and controls (OR = 1.296, p = 0.007 and OR = 1.206, p = 0.008, for genotype and alleles, respectively). The distribution of (CAG)n size was also different between patients carrying a CC and the other genotypes (TT and TC, p = 0.011 for expanded (CAG)n and p = 0.012 for normal size alleles), indicating that DNA methylation might modulate the (CAG)n instability. We found also that rs13420827 in DNMT3A and rs7354779 in DNMT3L contribute to AO of MJD (p = 0.019 and p = 0.008, respectively). In conclusion, our data provide the first evidence that SNPs in DNA methylation-related genes may contribute to (CAG)n instability and modulate the AO of this disease.

Magnetic resonance imaging relaxation time in Alzheimer's disease.

The magnetic resonance imaging (MRI) relaxation time constants, T1 and T2, are sensitive to changes in brain tissue microstructure integrity. Quantitative T1 and T2 relaxation times have been proposed to serve as non-invasive biomarkers of Alzheimer's disease (AD), in which alterations are believed to not only reflect AD-related neuropathology but also cognitive impairment. In this review, we summarize the applications and key findings of MRI techniques in the context of both AD subjects and AD transgenic mouse models. Furthermore, the possible mechanisms of relaxation time alterations in AD will be discussed. Future studies could focus on relaxation time alterations in the early stage of AD, and longitudinal studies are needed to further explore relaxation time alterations during disease progression.

Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines.

Whole-exome sequencing (WES), one of the next-generation sequencing (NGS), has become a powerful tool to identify exonic variants. Investigating causality of the sequence variants in human disease becomes an important part in NGS for the research and clinical applications. Recently, important guidelines on them have been published and will keep on updating. In our study, two Chinese families, with the clinical diagnosis of "Epilepsy", which presented with seizures, psychomotor retardation, hypotonia and etc. features, were sequenced by Trio-WES (including the proband and the unaffected parents), and a standard interpretation of the identified variants was performed referring to the recently updated guidelines. Finally, we identified three novel mutations (c.71 C > T, p.P24L; c.1387-1389delGAG, p.E463-; c.134 G > A, p.W45*; NM_000026) in ADSL in the two Chinese families, and confirmed them as the causal variants to the disease-Adenylosuccinate Lyase Deficiency. Previous reported specific therapy was also introduced to the patients after our refined molecular diagnosis, however, the effect was very limited success. In summary, our study demonstrated the power and advantages of WES in exploring the etiology of human disease. Using the constantly updated guidelines to conduct the WES study and to interpret the sequence variants are a necessary strategy to make the molecular diagnosis and to guide the individualized treatment of human disease.