Hideo Tohgi

Cilostazol Stroke Prevention Study: A Placebo-Controlled Double-Blind Trial for Secondary Prevention of Cerebral Infarction

Cilostazol, an antiplatelet drug that increases the cyclic adenosine monophosphate (AMP) levels in platelets via inhibition of cyclic AMP phosphodiesterase, has been used in chronic arterial occlusive disease. The purpose of the present study was to examine the effects of cilostazol on the recurrence of cerebral infarction using a multicenter, randomized, placebo-controlled, double-blind clinical trial method. Patients who suffered from cerebral infarction at 1 to 6 months before the trial were enrolled between April 1992 and March 1996. Oral administration of cilostazol (100 mg twice daily) or placebo was randomly assigned to the patients and continued until February 1997. The primary endpoint was the recurrence of cerebral infarction. In total, 1,095 patients were enrolled. An analysis based on 1,052 eligible patients (526 given cilostazol and 526 given placebo) showed that the cilostazol treatment achieved a significant relative-risk reduction (41.7%; confidence interval [CI], 9.2% to 62.5%) in the recurrence of cerebral infarction as compared with the placebo treatment (P=.0150). Intention-to-treat analysis of 1,067 patients also showed a significant relative-risk reduction (42.3%; CI, 10.3% to 62.9%, P=.0127). No clinically significant adverse drug reactions of cilostazol were encountered. Long-term administration of cilostazol was effective and safe in the secondary prevention of cerebral infarction.

Selective reduction of diffusion anisotropy in white matter of Alzheimer disease brains measured by 3.0 Tesla magnetic resonance imaging.

Alzheimer disease (AD) is pathologically characterized by cortical atrophy. Changes in the white matter and their relation to the pathogenesis of AD remain to be studied. To quantitatively investigate the integrity and organization of white matter fiber tracts in patients with AD, we used diffusion tensor (DT) imaging to study the diffusion anisotropy of white matter regions. DT imaging was performed using a 3.0 Tesla magnetic resonance scanner in ten probable AD patients with no or only mild changes in the white matter in T2 weighted magnetic resonance imagings and ten group-matched controls. The values of fractional anisotropy were significantly lower in the temporal subcortical white matter, posterior part of the corpus callosum, and anterior and posterior cingulate bundles in patients with AD compared with controls. Possible relationships of these selective impairments in the white matter with pathological changes in the posterior cerebral cortices and hippocampus were discussed.

Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin.

Background and Purpose: The purpose of this study was to compare the effects of low‐to‐high doses of aspirin on platelet aggregability determined by different methods and on the metabolism of thromboxane A2 and prostacyclin. Methods: We administered increasing doses (40, 320, and 1,280 mg/day) of aspirin to 19 poststroke patients and studied the differences in 1) the changes in platelet aggregability depending on the methods of evaluation and 2) the concentrations of prostaglandin metabolites in the blood and urine. Results: Aggregation of platelet‐rich plasma induced by a strong stimulus (10 &mgr;M ADP) was significantly reduced after 40 mg/day aspirin (p < 0.005), and this reduction was similar to that after higher aspirin doses. In contrast, aggregation of platelet‐rich plasma induced by weaker stimuli (1 and 5 &mgr;M ADP) decreased less significantly after 40 mg/day aspirin compared with that after higher aspirin doses. The serum thromboxane B2 generated after ex vivo incubation was reduced significantly (by 85%) after 40 mg/day aspirin and decreased further after 320 mg/day (by 96%) and 1,280 mg/day (by > 99%) of aspirin. The urinary 11‐dehydro‐thromboxane B2 concentration decreased less significantly after 40 mg/day aspirin (by 42%) compared with that after 320 mg/day (by 78%) and 1,280 mg/day (by 91%) aspirin doses. The urinary concentration of 2, 3‐dinor‐6‐keto‐prostaglandin f1&agr; did not decrease after 40 mg/day aspirin but decreased significantly after higher doses of aspirin. Conclusions: These findings suggest that different doses of aspirin may be necessary to prevent thrombogenesis induced by different triggers of different strengths and that 40 mg/day aspirin is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition. (Stroke 1992;23:1400‐1403)

Importance of the hematocrit as a risk factor in cerebral infarction.

The relationship between the incidence of cerebral infarction and the hematocrit was studied using 432 consecutive autopsied patients with the average age of 77.1 years. The incidence of cerebral infarction was higher in patients with hematocrit values of more than 46%, (the average in younger adult subjects). The increase in the frequency of cerebral infarction with highhematocrit values was more conspicuous in patients with severe cerebral atherosclerosis than in those with slight cerebral atherosclerosis. High blood pressure per se did not influence the relationship between the hematocrit value and the incidence of cerebral infarction. With hematocrit values of more than 41%, cerebral infarction occurred more frequently in patients over 78 years of age than in the younger patients, but the difference was not significant statistically. High hematocrit values are associated with a higher risk of cerebral infarction in deep subcortical structures of the brain than for cortical infarctions. The pathogenetic and preventive implications of these results are discussed in the light of blood rheology.

Alterations of 3-nitrotyrosine concentration in the cerebrospinal fluid during aging and in patients with Alzheimer's disease

To investigate the significance of nitric oxide (NO)-mediated neuron death in aging and Alzheimers disease (AD), the 3-nitrotyrosine concentration in the cerebrospinal fluid (CSF) was investigated in neurologically normal controls and patients with AD. The 3-nitrotyrosine concentration and the 3-nitrotyrosine/tyrosine ratio significantly increased with advancing age, whereas the tyrosine concentration was unaltered. In patients with AD, the 3-nitrotyrosine concentration and the 3-nitrotyrosine/tyrosine ratio increased significantly (>six-fold) compared with controls of similar age, and increased significantly with decreasing cognitive functions, whereas the tyrosine concentration did not change. These findings suggest that an activation of tyrosine nitration, increase in nitrated tyrosine-containing proteins, and/or its degradation may be involved in brain aging and play an important role in the pathogenesis of AD.

Remarkable increase in cerebrospinal fluid 3‐nitrotyrosine in patients with sporadic amyotrophic lateral sclerosis

To investigate the significance of peroxynitrite‐mediated oxidative damage in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS), the concentrations of 3‐nitrotyrosine and tyrosine in the cerebrospinal fluid (CSF) of patients with SALS were determined. The concentration of 3‐nitrotyrosine and the 3‐nitrotyrosine/ tyrosine ratio in patients with SALS were approximately seven times those of controls. Thus, the present findings in living patients provide in vivo evidence for a possible role of peroxynitrite, a mediator of oxidative stress, and increased nitration of tyrosine residues in the pathogenesis of SALS. Ann Neurol 1999;46:129–131

Cerebellar infarction. Clinical and neuroimaging analysis in 293 patients. The Tohoku Cerebellar Infarction Study Group.

Background and Purpose We performed this multicenter study to explore the full spectrum of the clinical characteristics and neuroimaging findings of cerebellar infarction, including patients with mild to severe illnesses. Methods We studied 293 consecutive patients with cerebellar infarction diagnosed by computed tomography and/or magnetic resonance imaging who were admitted to 36 hospitals during 5 years. Results Cerebellar infarcts constituted 2.3% of the total patients with acute brain infarction. The backgrounds and risk factors were similar to those in patients with infarctions of the cerebral hemispheres. At least 24% were embolic, and the diagnosis of embolism could not be ruled out in 27%. Infarcts involving the superior cerebellar artery (SCA) region (52%) and the posterior inferior cerebellar artery (PICA) region (49%) were far more frequent than those involving the anterior inferior cerebellar artery (AICA) region (20%). Patients with SCA infarcts exhibited obtunded consciousness and ataxia more frequently than those with PICA infarcts (P<.05). Infarcts in the PICA regions were associated with abnormalities of the PICA (64%) or the vertebral arteries (57%), whereas infarcts in the SCA and AICA regions were associated with abnormalities in the SCA or AICA, respectively, in approximately 30% of patients, in the basilar artery in approximately 16%, and in the vertebral artery in more than 60% of patients. Outcomes were poorer with SCA infarcts than with AICA and PICA infarcts. Conclusions These data indicate similar frequencies of SCA and PICA infarcts and illustrate the difference in clinical presentation and outcomes between SCA and PICA infarcts. They also indicate that not only in situ thrombosis but also cardiogenic or artery-to-artery embolism and the insufficiency of collateral circulation play important roles in the pathogenesis of cerebellar infarction. (Stroke. 1993;24:1697-1701.)

Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia

SummaryThe acetylcholine (ACh) and choline (Ch) concentrations in the cerebrospinal fluid were investigated in patients with vascular dementia of the Binswanger type (VDBT) or multiple small infarct type (MSID) as compared with patients with Alzheimer-type dementia (ATD). The ACh concentration in patients with ATD was found to be significantly lower than in controls (73%, p < 0.0001), and showed a significant positive correlation with dementia scale scores (rs=0.63, p < 0.03). The Ch concentration in the CSF of ATD patients was approximately the same as in controls. In VDBT/MSID patients, the ACh concentration was significantly lower than in controls (p < 0.001), also showing a significant positive correlation with dementia scale scores (rs=0.62, p < 0.02), but was significantly higher than in ATD patients (p < 0.001). Moreover, the Ch concentration in VDBT/MSID patients was significantly higher than in controls (p < 0.001) or ATD patients (p < 0.001). These results suggest that simultaneous determination of ACh and Ch concentrations in CSF may be useful for differentiating VDBT/MSID from ATD and that increasing the ACh level using cholinergic agents may be a beneficial therapeutic strategy for the treatment of ATD as well as VDBT/MSIT, and is worthy of further investigation.

Reduction with age in methylcytosine in the promoter region -224∼ - 101 of the amyloid precursor protein gene in autopsy human cortex

Methylation status of cytosines and its changes with age in the promoter region (−226∼−101) of the amyloid precursor protein (APP) was analyzed using bisulfite genomic sequencing in the cerebral cortex of human autopsy brain. Cytosines at 13 locations were methylated in at least one of the cases studied. Methylcytosines at these locations was more frequent in cases ≤70 years old (26%) than in cases >70 years old (8%) (p 70 years old (5%) (p<0.01). These cytosines constituted one of the 9-bp-long GC-rich elements (GGGCGC G/A GG) or an 11-bp inverted repeat (GGCCGT CGGCC). The present findings indicate that some cytosines, particularly those at −207∼−182, in the promoter region of the APP gene are frequently methylated and suggest that their demethylation with age may have some significance in the development of Aβ deposition in the aged brain. The relative importance of these elements in the total promoter activity of the APP gene remains to be definitively established.

Twenty-four-hour variation of blood pressure in vascular dementia of the Binswanger type.

Using a noninvasive portable blood pressure recorder, we compared 24-hour variations of blood pressure among 1) 35 patients with Binswanger-type dementia, 2) 43 with lacunar-type dementia, 3) 26 with a single lacunar stroke, and 4) 30 controls. Each group was divided into antihypertensive-treated and -untreated subgroups. Among the untreated subgroups, patients with Binswanger-type dementia had significantly greater 24-hour mean systolic blood pressures, 24-hour systolic blood pressure standard deviations, and maximal systolic blood pressure variations than the controls (p less than 0.05). Among the treated patients, blood pressure variability increased similarly in all subgroups with cerebrovascular lesions compared with the controls (p less than 0.05). The nocturnal blood pressure decreases seen in the controls were absent among both untreated and treated patients with Binswanger- or lacunar-type dementia (p less than 0.05). Our results suggest the importance of hypertension, short-term variations in blood pressure, and a sustained nighttime elevation of blood pressure for the pathogenesis of both Binswanger-type and lacunar-type dementia in patients receiving antihypertensive medication.