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Early brain injury alters the blood-brain barrier phenotype in parallel with ?-amyloid and cognitive changes in adulthood.

ABSTRACT: Clinical studies suggest that traumatic brain injury (TBI) hastens cognitive decline and development of neuropathology resembling brain aging. Blood-brain barrier (BBB) disruption following TBI may contribute to the aging process by deregulating substance exchange between the brain and blood. We evaluated the effect of juvenile TBI (jTBI) on these processes by examining long-term alterations of BBB proteins, ?-amyloid (A?) neuropathology, and cognitive changes. A controlled cortical impact was delivered to the parietal cortex of male rats at postnatal day 17, with behavioral studies and brain tissue evaluation at 60 days post-injury (dpi). Immunoglobulin G extravasation was unchanged, and jTBI animals had higher levels of tight-junction protein claudin 5 versus shams, suggesting the absence of BBB disruption. However, decreased P-glycoprotein (P-gp) on cortical blood vessels indicates modifications of BBB properties. In parallel, we observed higher levels of endogenous rodent A? in several brain regions of the jTBI group versus shams. In addition at 60?dpi, jTBI animals displayed systematic search strategies rather than relying on spatial memory during the water maze. Together, these alterations to the BBB phenotype after jTBI may contribute to the accumulation of toxic products, which in turn may induce cognitive differences and ultimately accelerate brain aging.

SUBMITTER: Pop V

PROVIDER: S-EPMC3564189 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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Early brain injury alters the blood-brain barrier phenotype in parallel with β-amyloid and cognitive changes in adulthood.

Pop Viorela V Sorensen Dane W DW Kamper Joel E JE Ajao David O DO Murphy M Paul MP Head Elizabeth E Hartman Richard E RE Badaut Jérôme J

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20121114 2

Clinical studies suggest that traumatic brain injury (TBI) hastens cognitive decline and development of neuropathology resembling brain aging. Blood-brain barrier (BBB) disruption following TBI may contribute to the aging process by deregulating substance exchange between the brain and blood. We evaluated the effect of juvenile TBI (jTBI) on these processes by examining long-term alterations of BBB proteins, β-amyloid (Aβ) neuropathology, and cognitive changes. A controlled cortical impact was d ...[more]

PMID: 23149553

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Project description:The meninges serve as a functional barrier surrounding the brain, critical to the immune response, and can be compromised following head trauma. Meningeal enhancement can be detected on contrast-enhanced MRI in patients presenting with acute traumatic brain injury, even when head CT is negative. Following head trauma, gadolinium-based contrast appears to extravasate from the vasculature, enhancing the dura within minutes, and later permeates the subarachnoid space. The aims of this study were to characterize the initial kinetics of the uptake of contrast agent after injury and the delayed redistribution of contrast enhancement in the subarachnoid space in hyperacute patients. Neuroimaging was obtained prospectively in two large ongoing observational studies of patients aged 18 years or older presenting to the emergency department with suspected acute head injury. Dynamic contrast-enhanced MRI studies in a cohort of consecutively enrolling patients with mild traumatic brain injury (n = 36) determined that the kinetic half-life of dural-related meningeal enhancement was 1.3 ± 0.6 min (95% enhancement within 6 min). The extravasation of contrast into the subarachnoid space was investigated in a cohort of CT negative mild traumatic brain injury patients initially imaged within 6 h of injury (hyperacute) who subsequently underwent a delayed MRI, with no additional contrast administration, several hours after the initial MRI. Of the 32 patients with delayed post-contrast imaging, 18 (56%) had conspicuous expansion of the contrast enhancement into the subarachnoid space, predominantly along the falx and superior sagittal sinus. Patients negative for traumatic meningeal enhancement on initial hyperacute MRI continued to have no evidence of meningeal enhancement on the delayed MRI. These studies demonstrate that (i) the initial enhancement of the traumatically injured meninges occurs within minutes of contrast injection, suggesting highly permeable meningeal vasculature, and that (ii) contrast in the meninges redistributes within the subarachnoid space over the period of hours, suggesting a compromise in the blood-brain and/or blood-cerebrospinal barriers. Data from the parent study indicate that up to one in two patients with mild traumatic brain injury have traumatic brain injury on acute (<48 h) MRI, with a higher prevalence seen in patients with moderate or severe traumatic brain injury. The current study's findings of traumatic meningeal enhancement and the subsequent delayed extravasation of contrast into the subarachnoid spaces indicate that a substantial percentage of patients with even mild traumatic brain injury may have a transient disruption in barriers separating the vasculature from the brain.

Project description:Disruption of the blood-brain barrier has been proposed to be important in vascular cognitive impairment. Increased cerebrospinal fluid albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the blood-brain barrier permeability in patients with vascular cognitive impairment is lacking. Therefore, we acquired dynamic contrast-enhanced MRI to quantify blood-brain barrier permeability in vascular cognitive impairment. Method- We studied 60 patients with suspected vascular cognitive impairment. They had neurological and neuropsychological testing, permeability measurements with dynamic contrast-enhanced MRI, and lumbar puncture to measure albumin index. Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts, and leukoaraiosis. Twenty volunteers were controls for the dynamic contrast-enhanced MRI studies, and control cerebrospinal fluid was obtained from 20 individuals undergoing spinal anesthesia for nonneurological problems.Thirty-six patients were classified as SIVD, 8 as multiple and lacunar infarcts, and 9 as leukoaraiosis. The albumin index was significantly increased in the SIVD group compared with 20 control subjects. Permeabilities for the patients with vascular cognitive impairment measured by dynamic contrast-enhanced MRI were significantly increased over control subjects (P<0.05). Patient age did not correlate with either the blood-brain barrier permeability or albumin index. Highest albumin index values were seen in the SIVD group (P<0.05) and were significantly increased over multiple and lacunar infarcts. K(i) values were elevated over control subjects in SIVD but were similar to multiple and lacunar infarcts.There was abnormal permeability in white matter in patients with SIVD as shown by dynamic contrast-enhanced MRI and albumin index. Future studies will be needed to determine the relationship of blood-brain barrier damage and development of white matter hyperintensities.

Project description:Background and Purpose- Cerebral amyloid angiopathy (CAA) is a common small vessel disease that independently effects cognition in older individuals. The pathophysiology of CAA and CAA-related bleeding remains poorly understood. In this postmortem study, we explored whether blood-brain barrier leakage is associated with CAA and microvascular lesions. Methods- Eleven CAA cases (median [IQR] age=69 years [65-79 years], 8 males) and 7 cases without neurological disease or brain lesions (median [IQR] age=77 years [68-92 years], 4 males) were analyzed. Cortical sections were sampled from each lobe, and IgG and fibrin extravasation (markers of blood-brain barrier leakage) were assessed with immunohistochemistry. We hypothesized that IgG and fibrin extravasation would be increased in CAA cases compared with controls, that this would be more pronounced in parietooccipital brain regions compared with frontotemporal brain regions in parallel with the posterior predilection of CAA, and would be associated with CAA severity and number of cerebral microbleeds and cerebral microinfarcts counted on ex vivo magnetic resonance imaging of the intact brain hemisphere. Results- Our results demonstrated increased IgG positivity in the frontotemporal ( P=0.044) and parietooccipital ( P=0.001) cortex in CAA cases compared with controls. Within CAA cases, both fibrin and IgG positivity were increased in parietooccipital brain regions compared with frontotemporal brain regions ( P=0.005 and P=0.006, respectively). The percentage of positive vessels for fibrin and IgG was associated with the percentage of amyloid-β-positive vessels (Spearman ρ=0.71, P=0.015 and Spearman ρ=0.73, P=0.011, respectively). Moreover, the percentage of fibrin and IgG-positive vessels, but not amyloid-β-positive vessels, was associated with the number of cerebral microbleeds on magnetic resonance imaging (Spearman ρ=0.77, P=0.005 and Spearman ρ=0.70, P=0.017, respectively). Finally, we observed fibrin deposition in walls of vessels involved in cerebral microbleeds. Conclusions- Our results raise the possibility that blood-brain barrier leakage may be a contributory mechanism for CAA-related brain injury.

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Early brain injury alters the blood-brain barrier phenotype in parallel with ?-amyloid and cognitive changes in adulthood.

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Early brain injury alters the blood-brain barrier phenotype in parallel with β-amyloid and cognitive changes in adulthood.

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