Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Recent evidence indicates the efficacy of ß-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote ß-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage. Objective: To determine the safety and efficacy of cilostazol in mild cognitive impairment. Design, Setting, and Participants: The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020. Interventions: The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks. Main Outcomes and Measures: The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events. Results: The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically. Conclusions and Relevance: In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02491268.

Autoimmune glial fibrillary acidic protein astrocytopathy resembling isolated central nervous system lymphomatoid granulomatosis.

We report two patients with meningoencephalomyelitis without evidence of extra central nervous system (CNS) involvement. Brain MRI showed linear perivascular radial gadolinium enhancement patterns and spinal cord MRI showed longitudinal extensive T2-hyperintensity lesions. Pathological findings from brain biopsies were angiocentric T-cell predominant lymphoid infiltrates that lacked Epstein-Barr virus-positive atypical B cells. The patients were initially suspected to have isolated CNS-lymphomatoid granulomatosis (LYG). Thereafter, glial fibrillary acidic protein (GFAP)-immunoglobulin G were detected in their cerebrospinal fluid. This finding suggested autoimmune GFAP astrocytopathy. We speculate there is a link between isolated CNS-LYG and autoimmune GFAP astrocytopathy.

Hemicrania Continua Subsequent to Vertebral Artery Dissection: A Case Report.

We herein report the case of a 45-year-old woman who developed a continuous hemicranial headache subsequent to vertebral artery dissection (VAD). After remission of VAD, the patient repeatedly experienced right forehead and temporal region throbbing headache, accompanied by nausea, ocular hyperemia and lacrimation of the right eye, nasal congestion, and rhinorrhea. Magnetic resonance angiography did not reveal the recurrence of dissection. Daily use of indomethacin (190.8 mg/day) showed an excellent effect on the headache, suggesting that the patient had developed hemicrania continua subsequent to VAD.

[Primary angiitis of the central nervous system with cerebral infarction and spinal hemorrhage].

A 61-year-old woman presented with acute intense lower back pain and weakness in her left leg. She also presented with throbbing headache on the same day. On admission, muscle weakness in her left leg, lower left quadrantanopia and left lower extremity deep sensory disturbance were observed. Laboratory data showed no coagulopathy and autoimmune antibody was negative. Cerebrospinal fluid examination showed bloody and inflammatory findings. Brain MRI revealed cerebral infarction with multiple intracranial arterial stenosis and convexal subarachnoid hemorrhage. Spinal MRI revealed spinal hemorrhage in the cervical, thoracic, and part of the lumbar spine. Because these lesions occurred simultaneously, we made a diagnosis of vasculitis. After high dose corticosteroids therapy was undertaken, the multiple arterial stenosis improved. Primary angiitis of the central nervous system is sometimes difficult to distinguish from reversible cerebral vasoconstriction syndrome in its initial stage; although symptoms, examination findings and treatment differ in both.

Suvorexant-Induced Dream Enactment Behavior in Parkinson Disease: A Case Report.

ABSTRACT: Suvorexant is a new insomnia drug, and it is generally safe and well tolerated. Here, we report a rare but potentially important adverse effect of suvorexant in a patient with Parkinson disease.

Cerebral Air Embolism with Pneumomediastinum Resulting from Emesis: A Case Report.

Cerebral air embolism (CAE) is a rare cause of stroke. Most cerebral air emboli are caused by iatrogenic factors, such as invasive cardiac and pulmonary procedures. Here, we report an unusual case of CAE not related to any medical intervention. An 87-year-old woman became unresponsive after vomiting. A computed tomography (CT) scan of the head 6 hours after the onset of the vomiting revealed multiple air emboli, mainly in the watershed area between the right anterior and middle cerebral arteries. Magnetic resonance imaging with T2* gradient echo showed the air emboli as granular hypointensities. Diffusion-weighted imaging revealed an area of hyperintensity along the cortical region of the right frontal lobe. Head CT scans showed that the size and number of the air emboli rapidly decreased on day 2 and disappeared on day 9. We also performed a chest CT and found pneumomediastinum, which gradually improved over the clinical course. We also found pulmonary fibrosis and bronchiectasis, suggesting an underlying pulmonary vulnerability. In this case, the emesis may have been a trigger for the CAE, which was followed by pneumomediastinum. This case suggests that CAE can occur in a noniatrogenic situation, especially in a patient with pulmonary vulnerability.

Unresectable colorectal liver metastases: the safety and efficacy of conversion therapy using hepatic arterial infusion immunochemotherapy with 5-fluorouracil and polyethylene glycol-interferon α-2a.

BACKGROUND: Hepatic arterial infusion (HAI) or systemic chemotherapy has been used to treat unresectable colorectal liver metastases. The prognosis of the disease in recent years has been improved because chemotherapy is performed before hepatectomy to reduce tumor size (conversion therapy). The purpose of this study was to investigate the safety and efficacy of conversion therapy following HAI immunochemotherapy. METHODS: Hepatic arterial infusion of 5-fluorouracil (5-FU)/polyethylene glycol (PEG)-IFNα-2a was performed in 21 patients. The primary endpoint was the safety of HAI and hepatectomy. The secondary endpoints were response rate, rate of conversion to hepatectomy, survival rate, and prognostic factors. RESULTS: With regard to side effects, drugs were discontinued temporarily in one patient because of a decrease in white blood cell count; however, other patients continued chemotherapy. The response rate with HAI was 61.9 %, and the conversion rate was 38.1 %. Hepatectomy was completed successfully without mortality. Median progression-free survival (PFS) was 11.5 months (with and without conversion, 16.7 and 4.8 months, respectively; p = 0.021). Median overall survival was 34.6 months (with and without conversion, 48.4 and 26.6 months, respectively; p = 0.003). Prognosis was poor when the number of metastatic tumors was ≥10 [PFS: hazard ratio (HR) 32.21, p = 0.003; overall survival (OS): HR 9.13, p = 0.07], but prognosis improved after hepatectomy (OS: HR 0.08, p = 0.09). CONCLUSIONS: Hepatic arterial infusion immunochemotherapy with 5-FU/PEG-IFNα-2a was performed safely without major side effects. Prognosis is expected to improve after successful conversion to hepatectomy.

The clinical characteristics of spinocerebellar ataxia 36: a study of 2121 Japanese ataxia patients.

Spinocerebellar ataxia 36 is caused by the expansion of the intronic GGCCTG hexanucleotide repeat in NOP56. The original article describing this condition demonstrated that patients with spinocerebellar ataxia 36 present with tongue atrophy, a finding that had not been seen in previous types of spinocerebellar ataxias. A total of 2121 patients with clinically diagnosed spinocerebellar ataxia participated in the study. We screened our patient samples for spinocerebellar ataxia 36 using the repeat-primed polymerase chain reaction method and also determined the clinical features of spinocerebellar ataxia 36. Of the ataxia cases examined, 12 were identified as spinocerebellar ataxia 36. Of these, 7 cases (6 families) were autosomal dominant, 4 cases (three families) had a positive family history but were not autosomal dominant, and 1 case was sporadic. The average age of onset was 51.7 years, and disease progression was slow. The main symptoms and signs of disease included ataxia, dysarthria, and hyperreflexia. Approximately half the affected patients demonstrated nystagmus, bulging eyes, and a positive pathological reflex, although dysphagia, tongue atrophy, and hearing loss were rare. Moreover, the observed atrophy of the cerebellum and brain stem was not severe. The patients identified in this study were concentrated in western Japan. The frequency of spinocerebellar ataxia 36 was approximately 1.2% in the autosomal dominant group, and the age of onset for this condition was later in comparison with other spinocerebellar ataxia subtypes.

[Successful treatment of methicillin-resistant staphylococcus aureus meningitis by intrathecal injection of vancomycin].

A 70-year-old Japanese man developed fever, headache, and lumbago, presumably due to an epidural abscess caused by methicillin-resistant Staphylococcus aureus (MRSA) in the L5-S2 region. On the night of admission to our hospital, he showed disorientation to places and abnormal eating behavior, indicating a complication of MRSA meningitis. Cerebrospinal fluid (CSF) examination confirmed this diagnosis. Although he was treated with venous infusion of vancomycin and meropenem, the CSF culture remained positive for MRSA even a week after the treatment, and Gram-positive cocci were also seen in the CSF. An intrathecal injection of vancomycin (10mg/day) was subsequently added, which resulted in absence of the organism on Gram-stained CSF smear and CSF culture a week later. His condition improved without any adverse effects. Vancomycin cannot freely penetrate the blood-brain barrier (BBB); therefore, when administered intravenously, its concentration in the CSF is insufficient. Therefore, intrathecal injection of vancomycin is necessary to achieve the desired bacteriocidal level in the CSF. Thus, intrathecal administration of vancomycin seems a very effective and safe treatment for MRSA meningitis.

[A case of complete response after treatment with UFT and leucovorin for synchronous multiple liver metastases of rectal cancer].

The patient was a 55-year-old female who had multiple liver metastases of rectal cancer. This patient underwent hepatic arterial infusion chemotherapy after low anterior resection for rectal cancer. Hepatic arterial infusion was discontinued due to severe diarrhea, and the administration of UFT (300 mg/day) and LV(75 mg/day) was then begun. The carcinoembryonic antigen (CEA) level was normalized immediately after the start of this administration. One year later, liver metastases disappeared on computed tomography (CT) and a complete response (CR) was achieved. No adverse events were noted, and CR was maintained for 2 years. This therapy can serve as one of the chemotherapies for advanced colorectal cancer.

Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwInd transgenic mice.

Chronic cerebral ischemia may accelerate clinicopathological changes in Alzheimer's disease. We have examined whether chronic cerebral hypoperfusion accelerates amyloid beta deposition in amyloid protein precursor transgenic (APP-Tg) mouse. At 5, 8, and 11 months of age, C57Bl/6J male mice overexpressing a mutant form of the human APP bearing the both Swedish (K670N/M671L) and the Indiana (V717F) mutations (APPSwInd) and their litterrmates were subjected to either sham operation or bilateral carotid artery stenosis (BCAS) using microcoils with an internal diameter of 0.18 mm (short-period group). One month after the sham operation or BCAS, these animals were examined by immunohistochemistry for glial fibrillary acidic protein, amyloid beta(1-40) (Abeta(1-40)), amyloid beta(1-42) (Abeta(1-42)), as well as Western blotting and filter assay for Abeta. Another batch of the littermates of APPSwInd mice were subjected to either sham operation or BCAS at 3 months and were examined in the same manner after survival for 9 months (long-period group). In the BCAS-treated group, the white matter was rarefied and astroglia was proliferated. Amyloid beta(1-40) immunoreactivity was found in a few axons in the white matter after BCAS, whereas Abeta(1-42) was accumulated in the scattered cortical neurons and the axons at ages of 6 months and thereafter in the short- and long-period groups. In the neuropil, both Abeta(1-40) and Abeta(1-42) were deposited in the sham-operated and BCAS-treated mice at ages of 9 and 12 months. There were no differences between the short-period group at ages of 12 months and the long-period group. Filter assay showed an increase of Abeta fibrils in the extracellular enriched fraction. Taken together, chronic cerebral hypoperfusion increased Abeta fibrils and induced Abeta deposition in the intracellular compartment and, therefore, may accelerate the pathological changes of Alzheimer's disease.

Capillary beds are decreased in Alzheimer's disease, but not in Binswanger's disease.

Morphological abnormalities of the cortical microvessels have been reported in Alzheimer's disease (AD), but not in Binswanger's disease (BD), a form of vascular dementia. Therefore, we compared the capillary beds in AD and BD brains, using a modified Gallyas silver impregnation method and immunohistochemistry for beta amyloid. Eight autopsied brains with AD and seven with BD were compared with six control brains. The cortical microvessels in AD were frequently narrowed, and torn off, especially in close proximity to the senile plaques. The capillary densities in AD were significantly decreased as compared with the control brains. In contrast, there were no significant changes in the capillary densities and their morphologies in BD brains. Immunohistochemistry for beta amyloid revealed numerous deposits in the vascular wall and perivascular neuropil exclusively in AD brains. Cortical microvascular changes in AD and their absence in BD may indicate a role of beta amyloid for the microvessel pathology in AD.

Expression of S100 protein and protective effect of arundic acid on the rat brain in chronic cerebral hypoperfusion.

S100 protein is expressed primarily by astroglia in the brain, and accumulates in and around the ischemic lesions. Arundic acid, a novel astroglia-modulating agent, is neuroprotective in acute cerebral infarction, whereas the protective effects remain unknown during chronic cerebral hypoperfusion. Rats undergoing chronic cerebral hypoperfusion were subjected to a bilateral ligation of the common carotid arteries, and were allowed to survive for 3, 7 and 14 days. The animals received a daily intraperitoneal injection of 5.0, 10.0 or 20.0 mg/kg of arundic acid, or vehicle, for 14 days. Alternatively, other groups of rats received a delayed intraperitoneal injection of 20.0 mg/kg of arundic acid or vehicle, which started from 1, 3 or 7 days after ligation and continued to 14 days. The degree of white matter (WM) lesions and the numerical density of S100 protein-immunoreactive astroglia were estimated. In the WM of rats with vehicle injections, the number of S100 protein-immunoreactive astroglia increased significantly after chronic cerebral hypoperfusion as compared to the sham-operation. A dosage of 10.0 and 20.0 mg/kg of arundic acid suppressed the numerical increase in S100 protein-immunoreactive astroglia and the WM lesions. These pathological changes were suppressed with delayed treatment up to 7 days in terms of astroglial activation, and up to 3 days in terms of the WM lesions. The protective effects of arundic acid against WM lesions were demonstrated in a dose-dependent manner, and even after postischemic treatments. These results suggest the potential usefulness of arundic acid in the treatment of cerebrovascular WM lesions.

Pharmacological characterization and feeding-suppressive property of FMS586 [3-(5,6,7,8-tetrahydro-9-isopropyl-carbazol-3-yl)-1-methyl-1-(2-pyridin-4-yl-ethyl)-urea hydrochloride], a novel, selective, and orally active antagonist for neuropeptide Y Y5 receptor.

We evaluated the pharmacological profiles of FMS586 [3-(5,6,7,8-tetrahydro-9-isopropyl-carbazol-3-yl)-1-methyl-1-(2-pyridin-4-yl-ethyl)-urea hydrochloride], a novel tetrahydrocarbazole derivative as a neuropeptide Y (NPY) Y5 receptor antagonist. This compound showed a highly selective in vitro affinity for Y5 (IC(50) = 4.3 +/- 0.4 nM) relative to other NPY receptor subtypes like Y1 or Y2. Its binding to Y5 was found to be fully antagonistic from cyclic AMP accumulation assays in human embryonic kidney 293 cells. Pharmacokinetic analysis revealed sufficient oral availability and brain permeability of this compound accompanied with clear dose relation. We attempted to assess the selectivity of FMS586 and, thereby, to infer the physiological role of Y5 in the following feeding experiments in normal rats. An intracerebroventricular injection of NPY and Y5-selective agonist peptide induced acute and robust feeding responses in satiated rats, and prior administration of FMS586 at the doses from 25 to 100 mg/kg clearly inhibited these responses by approximately 55 and 90%, respectively. This compound also showed dose-dependent but transient suppression in natural feeding models of both overnight fasting-induced hyperphagia and spontaneous daily intake. FMS586 did not modulate food intake induced by the topical injection of norepinephrine, galanin, or gamma-aminobutyric acid receptor agonist muscimol to the paraventricular nucleus. In addition, we confirmed the Y5-specific activity profile of FMS586 by immunohistochemical analysis. Taken together, we propose not only that our compound potentially expresses specific blockade of central Y5 signals but also that Y5 receptor would certainly contribute to physiological regulation of food intake in normal rats, as suggested from its origin.