Dataset Information

Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia.

ABSTRACT:

Background and purpose

We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS (Medical Research Council Cognitive Function and Ageing Study).

Methods

Using digital pathology, we quantified blood-brain barrier dysfunction (defined by immunohistochemical labeling for the plasma marker fibrinogen). This was assessed within subcortical white matter tissue samples harvested from postmortem T₂ magnetic resonance imaging (MRI)-detected white matter hyperintensities, from normal-appearing white matter (distant from coexistent MRI-defined hyperintensities), and from equivalent areas in MRI normal brains. Histopathologic lesions were defined using a marker for phagocytic microglia (CD68, clone PGM1).

Results

Extent of fibrinogen labeling was not significantly associated with white matter abnormalities defined either by MRI (odds ratio, 0.90; 95% confidence interval, 0.79-1.03; P=0.130) or by histopathology (odds ratio, 0.93; 95% confidence interval, 0.77-1.12; P=0.452). Among participants with normal MRI (no detectable white matter hyperintensities), increased fibrinogen was significantly related to decreased risk of clinical dementia (odds ratio, 0.74; 95% confidence interval, 0.58-0.94; P=0.013). Among participants with histological lesions, increased fibrinogen was related to increased risk of dementia (odds ratio, 2.26; 95% confidence interval, 1.25-4.08; P=0.007).

Conclusions

Our data suggest that some degree of blood-brain barrier dysfunction is common in older people and that this may be related to clinical dementia risk, additional to standard MRI biomarkers.

SUBMITTER: Hainsworth AH

PROVIDER: S-EPMC5986073 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia.

Hainsworth Atticus H AH Minett Thais T Andoh Joycelyn J Forster Gillian G Bhide Ishaan I Barrick Thomas R TR Elderfield Kay K Jeevahan Jamuna J Markus Hugh S HS Bridges Leslie R LR

Stroke 20170830 10

<h4>Background and purpose</h4>We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS (Medical Research Council Cognitive Function and Ageing Study).<h4>Methods</h4>Using digital pathology, we quantified blood-brain barrier dysfunction (defined by immunohistochemical labeling for the plasma marker fibrinogen). This was assessed wi ...[more]

PMID: 28855392

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Project description:BackgroundTraumatic brain injury (TBI) is a significant worldwide public health concern that necessitates attention. Apoptosis signal-regulating kinase 1 (ASK1), a key player in various central nervous system (CNS) diseases, has garnered interest for its potential neuroprotective effects against ischemic stroke and epilepsy when deleted. Nonetheless, the specific impact of ASK1 on TBI and its underlying mechanisms remain elusive. Notably, mutation of ATP-binding sites, such as lysine residues, can lead to catalytic inactivation of ASK1. To address these knowledge gaps, we generated transgenic mice harboring a site-specific mutant ASK1 Map3k5-e (K716R), enabling us to assess its effects and elucidate potential underlying mechanisms following TBI.MethodsWe employed the CRIPR/Cas9 system to generate a transgenic mouse model carrying the ASK1-K716R mutation, aming to investigate the functional implications of this specific mutant. The controlled cortical impact method was utilized to induce TBI. Expression and distribution of ASK1 were detected through Western blotting and immunofluorescence staining, respectively. The ASK1 kinase activity after TBI was detected by a specific ASK1 kinase activity kit. Cerebral microvessels were isolated by gradient centrifugation using dextran. Immunofluorescence staining was performed to evaluate blood-brain barrier (BBB) damage. BBB ultrastructure was visualized using transmission electron microscopy, while the expression levels of endothelial tight junction proteins and ASK1 signaling pathway proteins was detected by Western blotting. To investigate TBI-induced neuroinflammation, we conducted immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry analyses. Additionally, immunofluorescence staining and electrophysiological compound action potentials were conducted to evaluate gray and white matter injury. Finally, sensorimotor function and cognitive function were assessed by a battery of behavioral tests.ResultsThe activity of ASK1-K716R was significantly decreased following TBI. Western blotting confirmed that ASK1-K716R effectively inhibited the phosphorylation of ASK1, JNKs, and p38 in response to TBI. Additionally, ASK1-K716R demonstrated a protective function in maintaining BBB integrity by suppressing ASK1/JNKs activity in endothelial cells, thereby reducing the degradation of tight junction proteins following TBI. Besides, ASK1-K716R effectively suppressed the infiltration of peripheral immune cells into the brain parenchyma, decreased the number of proinflammatory-like microglia/macrophages, increased the number of anti-inflammatory-like microglia/macrophages, and downregulated expression of several proinflammatory factors. Furthermore, ASK1-K716R attenuated white matter injury and improved the nerve conduction function of both myelinated and unmyelinated fibers after TBI. Finally, our findings demonstrated that ASK1-K716R exhibited favorable long-term functional and histological outcomes in the aftermath of TBI.ConclusionASK1-K716R preserves BBB integrity by inhibiting ASK1/JNKs pathway in endothelial cells, consequently reducing the degradation of tight junction proteins. Additionally, it alleviates early neuroinflammation by inhibiting the infiltration of peripheral immune cells into the brain parenchyma and modulating the polarization of microglia/macrophages. These beneficial effects of ASK1-K716R subsequently result in a reduction in white matter injury and promote the long-term recovery of neurological function following TBI.

Dataset Information

Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia.

Background and purpose

Methods

Results

Conclusions

Publications

Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia.

Similar Datasets

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