Inferior Frontal Sulcal Hyperintensity on Fluid-Attenuated Inversion Recovery Is Related to Cerebrospinal Fluid Clearance via Putative Meningeal Lymphatics.

Inferior frontal sulcal hyperintensity (IFSH) on FLAIR sequence may indicate elevated cerebrospinal fluid (CSF) wastes. The objective of this study was to investigate its association with the clearance function of putative meningeal lymphatic vessels (mLVs). We included patients who underwent FLAIR sequence and dynamic contrast MRI with intrathecal administration of contrast agent. The visibility of IFSH was quantitatively assessed by measuring the mean signal intensity of inferior frontal sulci on 2D FLAIR. The clearance function of putative mLVs was defined as the percentage change of signal unite ratio in the parasagittal dura from baseline to 4.5, 15 and 39 hours after intrathecal injection on dynamic contrast MRI. Additionally, imaging markers of cerebral small vessel disease, including white matter hyperintensities and enlarged perivascular spaces, were measured. Correlation analysis and linear regression were employed to verify the association of IFSH with the clearance function of mLVs. A total of 76 patients were included in the study. The visibility of IFSH was found to be associated with the percentage change of signal unite ratio in parasagittal dura from baseline to 15 and 39 hours in adjusted analyses. Furthermore, the visibility of IFSH was positively related to the age, scores of both periventricular and deep white matter hyperintensities, and the grade of enlarged perivascular spaces in centrum semiovale. These findings suggest that the visibility of IFSH on 2D FLAIR may serve as an indicator of clearance dysfunction of mLVs and may be implicated in the development of cerebral small vessel disease.

Impaired Meningeal Lymphatics and Glymphatic Pathway in Patients with White Matter Hyperintensity.

White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno-associated virus delivery of vascular endothelial growth factor-C (VEGF-C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF-C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment.

A review on associated factors and management measures for sarcopenia in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia, insulin resistance, and insufficient insulin secretion. Sarcopenia, as a new complication of diabetes, is characterized by the loss of muscle mass and the progressive decline of muscle strength and function in T2DM patients, which has a serious impact on the physical and mental health of patients. Insulin resistance, mitochondrial dysfunction, and chronic inflammation are common mechanisms of diabetes and sarcopenia. Reasonable exercise training, nutrition supplement, and drug intervention may improve the quality of life of patients with diabetes combined with sarcopenia. This article reviews the relevant factors and management measures of sarcopenia in T2DM patients, in order to achieve early detection, diagnosis, and intervention.

Influencing factors of futile recanalization after endovascular intervention in patients with acute basilar artery occlusion. / æ€¥æ€§åŸºåº•åŠ¨è„‰é—­å¡žæ‚£è€ è¡€ç®¡å† æ²»ç–—åŽå‘ç”Ÿæ— æ•ˆå†é€šçš„å½±å“å› ç´ .

OBJECTIVES: To explore the influence factors for futile recanalization following endovascular treatment (EVT) in patients with acute basilar artery occlusion (BAO). METHODS: Clinical data of patients with acute BAO, who underwent endovascular treatment within 24 h of onset from January 2017 to November 2022, were retrospectively analyzed. The futile recanalization was defined as modified thrombolysis in cerebral infarction (mTICI) grade ≥2b or 3 after successful reperfusion, but the modified Rankin Scale score >2 at 3 months after EVT. Binary logistic regression model was used to analyze the influencing factors of futile recanalization. RESULTS: A total of 471 patients with a median age of 68 (57, 74) years were included and 68.9% were males, among whom 298 (63.27%) experienced futile recanalization. Multivariate analysis revealed that concomitant atrial fibrillation (OR=0.456, 95%CI: 0.282-0.737, P<0.01), bridging thrombolysis (OR=0.640, 95%CI: 0.416-0.985, P<0.05), achieving mTICI grade 3 (OR=0.554, 95%CI: 0.334-0.918, P<0.05), arterial occlusive lesion (AOL) grade 3 (OR=0.521, 95%CI: 0.326-0.834, P<0.01), and early postoperative statin therapy (OR=0.509, 95%CI: 0.273-0.948, P<0.05) were protective factors for futile recanalization after EVT in acute BAO patients. High baseline National Institutes of Health Stroke Scale (NIHSS) score (OR=1.068, 95%CI: 1.049-1.087, P<0.01), coexisting hypertension (OR=1.571, 95%CI: 1.017-2.427, P<0.05), multiple retrieval attempts (OR=1.237, 95%CI: 1.029-1.488, P<0.05) and postoperative hemorrhagic transformation (OR=8.497, 95%CI: 2.879-25.076, P<0.01) were risk factors. For trial of ORG 10172 in acute stroke treatment (TOAST) classification, cardiogenic embolism (OR=0.321, 95%CI: 0.193-0.534, P<0.01) and other types (OR=0.499, 95%CI: 0.260-0.961, P<0.05) were related to lower incidence of futile recanalization. CONCLUSIONS: The incidence of futile recanalization after EVT in patients with acute BAO is high. Bridging venous thrombolysis before operation and an early postoperative statin therapy may reduce the incidence of futile recanalization.

Treatment with intravenous alteplase in ischaemic stroke patients with onset time between 4.5 and 24 hours (HOPE): protocol for a randomised, controlled, multicentre study.

BACKGROUND: While intravenous thrombolysis is recommended for patients who had an acute ischaemic stroke (AIS) within 4.5 hours of symptom onset, there are few randomised trials investigating the benefits of thrombolysis beyond this therapeutic window. AIM: To determine whether patients who had an AIS selected with the presence of potentially salvageable tissue on CT perfusion at 4.5-24 hours after stroke onset (for stroke with unknown onset time, the midpoint of the time last known to be well and symptom recognition time; for wake-up stroke, the midpoint of the time last known to be well or sleep onset and wake up time) will benefit from intravenous thrombolysis. DESIGN: HOPE is a prospective, multicentre, randomised, open-label blinded endpoint trial with the stage of phase III. The treatment allocation employs 1:1 randomisation. The treatment arm under investigation is alteplase with standard therapy, the control arm is standard therapy. Eligibility imaging criteria include ischaemic core volume ≤70 mL, penumbra ≥10 mL and mismatch ≥20%. STUDY OUTCOMES: The primary outcome is non-disabled functional outcome (assessed as modified Rankin Scale score of 0-1 at 90 days). DISCUSSION: HOPE is the first trial to investigate whether intravenous thrombolysis with alteplase offers benefits in patients who had an AIS presenting within 4.5-24 hours, which has the potential to extend time window and expand eligible population for thrombolysis therapy.

Glymphatic function plays a protective role in ageing-related cognitive decline.

OBJECTIVE: The glymphatic pathway, characterised as a cerebral drainage system, influences cognitive function in neurodegenerative diseases; however, evidence is limited in a normal ageing population. The aim of this study was to investigate the effect of glymphatic function on ageing-related cognitive decline. METHODS: We retrospectively reviewed the Cognitive Impairment, Retinopathy, and Cerebrovascular Lesions in the Elderly (CIRCLE) study, and participants with multi-model magnetic resonance imaging (MRI) scans and Mini-Mental State Examinations (MMSE) were enrolled. Glymphatic function was evaluated via the diffusion tensor imaging along the perivascular space (DTI-ALPS) index. Regression models were used to estimate the impact of the DTI-ALPS index on cognitive decline cross-sectionally and longitudinally. We further analysed the mediation effect of the DTI-ALPS on age and cognitive function. RESULTS: A total of 633 participants were included in this study (48.2% female; mean age, 62.8 ± 8.9 years). The DTI-ALPS index was positively associated with cognitive function cross-sectionally (ß = 0.108, P = 0.003), and was an independent protective factor for cognitive decline longitudinally (odds ratio (OR) = 0.029, P = 0.007). The DTI-ALPS index declined progressively with ageing (r = -0.319, P <0.001), and the decrease was more pronounced after 65 years of age. Furthermore, the DTI-ALPS index mediated the relationship between age and MMSE score (ß = -0.016, P <0.001). The mediation effect accounted for 21.3%, which was higher in subjects aged over 65 years (25.3%) compared with those aged under 65 years (5.3%). CONCLUSION: Glymphatic function played a protective role in normal ageing-related cognitive decline, which may serve as a potential therapeutic target against cognitive decline in future.

Age- and time-of-day dependence of glymphatic function in the human brain measured via two diffusion MRI methods.

Advanced age, accompanied by impaired glymphatic function, is a key risk factor for many neurodegenerative diseases. To study age-related differences in the human glymphatic system, we measured the influx and efflux activities of the glymphatic system via two non-invasive diffusion magnetic resonance imaging (MRI) methods, ultra-long echo time and low-b diffusion tensor imaging (DTIlow-b) measuring the subarachnoid space (SAS) flow along the middle cerebral artery and DTI analysis along the perivascular space (DTI-ALPS) along medullary veins in 22 healthy volunteers (aged 21-75 years). We first evaluated the circadian rhythm dependence of the glymphatic activity by repeating the MRI measurements at five time points from 8:00 to 23:00 and found no time-of-day dependence in the awake state under the current sensitivity of MRI measurements. Further test-retest analysis demonstrated high repeatability of both diffusion MRI measurements, suggesting their reliability. Additionally, the influx rate of the glymphatic system was significantly higher in participants aged >45 years than in participants aged 21-38, while the efflux rate was significantly lower in those aged >45 years. The mismatched influx and efflux activities in the glymphatic system might be due to age-related changes in arterial pulsation and aquaporin-4 polarization.

Choroid Plexus Enlargement Exacerbates White Matter Hyperintensity Growth through Glymphatic Impairment.

OBJECTIVE: Choroid plexus (CP) is a key regulator in cerebrospinal fluid production, but its contribution to glymphatic clearance function and association with white matter hyperintensity (WMH) remains unclear. METHODS: This retrospective study included 2 prospective 3.0-T magnetic resonance imaging (MRI) cohorts. In cohort 1, patients with indications for lumbar puncture underwent 3-dimensional T1-weighted sequence (3D-T1) before and at 39 hours after intrathecal administration of contrast agent (glymphatic MRI). In cohort 2, patients with WMH were enrolled from the CIRCLE study and had a median follow-up time of 1.4 years. WMH and CP of the lateral ventricles were automatically segmented on T2 fluid-attenuated inversion recovery (FLAIR) and 3D-T1, respectively. CP volume was expressed as a ratio to intracranial volume. Glymphatic clearance was measured as signal percentage change from baseline to 39 hours at 8 brain locations based on glymphatic MRI in the first cohort, or as noninvasive diffusion tensor image analysis along the perivascular space (DTI-ALPS) index based on DTI in the second cohort. RESULTS: In cohort 1, a total of 52 patients were included. Higher CP volume was correlated with slower glymphatic clearance rate in all brain locations. In cohort 2, a total of 197 patients were included. Baseline CP volume was positively associated with WMH volume and its growth. Furthermore, DTI-ALPS index partially mediated the association of CP with both WMH load and growth. INTERPRETATIONS: Enlarged CP volume could be an indicator for larger growth of WMH, potentially involving impaired glymphatic clearance function. The exploration of CP may provide a novel perspective to clarify the mechanism of WMH pathogenesis, as well as other glymphatic-related disorders. ANN NEUROL 2023;94:182-195.

A modified nutrition risk screening 2002 predicts the risk of death among hospitalized patients with COVID-19.

OBJECTIVES: The aim of this study was to evaluate the ability of a modified Nutrition Risk Screening 2002 (modified NRS) compared with other nutrition screening tools such as NRS 2002, Mini Nutrition Assessment Short Form (MNA-SF), and Malnutrition Universal Screening Tool (MUST) on predicting the risk of death in patients with coronavirus disease 2019 (COVID-19). METHODS: We retrospectively collected data of patients who were admitted to the West campus of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 25th, 2020 to April 24th, 2020. The nutritional status of the patients was assessed by modified NRS, NRS 2002, MNA-SF, and MUST. According to the score of modified NRS, patients were divided into malnutrition risk group (score ≥3) and normal nutrition group (score <3). Clinical characteristics were compared between the two groups. Kaplan meier survival curve was used to analyze the difference of compositing survival rate between the two groups. The predictive efficacy of different nutritional scales on the outcome of death was detected by Receiver operating characteristic (ROC) analysis. RESULTS: The modified NRS, NRS 2002, MNA-SF, and MUST identified malnutrition risk in 71.4%, 57.9%, 73.9%, and 43.4% of the patients, respectively. The patients were divided into malnutrition risk group and normal nutrition group by modified NRS score. Patients in the malnutrition risk group were older (65 y vs. 56 y) and with more severe and critical cases (42.30% vs. 5.20%) and diabetes cases (21.50% vs. 9.80%), worse prognosis (death of 13.80% vs. 0.50%), longer hospital stay (29 days vs. 23 days), lower albumin (31.85 g/L vs. 38.55 g/L) and prealbumin (201.95 mg/L vs. 280.25 mg/L) compared with the normal nutrition group (P were <0.001, respectively). There were more patients with chronic respiratory disease in malnutrition risk group (9.70 vs. 2.10%, P = 0.001). BMI was lower in malnutrition risk group (23.45 kg/m2vs. 24.15 kg/m2, P = 0.017). Kaplan meier survival curve demonstrated that the survival of malnutrition risk group was significantly lower than normal nutrition group (P < 0.001). The area under the ROC curve (AUC) of the modified NRS scale (0.895) outperformed NRS 2002 (0.758), MNA-SF (0.688), and MUST (0.485). The former three scales could predict the risk of death (P were < 0.001), while MUST could not (P = 0.690). CONCLUSIONS: Patients with COVID-19 at risk of malnutrition have a worse prognosis than those with normal nutrition. The modified NRS scale could effectively predict the risk of death among patients with COVID-19.

Increased blood pressure variability during general anaesthesia is associated with worse outcomes after mechanical thrombectomy: a prospective observational cohort study.

OBJECTIVES: Optimal periprocedural blood pressure (BP) management during mechanical thrombectomy (MT) for acute ischaemic stroke is still controversial. The aim of this study was to investigate the association between intraprocedural BP variability (BPV) and outcomes in patients with large vessel occlusion (LVO) following MT with general anaesthesia. DESIGN: A prospective observational cohort study. SETTING: This study was conducted in a single tertiary hospital of Hangzhou in Zhejiang province. PARTICIPANTS: A total of 141 patients with LVO treated with MT were finally included between January 2018 and September 2020. MAIN OUTCOME MEASURES: Intraprocedural BP was recorded every 5 min throughout the procedure. BPV was measured as SD, coefficient of variation (CV), max-min (RANGE) and successive variation. Haemorrhagic transformation was assessed on 24-hour CT images according to European Cooperative Acute Stroke Study III trial. Poor functional outcome was defined as 90-day modified Rankin Scale score 3-6. Binary logistic regression analysis was used to investigate the association of BPV parameters with the incidence of parenchymal haemorrhage (PH) and poor functional outcome. RESULTS: After controlling for age, female, history of smoking, hypertension and atrial fibrillation, baseline National Institutes of Health Stroke Scale, baseline systolic BP (SBP), baseline Alberta Stroke Program Early CT Score, bridging thrombolysis and times of retrieval attempts, the results demonstrated that intraprocedural SBPRANGE (OR 1.029; 95% CI 1.003 to 1.055; p=0.027), SBPSD (OR 1.135; 95% CI 1.023 to 1.259; p=0.017) and SBPCV (OR 1.189; 95% CI 1.053 to 1.342; p=0.005) were independently associated with poor functional outcome. However, the independent association between intraprocedural BPV and PH at 24 hours has not been established in this study. CONCLUSIONS: Increased intraprocedural BPV was more likely to have poor functional outcome in patients with LVO following MT with general anaesthesia. This finding indicates that special precautions should be taken to minimise BP fluctuation during procedure.

MRI-visible perivascular spaces in basal ganglia but not centrum semiovale or hippocampus were related to deep medullary veins changes.

Our purpose is to assess the role of deep medullary veins (DMVs) in pathogenesis of MRI-visible perivascular spaces (PVS) in patients with cerebral small vessel disease (cSVD). Consecutive patients recruited in the CIRCLE study (ClinicalTrials.gov ID: NCT03542734) were included. Susceptibility Weighted Imaging-Phase images were used to evaluate DMVs based on a brain region-based visual score. T2 weighted images were used to evaluate PVS based on the five-point score, and PVS in basal ganglia (BG-PVS), centrum semiovale (CSO-PVS) and hippocampus (H-PVS) were evaluated separately. 270 patients were included. The severity of BG-PVS, CSO-PVS and H-PVS was positively related to the increment of age (all p < 0.05). The severity of BG-PVS and H-PVS was positively related to DMVs score (both p < 0.05). Patients with more severe BG-PVS had higher Fazekas scores in both periventricle and deep white matter (both p < 0.001) and higher frequency of hypertension (p = 0.008). Patients with more severe H-PVS had higher frequency of diabetes (p < 0.001). Besides, high DMVs score was an independent risk factor for more severe BG-PVS (ß = 0.204, p = 0.001). Our results suggested that DMVs disruption might be involved in the pathogenesis of BG-PVS.

Analysis of Factors Associated With Depression in Community-Dwelling Older Adults in Wuhan, China.

Objectives: This study aimed to identify the independent factors associated with depression in community-dwelling older adults in Wuhan, China. Methods: Four hundred and seventy older adults (aged ≥65 years) from four communities dwelling on Junshan Street in Wuhan, China were included in this study. Participants completed a questionnaire that asked questions pertaining to age, gender, educational level, income, living situation, care situation, social support, and social engagement. The 30-item Geriatric Depression Scale (GDS-30), the Fried frailty phenotype scale, the activities of daily living (ADL) scale, the mini nutritional assessment scale-short form (MNA-SF), and the Mini-cog scale were used to assess depression, frailty, self-care ability, malnutritional risk, and cognitive dysfunction, respectively. Differences in age, gender, educational level, income, living situation, care situation, social support, social engagement, ADL score, risk of malnutrition, frailty, and cognitive dysfunction between the non-depression (GDS-30 score <10 points) and depression groups (GDS-30 score ≥10 points) were compared using a chi-square test. Moreover, correlations between factors and depression were analyzed using Pearson's correlation. Then, significant variables (p < 0.05) from the chi-square test were included in a multivariable logistic regression model to identify the independent factors associated with depression. Results: The incidence of depression among the participants was 14.04%. Age (p < 0.001), educational level (p < 0.001), living situation (p < 0.001), social support (p = 0.001), ADL score (p = 0.023), frailty (p < 0.001), and cognitive dysfunction (p < 0.001) were all significantly associated with depression, in which age, poor social support, frailty, and cognitive dysfunction were identified as independent factors. Conclusion: Improving social support and effective interventions for frailty and cognitive dysfunction may help relieve depression in community-dwelling older adults.

Minor Non-Disabling Stroke Patients with Large Vessel Severe Stenosis or Occlusion Might Benefit from Thrombolysis.

BACKGROUND: The benefit of alteplase in minor non-disabling acute ischemic stroke (AIS) is unknown. We aimed to explore the clinical efficacy of alteplase-treatment in minor non-disabling stroke in clinical practice. METHODS: We used a prospectively collected database of AIS patients who were being assessed for thrombolysis with alteplase. Minor non-disabling AIS was identified as patients with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤ 5 and a score 0 or 1 on each baseline NIHSS score item (items 1a to 1c being 0). RESULTS: A total of 461 patients with minor non-disabling AIS were included and among them 240 (52.1%) patients were treated with alteplase and 113 (24.5%) patients had severe stenosis/occlusion of large vessels. No significant association of 90-day excellent outcome was found with alteplase-treatment (77.1% vs. 80.5%, p 1 = 0.425; OR 0.911, 95% CI 0.428 to 1.940; p 2 = 0.808). However, among patients with severe stenosis/occlusion of large vessels, alteplase-treatment was independently associated with excellent outcome (74.4% vs. 45.7%, p 1 = 0.005; OR 4.709, 95% CI 1.391 to 11.962; p 2 = 0.010). CONCLUSION: Although alteplase-treatment did not result in an excellent outcome in general minor non-disabling stroke patients, it may work in those specific patients who had severe stenosis/occlusion of large vessels.

Suppression of oxidative phosphorylation and IDH2 sensitizes colorectal cancer to a naphthalimide derivative and mitoxantrone.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Oxidative phosphorylation (OXPHOS) has attracted a considerable attention in CRC. It is of great interest to explore novel therapies that inhibit OXPHOS for CRC treatment. Compound 6c is a novel naphthalimide derivative. However, the effects of 6c on CRC and the underlying mechanism are unclear. In this study, 6c suppressed CRC tumor growth and metastasis. RNA-seq data showed that 6c triggered the inhibition of OXPHOS and tricarboxylic acid cycle. 6c specifically inhibited mitochondrial complex III activity and the expression of isocitrate dehydrogenase 2 (IDH2), resulting in oxidative stress. Antioxidants reversed 6c-induced cell death, senescence, and autophagosomes formation. 6c inhibited autophagy flux; however, pretreatment with autophagy inhibitors resulted in the reduction of 6c-induced cytoplasmic vacuolization and proliferation inhibition. Moreover, combinatory treatment of 6c and mitoxantrone (MIT) showed stronger inhibitory effects on CRC compared with the single agent. Downregulation of IDH2 induced reactive oxygen species production, leading to MIT accumulation and autophagic cell death after co-treatment with 6c and MIT. In summary, our findings indicated 6c as a promising candidate for CRC treatment.

Identification of molecular anti-metastasis mechanisms of lycorine in colorectal cancer by RNA-seq analysis.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide. Metastasis is the major cause of death in patients with CRC. Lycorine, the phenanthridine alkaloid most commonly found in spp of the Amaryllidaceae family, has shown promising anticancer activities with minor side effects. However, the effects and the detailed mechanism of lycorine against metastasis of CRC remains unclear. STUDY DESIGN/METHODS: The purpose of this study was to investigate the effects of lycorine on CRC and characterize the molecular mechanisms observed in lycorine-treated CRC cells using RNA-sequencing. MTT assay, colony formation assay, acridine orange/ethidium bromide (AO/EB) staining and Annexin V-FITC/Propidium iodide (PI) staining were conducted to examine the effects of lycorine on cell proliferation and apoptosis in CRC cells. RNA sequencing, real-time PCR assays and western blot were performed. Migration and invasion abilities of lycorine-treated CRC cells were investigated by wound healing and transwell invasion assays. The mouse CRC lung metastasis model was established and was used to detect the effect of lycorine on CRC in vivo. RESULTS: Our results demonstrated that lycorine inhibited the proliferation and colony formation of CRC cells in a concentration-dependent manner. AO/EB staining and Annexin V-FITC/PI staining showed that lycorine induced apoptosis in a concentration-dependent manner. Lycorine also reduced lung metastasis of CRC in vivo. Moreover, transcriptomic analysis suggested that lycorine regulated the expression of 3556 genes. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was implicated according to the differentially expressed genes (DEGs), and multiple pathways including those of mitogen-activated protein kinase (MAPK), relaxin, Ras, phosphatidylinositol 3­kinase (PI3K)-protein kinase B (Akt) and Wnt/ß-catenin were selected by functional enrichment analyses. Furthermore, based on transcriptomic analysis, we found that the tumor necrosis factor (TNF) pathway and endoplasmic reticulum stress were responsible for lycorine-induced apoptosis. CONCLUSIONS: These results obtained in this study demonstrated that lycorine has the potential to suppress CRC in vitro and in vivo through the lycorine-regulated multiple signaling pathways.

Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human.

OBJECTIVE: Aging is a major risk factor for numerous neurological disorders, and the mechanisms underlying brain aging remain elusive. Recent animal studies demonstrated a tight relationship between impairment of the glymphatic pathway, meningeal lymphatic vessels, and aging. However, the relationship in the human brain remains uncertain. METHODS: In this observational cohort study, patients underwent magnetic resonance imaging before and at multiple time points after intrathecal administration of a contrast agent. Head T1-weighted imaging was performed to assess the function of the glymphatic pathway and head high-resolution T2-fluid attenuated inversion recovery imaging to visualize putative meningeal lymphatic vessels (pMLVs). We measured the signal unit ratio (SUR) of 6 locations in the glymphatic pathway and pMLVs, defined the percentage change in SUR from baseline to 39 hours as the clearance of the glymphatic pathway and pMLVs, and then analyzed their relationships with aging. RESULTS: In all patients (N = 35), the SUR of the glymphatic pathway and pMLVs changed significantly after intrathecal injection of the contrast agent. The clearance of both the glymphatic pathway and pMLVs was related to aging (all p < 0.05). The clearance of pMLVs was significantly related to the clearance of the glymphatic pathway (all p < 0.05), and the clearance of the glymphatic pathway was significantly faster in patients with early filling of pMLVs than those with late filling (all p < 0.05). INTERPRETATION: We revealed that both the glymphatic pathway and pMLVs might be impaired in the aging human brain through the novel, clinically available method to simultaneously visualize their clearance. Our findings also support that in humans, pMLVs are the downstream of the glymphatic pathway. Ann Neurol 2020;87:357-369.

A multiplex PCR method for the simultaneous detection of three viruses associated with canine viral enteric infections.

The aim of this study was to establish a multiplex PCR (mPCR) method that can simultaneously detect canine parvovirus (CPV-2), canine coronavirus (CCoV) and canine adenovirus (CAV), thereby eliminating the need to detect these pathogens individually. Based on conserved regions in the genomes of these three viruses, the VP2 gene of CPV-2, the endoribonuclease nsp15 gene of CCoV, and the 52K gene of CAV were selected for primer design. The specificity of the mPCR results showed no amplification of canine distemper virus (CDV), canine parainfluenza virus (CPIV), or pseudorabies virus (PRV), indicating that the method had good specificity. A sensitivity test showed that the detection limit of the mPCR method was 1 × 104 viral copies. A total of 63 rectal swabs from dogs with diarrheal symptoms were evaluated using mPCR and routine PCR. The ratio of positive samples to total samples for CPV-2, CCoV, and CAV was 55.6% (35/63) for mPCR and 55.6% (35/63) for routine PCR. Thirty-five positive samples were detected by both methods, for a coincidence ratio of 100%. This mPCR method can simultaneously detect CCoV (CCoV-II), CAV (CAV-1, CAV-2) and CPV-2 (CPV-2a, CPV-2b, CPV-2c), which are associated with viral enteritis, thereby providing an efficient, inexpensive, specific, and accurate new tool for clinical diagnosis and laboratory epidemiological investigations.