Giuseppe Barisano, MD, PhD

All Publications

• A "multi-omics" analysis of blood-brain barrier and synaptic dysfunction in APOE4 mice. The Journal of experimental medicine Barisano, G., Kisler, K., Wilkinson, B., Nikolakopoulou, A. M., Sagare, A. P., Wang, Y., Gilliam, W., Huuskonen, M. T., Hung, S. T., Ichida, J. K., Gao, F., Coba, M. P., Zlokovic, B. V. 2022; 219 (11)

  Abstract

  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. NeuroImage Barisano, G., Lynch, K. M., Sibilia, F., Lan, H., Shih, N. C., Sepehrband, F., Choupan, J. 2022; 257: 119329

  Abstract

  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 Barisano, G., Sepehrband, F., Collins, H. R., Jillings, S., Jeurissen, B., Taylor, J. A., Schoenmaekers, C., De Laet, C., Rukavishnikov, I., Nosikova, I., Litvinova, L., Rumshiskaya, A., Annen, J., Sijbers, J., Laureys, S., Van Ombergen, A., Petrovichev, V., Sinitsyn, V., Pechenkova, E., Grishin, A., Zu Eulenburg, P., Law, M., Sunaert, S., Parizel, P. M., Tomilovskaya, E., Roberts, D. R., Wuyts, F. L. 2022; 119 (17): e2120439119

  Abstract

  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 Barisano, G., Sheikh-Bahaei, N., Law, M., Toga, A. W., Sepehrband, F. 2021; 41 (7): 1563-1578

  Abstract

  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. Nature Montagne, A., Nation, D. A., Sagare, A. P., Barisano, G., Sweeney, M. D., Chakhoyan, A., Pachicano, M., Joe, E., Nelson, A. R., D'Orazio, L. M., Buennagel, D. P., Harrington, M. G., Benzinger, T. L., Fagan, A. M., Ringman, J. M., Schneider, L. S., Morris, J. C., Reiman, E. M., Caselli, R. J., Chui, H. C., Tcw, J., Chen, Y., Pa, J., Conti, P. S., Law, M., Toga, A. W., Zlokovic, B. V. 2020; 581 (7806): 71-76

  Abstract

  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

• White matter hyperintensities modify relationships between corticospinal tract damage and motor outcomes after stroke. medRxiv : the preprint server for health sciences Ferris, J. K., Lo, B. P., Barisano, G., Brodtmann, A., Buetefisch, C. M., Conforto, A. B., Donnelly, M. H., Egorova-Brumley, N., Hayward, K. S., Khlif, M. S., Revill, K. P., Zavaliangos-Petropulu, A., Boyd, L. A., Liew, S. 2023

  Abstract

  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 (beta = 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 (beta = 0.888, p < 0.001) with a CST-LL x WMH interaction (beta = -0.211, 0.026). In individuals with moderate-severe WMHs, motor impairment related to WMH volume (beta = 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.

  View details for DOI 10.1101/2023.10.29.23297734

  View details for PubMedID 37961329

• Editorial: Vascular and perivascular contributions to neurodegeneration. Frontiers in neuroscience Barisano, G., Bos, D., Ma, Y. 2023; 17: 1290102

  View details for DOI 10.3389/fnins.2023.1290102

  View details for PubMedID 37841677

  View details for PubMedCentralID PMC10570795

• Effects of sleep on brain perivascular space in a cognitively healthy population. Sleep medicine Shih, N. C., Barisano, G., Lincoln, K. D., Mack, W. J., Sepehrband, F., Choupan, J. 2023; 111: 170-179

  Abstract

  The magnetic resonance imaging (MRI) visible perivascular space (PVS) reportedly clears amyloid-β 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.

  View details for DOI 10.1016/j.sleep.2023.09.024

  View details for PubMedID 37782994

• Functional MRI and Diffusion Tensor Imaging in Migraine: A Review of Migraine Functional and White Matter Microstructural Changes JOURNAL OF CENTRAL NERVOUS SYSTEM DISEASE Chou, B. C., Lerner, A., Barisano, G., Phung, D., Xu, W., Pinto, S. N., Sheikh-Bahaei, N. 2023; 15: 11795735231205413

  Abstract

  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.

  View details for DOI 10.1177/11795735231205413

  View details for Web of Science ID 001087736700001

  View details for PubMedID 37900908

  View details for PubMedCentralID PMC10612465

• Longitudinal Changes in Cerebral Perfusion, Perivascular Space Volume, and Ventricular Volume in a Healthy Cohort Undergoing a Spaceflight Analog. AJNR. American journal of neuroradiology Tidwell, J. B., Taylor, J. A., Collins, H. R., Chamberlin, J. H., Barisano, G., Sepehrband, F., Turner, M. D., Gauthier, G., Mulder, E. R., Gerlach, D. A., Roberts, D. R. 2023

  Abstract

  BACKGROUND AND PURPOSE: A global decrease in brain perfusion has recently been reported during exposure to a ground-based spaceflight analog. Considering that CSF and glymphatic flow are hypothesized to be propelled by arterial pulsations, it is unknown whether a change in perfusion would impact these CSF compartments. The aim of the current study was to evaluate the relationship among changes in cerebral perfusion, ventricular volume, and perivascular space volume before, during, and after a spaceflight analog.MATERIALS AND METHODS: Eleven healthy participants underwent 30 days of bed rest at 6° head-down tilt with 0.5% atmospheric CO2 as a spaceflight analog. For each participant, 6 MR imaging brain scans, including perfusion and anatomic-weighted T1 sequences, were obtained before, during, and after the analog period. Global perfusion, ventricular volume, and perivascular space volume time courses were constructed and evaluated with repeated measures ANOVAs.RESULTS: Global perfusion followed a divergent time trajectory from ventricular and perivascular space volume, with perfusion decreasing during the analog, whereas ventricular and perivascular space volume increased (P<.001). These patterns subsequently reversed during the 2-week recovery period.CONCLUSIONS: The patterns of change in brain physiology observed in healthy participants suggest a relationship between cerebral perfusion and CSF homeostasis. Further study is warranted to determine whether a causal relationship exists and whether similar neurophysiologic responses occur during spaceflight.

  View details for DOI 10.3174/ajnr.A7949

  View details for PubMedID 37562828

• Cross-Vendor Test-Retest Validation of Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS) for Evaluating Glymphatic System Function. Aging and disease Liu, X., Barisano, G., Shao, X., Jann, K., Ringman, J. M., Lu, H., Arfanakis, K., Caprihan, A., DeCarli, C., Gold, B. T., Maillard, P., Satizabal, C. L., Fadaee, E., Habes, M., Stables, L., Singh, H., Fischl, B., Kouwe, A. v., Schwab, K., Helmer, K. G., Greenberg, S. M., Wang, D. J. 2023

  Abstract

  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.

  View details for DOI 10.14336/AD.2023.0321-2

  View details for PubMedID 37307817

• Structural MRI in Migraine: A Review of Migraine Vascular and Structural Changes in Brain Parenchyma. Journal of central nervous system disease Xu, W. J., Barisano, G., Phung, D., Chou, B., Pinto, S. N., Lerner, A., Sheikh-Bahaei, N. 2023; 15: 11795735231167868

  Abstract

  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.

  View details for DOI 10.1177/11795735231167868

  View details for PubMedID 37077432

  View details for PubMedCentralID PMC10108417

• Association of Brain Age, Lesion Volume, and Functional Outcome in Patients With Stroke. Neurology Liew, S. L., Schweighofer, N., Cole, J. H., Zavaliangos-Petropulu, A., Lo, B. P., Han, L. K., Hahn, T., Schmaal, L., Donnelly, M. R., Jeong, J. N., Wang, Z., Abdullah, A., Kim, J. H., Hutton, A. M., Barisano, G., Borich, M. R., Boyd, L. A., Brodtmann, A., Buetefisch, C. M., Byblow, W. D., Cassidy, J. M., Charalambous, C. C., Ciullo, V., Conforto, A. B., Dacosta-Aguayo, R., DiCarlo, J. A., Domin, M., Dula, A. N., Egorova-Brumley, N., Feng, W., Geranmayeh, F., Gregory, C. M., Hanlon, C. A., Hayward, K., Holguin, J. A., Hordacre, B., Jahanshad, N., Kautz, S. A., Khlif, M. S., Kim, H., Kuceyeski, A., Lin, D. J., Liu, J., Lotze, M., MacIntosh, B. J., Margetis, J. L., Mataro, M., Mohamed, F. B., Olafson, E. R., Park, G., Piras, F., Revill, K. P., Roberts, P., Robertson, A. D., Sanossian, N., Schambra, H. M., Seo, N. J., Soekadar, S. R., Spalletta, G., Stinear, C. M., Taga, M., Tang, W. K., Thielman, G. T., Vecchio, D., Ward, N. S., Westlye, L. T., Winstein, C. J., Wittenberg, G. F., Wolf, S. L., Wong, K. A., Yu, C., Cramer, S. C., Thompson, P. M. 2023

  Abstract

  Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. Here, we examined the impact of brain age, a measure of neurobiological aging derived from whole brain structural neuroimaging, on post-stroke outcomes, with a focus on sensorimotor performance. We hypothesized that more lesion damage would result in older brain age, which would in turn be associated with poorer outcomes. Related, we expected that brain age would mediate the relationship between lesion damage and outcomes. Finally, we hypothesized that structural brain resilience, which we define in the context of stroke as younger brain age given matched lesion damage, would differentiate people with good versus poor outcomes.We conducted a cross-sectional observational study using a multi-site dataset of 3D brain structural MRIs and clinical measures from ENIGMA Stroke Recovery. Brain age was calculated from 77 neuroanatomical features using a ridge regression model trained and validated on 4,314 healthy controls. We performed a three-step mediation analysis with robust mixed-effects linear regression models to examine relationships between brain age, lesion damage, and stroke outcomes. We used propensity score matching and logistic regression to examine whether brain resilience predicts good versus poor outcomes in patients with matched lesion damage.We examined 963 patients across 38 cohorts. Greater lesion damage was associated with older brain age (β=0.21; 95% CI 0.04,0.38, P=0.015), which in turn was associated with poorer outcomes, both in the sensorimotor domain (β=-0.28; 95% CI: -0.41,-0.15, P<0.001) and across multiple domains of function (β=-0.14; 95% CI: -0.22,-0.06, P<0.001). Brain age mediated 15% of the impact of lesion damage on sensorimotor performance (95% CI: 3%,58%, P=0.01). Greater brain resilience explained why people have better outcomes, given matched lesion damage (OR=1.04, 95% CI: 1.01,1.08, P=0.004).We provide evidence that younger brain age is associated with superior post-stroke outcomes and modifies the impact of focal damage. The inclusion of imaging-based assessments of brain age and brain resilience may improve the prediction of post-stroke outcomes compared to focal injury measures alone, opening new possibilities for potential therapeutic targets.

  View details for DOI 10.1212/WNL.0000000000207219

  View details for PubMedID 37015818

• Manual lesion segmentations for traumatic brain injury characterization. Frontiers in neuroimaging Bennett, A., Garner, R., Morris, M. D., La Rocca, M., Barisano, G., Cua, R., Loon, J., Alba, C., Carbone, P., Gao, S., Pantoja, A., Khan, A., Nouaili, N., Vespa, P., Toga, A. W., Duncan, D. 2023; 2: 1068591

  Abstract

  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.

  View details for DOI 10.3389/fnimg.2023.1068591

  View details for PubMedID 37554636

  View details for PubMedCentralID PMC10406209

• Decreased functional connectivity is associated with increased levels of Cerebral Spinal Fluid soluble-PDGFRβ, a marker of blood brain barrier breakdown, in older adults. Research square Contreras, J. A., Fujisaki, K., Ortega, N., Barisano, G., Sagare, A., Pappas, I., Chui, H., Ringman, J. M., Joe, E. B., Zlokovic, B., Toga, A. W., Pa, J. 2023

  Abstract

  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-β (CSF sPDGFRβ, a marker of BBB breakdown) but have not demonstrated if this vascular impairment affects neuronal dysfunction. It's possible that increased levels of sPDGFRβ 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 sPDGFRβ 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 sPDGFRβ 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 sPDGFRβ affects neural networks resulting in decreased functional connections that leads to cognitive dysfunction.

  View details for DOI 10.21203/rs.3.rs-2644974/v1

  View details for PubMedID 36945439

  View details for PubMedCentralID PMC10029080

• Functional connectivity alterations in traumatic brain injury patients with late seizures. Neurobiology of disease La Rocca, M., Barisano, G., Garner, R., Ruf, S. F., Amoroso, N., Monti, M., Vespa, P., Bellotti, R., Erdoğmuş, D., Toga, A. W., Duncan, D. 2023: 106053

  Abstract

  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 Pinto, S. N., Lerner, A., Phung, D., Barisano, G., Chou, B., Xu, W., Sheikh-Bahaei, N. 2023; 15

  View details for DOI 10.1177/11795735231160032

  View details for Web of Science ID 000941168900001

• Brain perivascular spaces and autism: clinical and pathogenic implications from an innovative volumetric MRI study. Frontiers in neuroscience Sotgiu, M. A., Lo Jacono, A., Barisano, G., Saderi, L., Cavassa, V., Montella, A., Crivelli, P., Carta, A., Sotgiu, S. 2023; 17: 1205489

  Abstract

  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.

  View details for DOI 10.3389/fnins.2023.1205489

  View details for PubMedID 37425010

• Neuroimaging aspects and clinical significance of giant perivascular spaces in the brain. Precision cancer medicine Barisano, G. 2022; 5

  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 Barisano, G., Tomilovskaya, E., Roberts, D. R., Wuyts, F. L. 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. Scientific data Liew, S. L., Lo, B. P., Donnelly, M. R., Zavaliangos-Petropulu, A., Jeong, J. N., Barisano, G., Hutton, A., Simon, J. P., Juliano, J. M., Suri, A., Wang, Z., Abdullah, A., Kim, J., Ard, T., Banaj, N., Borich, M. R., Boyd, L. A., Brodtmann, A., Buetefisch, C. M., Cao, L., Cassidy, J. M., Ciullo, V., Conforto, A. B., Cramer, S. C., Dacosta-Aguayo, R., de la Rosa, E., Domin, M., Dula, A. N., Feng, W., Franco, A. R., Geranmayeh, F., Gramfort, A., Gregory, C. M., Hanlon, C. A., Hordacre, B. G., Kautz, S. A., Khlif, M. S., Kim, H., Kirschke, J. S., Liu, J., Lotze, M., MacIntosh, B. J., Mataró, M., Mohamed, F. B., Nordvik, J. E., Park, G., Pienta, A., Piras, F., Redman, S. M., Revill, K. P., Reyes, M., Robertson, A. D., Seo, N. J., Soekadar, S. R., Spalletta, G., Sweet, A., Telenczuk, M., Thielman, G., Westlye, L. T., Winstein, C. J., Wittenberg, G. F., Wong, K. A., Yu, C. 2022; 9 (1): 320

  Abstract

  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 Zavaliangos-Petropulu, A., Lo, B., Donnelly, M. R., Schweighofer, N., Lohse, K., Jahanshad, N., Barisano, G., Banaj, N., Borich, M. R., Boyd, L. A., Buetefisch, C. M., Byblow, W. D., Cassidy, J. M., Charalambous, C. C., Conforto, A. B., DiCarlo, J. A., Dula, A. N., Egorova-Brumley, N., Etherton, M. R., Feng, W., Fercho, K. A., Geranmayeh, F., Hanlon, C. A., Hayward, K. S., Hordacre, B., Kautz, S. A., Khlif, M. S., Kim, H., Kuceyeski, A., Lin, D. J., Liu, J., Lotze, M., MacIntosh, B. J., Margetis, J. L., Mohamed, F. B., Piras, F., Ramos-Murguialday, A., Revill, K. P., Roberts, P. S., Robertson, A. D., Schambra, H. M., Seo, N. J., Shiroishi, M. S., Stinear, C. M., Soekadar, S. R., Spalletta, G., Taga, M., Tang, W. K., Thielman, G. T., Vecchio, D., Ward, N. S., Westlye, L. T., Werden, E., Winstein, C., Wittenberg, G. F., Wolf, S. L., Wong, K. A., Yu, C., Brodtmann, A., Cramer, S. C., Thompson, P. M., Liew, S. L. 2022; 11 (10): e025109

  Abstract

  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 Gatz, M., Mack, W. J., Chui, H. C., Law, E. M., Barisano, G., Sutherland, M. L., Sutherland, J. D., Eid Rodriguez, D., Quispe Gutierrez, R., Copajira Adrian, J., Bani Cuata, J., Borenstein, A. R., Walters, E. E., Irimia, A., Rowan, C. J., Wann, L. S., Allam, A. H., Thompson, R. C., Miyamoto, M. I., Michalik, D. E., Cummings, D. K., Seabright, E., Garcia, A. R., Hooper, P. L., Kraft, T. S., Finch, C. E., Thomas, G. S., Stieglitz, J., Trumble, B. C., Gurven, M. D., Kaplan, H. 2022

  Abstract

  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 Barisano, G., Montagne, A., Kisler, K., Schneider, J. A., Wardlaw, J. M., Zlokovic, B. V. 2022; 1 (2): 108-115

  Abstract

  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

• A standardized protocol for manually segmenting stroke lesions on high-resolution T1-weighted MR images. Frontiers in neuroimaging Lo, B. P., Donnelly, M. R., Barisano, G., Liew, S. L. 2022; 1: 1098604

  Abstract

  Although automated methods for stroke lesion segmentation exist, many researchers still rely on manual segmentation as the gold standard. Our detailed, standardized protocol for stroke lesion tracing on high-resolution 3D T1-weighted (T1w) magnetic resonance imaging (MRI) has been used to trace over 1,300 stroke MRI. In the current study, we describe the protocol, including a step-by-step method utilized for training multiple individuals to trace lesions ("tracers") in a consistent manner and suggestions for distinguishing between lesioned and non-lesioned areas in stroke brains. Inter-rater and intra-rater reliability were calculated across six tracers trained using our protocol, resulting in an average intraclass correlation of 0.98 and 0.99, respectively, as well as a Dice similarity coefficient of 0.727 and 0.839, respectively. This protocol provides a standardized guideline for researchers performing manual lesion segmentation in stroke T1-weighted MRI, with detailed methods to promote reproducibility in stroke research.

  View details for DOI 10.3389/fnimg.2022.1098604

  View details for PubMedID 37555152

  View details for PubMedCentralID PMC10406195

• 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 La Rocca, M., Barisano, G., Bennett, A., Garner, R., Engel, J., Gilmore, E. J., McArthur, D. L., Rosenthal, E., Stanis, J., Vespa, P., Willyerd, F., Zimmermann, L. L., Toga, A. W., Duncan, D. 2021; 15 (6): 2804-2812

  Abstract

  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 Huuskonen, M. T., Barisano, G., Chakhoyan, A., Zlokovic, B. V. 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 Strickland, B. A., Barisano, G., Abedi, A., Shiroishi, M. S., Cen, S., Emanuel, B., Bulic, S., Kim-Tenser, M., Nguyen, P., Giannotta, S. L., Mack, W., Russin, J. 2021: 1-9

  Abstract

  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. Brain communications Liew, S. L., Zavaliangos-Petropulu, A., Schweighofer, N., Jahanshad, N., Lang, C. E., Lohse, K. R., Banaj, N., Barisano, G., Baugh, L. A., Bhattacharya, A. K., Bigjahan, B., Borich, M. R., Boyd, L. A., Brodtmann, A., Buetefisch, C. M., Byblow, W. D., Cassidy, J. M., Charalambous, C. C., Ciullo, V., Conforto, A. B., Craddock, R. C., Dula, A. N., Egorova, N., Feng, W., Fercho, K. A., Gregory, C. M., Hanlon, C. A., Hayward, K. S., Holguin, J. A., Hordacre, B., Hwang, D. H., Kautz, S. A., Khlif, M. S., Kim, B., Kim, H., Kuceyeski, A., Lo, B., Liu, J., Lin, D., Lotze, M., MacIntosh, B. J., Margetis, J. L., Mohamed, F. B., Nordvik, J. E., Petoe, M. A., Piras, F., Raju, S., Ramos-Murguialday, A., Revill, K. P., Roberts, P., Robertson, A. D., Schambra, H. M., Seo, N. J., Shiroishi, M. S., Soekadar, S. R., Spalletta, G., Stinear, C. M., Suri, A., Tang, W. K., Thielman, G. T., Thijs, V. N., Vecchio, D., Ward, N. S., Westlye, L. T., Winstein, C. J., Wittenberg, G. F., Wong, K. A., Yu, C., Wolf, S. L., Cramer, S. C., Thompson, P. M. 2021; 3 (4): fcab254

  Abstract

  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

• Lesion Normalization and Supervised Learning in Post-traumatic Seizure Classification with Diffusion MRI. Computational diffusion MRI : MICCAI Workshop Akbar, M. N., Ruf, S., La Rocca, M., Garner, R., Barisano, G., Cua, R., Vespa, P., Erdoğmuş, D., Duncan, D. 2021; 13006: 133-143

  Abstract

  Traumatic brain injury (TBI) is a serious condition, potentially causing seizures and other lifelong disabilities. Patients who experience at least one seizure one week after TBI (late seizure) are at high risk for lifelong complications of TBI, such as post-traumatic epilepsy (PTE). Identifying which TBI patients are at risk of developing seizures remains a challenge. Although magnetic resonance imaging (MRI) methods that probe structural and functional alterations after TBI are promising for biomarker detection, physical deformations following moderate-severe TBI present problems for standard processing of neuroimaging data, complicating the search for biomarkers. In this work, we consider a prediction task to identify which TBI patients will develop late seizures, using fractional anisotropy (FA) features from white matter tracts in diffusion-weighted MRI (dMRI). To understand how best to account for brain lesions and deformations, four preprocessing strategies are applied to dMRI, including the novel application of a lesion normalization technique to dMRI. The pipeline involving the lesion normalization technique provides the best prediction performance, with a mean accuracy of 0.819 and a mean area under the curve of 0.785. Finally, following statistical analyses of selected features, we recommend the dMRI alterations of a certain white matter tract as a potential biomarker.

  View details for DOI 10.1007/978-3-030-87615-9_12

  View details for PubMedID 37489155

  View details for PubMedCentralID PMC10365258

• Volumetric distribution of perivascular space in relation to mild cognitive impairment. Neurobiology of aging Sepehrband, F., Barisano, G., Sheikh-Bahaei, N., Choupan, J., Cabeen, R. P., Lynch, K. M., Crawford, M. S., Lan, H., Mack, W. J., Chui, H. C., Ringman, J. M., Toga, A. W. 2021; 99: 28-43

  Abstract

  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 Barisano, G., Law, M., Custer, R. M., Toga, A. W., Sepehrband, F. 2021; 29 (1): 67-75

  Abstract

  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 Jann, K., Shao, X., Ma, S. J., Cen, S. Y., D'Orazio, L., Barisano, G., Yan, L., Casey, M., Lamas, J., Staffaroni, A. M., Kramer, J. H., Ringman, J. M., Wang, D. J. 2021; 15: 627627

  Abstract

  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 Shkirkova, K., Lamorie-Foote, K., Connor, M., Patel, A., Barisano, G., Baertsch, H., Liu, Q., Morgan, T. E., Sioutas, C., Mack, W. J. 2020; 23 (7): 319-350

  Abstract

  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) Sepehrband, F., Cabeen, R. P., Barisano, G., Sheikh-Bahaei, N., Choupan, J., Law, M., Toga, A. W. 2019; 11: 348-354

  Abstract

  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. Scientific reports Sepehrband, F., Barisano, G., Sheikh-Bahaei, N., Cabeen, R. P., Choupan, J., Law, M., Toga, A. W. 2019; 9 (1): 12351

  Abstract

  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. NeuroImage Sepehrband, F., Cabeen, R. P., Choupan, J., Barisano, G., Law, M., Toga, A. W. 2019; 197: 243-254

  Abstract

  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

• Assessing test-retest reliability of phase contrast MRI for measuring cerebrospinal fluid and cerebral blood flow dynamics. Magnetic resonance in medicine Sakhare, A. R., Barisano, G., Pa, J. 2019; 82 (2): 658-670

  Abstract

  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

• 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 Barisano, G., Bigjahan, B., Metting, S., Cen, S., Amezcua, L., Lerner, A., Toga, A. W., Law, M. 2019; 40 (8): 1274-1281

  Abstract

  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

• A MACHINE LEARNING MODEL TO PREDICT SEIZURE SUSCEPTIBILITY FROM RESTING-STATE FMRI CONNECTIVITY. Spring simulation conference (SpringSim) Garner, R., La Rocca, M., Barisano, G., Toga, A. W., Duncan, D., Vespa, P. 2019; 2019

  Abstract

  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 Barisano, G., Culo, B., Shellock, F. G., Sepehrband, F., Martin, K., Stevens, M., Wang, D. J., Toga, A. W., Law, M. 2019; 57: 313-316

  Abstract

  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 Barisano, G., Sepehrband, F., Ma, S., Jann, K., Cabeen, R., Wang, D. J., Toga, A. W., Law, M. 2019; 92 (1094): 20180492

  Abstract

  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 Duncan, D., Barisano, G., Cabeen, R., Sepehrband, F., Garner, R., Braimah, A., Vespa, P., Pitkänen, A., Law, M., Toga, A. W. 2018; 12: 86

  Abstract

  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. Neurographics (2011) Barisano, G., Bergamaschi, S., Acharya, J., Rajamohan, A., Gibbs, W., Kim, P., Zada, G., Chang, E., Law, M. 2018; 8 (3): 167-187

  Abstract

  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