Altered properties of amyloidogenic prion protein in genetic Creutzfeldt-Jakob disease with PRNP V180I mutation in response to pentosan polysulfate.

Genetic Creutzfeldt-Jakob disease (gCJD) with V180I prion protein gene (PRNP) mutation shows weaker prion protein (PrP) deposition histologically compared with sporadic CJD, and it is more difficult to detect protease-resistant prion protein in immunoblotting. However, we previously reported the autopsy case of a patient with V180I gCJD who was treated with pentosan polysulfate sodium (PPS); this case had increased protease-resistant PrP deposition. It has been suggested that PPS might reduce protease-resistant PrP; however, the detailed pharmacological and histopathological effects of PPS in humans remain unknown. We examined autopsied human brain tissue from four cases with V180I gCJD that were added to our archives between 2011 and 2021: two cases treated with PPS and two cases without PPS. We conducted a neuropathological assessment, including immunohistochemistry for PrP. We also performed immunoblotting for PrP on homogenate samples from each brain to detect protease-resistant PrP using both a conventional procedure and size-exclusion gel chromatography for the purification of oligomeric PrP. Both PPS-treated cases showed long survival time over 5 years from onset and increased PrP deposition with a characteristic pattern of coarse granular depositions and congophilic PrP microspheres, whereas the cases without PPS showed around 1-year survival from onset and relatively mild neuronal loss and synaptic PrP deposition. Although cortical gliosis seemed similar among all cases, aquaporin 4-expression as a hallmark of astrocytic function was increased predominantly in PPS cases. Immunoblotting of non-PPS cases revealed protease-resistant PrP in the oligomeric fraction only, whereas the PPS-treated cases showed clear signals using conventional procedures and in the oligomeric fraction. These unique biochemical and histopathological changes may reflect the progression of V180I gCJD and its modification by PPS, suggesting the possible existence of toxic PrP-oligomer in the pathophysiology of V180I gCJD and beneficial effects of PPS toward the aggregation and detoxication of toxic PrP-oligomer.

Effects of hydrochlorothiazide on oxidative stress and pulse pressure in hypertensive patients with chronic stroke: the EMINENT study.

OBJECTIVE: Thiazide diuretics are reported to have antioxidant effects and reduce pulse pressure (PP). The aim of this study was to elucidate whether hydrochlorothiazide additionally exerts such effects in stroke patients under treatment with losartan. METHODS: This study was an open-label, randomized, multicenter study. Patients with a history of chronic stroke and treatment with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors for essential hypertension were enrolled. Fifty-five hypertensive patients were randomly assigned to two groups: those further treated with hydrochlorothiazide and those further treated with non-diuretic antihypertensive drugs. RESULTS: Both groups showed a significant decrease in PP over six months (hydrochlorothiazide group: 67±12 mmHg to 58±12, p<0.001; non-diuretic group: 72±12 to 61±12, p<0.001), although no significant differences were observed between the two groups. The malondialdehyde-modified low-density lipoprotein levels did not change significantly after treatment in either group. CONCLUSION: In this study, hydrochlorothiazide treatment did not provide any additional benefits over non-diuretic antihypertensive drugs in terms of antioxidant effects or reducing PP.

Microsphere-induced embolic stroke: an MRI study.

Despite the many studies of the middle cerebral artery occlusion (MCAO) model, efficient therapy for stroke is still lacking, emphasizing the need for further development and characterization of experimental stroke models. In the present study, the rather unexplored multifocal microsphere-induced stroke model in rats was characterized by multiparametric MRI. We induced microembolic infarction in a group of Sprague-Dawley rats by injecting a dose of about 1000 50-microm polyethylene microspheres intracranially from the external carotid artery. Diffusion-, perfusion-, and T(2)-weighted MRI were used to evaluate the infarct development during and following the first 3 hr after microsphere injection (N = 20). The animals were also imaged at 12-hr (N = 8), 24-hr (N = 17), and 48-hr (N = 5) time points. After the final imaging time point, the brains were removed and sectioned into 2-mm-thick slices, and infarct volumes were measured by 2,3,4-triphenyltetrazolium chloride (TTC) staining. From calculated apparent diffusion coefficient (ADC) maps, a volume of reduced ADC appeared 0.5-1.0 hr postinjection, and by the 3-hr time point the volume of ADC reduction had increased to a size of 5% +/- 1% (mean +/- SEM) of the brain hemisphere. The lesion volume increased significantly (P < 0.01) to 16% +/- 2% of the hemisphere volume at the 12-hr time point, while at 24 hr the lesion (15% +/- 2% of the hemisphere) was also significantly larger (P < 0.001) than at 3 hr. The perfusion deficit resulting from the microsphere injection was immediate, going from a cerebral blood flow index (CBF(i)) of 74% +/- 3% at the time of microsphere injection to 68% +/- 2% of the contralateral mean at 3 hr (P < 0.05), to 55% +/- 4% of the contralateral values at 12 hr (P < 0.05), and to 57% +/- 2% of the contralateral mean at 24 hr (P < 0.001). The lesion development in the microsphere-induced stroke model was found to be slower than in the MCAO model, and continued up to the 24-48-hr time point.

Ultrasonographically predicting the extent of collateral flow through superficial temporal artery-to-middle cerebral artery anastomosis.

BACKGROUND AND PURPOSE: This study was performed to elucidate whether the extent of bypass flow through superficial temporal artery-to-middle cerebral artery (STA-MCA) anastomosis could be indirectly estimated by measuring the blood flow velocity in the superficial temporal artery (STA) by using duplex ultrasonography. METHODS: We analyzed 29 patients (31 sides) who underwent STA-MCA bypass surgery for occlusive cerebrovascular disease (28 sides) or unclippable cerebral aneurysm that required therapeutic occlusion of the internal carotid artery (three sides). The flow velocities of the STA were measured by using ultrasonography. For patients who underwent the surgery unilaterally, the flow velocity ratios of the operated side to the contralateral side for the individual arteries were calculated. The correlation between these flow velocity parameters and the extent of bypass flow, which was graded based on the findings of cerebral angiography, was investigated. RESULTS: Both the affected STA flow velocity and the STA flow velocity ratio, particularly those in the end diastole, increased in patients with more extensive bypass flow. In patients with extensive, moderate, and poor bypass flow, the end diastolic flow velocities of the operated STA were 27.4 +/- 8.8, 23.0 +/- 7.8, and 13.5 +/- 7.5 cm/s, respectively and the end diastolic flow velocity ratios of the STA were 3.4 +/- 0.8, 2.1 +/- 0.5 and 1.3 +/- 0.4, respectively. The pulsatility index and resistance index of the affected STA were significantly lower in the patients with more extensive bypass flow. The optimal threshold value of the end diastolic flow velocity ratio of STA for the group with extensive bypass flow was 2.75, whereas that for the group with poor bypass flow was 1.60. With the obtained values, the sensitivity and specificity were 87.5% and 93.9% for the group with extensive bypass flow and 95.2% and 95.0% for the group with poor bypass flow, respectively. CONCLUSION: The blood flow velocity in the operated STA seems to be a highly sensitive parameter for predicting the extent of bypass flow in patients undergoing STA-MCA anastomosis.

Separating changes in the intra- and extracellular water apparent diffusion coefficient following focal cerebral ischemia in the rat brain.

Selective intracellular (IC) and extracellular (EC) brain water apparent diffusion coefficient (ADC) values were measured in normal and ischemic rat brain. Selective T(1)-relaxation enhancement of the EC water, using intracerebroventricular (ICV) infusion of an NMR contrast reagent (CR), was used to separate the IC and EC signal contributions. In the CR-infused, normal brain (n = 4), T(1) = 235 +/- 10 ms and T(2) = 46 +/- 2 ms for IC water (85%) and T(1) = 48 +/- 8 ms and T(2) = 6 +/- 2 ms for EC water (15%). Volume-localized ADC(z) (z-gradient axis) values were 0.90 +/- 0.02 (EC+IC), 0.81 +/- 0.05 (IC), 0.51 +/- 0.02 (EC+IC), and 0.53 +/- 0.07 (IC), for normal, CR-infused, ischemic, and ischemic/CR-infused groups, respectively (ADC values are x10(-3) mm(2)/s; n = 5 for each group). Imaging ADC(z) values were 0.81 +/- 0.03 (EC+IC), 0.75 +/- 0.05 (IC), 0.51 +/- 0.04 (EC+IC), and 0.52 +/- 0.05 (IC), respectively, for the same groups. Imaging ADC(av) (average diffusivity) values for the same groups were 0.70 +/- 0.05 (EC+IC), 0.69 +/- 0.06 (IC), 0.45 +/- 0.06 (EC+IC), and 0.44 +/- 0.06 (IC), respectively. These results suggest that the IC water ADC determines the overall water ADC value in normal and ischemic rat brain.