APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-ß or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRß7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-ß and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.

The effect of prolonged spaceflight on cerebrospinal fluid and perivascular spaces of astronauts and cosmonauts.

Long-duration spaceflight induces changes to the brain and cerebrospinal fluid compartments and visual acuity problems known as spaceflight-associated neuro-ocular syndrome (SANS). The clinical relevance of these changes and whether they equally affect crews of different space agencies remain unknown. We used MRI to analyze the alterations occurring in the perivascular spaces (PVS) in NASA and European Space Agency astronauts and Roscosmos cosmonauts after a 6-mo spaceflight on the International Space Station (ISS). We found increased volume of basal ganglia PVS and white matter PVS (WM-PVS) after spaceflight, which was more prominent in the NASA crew than the Roscosmos crew. Moreover, both crews demonstrated a similar degree of lateral ventricle enlargement and decreased subarachnoid space at the vertex, which was correlated with WM-PVS enlargement. As all crews experienced the same environment aboard the ISS, the differences in WM-PVS enlargement may have been due to, among other factors, differences in the use of countermeasures and high-resistive exercise regimes, which can influence brain fluid redistribution. Moreover, NASA astronauts who developed SANS had greater pre- and postflight WM-PVS volumes than those unaffected. These results provide evidence for a potential link between WM-PVS fluid and SANS.

Functional connectivity alterations in traumatic brain injury patients with late seizures.

PTE is a neurological disorder characterized by recurrent and spontaneous epileptic seizures. PTE is a major public health problem occurring in 2-50% of TBI patients. Identifying PTE biomarkers is crucial for the development of effective treatments. Functional neuroimaging studies in patients with epilepsy and in epileptic rodents have observed that abnormal functional brain activity plays a role in the development of epilepsy. Network representations of complex systems ease quantitative analysis of heterogeneous interactions within a unified mathematical framework. In this work, graph theory was used to study resting state functional magnetic resonance imaging (rs-fMRI) and reveal functional connectivity abnormalities that are associated with seizure development in traumatic brain injury (TBI) patients. We examined rs-fMRI of 75 TBI patients from Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) which aims to identify validated Post-traumatic epilepsy (PTE) biomarkers and antiepileptogenic therapies using multimodal and longitudinal data acquired from 14 international sites. The dataset includes 28 subjects who had at least one late seizure after TBI and 47 subjects who had no seizures within 2 years post-injury. Each subject's neural functional network was investigated by computing the correlation between the low frequency time series of 116 regions of interest (ROIs). Each subject's functional organization was represented as a network consisting of nodes, brain regions, and edges that show the relationship between the nodes. Then, several graph measures concerning the integration and the segregation of the functional brain networks were extracted in order to highlight changes in functional connectivity between the two TBI groups. Results showed that the late seizure-affected group had a compromised balance between integration and segregation and presents functional networks that are hyperconnected, hyperintegrated but at the same time hyposegregated compared with seizure-free patients. Moreover, TBI subjects who developed late seizures had more low betweenness hubs.

Prevalence of dementia and mild cognitive impairment in indigenous Bolivian forager-horticulturalists.

INTRODUCTION: We evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle. METHODS: Participants from population-based samples ≥ 60 years of age (n = 623) were assessed using adapted versions of the Modified Mini-Mental State Examination, informant interview, longitudinal cognitive testing and brain computed tomography (CT) scans. RESULTS: Tsimane exhibited five cases of dementia (among n = 435; crude prevalence = 1.2%, 95% confidence interval [CI]: 0.4, 2.7); Moseten exhibited one case (among n = 169; crude prevalence = 0.6%, 95% CI: 0.0, 3.2), all age ≥ 80 years. Age-standardized MCI prevalence was 7.7% (95% CI: 5.2, 10.3) in Tsimane and 9.8% (95% CI: 4.9, 14.6) in Moseten. Cognitive impairment was associated with visuospatial impairments, parkinsonian symptoms, and vascular calcification in the basal ganglia. DISCUSSION: The prevalence of dementia in this cohort is among the lowest in the world. Widespread intracranial medial arterial calcifications suggest a previously unrecognized, non-Alzheimer's disease (AD) dementia phenotype.

Imaging perivascular space structure and function using brain MRI.

In this article, we provide an overview of current neuroimaging methods for studying perivascular spaces (PVS) in humans using brain MRI. In recent years, an increasing number of studies highlighted the role of PVS in cerebrospinal/interstial fluid circulation and clearance of cerebral waste products and their association with neurological diseases. Novel strategies and techniques have been introduced to improve the quantification of PVS and to investigate their function and morphological features in physiological and pathological conditions. After a brief introduction on the anatomy and physiology of PVS, we examine the latest technological developments to quantitatively analyze the structure and function of PVS in humans with MRI. We describe the applications, advantages, and limitations of these methods, providing guidance and suggestions on the acquisition protocols and analysis techniques that can be applied to study PVS in vivo. Finally, we review the human neuroimaging studies on PVS across the normative lifespan and in the context of neurological disorders.

Effects of ambient particulate matter on vascular tissue: a review.

Fine and ultra-fine particulate matter (PM) are major constituents of urban air pollution and recognized risk factors for cardiovascular diseases. This review examined the effects of PM exposure on vascular tissue. Specific mechanisms by which PM affects the vasculature include inflammation, oxidative stress, actions on vascular tone and vasomotor responses, as well as atherosclerotic plaque formation. Further, there appears to be a greater PM exposure effect on susceptible individuals with pre-existing cardiovascular conditions.

Perivascular space fluid contributes to diffusion tensor imaging changes in white matter.

Diffusion tensor imaging (DTI) has been extensively used to map changes in brain tissue related to neurological disorders. Among the most widespread DTI findings are increased mean diffusivity and decreased fractional anisotropy of white matter tissue in neurodegenerative diseases. Here we utilize multi-shell diffusion imaging to separate diffusion signal of the brain parenchyma from non-parenchymal fluid within the white matter. We show that unincorporated anisotropic water in perivascular space (PVS) significantly, and systematically, biases DTI measures, casting new light on the biological validity of many previously reported findings. Despite the challenge this poses for interpreting these past findings, our results suggest that multi-shell diffusion MRI provides a new opportunity for incorporating the PVS contribution, ultimately strengthening the clinical and scientific value of diffusion MRI.

Assessing test-retest reliability of phase contrast MRI for measuring cerebrospinal fluid and cerebral blood flow dynamics.

PURPOSE: Pathological states occur when cerebrospinal fluid (CSF) and cerebral blood flow (CBF) dynamics become dysregulated in the brain. Phase-contrast MRI (PC-MRI) is a noninvasive imaging technique that enables quantitative measurements of CSF and CBF flow. While studies have validated PC-MRI as an imaging technique for flow, few studies have evaluated its reliability for CSF and CBF flow parameters commonly associated with neurological disease. The purpose of this study was to evaluate test-retest reliability at the cerebral aqueduct (CA) and C2-C3 area using PC-MRI to assess the feasibility of investigating CSF and CBF flow dynamics. METHODS: This study was performed on 27 cognitively normal young adults (ages 20-35 years). Flow data was acquired on a 3T Siemens Prisma using a 2D cine-PC pulse sequence. Three consecutive flow measurements were acquired at the CA and C2-C3 area. Intraclass correlation coefficient (ICC) and coefficient of variance (CV) were used to evaluate intrarater, inter-rater, and test-retest reliability. RESULTS: Among the 26 flow parameters analyzed, 22 had excellent reliability (ICC > 0.80), including measurements of CSF stroke volume, flush peak, and fill peak, and 4 parameters had good reliability (ICC 0.60-0.79). 16 flow parameters had a mean CV ≤ 10%, 7 had a CV ≤ 15%, and 3 had a CV ≤ 30%. All CSF and CBF flow measurements had excellent inter-rater and intrarater reliability (ICC > 0.80). CONCLUSION: This study shows that CSF and CBF flow can be reliably measured at the CA and C2-C3 area using PC-MRI, making it a promising tool for studying flow dynamics in the central nervous system.

Cerebral perivascular spaces as predictors of dementia risk and accelerated brain atrophy.

Cerebral small vessel disease, an important risk factor for dementia, lacks robust, in vivo measurement methods. Perivascular spaces (PVS) on brain MRI are surrogates for small parenchymal blood vessels and their perivascular compartment, and may relate to brain health. We developed a novel, robust algorithm to automatically assess PVS count and size on MRI, and investigated their relationship with dementia risk and brain atrophy. We analyzed 46,478 clinical measurements of cognitive functioning and 20,845 brain MRI scans from 10,004 participants (71.1±9.7 years-old, 56.6% women). Fewer PVS and larger PVS diameter at baseline were associated with higher dementia risk and accelerated brain atrophy. Longitudinal trajectories of PVS markers were significantly different in non-demented individuals who converted to dementia compared with non-converters. In simulated placebo-controlled trials for treatments targeting cognitive decline, screening out participants less likely to develop dementia based on our PVS markers enhanced the power of the trial. These novel radiographic cerebrovascular markers may improve risk-stratification of individuals, potentially reducing cost and increasing throughput of clinical trials to combat dementia.

Modulation of the Association Between Corticospinal Tract Damage and Outcome After Stroke by White Matter Hyperintensities.

BACKGROUND AND OBJECTIVES: Motor outcomes after stroke relate to corticospinal tract (CST) damage. The brain leverages surviving neural pathways to compensate for CST damage and mediate motor recovery. Thus, concurrent age-related damage from white matter hyperintensities (WMHs) might affect neurologic capacity for recovery after CST injury. The role of WMHs in post-stroke motor outcomes is unclear. In this study, we evaluated whether WMHs modulate the relationship between CST damage and post-stroke motor outcomes. METHODS: We used data from the multisite ENIGMA Stroke Recovery Working Group with T1 and T2/fluid-attenuated inversion recovery imaging. CST damage was indexed with weighted CST lesion load (CST-LL). WMH volumes were extracted with Freesurfer's SAMSEG. Mixed-effects beta-regression models were fit to test the impact of CST-LL, WMH volume, and their interaction on motor impairment, controlling for age, days after stroke, and stroke volume. RESULTS: A total of 223 individuals were included. WMH volume related to motor impairment above and beyond CST-LL (ß = 0.178, 95% CI 0.025-0.331, p = 0.022). Relationships varied by WMH severity (mild vs moderate-severe). In individuals with mild WMHs, motor impairment related to CST-LL (ß = 0.888, 95% CI 0.604-1.172, p < 0.001) with a CST-LL × WMH interaction (ß = -0.211, 95% CI -0.340 to -0.026, p = 0.026). In individuals with moderate-severe WMHs, motor impairment related to WMH volume (ß = 0.299, 95% CI 0.008-0.590, p = 0.044), but did not significantly relate to CST-LL or a CST-LL × WMH interaction. DISCUSSION: WMHs relate to motor outcomes after stroke and modify relationships between motor impairment and CST damage. WMH-related damage may be under-recognized in stroke research as a factor contributing to variability in motor outcomes. Our findings emphasize the importance of brain structural reserve in motor outcomes after brain injury.

Effects of sleep on brain perivascular space in a cognitively healthy population.

The magnetic resonance imaging (MRI) visible perivascular space (PVS) reportedly clears amyloid-ß and metabolic waste during sleep. Previous studies reported an association between sleep and the PVS in small vessel disease, traumatic brain injury, and Alzheimer's disease. However, this relationship in a healthy cohort is still unclear. Here, we used the Human Connectome Project Aging dataset to analyze the relationship between sleep and the PVS in cognitively healthy adults across the aging continuum. We measured sleep parameters using the self-reported Pittsburgh Sleep Quality Index questionnaire. We found that older adults who had better sleep quality and sleep efficiency presented with a larger PVS volume fraction in the basal ganglia (BG). However, sleep measures were not associated with PVS volume fraction in the centrum semiovale (CSO). In addition, we found that body mass index (BMI) influenced the BG-PVS across middle-aged and older participants. In the entire cognitively healthy cohort, the effect of sleep quality on PVS volume fraction was mediated by BMI. However, BMI did not influence this effect in the older cohort. Furthermore, there are significant differences in PVS volume fraction across racial/ethnic cohorts. In summary, the effect of sleep on the PVS volume alteration was different in the middle-aged adults and older adults.

Brain perivascular spaces and autism: clinical and pathogenic implications from an innovative volumetric MRI study.

Introduction: Our single-center case-control study aimed to evaluate the unclear glymphatic system alteration in autism spectrum disorder (ASD) through an innovative neuroimaging tool which allows to segment and quantify perivascular spaces in the white matter (WM-PVS) with filtering of non-structured noise and increase of the contrast-ratio between perivascular spaces and the surrounding parenchyma. Methods: Briefly, files of 65 ASD and 71 control patients were studied. We considered: ASD type, diagnosis and severity level and comorbidities (i.e., intellectual disability, attention-deficit hyperactivity disorder, epilepsy, sleep disturbances). We also examined diagnoses other than ASD and their associated comorbidities in the control group. Results: When males and females with ASD are included together, WM-PVS grade and WM-PVS volume do not significantly differ between the ASD group and the control group overall. We found, instead, that WM-PVS volume is significantly associated with male sex: males had higher WM-PVS volume compared to females (p = 0.01). WM-PVS dilation is also non-significantly associated with ASD severity and younger age (< 4 years). In ASD patients, higher WM-PVS volume was related with insomnia whereas no relation was found with epilepsy or IQ. Discussion: We concluded that WM-PVS dilation can be a neuroimaging feature of male ASD patients, particularly the youngest and most severe ones, which may rely on male-specific risk factors acting early during neurodevelopment, such as a transient excess of extra-axial CSF volume. Our findings can corroborate the well-known strong male epidemiological preponderance of autism worldwide.

Structural MRI in Migraine: A Review of Migraine Vascular and Structural Changes in Brain Parenchyma.

Migraine is a complex and common disorder that affects patients around the world. Despite recent advances in this field, the exact pathophysiology of migraine is still not completely understood. Structural MRI sequences have revealed a variety of changes to brain parenchyma associated with migraine, including white matter lesions, volume changes, and iron deposition. This Review highlights different structural imaging findings in various types of migraine and their relationship to migraine characteristics and subtypes in order to improve our understanding of migraine, its pathophysiologic mechanisms, and how to better diagnose and treat it.

Functional MRI and Diffusion Tensor Imaging in Migraine: A Review of Migraine Functional and White Matter Microstructural Changes.

Migraine is a complex and heterogenous disorder whose disease mechanisms remain disputed. This narrative review summarizes functional MRI (fMRI) and diffusion tensor imaging (DTI) findings and interprets their association with migraine symptoms and subtype to support and expand our current understanding of migraine pathophysiology. Our PubMed search evaluated and included fMRI and DTI studies involving comparisons between migraineurs vs healthy controls, migraineurs with vs without aura, and episodic vs chronic migraineurs. Migraineurs demonstrate changes in functional connectivity (FC) and regional activation in numerous pain-related networks depending on migraine phase, presence of aura, and chronicity. Changes to diffusion indices are observed in major cortical white matter tracts extending to the brainstem and cerebellum, more prominent in chronic migraine and associated with FC changes. Reported changes in FC and regional activation likely relate to pain processing and sensory hypersensitivities. Diffuse white matter microstructural changes in dysfunctional cortical pain and sensory pathways complement these functional differences. Interpretations of reported fMRI and DTI measure trends have not achieved a clear consensus due to inconsistencies in the migraine neuroimaging literature. Future fMRI and DTI studies should establish and implement a uniform methodology that reproduces existing results and directly compares migraineurs with different subtypes. Combined fMRI and DTI imaging may provide better pathophysiological explanations for nonspecific FC and white matter microstructural differences.

Decreased functional connectivity is associated with increased levels of Cerebral Spinal Fluid soluble-PDGFRß, a marker of blood brain barrier breakdown, in older adults.

Resting-state functional connectivity (FC) is suggested to be cross-sectionally associated with both vascular burden and Alzheimer's disease (AD) pathology. For instance, studies in pre-clinical AD subjects have shown increases of cerebral spinal fluid soluble platelet-derived growth factor receptor-ß (CSF sPDGFRß, a marker of BBB breakdown) but have not demonstrated if this vascular impairment affects neuronal dysfunction. It's possible that increased levels of sPDGFRß in the CSF may correlate with impaired FC in metabolically demanding brain regions (i.e. Default Mode Network, DMN). Our study aimed to investigate the relationship between these two markers in older individuals that were cognitively normal and had cognitive impairment. Eighty-nine older adults without dementia from the University of Southern California were selected from a larger cohort. Region of interest (ROI) to ROI analyses were conducted using DMN seed regions. Linear regression models measured significant associations between BOLD FC strength among seed-target regions and sPDGFRß values, while covarying for age and sex. Comparison of a composite ROI created by averaging FC values between seed and all target regions among cognitively normal and impaired individuals was also examined. Using CSF sPDGFRß as a biomarker of BBB breakdown, we report that increased breakdown correlated with decreased functional connectivity in DMN areas, specifically the PCC while the hippocampus exhibited an interaction effect using CDR score. We conclude that BBB breakdown as measured by CSF sPDGFRß affects neural networks resulting in decreased functional connections that leads to cognitive dysfunction.

Manual lesion segmentations for traumatic brain injury characterization.

Traumatic brain injury (TBI) often results in heterogenous lesions that can be visualized through various neuroimaging techniques, such as magnetic resonance imaging (MRI). However, injury burden varies greatly between patients and structural deformations often impact usability of available analytic algorithms. Therefore, it is difficult to segment lesions automatically and accurately in TBI cohorts. Mislabeled lesions will ultimately lead to inaccurate findings regarding imaging biomarkers. Therefore, manual segmentation is currently considered the gold standard as this produces more accurate masks than existing automated algorithms. These masks can provide important lesion phenotype data including location, volume, and intensity, among others. There has been a recent push to investigate the correlation between these characteristics and the onset of post traumatic epilepsy (PTE), a disabling consequence of TBI. One motivation of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is to identify reliable imaging biomarkers of PTE. Here, we report the protocol and importance of our manual segmentation process in patients with moderate-severe TBI enrolled in EpiBioS4Rx. Through these methods, we have generated a dataset of 127 validated lesion segmentation masks for TBI patients. These ground-truths can be used for robust PTE biomarker analyses, including optimization of multimodal MRI analysis via inclusion of lesioned tissue labels. Moreover, our protocol allows for analysis of the refinement process. Though tedious, the methods reported in this work are necessary to create reliable data for effective training of future machine-learning based lesion segmentation methods in TBI patients and subsequent PTE analyses.

White matter hyperintensities modify relationships between corticospinal tract damage and motor outcomes after stroke.

Motor outcomes after stroke relate to corticospinal tract (CST) damage. Concurrent damage from white matter hyperintensities (WMHs) might impact neurological capacity for recovery after CST injury. Here, we evaluated if WMHs modulate the relationship between CST damage and post-stroke motor impairment outcome. We included 223 individuals from the ENIGMA Stroke Recovery Working Group. CST damage was indexed with weighted CST lesion load (CST-LL). Mixed effects beta-regression models were fit to test the impact of CST-LL, WMH volume, and their interaction on motor impairment. WMH volume related to motor impairment above and beyond CST-LL (ß = 0.178, p = 0.022). We tested if relationships varied by WMH severity (mild vs. moderate-severe). In individuals with mild WMHs, motor impairment related to CST-LL (ß = 0.888, p < 0.001) with a CST-LL x WMH interaction (ß = -0.211, 0.026). In individuals with moderate-severe WMHs, motor impairment related to WMH volume (ß = 0.299, p = 0.044), but did not significantly relate to CST-LL or a CST-LL x WMH interaction. WMH-related damage may be under-recognised in stroke research as a factor contributing to variability in motor outcomes. Our findings emphasize the importance of brain structural reserve in motor outcomes after brain injury.

Cross-Vendor Test-Retest Validation of Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS) for Evaluating Glymphatic System Function.

The diffusion tensor image analysis along the perivascular space (DTI-ALPS) method was proposed to evaluate glymphatic system (GS) function. However, few studies have validated its reliability and reproducibility. Fifty participants' DTI data from the MarkVCID consortium were included in this study. Two pipelines by using DSI studio and FSL software were developed for data processing and ALPS index calculation. The ALPS index was obtained by the average of bilateral ALPS index and was used for testing the cross-vendor, inter-rater and test-retest reliability by using R studio software. The ALPS index demonstrated favorable inter-scanner reproducibility (ICC=0.77 to 0.95, P < 0.001), inter-rater reliability (ICC=0.96 to 1, P< 0.001) and test-retest repeatability (ICC=0.89 to 0.95, P< 0.001), offering a potential biomarker for in vivo evaluation of GS function.