Objective: The glymphatic system cleans amyloid and tau proteins from the brain in animal studies of Alzheimer disease (AD). However, there is no direct evidence showing this in humans.Methods: Participants (n = 50, 62.6 ± 5.4 years old, 36 women) with AD and normal controls underwent amyloid positron emission tomography (PET), tau PET, structural T1‐weighted magnetic resonance imaging, and neuropsychological evaluation. Whole‐brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI‐ALPS).Results: ALPS‐indexes showed negative correlations with deposition of amyloid and tau on PET images and positive correlations with cognitive scores even after adjusting for age, sex, years of education, andAPOE4genotype covariates in multiple AD‐related brain regions (allp < 0.05). Mediation analysis showed that ALPS‐index acted as a significant mediator between regional standardized uptake value ratios of amyloid and tau images and cognitive dysfunction even after correcting for multiple covariates in AD‐related brain regions. These regions are responsible for attention, memory, and executive function, which are vulnerable to sleep deprivation.Interpretation: Glymphatic system activity may act as a significant mediator in AD‐related cognitive dysfunction even after adjusting for multiple covariates and gray matter volumes. ALPS‐index may provide useful disease progression or treatment biomarkers for patients with AD as an indicator of modulation of glymphatic activity. ANN NEUROL 2023;93:164–174

BACKGROUND AND PURPOSE: Unlike conventional functional MR imaging where external sensory/cognitive paradigms are needed to specifically activate different regions of the brain, resting functional connectivity MR imaging acquires images in the absence of cognitive demands (a resting condition) and detects brain regions, which are highly temporally correlated. Therefore, resting functional MR imaging is highly suited for the study of brain functional development in pediatric subjects. This study aimed to determine the temporal and spatial patterns of rfc in healthy pediatric subjects between 2 weeks and 2 years of age. MATERIALS AND METHODS: Rfc studies were performed on 85 children: 38 neonates (2–4 weeks of age), 26 one-year-olds, and 21 two-year-olds. All subjects were imaged while asleep; no sedation was used. Six regions of interest were chosen, including the primary motor, sensory, and visual cortices in each hemisphere. Mean signal intensity of each region of interest was used to perform correlation analysis pixel by pixel throughout the entire brain, identifying regions with high temporal correlation. RESULTS: Functional connectivity was observed in all subjects in the sensorimotor and visual areas. The percent brain volume exhibiting rfc and the strength of rfc continued to increase from 2 weeks to 2 years. The growth trajectories of the percent brain volume of rfc appeared to differ between the sensorimotor and visual areas, whereas the z-score was similar. The percent brain volume of rfc in the sensorimotor area was significantly larger than that in the visual area for subjects 2 weeks of age (P = .008) and 1-year-olds (P = .017) but not for the 2-year-olds. CONCLUSIONS: These findings suggest that rfc in the sensorimotor precedes that in the visual area from 2 weeks to 1 year but becomes comparable at 2 years. In contrast, the comparable z-score values between the sensorimotor and visual areas for all age groups suggest a disassociation between percent brain volume and the strength of cortical rfc.

BACKGROUND AND PURPOSE: Differentiating between primary cerebral lymphoma and glioblastoma multiforme (GBM) based on conventional MR imaging sequences may be impossible. Our hypothesis was that there are significant differences in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) between lymphoma and GBM, which will allow for differentiation between them.

Background and Objectives: The glymphatic system, which is robustly enabled during some stages of sleep, is a fluid-transport pathway that clears cerebral waste products. Most contemporary knowledge regarding glymphatic system is inferred from rodent experiments and human research is limited. The objective of the research is to explore the associations between human glymphatic function, sleep, neuropsychological performances, and cerebral gray matter volumes. Methods: This cross-sectional study included individuals 60 years or older who had participated in the Integrating Systemic Data of Geriatric Medicine to Explore the Solution for Health Aging study between September 2019 and October 2020. Community-dwelling older adults were enrolled at 2 different sites. Participants with dementia, major depressive disorders, and other major organ system abnormalities were excluded. Sleep profile was accessed using questionnaires and polysomnography. Administered neuropsychological test batteries included Everyday Cognition (ECog) and the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD-NB). Gray matter volumes were estimated based on magnetic resonance imaging (MRI). Diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS) index was used as the MRI marker of glymphatic function. Results: A total of 84 participants (mean [SD] age, 73.3 [7.1] years, 47 [56.0%] women) were analyzed. Multivariate linear regression model determined that age (unstandardized β, -0.0025 [SE, 0.0001]; P = 0.02), N2 sleep duration (unstandardized β, 0.0002 [SE, 0.0001]; P = 0.04), and the apnea-hypopnea index (unstandardized β, -0.0011 [SE, 0.0005]; P = 0.03) were independently associated with DTI-ALPS. Higher DTI-ALPS was associated with better ECog language scores (unstandardized β, -0.59 [SE, 0.28]; P = 0.04) and better CERAD-NB word-list-learning delayed recall subtest scores (unstandardized β, 6.17 [SE, 2.31]; P = 0.009) after co-varying for age and education. Higher DTI-ALPS was also associated with higher gray matter volume (unstandardized β, 107.00 [SE, 43.65]; P = 0.02) after controlling for age, gender, and total intracranial volume. Discussion: Significant associations were identified between glymphatic function and sleep stressing the importance of sleep for brain health. This study also revealed associations between DTI-ALPS, neuropsychological performances, and cerebral gray matter volumes suggesting the potential of DTI-ALPS as a biomarker for cognitive disorders.

Objectives: Rodent experiments have provided some insight into the changes of glymphatic function in ischemic stroke. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) method offers an opportunity for the noninvasive investigation of the glymphatic system in patients with ischemic stroke. We aimed to investigate the changes of glymphatic function in ischemic stroke and the factors associated with the changes.Materials and Methods: A total of 50 patients (mean age 56.7 years; 30 men) and 44 normal subjects (mean age 53.3 years; 23 men) who had preoperative diffusion-tensor imaging for calculation of the analysis along the perivascular space (ALPS) index were retrospectively included. Information collected from each patient included sex, age, time since stroke onset, infarct location, hemorrhagic change, infarct volume, infarct apparent diffusion coefficient (ADC), infarct fractional anisotropy (FA), and ALPS index of both hemispheres. Interhemispheric differences in ALPS index (infarct side vs. contralateral normal side) were assessed with a paired t-test in all patients. ALPS index was normalized by calculating ALPS ratios (right-to-left and left-to-right) for comparisons between patients and normal subjects. Comparisons of ALPS ratios between patients and normal subjects were performed using analysis of covariance with adjustments for age and sex. Linear regression analyses were performed to identify factors associated with the ALPS index.Results: In patients, the mean ALPS index ipsilateral to infarct was 1.162 ± 0.126, significantly lower (P < 0.001) than that of the contralateral side (1.335 ± 0.160). The right-to-left ALPS index ratio of patients with right cerebral infarct was 0.84 ± 0.08, significantly lower (P < 0.001) than that of normal subjects (0.95 ± 0.07). The left-to-right ALPS ratio of patients with left cerebral infarct was 0.92 ± 0.09, significantly (P < 0.001) lower than that of normal subjects (1.05 ± 0.08). On multiple linear regression analysis, time since stroke onset (β = 0.794, P < 0.001) was the only factor associated with the ALPS index.Conclusion: The ALPS index showed lower values in ischemic stroke suggesting impaired glymphatic function. Following initial impairment, the ALPS index increased with the time since stroke onset, which is suggestive of glymphatic function recovery.

Purpose: Even when diagnosed prior to metastasis, pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with almost 90% lethality, emphasizing the need for new therapies optimally targeting the tumors of individual patients. Experimental Design: We first developed a panel of new physiologic models for study of PDAC, expanding surgical PDAC tumor samples in culture using short-term culture and conditional reprogramming with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). These were evaluated for sensitivity to a large panel of clinical agents, and promising leads further evaluated mechanistically. Results: Only a small minority of tested agents was cytotoxic in minimally passaged PDAC cultures in vitro. Drugs interfering with protein turnover and transcription were among most cytotoxic. Among transcriptional repressors, triptolide, a covalent inhibitor of ERCC3, was most consistently effective in vitro and in vivo causing prolonged complete regression in multiple PDX models resistant to standard PDAC therapies. Importantly, triptolide showed superior activity in MYC-amplified PDX models and elicited rapid and profound depletion of the oncoprotein MYC, a transcriptional regulator. Expression of ERCC3 and MYC was interdependent in PDACs, and acquired resistance to triptolide depended on elevated ERCC3 and MYC expression. The Cancer Genome Atlas analysis indicates ERCC3 expression predicts poor prognosis, particularly in CDKN2A-null, highly proliferative tumors. Conclusions: This provides initial preclinical evidence for an essential role of MYC–ERCC3 interactions in PDAC, and suggests a new mechanistic approach for disruption of critical survival signaling in MYC-dependent cancers. Clin Cancer Res; 22(24); 6153–63. ©2016 AACR.