PhD, University of Southern California, Neuroscience (2022)
Diploma, Padua University, Aerospace Medicine (2017)
Internship, Vita-Salute San Raffaele University, Neurosurgery (2017)
MD, Vita-Salute San Raffaele University (2016)
Melanie Hayden Gephart, Postdoctoral Faculty Sponsor
A "multi-omics" analysis of blood-brain barrier and synaptic dysfunction in APOE4 mice.
The Journal of experimental medicine
2022; 219 (11)
Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer's disease, leads to blood-brain barrier (BBB) breakdown in humans and mice. Remarkably, BBB dysfunction predicts cognitive decline and precedes synaptic deficits in APOE4 human carriers. How APOE4 affects BBB and synaptic function at a molecular level, however, remains elusive. Using single-nucleus RNA-sequencing and phosphoproteome and proteome analysis, we show that APOE4 compared with APOE3 leads to an early disruption of the BBB transcriptome in 2-3-mo-old APOE4 knock-in mice, followed by dysregulation in protein signaling networks controlling cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, as well as transcription and RNA splicing suggestive of DNA damage in pericytes. Changes in BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes, which preceded postsynaptic interactome disruption and behavioral deficits that developed 2-5 mo later. Thus, dysregulated signaling mechanisms in endothelium and pericytes in APOE4 mice reflect a molecular signature of a progressive BBB failure preceding changes in synaptic function and behavior.
View details for DOI 10.1084/jem.20221137
View details for PubMedID 36040482
Imaging perivascular space structure and function using brain MRI.
2022; 257: 119329
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.
View details for DOI 10.1016/j.neuroimage.2022.119329
View details for PubMedID 35609770
View details for PubMedCentralID PMC9233116
The effect of prolonged spaceflight on cerebrospinal fluid and perivascular spaces of astronauts and cosmonauts.
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (17): e2120439119
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.
View details for DOI 10.1073/pnas.2120439119
View details for PubMedID 35412862
View details for PubMedCentralID PMC9169932
Body mass index, time of day and genetics affect perivascular spaces in the white matter.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
2021; 41 (7): 1563-1578
The analysis of cerebral perivascular spaces (PVS) using magnetic resonance imaging (MRI) allows to explore in vivo their contributions to neurological disorders. To date the normal amount and distribution of PVS in healthy human brains are not known, thus hampering our ability to define with confidence pathogenic alterations. Furthermore, it is unclear which biological factors can influence the presence and size of PVS on MRI. We performed exploratory data analysis of PVS volume and distribution in a large population of healthy individuals (n = 897, age = 28.8 ± 3.7). Here we describe the global and regional amount of PVS in the white matter, which can be used as a reference for clinicians and researchers investigating PVS and may help the interpretation of the structural changes affecting PVS in pathological states. We found a relatively high inter-subject variability in the PVS amount in this population of healthy adults (range: 1.31-14.49 cm3). The PVS volume was higher in older and male individuals. Moreover, we identified body mass index, time of day, and genetics as new elements significantly affecting PVS in vivo under physiological conditions, offering a valuable foundation to future studies aimed at understanding the physiology of perivascular flow.
View details for DOI 10.1177/0271678X20972856
View details for PubMedID 33183133
View details for PubMedCentralID PMC8221772
APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.
2020; 581 (7806): 71-76
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-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β 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.
View details for DOI 10.1038/s41586-020-2247-3
View details for PubMedID 32376954
View details for PubMedCentralID PMC7250000
Functional connectivity alterations in traumatic brain injury patients with late seizures.
Neurobiology of disease
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.
View details for DOI 10.1016/j.nbd.2023.106053
View details for PubMedID 36871641
Arterial Spin Labeling in Migraine: A Review of Migraine Categories and Mimics
JOURNAL OF CENTRAL NERVOUS SYSTEM DISEASE
View details for DOI 10.1177/11795735231160032
View details for Web of Science ID 000941168900001
Neuroimaging aspects and clinical significance of giant perivascular spaces in the brain.
Precision cancer medicine
View details for DOI 10.21037/pcm-22-27
View details for PubMedID 36619900
View details for PubMedCentralID PMC9817033
Reply to Wostyn et al.: Potential models for perivascular space (PVS) enlargement and spaceflight-associated neuro-ocular syndrome (SANS).
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (32): e2208241119
View details for DOI 10.1073/pnas.2208241119
View details for PubMedID 35858379
View details for PubMedCentralID PMC9371741
A large, curated, open-source stroke neuroimaging dataset to improve lesion segmentation algorithms.
2022; 9 (1): 320
Accurate lesion segmentation is critical in stroke rehabilitation research for the quantification of lesion burden and accurate image processing. Current automated lesion segmentation methods for T1-weighted (T1w) MRIs, commonly used in stroke research, lack accuracy and reliability. Manual segmentation remains the gold standard, but it is time-consuming, subjective, and requires neuroanatomical expertise. We previously released an open-source dataset of stroke T1w MRIs and manually-segmented lesion masks (ATLAS v1.2, N = 304) to encourage the development of better algorithms. However, many methods developed with ATLAS v1.2 report low accuracy, are not publicly accessible or are improperly validated, limiting their utility to the field. Here we present ATLAS v2.0 (N = 1271), a larger dataset of T1w MRIs and manually segmented lesion masks that includes training (n = 655), test (hidden masks, n = 300), and generalizability (hidden MRIs and masks, n = 316) datasets. Algorithm development using this larger sample should lead to more robust solutions; the hidden datasets allow for unbiased performance evaluation via segmentation challenges. We anticipate that ATLAS v2.0 will lead to improved algorithms, facilitating large-scale stroke research.
View details for DOI 10.1038/s41597-022-01401-7
View details for PubMedID 35710678
View details for PubMedCentralID PMC9203460
Chronic Stroke Sensorimotor Impairment Is Related to Smaller Hippocampal Volumes: An ENIGMA Analysis.
Journal of the American Heart Association
2022; 11 (10): e025109
Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper-limb sensorimotor impairment. We investigated associations between non-lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross-sectional T1-weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta-Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA-UE (Fugl-Meyer Assessment of Upper Extremity). Robust mixed-effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni-corrected, P<0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional (P=0.005; β=0.16) but not contralesional (P=0.96; β=0.003) hippocampal volume, independent of lesion volume and other covariates (P=0.001; β=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional (P=0.008; β=-0.26) and contralesional (P=0.006; β=-0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size (P<0.001; β=-0.21) and extent of sensorimotor damage (P=0.003; β=-0.15). Conclusions The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women.
View details for DOI 10.1161/JAHA.121.025109
View details for PubMedID 35574963
View details for PubMedCentralID PMC9238563
Prevalence of dementia and mild cognitive impairment in indigenous Bolivian forager-horticulturalists.
Alzheimer's & dementia : the journal of the Alzheimer's Association
We evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle.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.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.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.
View details for DOI 10.1002/alz.12626
View details for PubMedID 35262289
View details for PubMedCentralID PMC9458772
Blood-brain barrier link to human cognitive impairment and Alzheimer's Disease.
Nature cardiovascular research
2022; 1 (2): 108-115
Vascular dysfunction is frequently seen in disorders associated with cognitive impairment, dementia and Alzheimer's disease (AD). Recent advances in neuroimaging and fluid biomarkers suggest that vascular dysfunction is not an innocent bystander only accompanying neuronal dysfunction. Loss of cerebrovascular integrity, often referred to as breakdown in the blood-brain barrier (BBB), has recently shown to be an early biomarker of human cognitive dysfunction and possibly underlying mechanism of age-related cognitive decline. Damage to the BBB may initiate or further invoke a range of tissue injuries causing synaptic and neuronal dysfunction and cognitive impairment that may contribute to AD. Therefore, better understanding of how vascular dysfunction caused by BBB breakdown interacts with amyloid-β and tau AD biomarkers to confer cognitive impairment may lead to new ways of thinking about pathogenesis, and possibly treatment and prevention of early cognitive impairment, dementia and AD, for which we still do not have effective therapies.
View details for DOI 10.1038/s44161-021-00014-4
View details for PubMedID 35450117
View details for PubMedCentralID PMC9017393
Distribution and volume analysis of early hemorrhagic contusions by MRI after traumatic brain injury: a preliminary report of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx).
Brain imaging and behavior
2021; 15 (6): 2804-2812
Traumatic brain injury (TBI) can produce heterogeneous injury patterns including a variety of hemorrhagic and non-hemorrhagic lesions. The impact of lesion size, location, and interaction between total number and location of contusions may influence the occurrence of seizures after TBI. We report our methodologic approach to this question in this preliminary report of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx). We describe lesion identification and segmentation of hemorrhagic contusions by early posttraumatic magnetic resonance imaging (MRI). We describe the preliminary methods of manual lesion segmentation in an initial cohort of 32 TBI patients from the EpiBioS4Rx cohort and the preliminary association of hemorrhagic contusion and edema location and volume to seizure incidence.
View details for DOI 10.1007/s11682-021-00603-8
View details for PubMedID 34985618
View details for PubMedCentralID PMC9433738
Editorial for "MRI-Based Investigation of Association Between Cerebrovascular Structural Alteration and White Matter Hyperintensity Induced by High Blood Pressure".
Journal of magnetic resonance imaging : JMRI
2021; 54 (5): 1527-1528
View details for DOI 10.1002/jmri.27854
View details for PubMedID 34331486
View details for PubMedCentralID PMC8976593
Minocycline decreases blood-brain barrier permeability following aneurysmal subarachnoid hemorrhage: a randomized, double-blind, controlled trial.
Journal of neurosurgery
Aneurysmal subarachnoid hemorrhage (aSAH)-induced vasospasm is linked to increased inflammatory cell trafficking across a permeable blood-brain barrier (BBB). Elevations in serum levels of matrix metalloprotease 9 (MMP9), a BBB structural protein, have been implicated in the pathogenesis of vasospasm onset. Minocycline is a potent inhibitor of MMP9. The authors sought to detect an effect of minocycline on BBB permeability following aSAH.Patients presenting within 24 hours of symptom onset with imaging confirmed aSAH (Fisher grade 3 or 4) were randomized to high-dose (10 mg/kg) minocycline or placebo. The primary outcome of interest was BBB permeability as quantitated by contrast signal intensity ratios in vascular regions of interest on postbleed day (PBD) 5 magnetic resonance permeability imaging. Secondary outcomes included serum MMP9 levels and radiographic and clinical evidence of vasospasm.A total of 11 patients were randomized to minocycline (n = 6) or control (n = 5) groups. No adverse events or complications attributable to minocycline were reported. High-dose minocycline administration was associated with significantly lower permeability indices on imaging analysis (p < 0.01). There was no significant difference with respect to serum MMP9 levels between groups, although concentrations trended upward in both cohorts. Radiographic vasospasm was noted in 6 patients (minocycline = 3, control = 3), with only 1 patient developing symptoms of clinical vasospasm in the minocycline cohort. There was no difference between cohorts with respect to Lindegaard ratios, transcranial Doppler values, or onset of vasospasm.Minocycline at high doses is well tolerated in the ruptured cerebral aneurysm population. Minocycline curtails breakdown of the BBB following aSAH as evidenced by lower permeability indices, though minocycline did not significantly alter serum MMP9 levels. Larger randomized clinical trials are needed to assess minocycline as a neuroprotectant against aSAH-induced vasospasm. Clinical trial registration no.: NCT04876638 (clinicaltrials.gov).
View details for DOI 10.3171/2021.6.JNS211270
View details for PubMedID 35349976
Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide.
2021; 3 (4): fcab254
Up to two-thirds of stroke survivors experience persistent sensorimotor impairments. Recovery relies on the integrity of spared brain areas to compensate for damaged tissue. Deep grey matter structures play a critical role in the control and regulation of sensorimotor circuits. The goal of this work is to identify associations between volumes of spared subcortical nuclei and sensorimotor behaviour at different timepoints after stroke. We pooled high-resolution T1-weighted MRI brain scans and behavioural data in 828 individuals with unilateral stroke from 28 cohorts worldwide. Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behaviour to non-lesioned subcortical volumes (Bonferroni-corrected, P < 0.004). We tested subacute (≤90 days) and chronic (≥180 days) stroke subgroups separately, with exploratory analyses in early stroke (≤21 days) and across all time. Sub-analyses in chronic stroke were also performed based on class of sensorimotor deficits (impairment, activity limitations) and side of lesioned hemisphere. Worse sensorimotor behaviour was associated with a smaller ipsilesional thalamic volume in both early (n = 179; d = 0.68) and subacute (n = 274, d = 0.46) stroke. In chronic stroke (n = 404), worse sensorimotor behaviour was associated with smaller ipsilesional putamen (d = 0.52) and nucleus accumbens (d = 0.39) volumes, and a larger ipsilesional lateral ventricle (d = -0.42). Worse chronic sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n = 256) was associated with smaller ipsilesional putamen (d = 0.72) and larger lateral ventricle (d = -0.41) volumes, while several measures of activity limitations (n = 116) showed no significant relationships. In the full cohort across all time (n = 828), sensorimotor behaviour was associated with the volumes of the ipsilesional nucleus accumbens (d = 0.23), putamen (d = 0.33), thalamus (d = 0.33) and lateral ventricle (d = -0.23). We demonstrate significant relationships between post-stroke sensorimotor behaviour and reduced volumes of deep grey matter structures that were spared by stroke, which differ by time and class of sensorimotor measure. These findings provide additional insight into how different cortico-thalamo-striatal circuits support post-stroke sensorimotor outcomes.
View details for DOI 10.1093/braincomms/fcab254
View details for PubMedID 34805997
View details for PubMedCentralID PMC8598999
Volumetric distribution of perivascular space in relation to mild cognitive impairment.
Neurobiology of aging
2021; 99: 28-43
Vascular contributions to early cognitive decline are increasingly recognized, prompting further investigation into the nature of related changes in perivascular spaces (PVS). Using magnetic resonance imaging, we show that, compared to a cognitively normal sample, individuals with early cognitive dysfunction have altered PVS presence and distribution, irrespective of Amyloid-β. Surprisingly, we noted lower PVS presence in the anterosuperior medial temporal lobe (asMTL) (1.29 times lower PVS volume fraction in cognitively impaired individuals, p < 0.0001), which was associated with entorhinal neurofibrillary tau tangle deposition (beta (standard error) = -0.98 (0.4); p = 0.014), one of the hallmarks of early Alzheimer's disease pathology. We also observed higher PVS volume fraction in centrum semi-ovale of the white matter, but only in female participants (1.47 times higher PVS volume fraction in cognitively impaired individuals, p = 0.0011). We also observed PVS changes in participants with history of hypertension (higher in the white matter and lower in the asMTL). Our results suggest that anatomically specific alteration of the PVS is an early neuroimaging feature of cognitive impairment in aging adults, which is differentially manifested in female.
View details for DOI 10.1016/j.neurobiolaging.2020.12.010
View details for PubMedID 33422892
View details for PubMedCentralID PMC7902350
Perivascular Space Imaging at Ultrahigh Field MR Imaging.
Magnetic resonance imaging clinics of North America
2021; 29 (1): 67-75
The recent Food and Drug Administration approval of 7 T MR imaging scanners for clinical use has introduced the possibility to study the brain not only in physiologic but also in pathologic conditions at ultrahigh field (UHF). Because UHF MR imaging offers higher signal-to-noise ratio and spatial resolution compared with lower field clinical scanners, the benefits of UHF MR imaging are particularly evident for imaging small anatomic structures, such as the cerebral perivascular spaces (PVS). In this article, the authors describe the application of UHF MR imaging for the investigation of PVS.
View details for DOI 10.1016/j.mric.2020.09.005
View details for PubMedID 33237016
View details for PubMedCentralID PMC7694884
Evaluation of Cerebral Blood Flow Measured by 3D PCASL as Biomarker of Vascular Cognitive Impairment and Dementia (VCID) in a Cohort of Elderly Latinx Subjects at Risk of Small Vessel Disease.
Frontiers in neuroscience
2021; 15: 627627
Cerebral small vessel disease (cSVD) affects arterioles, capillaries, and venules and can lead to cognitive impairments and clinical symptomatology of vascular cognitive impairment and dementia (VCID). VCID symptoms are similar to Alzheimer's disease (AD) but the neurophysiologic alterations are less well studied, resulting in no established biomarkers. The purpose of this study was to evaluate cerebral blood flow (CBF) measured by 3D pseudo-continuous arterial spin labeling (pCASL) as a potential biomarker of VCID in a cohort of elderly Latinx subjects at risk of cSVD. Forty-five elderly Latinx subjects (12 males, 69 ± 7 years) underwent repeated MRI scans ∼6 weeks apart. CBF was measured using 3D pCASL in the whole brain, white matter and 4 main vascular territories (leptomeningeal anterior, middle, and posterior cerebral artery (leptoACA, leptoMCA, leptoPCA), as well as MCA perforator). The test-retest repeatability of CBF was assessed by intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Absolute and relative CBF was correlated with gross cognitive measures and domain specific assessment of executive and memory function, vascular risks, and Fazekas scores and volumes of white matter hyperintensity (WMH). Neurocognitive evaluations were performed using Montreal Cognitive Assessment (MoCA) and neuropsychological test battery in the Uniform Data Set v3 (UDS3). Good to excellent test-retest repeatability was achieved (ICC = 0.77-0.85, wsCV 3-9%) for CBF measurements in the whole brain, white matter, and 4 vascular territories. Relative CBF normalized by global mean CBF in the leptoMCA territory was positively correlated with the executive function composite score, while relative CBF in the leptoMCA and MCA perforator territory was positively correlated with MoCA scores, controlling for age, gender, years of education, and testing language. Relative CBF in WM was negatively correlated with WMH volume and MoCA scores, while relative leptoMCA CBF was positively correlated with WMH volume. Reliable 3D pCASL CBF measurements were achieved in the cohort of elderly Latinx subjects. Relative CBF in the leptomeningeal and perforator MCA territories were the most likely candidate biomarker of VCID. These findings need to be replicated in larger cohorts with greater variability of stages of cSVD.
View details for DOI 10.3389/fnins.2021.627627
View details for PubMedID 33584191
View details for PubMedCentralID PMC7873482
Effects of ambient particulate matter on vascular tissue: a review.
Journal of toxicology and environmental health. Part B, Critical reviews
2020; 23 (7): 319-350
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.
View details for DOI 10.1080/10937404.2020.1822971
View details for PubMedID 32972334
View details for PubMedCentralID PMC7758078
Nonparenchymal fluid is the source of increased mean diffusivity in preclinical Alzheimer's disease.
Alzheimer's & dementia (Amsterdam, Netherlands)
2019; 11: 348-354
Although increased mean diffusivity of the white matter has been repeatedly linked to Alzheimer's disease pathology, the underlying mechanism is not known.Here, we used ADNI-3 multishell diffusion magnetic resonance imaging data to separate the diffusion signal of the parenchyma from less hindered fluid pools within the white matter such as perivascular space fluid and fluid-filled cavities.We found that the source of the pathological increase of the mean diffusivity is the increased nonparenchymal fluid, often found in lacunes and perivascular spaces. In this cohort, the cognitive decline was significantly associated with the fluid increase and not with the microstructural changes of the white matter parenchyma itself. The white matter fluid increase was dominantly observed in the sagittal stratum and anterior thalamic radiation.These findings are positive steps toward understanding the pathophysiology of white matter alteration and its role in the cognitive decline.
View details for DOI 10.1016/j.dadm.2019.03.002
View details for PubMedID 31049392
View details for PubMedCentralID PMC6479267
Image processing approaches to enhance perivascular space visibility and quantification using MRI.
2019; 9 (1): 12351
Imaging the perivascular spaces (PVS), also known as Virchow-Robin space, has significant clinical value, but there remains a need for neuroimaging techniques to improve mapping and quantification of the PVS. Current technique for PVS evaluation is a scoring system based on visual reading of visible PVS in regions of interest, and often limited to large caliber PVS. Enhancing the visibility of the PVS could support medical diagnosis and enable novel neuroscientific investigations. Increasing the MRI resolution is one approach to enhance the visibility of PVS but is limited by acquisition time and physical constraints. Alternatively, image processing approaches can be utilized to improve the contrast ratio between PVS and surrounding tissue. Here we combine T1- and T2-weighted images to enhance PVS contrast, intensifying the visibility of PVS. The Enhanced PVS Contrast (EPC) was achieved by combining T1- and T2-weighted images that were adaptively filtered to remove non-structured high-frequency spatial noise. EPC was evaluated on healthy young adults by presenting them to two expert readers and also through automated quantification. We found that EPC improves the conspicuity of the PVS and aid resolving a larger number of PVS. We also present a highly reliable automated PVS quantification approach, which was optimized using expert readings.
View details for DOI 10.1038/s41598-019-48910-x
View details for PubMedID 31451792
View details for PubMedCentralID PMC6710285
Perivascular space fluid contributes to diffusion tensor imaging changes in white matter.
2019; 197: 243-254
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.
View details for DOI 10.1016/j.neuroimage.2019.04.070
View details for PubMedID 31051291
View details for PubMedCentralID PMC6591070
Signal Hyperintensity on Unenhanced T1-Weighted Brain and Cervical Spinal Cord MR Images after Multiple Doses of Linear Gadolinium-Based Contrast Agent.
AJNR. American journal of neuroradiology
2019; 40 (8): 1274-1281
The clinical implications of gadolinium deposition in the CNS are not fully understood, and it is still not known whether gadolinium tends to be retained more in the brain compared with the spinal cord. In this study, we assessed the effects of linear gadolinium-based contrast agents on the T1 signal intensity of 3 cerebral areas (dentate nucleus, globus pallidus, and the less studied substantia nigra) and the cervical spinal cord in a population of patients with MS.A single-center population of 100 patients with MS was analyzed. Patients underwent 2-16 contrast-enhanced MRIs. Fifty patients received ≤5 linear gadolinium injections, and 50 patients had ≥6 injections: Fifty-two patients had both Gd-DTPA and gadobenate dimeglumine injections, and 48 patients received only gadobenate dimeglumine. A quantitative analysis of signal intensity changes was independently performed by 2 readers on the first and last MR imaging scan. The globus pallidus-to-thalamus, substantia nigra-to-midbrain, dentate nucleus-to-middle cerebellar peduncle, and the cervical spinal cord-to-pons signal intensity ratios were calculated.An increase of globus pallidus-to-thalamus (mean, +0.0251 ± 0.0432; P < .001), dentate nucleus-to-middle cerebellar peduncle (mean, +0.0266 ± 0.0841; P = .002), and substantia nigra-to-midbrain (mean, +0.0262 ± 0.0673; P < .001) signal intensity ratios after multiple administrations of linear gadolinium-based contrast agents was observed. These changes were significantly higher in patients who received ≥6 injections (P < .001) and positively correlated with the number of injections and the accumulated dose of contrast. No significant changes were detected in the spinal cord (mean, +0.0008 ± 0.0089; P = .400).Patients with MS receiving ≥6 linear gadolinium-based contrast agent injections showed a significant increase in the signal intensity of the globus pallidus, dentate nucleus, and substantia nigra; no detectable changes were observed in the cervical spinal cord.
View details for DOI 10.3174/ajnr.A6148
View details for PubMedID 31345942
View details for PubMedCentralID PMC7048477
Assessing test-retest reliability of phase contrast MRI for measuring cerebrospinal fluid and cerebral blood flow dynamics.
Magnetic resonance in medicine
2019; 82 (2): 658-670
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.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.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).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.
View details for DOI 10.1002/mrm.27752
View details for PubMedID 31020721
View details for PubMedCentralID PMC6510617
A MACHINE LEARNING MODEL TO PREDICT SEIZURE SUSCEPTIBILITY FROM RESTING-STATE FMRI CONNECTIVITY.
Spring simulation conference (SpringSim)
Traumatic brain injury (TBI) is a leading cause of disability globally. Many patients develop post-traumatic epilepsy, or recurrent seizures following TBI. In recent years, significant efforts have been made to identify biomarkers of epileptogenesis that may assist in preventing seizure occurrence by identifying high-risk patients. We present a novel method of assessing seizure susceptibility using data from 49 patients enrolled in the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx). We employ a machine learning paradigm that utilizes a Random Forest classifier trained with resting-state functional magnetic resonance imaging (fMRI) data to predict seizure outcomes. Following 100 rounds of stratified cross-validation with 70% of resting state fMRI scans as the training set and 30% as the testing set, our model was found to assess seizure outcome in the testing set with 69% accuracy. To validate the method, we compared our results with classification by Support Vector Machines and Neural Network classifiers.
View details for DOI 10.23919/springsim.2019.8732859
View details for PubMedID 36541915
View details for PubMedCentralID PMC9760283
7-Tesla MRI of the brain in a research subject with bilateral, total knee replacement implants: Case report and proposed safety guidelines.
Magnetic resonance imaging
2019; 57: 313-316
Recently, the first 7-T MR system was approved for clinical use in the United States. Unfortunately, relatively few metallic implants have undergone testing to determine if they are acceptable or pose hazards to research subjects and patients at this ultra-high-field strength. Therefore, in lieu of not performing a research or clinical MRI exam at 7-T, the supervising physician may make a decision to scan the individual with an untested metallic implant based on an analysis of the risks vs. the benefits. We present a case report of a research subject with bilateral, total knee replacement implants that safely underwent MRI of the brain at 7-T and provide guidelines for healthcare professionals to follow in order to ensure safety in research subjects or patients with metallic implants referred for 7-T scans.
View details for DOI 10.1016/j.mri.2018.11.016
View details for PubMedID 30496792
View details for PubMedCentralID PMC9154312
Clinical 7 T MRI: Are we there yet? A review about magnetic resonance imaging at ultra-high field.
The British journal of radiology
2019; 92 (1094): 20180492
In recent years, ultra-high field MRI (7 T and above) has received more interest for clinical imaging. Indeed, a number of studies have shown the benefits from the application of this powerful tool not only for research purposes, but also in realms of improved diagnostics and patient management. The increased signal-to-noise ratio and higher spatial resolution compared with conventional and high-field clinical scanners allow imaging of small anatomical detail and subtle pathological findings. Furthermore, greater spectral resolution achieved at ultra-high field allows the resolution of metabolites for MR spectroscopic imaging. All these advantages have a significant impact on many neurological diseases, including multiple sclerosis, cerebrovascular disease, brain tumors, epilepsy and neurodegenerative diseases, in part because the pathology can be subtle and lesions small in these diseases, therefore having higher signal and resolution will help lesion detection. In this review, we discuss the main clinical neurological applications and some technical challenges which remain with ultra-high field MRI.
View details for DOI 10.1259/bjr.20180492
View details for PubMedID 30359093
View details for PubMedCentralID PMC6404849
Analytic Tools for Post-traumatic Epileptogenesis Biomarker Search in Multimodal Dataset of an Animal Model and Human Patients.
Frontiers in neuroinformatics
2018; 12: 86
Epilepsy is among the most common serious disabling disorders of the brain, and the global burden of epilepsy exerts a tremendous cost to society. Most people with epilepsy have acquired forms of the disorder, and the development of antiepileptogenic interventions could potentially prevent or cure epilepsy in many of them. However, the discovery of potential antiepileptogenic treatments and clinical validation would require a means to identify populations of patients at very high risk for epilepsy after a potential epileptogenic insult, to know when to treat and to document prevention or cure. A fundamental challenge in discovering biomarkers of epileptogenesis is that this process is likely multifactorial and crosses multiple modalities. Investigators must have access to a large number of high quality, well-curated data points and study subjects for biomarker signals to be detectable above the noise inherent in complex phenomena, such as epileptogenesis, traumatic brain injury (TBI), and conditions of data collection. Additionally, data generating and collecting sites are spread worldwide among different laboratories, clinical sites, heterogeneous data types, formats, and across multi-center preclinical trials. Before the data can even be analyzed, these data must be standardized. The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is a multi-center project with the overarching goal that epileptogenesis after TBI can be prevented with specific treatments. The identification of relevant biomarkers and performance of rigorous preclinical trials will permit the future design and performance of economically feasible full-scale clinical trials of antiepileptogenic therapies. We have been analyzing human data collected from UCLA and rat data collected from the University of Eastern Finland, both centers collecting data for EpiBioS4Rx, to identify biomarkers of epileptogenesis. Big data techniques and rigorous analysis are brought to longitudinal data collected from humans and an animal model of TBI, epilepsy, and their interaction. The prolonged continuous data streams of intracranial, cortical surface, and scalp EEG from humans and an animal model of epilepsy span months. By applying our innovative mathematical tools via supervised and unsupervised learning methods, we are able to subject a robust dataset to recently pioneered data analysis tools and visualize multivariable interactions with novel graphical methods.
View details for DOI 10.3389/fninf.2018.00086
View details for PubMedID 30618695
View details for PubMedCentralID PMC6307529
Complications of Radiotherapy and Radiosurgery in the Brain and Spine.
2018; 8 (3): 167-187
Radiation therapy is an integral part of the standard of care for many patients with brain and spine tumors. Stereotactic radiation surgery is increasingly being used as an adjuvant therapy as well as a sole treatment. However, despite newer and more focused techniques, radiation therapy still causes significant neurotoxicity. In this article, we reviewed the scientific literature, presented cases of patients who had developed different complications related to conventional radiation therapy or radiosurgery (gamma knife), demonstrated the imaging findings, and discussed the relevant clinical information for the correct diagnoses. Radiation therapy can cause injury in different ways: directly damaging the structures included in the radiation portal, indirectly affecting the blood vessels, and increasing the chance of tumor development. We also divided radiation complications according to the time of occurrence: acute (0 to 4 weeks), early delayed (4 weeks to months), and late delayed (months to years). With the increasing application of radiation therapy for the treatment of CNS tumors, it is important for the neuroradiologist to recognize the many possible complications of radiation therapy. Although this may cause significant diagnostic challenges, understanding the pathophysiology, time course of onset, and imaging features may help institute early therapy and prevent possible deleterious outcomes.To recognize the main complications of radiation therapy and stereotactic radiosurgery in the brain and spine, and to highlight the imaging findings to improve the diagnostic process and treatment planning.
View details for DOI 10.3174/ng.1700066
View details for PubMedID 35388375
View details for PubMedCentralID PMC8981962