A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Teprenone in Patients with Alzheimer's Disease.

BACKGROUND: Teprenone (geranylgeranylacetone), an anti-ulcer agent, has been reported to inhibit amyloid-ß increase, senile plaque formation, and neuronal degeneration, and improve memory in mouse models of Alzheimer's disease (AD). OBJECTIVE: We conducted a randomized, double-blind, placebo-controlled study to ascertain teprenone's therapeutic ability for AD. METHODS: Patients with mild to moderate AD, with a Mini-Mental State Examination (MMSE) score of 13 to 26, were randomly allocated into two groups depending on the administered drug: donepezil +  placebo (placebo group) and donepezil + teprenone (teprenone group). The primary and secondary endpoints included changes in scores of the Japanese version of the AD Assessment Scale-cognitive subscale (ADAS-J cog) and other evaluations, respectively, including MMSE scores, during a 12-month period after the first administration. RESULTS: Forty-two and thirty-seven patients were allocated to the teprenone and placebo groups, respectively. ADAS-J cog score changes were not different between groups (placebo, 0.6±0.8; teprenone, 0.4±0.8; p = 0.861). However, MMSE scores significantly improved in the teprenone group (placebo, - 1.2±0.5; teprenone, 0.2±0.5; p = 0.044). Subgroup analysis considering the severity of medial temporal area atrophy revealed that this improvement by teprenone was significant in patients with mild (p = 0.013) but not with severe atrophy (p = 0.611). Adverse events were observed in 17.8 and 10.4% of patients in the placebo and teprenone group, respectively. CONCLUSION: Teprenone may be effective for AD when administered before atrophy progression in the medial temporal areas. TRIAL REGISTRATION: UMIN ID: UMIN000016843.

Combined assessment of serum folate and hemoglobin as biomarkers of brain amyloid ß accumulation.

A relationship between Alzheimer's disease (AD) and folate has been reported. Amyloid positron emission tomography (PET) is currently one of the most reliable biomarkers for AD. We investigated the correlation between serum folate levels and amyloid imaging to clarify whether serum folate could be a biomarker for AD. We also examined the usefulness of a combined assessment of serum folate levels and red blood cell hemoglobin content. Apolipoprotein E (APOE) gene polymorphisms were also assessed. Serum folate levels and hemoglobin content were evaluated by receiver operating characteristic analysis for their diagnostic capability as AD biomarkers relating to brain amyloid ß accumulation. The area under the ROC curve (AUC) for serum folate was 0.136 (95% confidence interval [CI]: 0.000-0.312; p = 0.016). The AUC for hemoglobin content was 0.848 (95% CI: 0.661-1.000; p = 0.021). Therefore, the folate deficiency with low folate levels or the non-anaemia with high hemoglobin content levels were found to have a high probability of also testing positive for amyloid. Furthermore, eight patients were found to be folate deficiency and non-anaemia, those who were consist of 7 amyloid positive patients (87.5%), and only one of the amyloid negative patients (12.5%). These results suggest that a deficiency of serum folate and high hemoglobin levels may reflect an increased risk of amyloid ß accumulation in the brain. Additionally, we demonstrated that these biomarkers could enhance the effectiveness of APOE as an AD biomarker. This study reveals that the combined assessment of serum folate levels and red blood cell hemoglobin content may be a useful biomarker for amyloid ß accumulation in the brain. We also found that the combination of serum folate levels and hemoglobin content is a more specific and sensitive blood biomarker for AD than APOE or folate alone. These findings may be used to support clinical diagnosis of AD using a simple blood test.

Imaging discrepancies between magnetic resonance imaging and brain perfusion single-photon emission computed tomography in the diagnosis of Alzheimer's disease, and verification with amyloid positron emission tomography.

BACKGROUND: In the diagnosis of Alzheimer's disease (AD), discrepancies are often observed between magnetic resonance imaging (MRI) and brain perfusion single-photon emission computed tomography (SPECT) findings. MRI, brain perfusion SPECT, and amyloid positron emission tomography (PET) findings were compared in patients with mild cognitive impairment or early AD to clarify the discrepancies between imaging modalities. METHODS: Several imaging markers were investigated, including the cortical average standardized uptake value ratio on amyloid PET, the Z-score of a voxel-based specific regional analysis system for AD on MRI, periventricular hyperintensity grade, deep white matter hyperintense signal grade, number of microbleeds, and three indicators of the easy Z-score imaging system for a specific SPECT volume-of-interest analysis. Based on the results of the regional analysis and the three indicators, we classified patients into four groups and then compared the results of amyloid PET, periventricular hyperintensity grade, deep white matter hyperintense signal grade, and the numbers of microbleeds among the groups. RESULTS: The amyloid deposition was the highest in the group that presented typical AD findings on both the regional analysis and the three indicators. The two groups that showed an imaging discrepancy between the regional analysis and the three indicators demonstrated intermediate amyloid deposition findings compared with the typical and atypical groups. The patients who showed hippocampal atrophy on the regional analysis and atypical AD findings using the three indicators were approximately 60% amyloid-negative. The mean periventricular hyperintensity grade was highest in the typical group. CONCLUSIONS: Patients showing discrepancies between MRI and SPECT demonstrated intermediate amyloid deposition findings compared with patients who showed typical or atypical findings. Strong white matter signal abnormalities on MRI in patients who presented typical AD findings provided further evidence for the involvement of vascular factors in AD.

MRI T2 hypointensity of metastatic brain tumors from gastric and colonic cancers.

BACKGROUND: Metastatic brain tumors from gastric and colon cancers are frequently revealed by hypointensity on T2-weighted magnetic resonance images (MRIs). However, the reason for this T2 hypointensity has yet to be clarified. We hypothesize that it is due to collagen deposition within the tissues. METHODS: Seven metastatic brain tumors, from 3 gastric cancers and 4 colon cancers were investigated. The degree of hypointensity of these tumors in T2-weighted images was quantitatively assessed as the ratio of gray-scale densities of tumor to brain using ImageJ. The result was compared with the amount of collagen in the resected specimens, which was quantified by ImageJ analysis software, utilizing the colour deconvolution method following Azan-Mallory staining. The degree of hypointensity was also compared with the ratio of viable epithelial component area/whole tissue area. Additionally, collagen distribution was studied by immunohistochemical staining. RESULTS: There was a clear negative correlation between intensity in T2-weighted images of these metastatic tumors and the amount of collagen they contained (R (2) = 0.766). However, there was no significant correlation between the T2 intensity and the ratio of viable epithelial component. Immunohistochemical analysis revealed that collagen types I, III, VII, X, and XI were expressed in the epithelial components and types IV, V, and VI were expressed in the stromal areas of the metastatic tumors. Collagen deposition was observed not only in stromal fibrous areas, but also in cytoplasmic areas in these metastatic tumors. CONCLUSIONS: Hypointensity of metastatic brain tumors arising from gastric and colonic cancers may be due to the accumulation of collagen in the tissues.

Clinical presentation and treatment of distal anterior inferior cerebellar artery aneurysms.

Aneurysms located at the distal portion of the anterior inferior cerebellar artery (AICA) are rare, and their clinical features are not fully understood. We report the clinical features and management of nine distal AICA aneurysms in nine patients treated during the past decade at Kagoshima University Hospital and affiliated hospitals. Our series includes seven women and two men. Of their nine aneurysms, eight were ruptured and one was unruptured; six were saccular and three were dissecting aneurysms. The most prevalent location was the meatal loop (n = 5) followed by the postmeatal (n = 3) and premeatal segment (n = 1) of the AICA, suggesting hemodynamic stress as an etiology of these distal AICA aneurysms. Of the nine patients, five presented with angiographic features suggestive of increased hemodynamic stress to the AICA and the common trunk of the posterior inferior cerebellar artery, with vertebral artery stenosis, marked laterality, and a primitive hypoglossal artery. We addressed eight aneurysms (eight patients) surgically; one aneurysm in one patient disappeared in the course of 3 months without surgical treatment. Of the eight surgically treated aneurysms, seven were ruptured and one was unruptured, five were clipped via lateral suboccipital craniotomy, two were trapped via lateral suboccipital craniotomy, and one was embolized. Good outcomes were obtained in six of the eight patients who underwent operation (75 %). We consider increased hemodynamic stress attributable to anatomic variations in the AICA and related posterior circulation to be the predominant contributor to the development of distal AICA aneurysms. Direct clipping and trapping yielded favorable outcomes in our series.

[Three cases demonstrating the characteristic neuroimaging of reversible posterior leukoencephalopathy syndrome].

Revisible posterior leukoencephalopathy syndrome (RPLS) is a syndrome defined predominantly by a characteristic pattern of MR images but heterogeneity and reversibility of the abnormalities is unclear. Three patients with characteristic neuroimaging of RPLS are described. Case 1. A 29-year-old woman underwent cesarean section 3 days before developing headache, visual disturbance, mild conscious deterioration and increased blood pressure. MRI on admission showed predominantly white matter edema bilaterally affecting the occipital, temporal and posterior parietal lobes. Lesions were iso-, hypointense on T1 weighted and hyperintense on T2 weighted and fluid-attenuated inversion recovery (FLAIR) images. Diffusion-weighted image (DWI) did not demonstrate hyperintensity in the same regions. She responded well to initial treatment and showed complete recovery. Case 2. A 67-year-old man had headache and visual disturbance after thromboendarterectomy of the left femoral artery. Initial DWI demonstrated hyperintensity in the occipital lobe. The patient had visual abnormality at discharge. Case 3. A 40-year-old woman with early gastric cancer had headache immediately after the injection of contrast material during abdominal computed tomography (CT) examination followed by generalized convulsion. On the third day, she had severe headache and vomiting. Her consciousness deteriorated to lethargy. CT showed marked brain edema, intracerebral hemorrhage, thin subdural hematoma and midline shift. External decompression and hematoma evacuation was performed. She had left hemianopia and left hemiplegia 1 month later. This report has important implications concerning the accurate early diagnosis of RPLS using MRI including DWI and its utility in prompting initial treatment. It should be noted that some cases demonstrating the characteristic neuroimaging pattern of RPLS do not attain full recovery and that surgical intervention is required in some cases.

[The correlation between lacunes and microbleeds on magnetic resonance imaging in consecutive 180 patients].

BACKGROUND AND OBJECTIVE: Microbleeds on T2*-weighted magnetic resonance imaging (MRI) represent a hemorrhagic type of small vessel disease. Small vessel disease causes both intracerebral hemorrhages and lacunar infarctions. We studied clinical background and MRI findings of the patients to clarify the correlation between microbleeds and lacunes. METHOD: This study consisted of 180 consecutive patients who underwent brain MRI using 1.5T system in our hospital for a year. We obtained T2*-weighted gradient-echo imaging as well as T1 and T2-weighted images. We statistically identified the factors related to the presence of microbleeds in all patients. The distribution of lacunes and microbleeds on MRI was compared to clarify the correlation of the lesions in the patients who had both lesions. RESULT: The overall prevalence of microbleeds was 41.1% (74 of 180 patients). Logistic regression analysis indicated that previous stroke, leukoaraiosis and lacunes were significantly correlated with microbleeds. In the patients who have both microbleeds and lacunes, lesions are tended to locate in thalamus and basal ganglia, especially incidence of lacunes are significantly greater compared with other regions. Thirty-six of 398 lesions (9.05%) diagnosed as lacunes with T1- and T2-weighted imaging were demonstrated as microbleeds with T2*-weighted gradient-echo imaging. CONCLUSION: Lacunes, leukoaraiosis as a hypertensive change on MRI had statistically significant correlation with the presence of microbleeds. T2*-weighted gradient-echo imaging should be included in the imaging protocol for cerebrovascular disease, because T1- and T2-weighted imaging recognizing some of the microbleeds as lacunar infarction.

High incidence of microbleeds in hemodialysis patients detected by T2*-weighted gradient-echo magnetic resonance imaging.

The incidence and characteristics of microbleeds in hemodialysis (HD) patients were investigated to elucidate the clinical significance with T(2)(*)-weighted gradient-echo magnetic resonance (MR) imaging. The 57 patients with chronic renal failure maintained by HD had no previous history of stroke. The control group consisted of 53 patients without previous history of stroke or chronic renal failure. The incidence and the number of microbleeds were assessed in the HD and control groups. The findings of microbleeds with T(2)(*)-weighted gradient-echo MR imaging were compared with those of T(1)- and T(2)-weighted MR imaging in HD patients. The incidence of microbleeds was significantly greater in the HD patients compared with the control patients. T(2)(*)-weighted gradient-echo imaging revealed a total of 44 microbleeds in 11 HD patients. T(2)-weighted imaging demonstrated 13 of 44 microbleeds as hyperintensity, whereas T(1)-weighted imaging demonstrated 12 lesions as hypointensity. T(2)- and T(1)-weighted imagings did not demonstrate any findings in 31 and 32 lesions, respectively. T(2)(*)-weighted gradient-echo MR imaging is effective to detect microbleeds which may be a predictor of intracerebral hemorrhage in HD patients and should be included in the protocol for the study of cerebrovascular disease, because T(2)- and T(1)-weighted MR imaging recognizes microbleeds as lacunar infarction.

Xanthogranulomatous hypophysitis mimicking a pituitary neoplasm.

Hypophysitis is an inflammatory disease of the pituitary gland that clinically and radiologically mimics pituitary tumors. We report here a case of xanthogranulomatous hypophysitis mimicking a pituitary neoplasm.A 65-yr-old woman presented with weight loss, fatigue, and visual disturbance. Computed tomography demonstrated a round cystic low-density mass with calcification in the sella. A T1-weighted magnetic resonance imaging scan showed most of the mass as hyperintense. The capsule of the mass was strongly enhanced by gadolinium. Endocrinologic examination revealed hypocorticism and hypothyroidism. Diabetes insipidus (DI) developed after the administration of hydrocortisone. The patient also had hallucination and delusions of persecution. Transsphenoidal surgery was performed. Histologic examination of the removed tissue showed central necrosis surrounded by accumulation of foamy cells and epithelioid cells. Several multinucleated giant cells were also seen. The foamy cells and epithelioid cells were immunopositive for Kp-1, a marker of macrophages. The patient made an uneventful postoperative recovery. Although DI and hypofunction of adenohypophysis persisted, the visual disturbance and psychiatric disorder were resolved. We have described an unusual inflammatory lesion of the pituitary in the sellar region that was mimicking neoplasm. A high level of clinical suspicion of inflammatory disorders is necessary for correct diagnosis and optimal management.

Pontine malignant astrocytoma with hemorrhagic onset--case report.

A 7-year-old boy presented with acute onset of left hemiparesis and headache, followed by disturbance of consciousness. Neuroimaging studies showed pontine hemorrhage. Surgery was performed to remove a massive hematoma. Histological examination of the wall revealed anaplastic astrocytoma. Postoperative radiation therapy and several types of chemotherapy were administered. However, the tumor recurred and he died 9 months after onset. Hemorrhagic onset of pontine glioma is rare and carries an extremely poor prognosis.

Germinoma with syncytiotrophoblastic giant cells recurring 13 years after radiotherapy for a pineal germinoma--case report.

A 28-year-old man presented with progressive mental deterioration. Thirteen years earlier he had undergone radiation therapy for a pineal germinoma. Neuroimaging showed a homogeneously enhanced mass lesion along the ventricular wall. The cerebrospinal fluid (CSF) level of human chorionic gonadotropin (HCG) was high. Endoscopic biopsy revealed that the tumor was a two-cell pattern germinoma. The diagnosis was germinoma with syncytiotrophoblastic giant cells (STGC). He first received three cycles of chemotherapy with carboplatin and etoposide and then two cycles with ifosfamide, cisplatin, and etoposide. Subsequently, the tumor size decreased markedly and the CSF level of HCG returned to normal. However, he died 22 months after the recurrence. Histological verification and measurement of tumor markers are necessary for the optimum treatment of germ cell tumors. Adequate initial chemotherapy and long-term follow up are essential for patients with germinoma with STGC.

Surgical treatment of spontaneous intracerebral hemorrhage in a full-term infant with coagulopathy--case report.

An 11-week-old male infant presented with intracerebral hemorrhage associated with coagulopathy manifesting as left hemiparesis, lethargy, and vomiting. Computed tomography demonstrated extensive right frontoparietal intracerebral hemorrhage extending into the ventricular system. Liver function tests revealed abnormal values of transaminases and bilirubin. Blood coagulation studies showed prolonged prothrombin time (PT) and activated partial thromboplastin time (APPT). PT and APTT immediately normalized after the administration of vitamin K and fresh frozen plasma. Right parietal craniotomy and evacuation of the hematoma were performed because of the deterioration in consciousness and left hemiparesis. No vascular abnormality was observed in the hematoma cavity. After surgery, he became alert and the left hemiparesis improved. There is a risk of intracerebral hemorrhage due to vitamin K deficiency even if prophylactic administration of vitamin K was given. Surgical treatment should be considered for the treatment of infantile spontaneous intracerebral hemorrhage, especially if neurological deterioration is present.

Optic nerve glioma manifesting as intratumoral hemorrhage in a pregnant woman--case report.

A 33-year-old pregnant woman presented with intratumoral hemorrhage in an astrocytoma of the left optic nerve and chiasm manifesting as poor vision in her left eye. Visual examination found no light perception in the left eye and deteriorated acuity with temporal hemianopsia in the right eye. Computed tomography demonstrated a round high-density mass in the suprasellar region. T2-weighted magnetic resonance (MR) imaging showed the center of the mass as mildly hypointense and T2-weighted MR imaging as hypointense. Both T1- and T2-weighted MR imaging showed the rim of the mass as hyperintense. She delivered a healthy baby by cesarean section. A left frontotemporal craniotomy was then performed. Incision of the lateral surface of the left optic nerve revealed clotted blood from the left optic nerve and the left side of the chiasm. No vascular malformation was noted in the hematoma cavity. Histological examination revealed a neoplasm composed of well-differentiated astrocytic cells. No Rosenthal fibers were identified. The patient made an uneventful postoperative recovery. Her right visual acuity returned to normal, but the temporal hemianopsia in the right eye and the blindness in the left eye persisted. Gliomas of the anterior visual pathways are rare, especially in adults. The hemorrhage may have been caused by the hypercoagulable state associated with pregnancy. Optic nerve astrocytic glioma with intratumoral hemorrhage should be considered in the differential diagnosis of suprasellar hematoma.

Pituitary adenoma with "honeycomb Golgi" appearance showing a phenotypic change at recurrence from clinically nonfunctioning to typical Cushing disease.

An adenoma resected from a 49-yr-old woman was clinically nonfunctioning but immunopositive for adrenocorticotropic hormone (ACTH) in a few cells. Electron microscopy demonstrated a vacuolar change in Golgi complexes known as "honeycomb Golgi." Recurrent adenoma resected 11 mo later was positive for ACTH in more cells than in the initial one. Two months later the patient presented with typical signs and symptoms of Cushing disease with elevated blood cortisol and ACTH levels and was treated by gamma knife radiotherapy. Among adenomas that are initially clinically silent but became functionally active with recurrence, corticotroph adenomas seem to be the most frequent. Study of transcription factors will be helpful to clarify whether adenomas with honeycomb Golgi represent exclusively gonadotroph adenomas.

Pituitary Adenoma with Cholesterol Clefts.

Histologically, cholesterol clefts are often observed in craniopharyngioma, Rathke's cleft cyst, and various granulomas. However, pituitary adenomas with cholesterol clefts are rare. A 46-year-old woman developed visual field disturbance. She had no history of severe headache that would suggest pituitary apoplexy. She presented with homonymous bitemporal hemianopsia and galactorrhea. Blood prolactin level was 63.1 ng/mL Other hypophysial hormone levels were within normal range. Magnetic resonance imaging revealed a pituitary tumor with intratumoral cyst. The cyst showed high intensity on T1- and T2-weighted images. The tumor was demonstrated with iso intensity on T1-weighted image and with high intensity on 12-weighted image. She underwent trans-sphenoidal surgery. The tumor was soft, with yellowish, oily fluid, probably the cyst content. By light microscopy with hematoxylin and eosin staining, a typical chromophobic adenoma of the pituitary was identified. Immunostaining revealed immunoreactivity for ACTH in several cells. Many cholesterol clefts and several hemosiderin pigment containing macrophages were observed. Electron microscopy demonstrated a pituitary adenoma with sparse and small secretory granules and numerous lysosomes. The cyst was most likely caused by focal hemorrhagic infarction, followed by the formation of cholesterol crystals, the appearance of hemosiderin containing macrophages, foreign body product cells, and accumulation of lysosomes.

Pituitary Insulin: Insulin-Like Growth Factors.

Insulin-like growth factor (IGF)-l and IGF-ll peptides as well as their mRNAs are produced in many organs, including the pituitary. Although IGFl and IGFII peptides are localized in endocrine cells of the anterior pituitary, IGF-l mRNA can be detected throughout the adenohypophysis, and IGF-ll mRNA is abundant in intermediate and neural lobes. It is well-established that both circulating and intrinsic IGF-l are negative regulators of pituitary GH production. Other functions of intrinsic IGFs in normal and tumorous pituitary are just emerging. IGF-l may play a role in the stimulation of PRL synthesis and mediation of proliferative effects of estrogen on lactotroph. Compared with IGF-l, the function of IGE-Il has not been clarified so far. The growth-promoting actions of IGFs are mediated by IGF-l receptor. The role of local and circulating IGFBPs in pituitary are not yet documented. IGFBPs in other tissues have inhibitory and stimulatory effects on IGFs, and can act independently from the IGFs as well. IGFs have been reported to promote cell proliferation in many tumors. However, the extent to which IGFs contribute to pituitary tumor development and growth remains obscure.