Yoshiki Hase

Selective white matter abnormalities in a novel rat model of vascular dementia.

Rats subjected to bilateral common carotid artery (CCA) occlusion or 2-vessel occlusion (2VO) have been used as animal models of subcortical ischemic vascular dementia. However, this model possesses an inherent limitation in that cerebral blood flow (CBF) drops too sharply and substantially after ligation of CCAs. To circumvent such hypoxic-ischemic conditions, we tested implantation of the ameroid constrictor device on bilateral CCAs of male Wistar-Kyoto rats and more precisely replicated chronic cerebral hypoperfusion by gradual narrowing of the CCAs (2-vessel gradual occlusion; 2VGO). The acute cerebral blood flow reduction and resultant inflammatory responses observed in the 2VO rats were eliminated in the 2VGO rats. Thus, chronic cerebral hypoperfusion was segregated, and induced selective white matter changes with relatively preserved neurovascular coupling and substantially less metabolic and histological derangements in the gray matter including the hippocampus. This led to significant spatial working memory impairment of a magnitude similar to the 2VO rats at 28 days postoperation. The 2VGO model may more closely mimic cognitive impairment subsequent to selective white matter damage.

The Influence of Chronic Cerebral Hypoperfusion on Cognitive Function and Amyloid β Metabolism in APP Overexpressing Mice

Background and Purpose Cognitive impairment resulting from cerebrovascular insufficiency has been termed vascular cognitive impairment, and is generally accepted to be distinct from Alzheimers disease resulting from a neurodegenerative process. However, it is clear that this simple dichotomy may need revision in light of the apparent occurrence of several shared features between Alzheimers disease and vascular cognitive impairment. Nevertheless, it still remains largely unknown whether the burden of vascular- and Alzheimer-type neuropathology are independent or interdependent. Therefore, we investigated whether chronic cerebral hypoperfusion influences cognitive ability or amyloid β deposition in amyloid precursor protein (APP) overexpressing transgenic mice. Methods Two months old mice overexpressing a mutant form of the human APP bearing both the Swedish and Indiana mutations (APPSw/Ind-Tg mice), or their wild-type littermates, were subjected to chronic cerebral hypoperfusion with bilateral common carotid artery stenosis (BCAS) using microcoils or sham operation. Barnes maze test performance and histopathological findings were analyzed at eight months old by 2×2 factorial experimental designs with four groups. Results BCAS-operated APPSw/Ind-Tg mice showed significantly impaired learning ability compared to the other three groups of mice. Two-way repeated measures analysis of variance showed a synergistic interaction between the APP genotype and BCAS operation in inducing learning impairment. The cognitive performances were significantly correlated with the neuronal densities. BCAS significantly reduced the density of Nissl-stained neurons and silver-stained cored plaques in the hippocampus of APPSw/Ind-Tg mice but increased the amount of filter-trap amyloid β in the extracellular-enriched soluble brain fraction, compared to those from sham operated mice. Conclusions The results suggest interaction between chronic cerebral hypoperfusion and APPSw/Ind overexpression in cognitive decline in mice through enhanced neuronal loss and altered amyloid β metabolism.

Cilostazol, a phosphodiesterase inhibitor, prevents no-reflow and hemorrhage in mice with focal cerebral ischemia.

BACKGROUND AND PURPOSE The Cilostazol Stroke Prevention Study II has shown a similar efficacy in stroke prevention but markedly fewer hemorrhagic events with the phosphodiesterase inhibitor cilostazol versus aspirin. The purpose of this study is therefore to investigate how cilostazol affects cerebral hemodynamics and whether it prevents hemorrhagic transformation induced by recombinant tissue plasminogen activator (rtPA) in a mouse model of focal ischemia/reperfusion. Particular emphasis will be placed on the plasma-microvessel interface. METHODS After receiving food containing 0.3% cilostazol or standard food for 7 days, adult C57BL/6J mice were subjected to middle cerebral artery occlusion/reperfusion with or without rtPA (10mg/kg) intravenously administered prior to reperfusion. Cerebral blood flow was monitored at several time points by laser speckle imaging in the 24 hour period post reperfusion, before neurobehavioral and histological assessment. The long-term effect of cilostazol on cerebral ischemia was analyzed in the non-rtPA cohort. RESULTS In the non-rtPA cohort, pretreatment by cilostazol significantly decreased the endothelial expression of adhesion molecules (P-selectin and intercellular adhesion molecule-1) and prevented platelet aggregation and leukocyte plugging in the microvessels after cerebral ischemia/reperfusion in the acute phase. Cilostazol significantly reduced mortality rate and improved motor function at 7 days post-ischemia/reperfusion. In the rtPA cohort, cilostazol significantly suppressed edema formation and hemorrhagic transformation with reduced density of microglial cells positive for matrix metalloproteinase-9 in the cerebral cortex and the striatum. In both cohorts, cilostazol significantly suppressed focal no-reflow, mitigated cerebral infarct, and improved neurological outcome. CONCLUSIONS Cilostazol may possess protective properties against cerebral ischemic injury by preventing no-reflow and hemorrhagic transformation, via maintenance of microvascular integrity.

Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia

White matter hyperintensities are associated with post-stroke cognitive dysfunction, but the underlying mechanisms are unclear. Chen et al. provide evidence from human and experimental studies that clasmatodendrosis – a marker of irreversible astrocyte damage – and gliovascular abnormalities are increased in the frontal white matter of subjects who succumb to vascular dementia.

Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid

Brain amyloidosis is a key feature of Alzheimers disease (AD). It also incorporates cerebrovascular amyloid β (Aβ) in the form of cerebral amyloid angiopathy (CAA) involving neurovascular dysfunction. We have recently shown by retrospective analysis that patients with mild cognitive impairment receiving a vasoactive drug cilostazol, a selective inhibitor of phosphodiesterase (PDE) III, exhibit significantly reduced cognitive decline. Here, we tested whether cilostazol protects against the disruption of the neurovascular unit and facilitates the arterial pulsation‐driven perivascular drainage of Aβ in AD/CAA.

Association of physical activity with the visuospatial/executive functions of the montreal cognitive assessment in patients with vascular cognitive impairment.

BACKGROUND The Montreal Cognitive Assessment (MoCA) is more suitable than the Mini-Mental State Examination (MMSE) for the detection of vascular cognitive impairment. In this study, we performed a correlation analysis of MoCA/MMSE scores with daily physical activity in patients with subcortical ischemic white matter changes. METHODS Ten patients (average 75.9 ± 9.1 years old) with extensive leukoaraiosis detected on magnetic resonance imaging underwent cognitive testing, including the MMSE and the Japanese version of the MoCA (MoCA-J). Physical activity was monitored with the Kenz Lifecorder EX device (Suzuken, Nagoya, Japan) to assess daily physical activity in terms of caloric expenditure, motor activity, number of steps, and walking distance for 6 months. Correlations of individual physical activity with total and subscale scores of MMSE/MoCA-J or 6-month interval change of MoCA-J scores were assessed. RESULTS The total or subscale scores of the MMSE did not correlate with any parameters of physical activity. However, the mean number of steps and walking distance significantly correlated with the total MoCA-J scores (r = .67 and .64, respectively) and its visuospatial/executive subscores (r = .66 and .66, respectively). The mean interval change of MoCA-J was + .6; those who improved number of steps (n = 4; 80.5 ± 3.0 years of age) had significantly preserved MoCA-J scores compared to those who did not (n = 6; 73.0 ± 11.6 years of age; +2.0 versus - .3; P = .016). CONCLUSIONS These results suggest that MoCA is useful to detect a biologically determined specific relationship between physical activity and executive function. In addition, physical exercise, such as walking, may help enhance cognitive function in patients with vascular cognitive impairment of subcortical origin.

Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia

Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimers disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.

A novel mutation in the SPG3A gene (atlastin) in hereditary spastic paraplegia.

Sirs: Hereditary spastic paraplegia (HSP) is a neurodegenerative disease characterized by progressive spasticity in the lower extremities. An SPG3A mutation was recently identified in a patient with the pure form of autosomal dominant HSP [1]. The SPG3A gene encodes atlastin, which shows homology to guanylate binding protein-1 [1]. Herein, We identified a novel missense mutation in SPG3A in a Japanese family with autosomal dominant spastic paraplegia. To our knowledge, this is the first report of a mutation in SPG3A in Japanese patients, which indicates that SPG3A-hereditary spastic paraplegia exists in various ethnic populations, including those in Asia. The patient (Fig. 2A III:1) was a 29-year-old female. Her gait disturbance was originally identified at the age of 3 years. A wheelchair was necessary when she was a graduate student. The family history indicated an autosomaldominant inheritance pattern. A neurological examination showed weakness in the lower extremities and neck flexors. The patellar and achilles tendon reflexes were hyperactive. Bilateral Babinski signs were positive. WAIS-R were normal. Laboratory tests were unremarkable. A cranial MRI examination revealed a tumor-like nodule in the left lateral ventricle. There was no atrophy in the corpus callosum. Her father (Fig. 2A II:2) also showed gait disturbance since he was a childhood. Neurological examination revealed spasticity of the lower extremities. Her grandfather (Fig. 2A I:1) also had showed gait disturbance. After receiving informed consent, genomic DNA was isolated from whole blood using QIAGEN DNA extraction kits. Linkage analyses were performed at 6 autosomal dominant-HSP loci, SPG3A, SPG4, SPG6, SPG10, SPG12, and SPG13, using flanking microsatellite markers described previously [2]. Sequence analyses Fig. 1 Sequence analysis. The panels show the fluorescent chromatograms of the normal SPG3A exon 12 sequence compared to the mutant exon 12 detected in the patient, as well as the corresponding amino acid sequence

The effects of environmental enrichment on white matter pathology in a mouse model of chronic cerebral hypoperfusion

White matter (WM) disintegration is common in the older population and is associated with vascular cognitive impairment (VCI). This study explored the effects of environmental enrichment (EE) on pathological sequelae in a mouse model of chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS). Male C57BL/6 J mice underwent BCAS or sham surgery. One-week after surgery, mice were exposed to three different degrees of EE; either standard housing conditions (std), limited 3 h exposure to EE per day (3 h) or full-time exposure to EE (full) for 12 weeks. At 13 weeks after surgery, cognitive testing was performed using a three-dimensional 9-arm radial maze. At 16 weeks after surgery, nesting ability was assessed in each mouse immediately before euthanasia. Brains retrieved after perfusion fixation were examined for WM pathology. BCAS caused WM changes, as demonstrated by corpus callosum atrophy and greater WM disintegrity. BCAS also caused impaired nesting ability and cognitive function. These pathological changes and working memory deficits were attenuated, more so by limited rather than full-time exposure to EE regime. Our results suggest that limited exposure to EE delays the onset of WM degeneration. Therefore, the implementation of even limited EE may be beneficial for patients diagnosed with VCI.

In Vivo Imaging of Brain Ischemia Using an Oxygen-Dependent Degradative Fusion Protein Probe

Within the ischemic penumbra, blood flow is sufficiently reduced that it results in hypoxia severe enough to arrest physiological function. Nevertheless, it has been shown that cells present within this region can be rescued and resuscitated by restoring perfusion and through other protective therapies. Thus, the early detection of the ischemic penumbra can be exploited to improve outcomes after focal ischemia. Hypoxia-inducible factor (HIF)-1 is a transcription factor induced by a reduction in molecular oxygen levels. Although the role of HIF-1 in the ischemic penumbra remains unknown, there is a strong correlation between areas with HIF-1 activity and the ischemic penumbra. We recently developed a near-infrared fluorescently labeled-fusion protein, POH-N, with an oxygen-dependent degradation property identical to the alpha subunit of HIF-1. Here, we conduct in vivo imaging of HIF-active regions using POH-N in ischemic brains after transient focal cerebral ischemia induced using the intraluminal middle cerebral artery occlusion technique in mice. The results demonstrate that POH-N enables the in vivo monitoring and ex vivo detection of HIF-1-active regions after ischemic brain injury and suggest its potential in imaging and drug delivery to HIF-1-active areas in ischemic brains.