Hypoxia-Induced Neuroinflammatory White-Matter Injury Reduced by Minocycline in SHR/SP

350

284

The prevalence of dementia is increasing in our aging population at an alarming rate. Because of the heterogeneity of clinical presentation and complexity of disease neuropathology, dementia classifications remain controversial. Recently, the National Plan to address Alzheimer's Disease prioritized Alzheimer's disease-related dementias to include: Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and mixed dementias. While each of these dementing conditions has their unique pathologic signature, one common etiology shared among all these conditions is cerebrovascular dysfunction at some point during the disease process. The goal of this comprehensive review is to summarize the current findings in the field and address the important contributions of cerebrovascular, physiologic, and cellular alterations to cognitive impairment in these human dementias. Specifically, evidence will be presented in support of small-vessel disease as an underlying neuropathologic hallmark of various dementias, while controversial findings will also be highlighted. Finally, the molecular mechanisms shared among all dementia types including hypoxia, oxidative stress, mitochondrial bioenergetics, neuroinflammation, neurodegeneration, and bloodbrain barrier permeability responsible for disease etiology and progression will be discussed.

Section: Mechanisms Of Hypoperfusion-induced Neuroinflammation Insupporting

confidence: 72%

The neuropathology and cerebrovascular mechanisms of dementia

Raz

Knoefel

Bhaskar

2015

350

284

“…134 In the SHR/SP with the Japanese permissive diet and unilateral carotid artery occlusion, treatment with minocycline blocked the full development of white-matter injuries seen on MRI and improved behavior in the Morris water maze. 135 Based on mouse models of CADASIL, targeting the synthesis of NOTCH3 or the clearance of NOTCH3ECD deposits, might represent a first therapeutic option. 136 Upregulation of Kv1 channels in cerebral arteries has been shown to be the molecular mechanism underlying the diminished myogenic responses in mutant mice.…”

Section: Treatments In Animal Modelsmentioning

confidence: 99%

Consensus statement for diagnosis of subcortical small vessel disease

Rosenberg

Wallin

Wardlaw

et al. 2015

Self Cite

181

132

Vascular cognitive impairment (VCI) is the diagnostic term used to describe a heterogeneous group of sporadic and hereditary diseases of the large and small blood vessels. Subcortical small vessel disease (SVD) leads to lacunar infarcts and progressive damage to the white matter. Patients with progressive damage to the white matter, referred to as Binswanger's disease (BD), constitute a spectrum from pure vascular disease to a mixture with neurodegenerative changes. Binswanger's disease patients are a relatively homogeneous subgroup with hypoxic hypoperfusion, lacunar infarcts, and inflammation that act synergistically to disrupt the blood-brain barrier (BBB) and break down myelin. Identification of this subgroup can be facilitated by multimodal disease markers obtained from clinical, cerebrospinal fluid, neuropsychological, and imaging studies. This consensus statement identifies a potential set of biomarkers based on underlying pathologic changes that could facilitate diagnosis and aid patient selection for future collaborative treatment trials.

“…We compared the FA/ADC values of our ARE model with those from a chronic white matter injury model (UCAO-JPD animals) as a representative of irreversible vasogenic edema. 18,26 The UCAO-JPD model has previously been shown to produce irreversible IgG leakage and demyelination in the corpus callosum (CC). 18,26 As expected, we saw a large increase of the ADC in the UCAO-JPD animals, suggesting the presence of vasogenic edema (Figure 2(e)).…”

Section: Brains Of Are Model Showed a Reversible Increase Of Famentioning

confidence: 99%

“…18,26 The UCAO-JPD model has previously been shown to produce irreversible IgG leakage and demyelination in the corpus callosum (CC). 18,26 As expected, we saw a large increase of the ADC in the UCAO-JPD animals, suggesting the presence of vasogenic edema (Figure 2(e)). On the contrary, the FA decreased in UCAO-JPD animals (Figure 2(c)).…”

Section: Brains Of Are Model Showed a Reversible Increase Of Famentioning

confidence: 99%

Transient increase of fractional anisotropy in reversible vasogenic edema

Kimura-Ohba

Yang

Thompson

et al. 2016

Self Cite

Brain vasogenic edema, involving disruption of the blood-brain barrier, is a common pathological condition in several neurological diseases, with a heterogeneous prognosis. It is sometimes reversible, as in posterior reversible encephalopathy syndrome, but often irreversible and our current clinical tools are insufficient to reveal its reversibility. Here, we show that increased fractional anisotropy in magnetic resonance imaging is associated with the reversibility of vasogenic edema. Spontaneously, hypertensive rats-stroke prone demonstrated posterior reversible encephalopathy syndrome-like acute encephalopathy in response to high-dose cyclosporine A treatment; the deteriorating neurological symptoms and worsening scores in behavioral tests, which were seen in acute phase, dissappered after recovery by cessation of cyclosporine A. In the acute phase of encephalopathy, the fractional anisotropy and apparent diffusion coefficient increased in areas with IgG leakage. This increase of fractional anisotropy occurred in the absence of demyelination: fluid leakage into the myelinated space increased the axial, but not the radial, diffusivity, resulting in the increased fractional anisotropy. This increased fractional anisotropy returned to pre-encephalopathy values in the recovery phase. Our results highlight the importance of the fractional anisotropy increase as a marker for the reversibility of brain edema, which can delineate the brain areas for which recovery is possible. KeywordsBlood-brain barrier, brain vasogenic edema, diffusion tensor imaging, fractional anisotropy, posterior reversible encephalopathy syndrome