Istradefylline Improves Impaired Smooth Pursuit Eye Movements in Parkinson's Disease.

INTRODUCTION: Patients with Parkinson's disease (PD) exhibit alterations in eye movement control, primarily diverse oculomotor deficits which include hypometric saccade and impaired smooth pursuit with reduced pursuit-gain necessitating catch-up saccades. The effects of dopaminergic treatment of PD on eye movements are controversial. Previous studies suggest that smooth pursuit eye movements (SPEMs) are not directly influenced by the dopaminergic system. The nondopaminergic drug istradefylline, a selective adenosine A2A receptor antagonist, reduces the OFF time and improves somatomotor function in levodopa-treated PD. Here, we investigated whether istradefylline improves SPEMs in PD, and determined whether oculomotor performance is associated with somatomotor performance. METHODS: Using an infrared video eye tracking system, we quantified horizontal SPEMs in six patients with PD before and 4-8 weeks after initiation of istradefylline administration. A further five patients with PD were tested before and after a 4-week interval without istradefylline to control for practice effects. We evaluated smooth pursuit gain (eye velocity/target velocity), accuracy of smooth pursuit velocity, and saccade rate during pursuit before and after istradefylline administration during the ON state. RESULTS: Patients received istradefylline by single daily oral administration at 20 to 40 mg. Eye tracking data were obtained 4-8 weeks after initiation of istradefylline administration. Istradefylline increased smooth pursuit gain and the accuracy of smooth pursuit velocity, and tended to decrease saccade rates during pursuit. CONCLUSIONS: Istradefylline ameliorated the oculomotor deficit in SPEM of patients with PD, although differences in somatomotor performance before and after istradefylline treatment were not significant during ON periods. The discrepancy observed between the oculomotor and somatomotor responses to istradefylline supports previous findings that SPEM is at least partially under nondopaminergic control.

Paradoxical contralateral hemiparesis in spontaneous spinal epidural hematoma: a case report.

BACKGROUND: Hemiparesis associated with spontaneous spinal epidural hematoma (SSEH) usually occurs ipsilateral to the hematoma. We here report the case of a patient with paradoxical hemiparesis contralateral to a spinal lesion due to SSEH. CASE PRESENTATION: A 70-year-old woman was identified in routine clinical practice; she presented with acute-onset neck pain and left hemiparesis. Neurological examination showed left-sided sensory-motor hemiparesis without facial involvement. Cervical MRI showed a dorsolateral epidural hematoma compressing the spinal cord at the C2 to C3 level. Axial imaging demonstrated a crescent hematoma on the right side, which is contralateral to the hemiparesis, and lateral displacement of the spinal cord. Spinal angiography revealed no abnormal vessels. Based on clinical presentation and MRI findings, a diagnosis of SSEH was made. The patient was managed conservatively. The symptoms completely resolved without any neurological deficits, and the hematoma disappeared on the follow-up MRI. CONCLUSIONS: Paradoxical contralateral hemiparesis is one of the possible presenting symptoms in patients with SSEH. This case demonstrates the existence of the paradoxical contralateral hemiparesis associated with spinal compressive lesions. A plausible mechanism of the phenomenon is discussed.

Effectiveness of a self-reporting yes/no survey for dementia screening-trial in Fukui, Japan.

Background: Early intervention for dementia patients is extremely important for the prevention of dementia. However, so far, it is not clear as to what kind of screening will be useful for the early detection of dementia. Objective: We aimed to investigate the relationship between the results of a short self-reporting yes/no survey selected in Kihon Checklist, developed by the Japanese Ministry of Health, Labor and Welfare to identify older adults who are at risk of requiring support/care, and other original items developed by Dementia Prevention Team, Fukui, Japan, and Mini-Mental State Examination (MMSE) scores, and determine the diagnostic efficacy of the self-reporting yes/no survey. Methods: Self-reporting yes/no surveys were conducted for 87,687 individuals aged ≥65 years, living in Fukui, Japan, and did not have Long-Term Care Insurance, Japan. According to the survey results, selected individuals were advised to visit a local hospital to be assessed with MMSE. Results: Individuals who could not make a call by looking up phone numbers and manage their own deposits and savings at the bank or automatic teller machine (ATM) had an increased risk of low MMSE score (≤23; odds ratio: 2.74 [1.89-3.97]; 95% confidence interval: 2.12 [1.46-3.07]). Conclusions: Self-reporting yes/no survey could effectively screen for dementia. Not being able to make a call by looking up phone numbers and not being able to manage their own deposits and savings at the bank or ATM are signs of dementia.

Rho-kinase ROCK inhibitors reduce oligomeric tau protein.

Neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, consist of highly phosphorylated tau proteins. Tau protein binds to microtubules and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3ß or cyclin-dependent kinase 5, or inactivated tau phosphatase, including protein phosphatase 2A, its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming neurofibrillary tangles. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The reduction of tau was considered to be due to Rho-associated coiled-coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clinically applied to prevent vasospasm postsubarachnoid hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examined the effects of ROCK inhibitors (H1152, Y-27632, and fasudil [HA-1077]) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. After ROCK inhibitor treatment, glycogen synthase kinase 3ß, cyclin-dependent kinase 5, and caspase were inactivated, protein phosphatase 2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including Alzheimer's disease.

Increased adiponectin is associated with cerebral white matter lesions in the elderly with cognitive impairment.

Adiponectin is an adipocyte-derived peptide that increases with age and is thought to protect against atherosclerotic vascular changes and organ damage. However, paradoxically, higher adiponectin levels are associated with increased risk for cardiovascular events and mortality. We investigated whether this adiponectin paradox occurs in elderly people with cognitive impairment. Fifty-two elderly participants with mild cognitive impairment or dementia (20 male and 32 female, aged 60-93 years, mean 80.0) were recruited. We evaluated serum adiponectin levels and cerebral white matter lesions (WML), which are involved in cognitive decline and dementia, by computed tomography. Body mass index (BMI), Mini-Mental State Examination score, history of hypertension (HT), chronic kidney disease, and diabetes mellitus were also assessed. Stepwise multiple regression analysis was used to reveal the relationships between serum adiponectin and age, sex, BMI, HT, diabetes mellitus, chronic kidney disease, Mini-Mental State Examination, and WML scores. High serum adiponectin levels correlated with more severe WML (P = 0.013). Low BMI (P < 0.001), female sex (P = 0.025), and high WML scores (P = 0.039) were significant determinants of high serum adiponectin. HT (P = 0.032) and high adiponectin levels (P = 0.021) were independent risk factors for WML. Overall, we observed an association between serum adiponectin levels and WML severity in elderly people with cognitive decline. Our findings reveal that the adiponectin paradox occurs in this population, and this study may help guide future treatments for elderly people with mild cognitive impairment or dementia.

Pincer nail deformity in a patient with amyotrophic lateral sclerosis.

Although several manifestations of skin involvement in cases of amyotrophic lateral sclerosis (ALS) have been reported, the pincer nail deformity has not been previously reported in a patient with ALS. The pincer nail deformity is characterized by distortion of the shape of the nail with transverse over curvature and may be associated with systemic diseases and certain medications. We herein describe the case of a patient presenting with a pincer nail deformity associated with rapidly advancing ALS. This case suggests a potential link between quickly advancing disease and the pincer nail deformity.

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.

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.

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.

Angiogenic roles of adrenomedullin through vascular endothelial growth factor induction.

Recently, we have reported that a vasoactive peptide adrenomedullin promotes angio/arteriogenesis and prevents cognitive decline after chronic cerebral hypoperfusion in mice. Adrenomedullin upregulated brain levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, although the regulation mechanism needs to be determined. In this study, we showed that VEGF neutralization partially suppressed adrenomedullin-induced neovascularization and cognitive restoration in vivo. In-vitro, adrenomedullin promoted capillary tube formation of the cultured endothelium, whereas VEGF neutralization abolished these effects. Adrenomedullin was found to upregulate VEGF and basic fibroblast growth factor through the adrenomedullin receptor and the phosphatidylinositol 3-kinase pathway. These results suggest that adrenomedullin has potential as therapy for dementia through enhancement of functional vascular growth.

Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice.

BACKGROUND AND PURPOSE: Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia. METHODS: A model of subcortical vascular dementia was reproduced in mice by placing microcoils bilaterally on the common carotid arteries. Using mice overexpressing circulating AM, we assessed the effect of AM on cerebral perfusion, cerebral angioarchitecture, oxidative stress, white matter change, cognitive function, and brain levels of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. RESULTS: After bilateral common carotid artery stenosis, mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice. Vascular changes were preceded by upregulation of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. White matter damage and working memory deficits induced by bilateral common carotid artery stenosis were subsequently restored in mice overexpressing circulating AM. CONCLUSIONS: These data indicate that AM promotes arteriogenesis and angiogenesis, inhibits oxidative stress, preserves white matter integrity, and prevents cognitive decline after chronic cerebral hypoperfusion. Thus, AM may serve as a strategy to tackle subcortical vascular dementia.

Early protective effect of bone marrow mononuclear cells against ischemic white matter damage through augmentation of cerebral blood flow.

BACKGROUND AND PURPOSE: To investigate the efficacy of bone marrow mononuclear cell (BMMNC) treatment against ischemic white matter (WM) damage in a hypoperfused brain. METHODS: Mice were administered intravenous treatment of vehicle, spleen-derived marrow mononuclear cells (MNCs), or BMMNCs (5 × 106 cells) obtained from enhanced green fluorescent protein transgenic mice 24 hours after bilateral common carotid artery stenosis (BCAS), and then euthanized at either 1 day or 30 days after treatment. RESULTS: Laser speckle perfusion imaging analyses revealed marked recovery of cerebral blood flow (CBF) in the early phase after BMMNC treatment (6 hours after administration), before histological evidence of angiogenesis was assessed by fluorescein-isothiocyanate-dextran perfusion assay. BMMNC treatment induced an increase in vascular endothelial growth factor and Ser1177 phosphorylated endothelial nitric oxide synthase levels in the BCAS-induced mouse brains at 1 day after the treatment. BCAS-induced ischemic WM lesions were significantly improved 30 days after BMMNC treatment despite any evidence of direct structural incorporation of donor BMMNCs into endothelial cells and oligodendrocytes. Instead, enhanced green fluorescent protein-positive donor cells with morphological features of pericytes were observed in the vessel walls. Post-BMMNC administration of an NOS inhibitor abolished early CBF recovery and produced protective effects against ischemic WM damage. CONCLUSIONS: BMMNC treatment provides marked protection against ischemic WM damage, enhancing CBF in the early phase and in subsequent angiogenesis, both of which involve nitric oxide synthase activation. These findings suggest promise for the application of BMMNCs for subcortical ischemic vascular dementia.

Nonhypotensive dose of telmisartan attenuates cognitive impairment partially due to peroxisome proliferator-activated receptor-gamma activation in mice with chronic cerebral hypoperfusion.

BACKGROUND AND PURPOSE: The effect of telmisartan, an angiotensin II Type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma-modulating activity, was investigated against spatial working memory disturbances in mice subjected to chronic cerebral hypoperfusion. METHODS: Adult C57BL/6J male mice were subjected to bilateral common carotid artery stenosis using external microcoils. Mice received a daily oral administration of low-dose telmisartan (1 mg/kg per day), high-dose telmisartan (10 mg/kg per day), or vehicle with or without peroxisome proliferator-activated receptor-gamma antagonist GW9662 (1 mg/kg per day) for all treatments for 30 days after bilateral common carotid artery stenosis. Cerebral mRNA expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha was measured 30 days after bilateral common carotid artery stenosis, and postmortem brains were analyzed for demyelinating change with Klüver-Barrera staining and immunostained for glial, oxidative stress, and vascular endothelial cell markers. Spatial working memory was assessed by the Y-maze test. RESULTS: Mean systolic blood pressure and cerebral blood flow did not decrease with low-dose telmisartan but significantly decreased with high-dose telmisartan. Low-dose telmisartan significantly attenuated, but high-dose telmisartan provoked, spatial working memory impairment with glial activation, oligodendrocyte loss, and demyelinating change in the white matter. Such positive effects of low-dose telmisartan were partially offset by cotreatment with GW9662. Consistent with this, low-dose telmisartan reduced the degree of oxidative stress of vascular endothelial cells and the mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha compared with vehicle. CONCLUSIONS: Anti-inflammatory and antioxidative effects of telmisartan that were exerted in part by peroxisome proliferator-activated receptor-gamma activation, but not its blood pressure-lowering effect, have protective roles against cognitive impairment and white matter damage after chronic cerebral hypoperfusion.

A mouse model characterizing features of vascular dementia with hippocampal atrophy.

BACKGROUND AND PURPOSE: We have previously described effects of chronic cerebral hypoperfusion in mice with bilateral common carotid artery stenosis (BCAS) using microcoils for 30 days. These mice specifically exhibit working memory deficits attributable to frontal-subcortical circuit damage without apparent gray matter changes, indicating similarities with subcortical ischemic vascular dementia. However, as subcortical ischemic vascular dementia progresses over time, the longer-term effects that characterize the mouse model are not known. METHODS: Comprehensive behavioral test batteries and histological examinations were performed in mice subjected to BCAS for up to 8 months. Laser speckle flowmetry and (18)F-fluorodeoxyglucose positron emission tomography were performed to assess cerebral blood flow and metabolism at several time points. RESULTS: At 2 hours after BCAS, cerebral blood flow in the cerebral cortex temporarily decreased to as much as 60% to 70% of the control value but gradually recovered to >80% at 1 to 3 months. At 5 to 6 months after BCAS, reference and working memory were impaired as demonstrated by the Barnes and radial arm maze tests, respectively. Furthermore, (18)F-fluorodeoxyglucose positron emission tomography demonstrated that hippocampal glucose utilization was impaired at 6 months after BCAS. Consistent with these behavioral and metabolic abnormalities, histological analyses demonstrated hippocampal atrophy with pyknotic and apoptotic cells at 8 months after BCAS. CONCLUSIONS: These results suggest that the longer-term BCAS model replicates advanced stages of subcortical ischemic vascular dementia when hippocampal neuronal loss becomes significant.

Mutations in LGI1 gene in Japanese families with autosomal dominant lateral temporal lobe epilepsy: the first report from Asian families.

Autosomal dominant lateral temporal lobe epilepsy (ADLTE) caused by LGI1 (leucine-rich gene, glioma-inactivated-1) mutations is a rare familial epileptic syndrome characterized by the auditory ictal manifestation and rare nocturnal generalized seizures. We have examined the sequence of the LGI1 gene in four Japanese families with lateral temporal lobe epilepsy having characteristic auditory features, and identified one novel (1421G>A), and one reported (1418C>T) point mutation each in two families. These two mutations were 3 bp apart in the LGI1 gene and caused adjoining amino acid substitutions. The two families presented different clinical phenotypes and seizure control to drug treatment. These findings suggest that LGI1 mutations in Japanese ADLTE families may not be uncommon, and that diverse clinical phenotypes make adequate diagnosis of ADLTE difficult when only based on clinical information.

Cortical microinfarcts in Alzheimer's disease and subcortical vascular dementia.

Cortical microinfarcts are reported in Alzheimer's disease, but not in subcortical vascular dementia; the disease specificity of cortical microinfarcts therefore remains unclear. The distribution of cortical microinfarcts in Alzheimer's disease (n = 8) and subcortical vascular dementia (n = 6) was analyzed. Cortical microinfarcts were frequently detected in Alzheimer's disease, whereas they were rarely observed in subcortical vascular dementia. In Alzheimer's disease, cortical microinfarcts were present predominantly in the occipital lobe, the area of predilection for amyloid angiopathy, and also in the vascular borderzone. Cortical microinfarcts were invariably located very close to amyloid beta-deposited vessels with intercellular adhesion molecule-1 expression. These results indicate that cortical microinfarcts are caused by the pathomechanism related to Alzheimer's disease, most likely to amyloid angiopathy.

[Clinical features in a Japanese patient with autosomal dominant lateral temporal epilepsy having LGI1 mutation].

We described a clinical feature of autosomal dominant lateral temporal epilepsy (ADLTE) in a Japanese patient having LGI1 mutation. The patient was a 27-year-old woman who had her first seizure at the age of 10 years, a nocturnal generalized seizure. She then had partial seizures manifesting auditory symptoms with or without anxiety, panic attack, déjà vu, sensory aphasia and visual symptoms. Repeated EEGs were normal. Brain MRI showed small left superior temporal gyrus. 18F-deoxyglucose positron emission tomography (PDG-PET) demonstrated glucose hypometabolism in the left lateral temporal lobe. Sequencing of the LGI1 revealed a single base substitution in exon 8 (1642C-->T) causing missense mutation at residue 473 of the LGI1 protein (S473 L). When one demonstrates ictal symptoms arising from the lateral temporal to occipital area with psychotic symptoms, ADLTE should be suspected and a detailed family history is warranted.

[Ictal Gerstmann's syndrome in a patient with symptomatic parietal lobe epilepsy].

A 34-year-old man with astrocytoma in the left parietal lobe had symptomatic partial epilepsy, and he presented transient episodes of acalculia, agraphia and finger agnosia. Occasionally he had difficulty in finding appropriate letters when making an e-mail, and difficulty in writing and calculation. Neurological examinations revealed ictal symptoms of Gerstmann's syndrome without right to left disorientation. No other higher cortical dysfunction or neurological deficits were noted. Scalp EEGs showed frequent, regional ictal discharges in the left parietal area lasting for 60-240 seconds. These clinico-electrographical observations strongly support that epileptic seizures produced a loss of cortical higher function manifesting Gerstmann's syndrome.

Cilostazol alleviates cerebral small-vessel pathology and white-matter lesions in stroke-prone spontaneously hypertensive rats.

Small-vessel pathology is believed to have a critical role in cerebrovascular white-matter (WM) lesions. However, the cellular aspect of vascular pathology, including the phenotypic modulation of smooth-muscle cells (SMCs) and its role in the small-vessel disease, remains undefined. The involvement or otherwise of the phenotypic modulation of SMCs in cerebral small-vessel pathology has been investigated, and the effect of cilostazol on both the small vessels and the WM lesions has been determined in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP and Wistar Kyoto rats were used. SHRSP were divided into two groups: the cilostazol-treated (20-week treatment) and vehicle-treated groups. Small-vessel pathology was analyzed using both histopathology and immunohistochemistry for smooth-muscle actin and nonmuscle myosin heavy chain (SMemb, a marker for the synthetic phenotype of SMC). The pathological changes in the WM were quantified in terms of the numerical density of activated microglia and the degree of WM lesions. Vascular wall thickening and perivascular fibrosis, determined by the wall area/lumen area ratio and the collagen area/total vessel area ratio, respectively, showed an increase in the vehicle-treated SHRSP, and this increase was significantly attenuated by cilostazol treatment. The percentage of small vessels immunopositive for SMemb was also reduced by cilostazol treatment. In the cilostazol-treated SHRSP, microglial activation and the degree of WM lesions were attenuated compared with the vehicle-treated SHRSP. The results indicated that cilostazol attenuates the phenotypic modulation of SMC associated with cerebral small-vessel pathology and WM lesions without causing changes in the blood pressure.

Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion.

BACKGROUND AND PURPOSE: We recently designed a mouse model of chronic cerebral hypoperfusion, in which the cerebral white matter is damaged without significant gray matter lesions. The behavioral characteristics of these mice were studied using a test battery for neurological and cognitive functions. METHODS: Adult C57Bl/6 male mice were subjected to either sham-operation or bilateral common carotid artery stenosis (BCAS) using microcoils with an internal diameter of 0.18 mm. At 30 days after BCAS, 70 animals were divided into 3 groups and subjected to behavioral test batteries. The first group underwent comprehensive behavioral test, including the neurological screen, prepulse inhibition, hot plate, open field, light/dark transition, Porsolt forced swim and contextual and cued fear conditioning (BCAS n=13; sham-operated n=11). The second group was for the working memory task of the 8-arm radial maze test (BCAS n=12; sham-operated n=10), and the third for the reference memory task of the 8-arm radial maze test (BCAS n=13; sham-operated n=11). Another batch of animals were examined for histological changes (BCAS n=11; sham-operated n=12). RESULTS: The white matter including the corpus callosum was consistently found to be rarefied without clear ischemic lesions in the hippocampus. No apparent differences were observed in the comprehensive test batteries between the control and BCAS mice. However, in the working memory tasks tested with the 8-arm radial maze, the BCAS mice made significantly more errors than the control mice (P<0.0001). Again, there were no detectable differences in the reference memory tasks between the groups. CONCLUSIONS: At 30 days after BCAS, working memory deficits as well as white matter changes were apparent in the mice. Working memory deficit was attributable to damage of the frontal-subcortical circuits, suggesting the BCAS model is useful to evaluate the substrates of subcortical vascular dementia.