Masayuki Matsuda

Four subgroups of Alzheimer's disease based on patterns of atrophy using VBM and a unique pattern for early onset disease.

To clarify the involvement of the posterior cingulate cortex (PCC) in Alzheimers disease (AD), we analyzed brain volume loss by voxel-based morphometry. Forty patients with non-familial AD and 20 patients with mild cognitive impairment (MCI) were recruited and compared to 88 elderly volunteers and 40 young volunteers. Local atrophy with aging was observed bilaterally in the perisylvian opercula, anterior cingulate cortex, caudate head, dorsomedial thalamus and parahippocampal cortex. In addition to those, atrophy in AD patients was observed in the amygdala, hippocampus, subcallosal region, posterior-associated cortices and PCC. We classified AD into four subgroups according to the atrophy pattern; atrophy in the amygdala/hippocampal formations (Hipp), in the Hipp and posterior cortices, in the Hipp and PCC and in the PCC and posterior cortices (PCC/-TOPa). As a result, the probability of PCC/-TOPa was 90% for ages <65 years, whereas that of the Hipp was 100% for disease duration >36 months. PCC atrophy was found in 16 of 40 AD patients and eight of 20 MCI patients. There seemed to be two subgroups with atrophy of the PCC, the one with disease progression and the other without. The latter had characteristic features of early onset and no significant atrophy in the amygdala/anterior hippocampus. There are at least four atrophy patterns that raise doubts about a single disease entity or progression in AD. This may reflect a different hierarchical pattern of progression in patients who have atrophy in PCC and posterior cortices when compared to the Braak staging scheme.

Proton magnetic resonance spectroscopy with dementia.

To provide new insights into metabolic changes in the brain of patients with dementia, we performed in vivo localized proton magnetic resonance spectroscopy in nine patients with primary degenerative dementia and in three patients with normal-pressure hydrocephalus. We compared the results with those in 26 healthy volunteers. Measurements of regional cerebral blood flow were performed in seven patients by means of single photon emission computed tomography with amphetamine I 123 as a tracer. The magnetic resonance spectra constantly showed three major peaks corresponding to N-acetylaspartate (NAA), creatine and phosphocreatine (Cr), and choline-containing compounds. There were no age-related changes in the mean area ratio of NAA to Cr in neurologically normal volunteers. The NAA/Cr ratio was significantly reduced in patients with primary degenerative dementia. The reduction of the NAA/Cr ratio was observed even in dementia patients with no significant brain atrophy or reduction in regional cerebral blood flow. No significant reduction of the NAA/Cr ratio was seen in patients with normal-pressure hydrocephalus. The NAA/Cr ratio might reflect the number and/or activity of neuronal cells in the brain. Proton magnetic resonance spectroscopy may well provide a useful tool for early detection of, and further pathophysiological study of, primary degenerative dementia.

Significance of MIB-1 staining indices in meningiomas: comparison of two counting methods.

The authors evaluated the predictability of MIB-1 immunohistochemistry for growth and recurrences of meningiomas using two different counting methods: 1) in the area of the highest MIB-1 labeling (HL method) and (2) in randomly selected fields (RS method). The MIB-1 staining indices (SIs) determined by the HL method were approximately twice as high as those by the RS method, and the correlation coefficient between them was high (R = 0.86) in 139 meningiomas when transformed logarithmically. The differences in SIs in histologic grades were significant with either method. Tumor doubling time (Td) was calculated in 22 meningiomas from serial radiologic examinations. The RS method yielded a slightly higher correlation coefficient between log Td and log SI than the HL method. When the authors examined the predictability of recurrence in 112 totally removed meningiomas, the RS method distinguished the recurrent group more definitively. Several benign meningiomas with low SIs by the RS method exhibited focal accumulation of MIB-1-positive cells. Although they were assigned high MIB-1 values by the HL method, these meningiomas did not recur, and therefore obscured the prognostic importance of the MIB-1 value with the HL method. Focal accumulation of MIB-1-positive cells in meningiomas is not likely to correlate with their biologic aggressiveness.

Immunohistochemical study for O6-methylguanine-DNA methyltransferase in the non-neoplastic and neoplastic components of gliomas.

Although the expression O6-methylguanine-DNA methyltransferase (MGMT) is an important hallmark for decision of nitrosourea chemotherapy for glioma patients, no immunohistochemical method for analysis of MGMT has been standardized yet. Gliomas usually contain non-neoplastic cells even deep in the tumor. It is not known which of these components expresses MGMT. To clarify this point, we investigated MGMT expression in the non-neoplastic cells in autopsy and surgical specimens by immuno-histochemistry. High grade gliomas were also studied to find a cut-off point for treatment decision. MGMT immunohistochemistry in the normal brain or brain with non-neoplastic disease revealed nuclear staining in some endothelial cells, inflammatory cells, ependymal cells, astrocytes and oligodendroglias. Some cells were double stained with CD68 (macrophages or microglias). The neurons were consistently MGMT-negative. High grade gliomas always contained an MGMT-positive non-neoplastic component. Although the endothelial cells were easily distinguished from the neoplastic cells, other cells were often mistaken for tumor cells. The population of MGMT-positive non-neoplastic cells was usually less than 10%. We set a cut off-point at 10% between the positive and negative groups because the statistical difference in the overall survival was most distinct at this value. In 51 high grade glioma patients, who received both radiotherapy and chemotherapy with nimustine (ACNU), the median overall survival of the MGMT-negative group (23months) was significantly longer than that of the MGMT-positive group (14months) (P<0.009). Multivariate analysis revealed that the negative MGMT expression was a significant prognostic variable next to the degree of surgical removal for the overall survival. In the MGMT-positive group, addition of platinum-based chemotherapy did not improve the survival.

Aneurysms of the proximal anterior cerebral artery

The authors report eight cases of aneurysm of the anterior cerebral artery proximal to the anterior communicating artery (A1 segment). In six of these cases, the aneurysms arose from the proximal anterior cerebral artery at the origin of either a cortical branch (on case), the accessory middle cerebral artery (one case), or a perforating branch (four cases). In another case the aneurysm arose at the proximal end of the fenestration, whereas in the one remaining case no branch was present at the site of the aneurysmal neck.

Cerebral aneurysms associated with Behçet's disease: a case report

Cerebral aneurysms in Behçets disease are very rare. The role of vasculitis in the aetiology of these aneurysms has not been clarified. A 57 year old man with Behçets disease is described, who had a subarachnoid hemorrhage due to rupture of a peripheral middle cerebral artery aneurysm. He underwent a successful aneurysmal clipping. Three years later he had seizures and was found to have a new aneurysm on the contralateral peripheral middle cerebral artery as well as some radiological features of vasculitis. After 3 months of steroid therapy, the aneurysm disappeared. Although surgical treatment is the first choice for ruptured aneurysms, steroid therapy may be effective for unruptured small aneurysms in patients with Behçets disease.

Glutamate Receptor Antagonists and Benzodiazepine Inhibit the Progression of Granule Cell Dispersion in a Mouse Model of Mesial Temporal Lobe Epilepsy

Summary:  Purpose: Unilateral intrahippocampal injection of kainic acid (KA) in adult mice induces the progressive dispersion of dentate granule cells, one of the characteristic pathologic changes of mesial temporal lobe epilepsy. However, little is known about the mechanisms that trigger this dispersion. In this study, the possible involvement of glutamatergic and γ‐aminobutyric acid (GABA)ergic neurotransmissions in the development of granule cell dispersion (GCD) was examined in this model.

Estimation of Cerebral Perfusion Reserve by Blood Oxygenation Level—Dependent Imaging: Comparison with Single-Photon Emission Computed Tomography

Measurement of cerebrovascular reserve capacity predicts the risk of ischemic insult in patients with major vessel occlusion. Blood oxygenation level-dependent (BOLD) imaging has the potential to estimate reserve capacity of the cerebral circulation noninvasively based on changes in the signal that reflect differences in the magnetic susceptibility of intravascular oxyhemoglobin and deoxyhemoglobin. The authors examined the feasibility of using the BOLD technique to assess cerebrovascular reserve capacity in patients with cerebrovascular occlusive disease by comparing results with an established method of measuring CBF. Ten patients with severe or complete occlusion of the internal carotid artery were compared with 17 healthy subjects to evaluate regional differences and identify variables that indicate a change in the BOLD signal. Dilation of cerebral vessels was induced by breath holding, and the R2* change was examined with gradient-echo, echo-planar imaging. Before measuring the regional change in the BOLD signal, actual timing of “activated” and “rest” periods was corrected by shifting the phase of a sine-wave template to obtain the largest correlation coefficient. Percent signal change was calculated on a pixel-by-pixel basis and was compared with CBF measured by single-photon emission computed tomography (SPECT) before and after acetazolamide challenge. The degree of impairment and the distribution of impaired areas detected by the BOLD study correlated with the results of SPECT. Overall sensitivity and specificity of the BOLD technique by visual inspection were 100% and 98.4%, respectively. A negative response (decreased CBF) frequently was observed in areas of exhausted reserve capacity, suggesting that a “steal” phenomenon exists. The percent change and the ΔCBF were well correlated (P < 0.01). The mean percent change in most areas of impaired reserve capacity was more than 2 SD below the mean values in healthy subjects. The present method of semiquantitative BOLD analysis can be used to create a map of the cerebral hemodynamic state. Furthermore, the development of reliable, generally accessible techniques for evaluating cerebral hemodynamics opens the door for clinical studies to monitor and treat patients with compromised reserve. This study is an attempt to develop such analysis.

Poor Recovery of Mitochondrial Redox State in CA1 After Transient Forebrain Ischemia in Gerbils

BACKGROUND AND PURPOSE Several investigations have detected evidence of apoptosis in delayed neuronal death, but controversy prevails regarding this point. Recent studies have implicated mitochondria in apoptotic events. To explore relationships between delayed neuronal death and dysfunction of the respiratory chain, we analyzed mitochondrial redox changes in the gerbil hippocampus. METHODS We assessed the mitochondrial redox state in gerbil hippocampus before, during, and at various time points after 5 minutes of forebrain ischemia. The redox state was examined with a low-temperature fluorometer. Fluorescence signals of flavoprotein and NADH were measured, and their fluorescence ratio was calculated as a mitochondrial redox ratio (MRR) equal to flavoprotein/(flavoprotein+NADH). RESULTS Ischemia increased NADH and decreased flavoprotein signals in all hippocampal areas, but reduction in MRR was greater in CA1 than in other areas of the hippocampus. Immediately after recirculation, MRR recovery was delayed in the CA1 and the dentate gyrus, and the reduction in MRR persisted in CA1. CONCLUSIONS These results suggest that during ischemia CA1 experiences more pronounced hypoxia (state V) than less vulnerable regions. Persistent MRR reduction in CA1 is attributed to dysfunction of the electron transport system, and this phenomenon may be importantly involved in apoptosis.

Monitoring of somatosensory-evoked potentials during aneurysm surgery

Somatosensory-evoked potentials were recorded during and after 31 operations for intracranial aneurysms, and the changes in the central conduction times, namely, the interpeak latencies between the N14 and N20 peaks in response to bipolar stimulation of the median nerve, were studied. Neuroleptanalgesia and routine intracranial operative procedures such as opening the dura mater, drainage of the cerebrospinal fluid, gentle retraction of the brain, and microsurgical dissection of the circle of Willis, were found to have no significant adverse effect on the evoked responses, whereas the temporary clipping of the major cerebral artery or premature rupture of the aneurysm associated with hypotension or both, often caused significant prolongation of the central conduction time. Prolongation of the central conduction time exceeding 1.2 ms or disappearance of the N20 peak adversely affected the postoperative conditions in 8 of 13 patients (62%).