Objectively measured prolonged sleep is associated with plasma cytokines in older adults with mild cognitive impairment.

This study aimed to determine whether objective sleep time is associated with the concentrations of various plasma cytokines in older adults with mild cognitive impairment (MCI). In total, 118 adults with MCI (66 women; mean age: 75.7 years) participated in this prospective cohort study. All participants were required to wear a wristband sensor for 7.8 days, on average, every 3 months for 1 year and undergo measurement of 27 plasma cytokines using multiplex immunoassays. After adjusting for potential confounders, the associations of total sleep time with cytokine concentrations were assessed by multiple linear regression analysis. The total sleep time was significantly correlated with plasma interleukin (IL)-9 and macrophage inflammatory protein (MIP)-1ß levels (r = 0.239, p = 0.009, and r = 0.242, p = 0.008, respectively). Moreover, these associations remained significant after adjusting for covariates, including demographic characteristics, lifestyle-related diseases, and apolipoprotein E status (ß = 0.272, 95% confidence interval: 0.095-0.448, p = 0.003, and ß = 0.27, 95% confidence interval: 0.092-0.449, p = 0.003, respectively). Thus, this study is the first to demonstrate the association between objective prolonged sleep and higher plasma IL-9 and MIP-1ß levels in older adults with MCI.

The Postpartum Period Can Worsen Myelin Oligodendrocyte Glycoprotein Antibody-associated Encephalomyelitis.

Myelin oligodendrocyte glycoprotein (MOG) antibodies are associated with relapsing inflammatory demyelinating disease. Pregnancy complicates the disease course, potentially leading to either symptom improvement or worsening. A 28-year-old woman with MOG antibody-associated encephalomyelitis had 2 pregnancies; her disease worsened during both postpartum periods despite continuing prednisolone and levetiracetam. The umbilical cord blood was positive for MOG antibodies following her second pregnancy, but neither baby had MOG antibody-associated disease. This is the first case report of MOG antibody-associated demyelinating disease that worsened postpartum despite continuous medication. Furthermore, we observed the placental transfer of MOG antibodies for the first time.

Cerebrospinal Fluid Interleukin-6 in Immune Checkpoint Inhibitor-Induced Autoimmune Meningoencephalitis.

Immune checkpoint inhibitors (ICIs) have proven clinical benefits in various advanced cancers. However, despite their significant therapeutic efficacy, ICIs induce immune-related adverse events. Among these events, autoimmune meningoencephalitis often has severe effects on patients' outcomes, but its specific clinical features are still unclear. Here, we report two cases of ICI-associated meningoencephalitis with elevated interleukin-6 (IL-6) levels in the cerebrospinal fluid (CSF). A 47-year-old woman (Case 1) with renal cell carcinoma developed severe headache after a seventh nivolumab administration. A neurological examination revealed jolt accentuation signs and hyperreflexia in all extremities. CSF analysis revealed a high IL-6 value (6,620 pg/mL) with marked pleocytosis. A 70-year-old woman (Case 2) who received an initial administration of nivolumab plus ipilimumab for renal cell carcinoma developed alterations of consciousness. She presented with impaired consciousness, neck stiffness, and hyperreflexia in all extremities. CSF analysis demonstrated a high IL-6 value (49.3 pg/mL) with mild pleocytosis. Both patients were treated with steroid pulse therapy (methylprednisolone 1,000 mg/day, 3 days), followed by the administration of oral predonisolone. The symptoms and laboratory findings improved in both cases. CSF IL-6 values were proportional to the severity of meningoencephalitis and other clinical parameters. These findings may help elucidate the mechanisms of central nervous system complications that are caused by ICIs.

Demons syndrome with pericardial effusion followed by intensive care unit-acquired weakness: A case report and literature review.

Demons syndrome is defined by hydrothorax and ascites associated with a benign genital tumor that resolves after resection of the tumor. However, Demons syndrome with pericardial effusion has never been reported. Intensive care unit-acquired weakness is a neurological sequela to sepsis/systemic inflammatory response syndrome, or multi-organ failure. A 47-year-old, nulligravid, Japanese woman, was transferred to our hospital for refractory heart failure and a ruptured ovarian tumor. She had an 11-cm left ovarian tumor with ascites, hydrothorax, and pericardial effusion; she was intubated for pulmonary hypertension and admitted to the intensive care unit for septic shock. Four days later, a left salpingo-oophorectomy was performed for Demons syndrome with pericardial effusion. The histological diagnosis indicated a serous cystadenoma with fibrotic changes. Following surgery, ventilator weaning was delayed due to intensive care unit-acquired weakness. The association between Demons syndrome and pericardial effusion should be recognized to ensure early treatment and for preventing sequalae from the disease.

[A case of laminopathy with the mutation of LMNA gene identified by the exome analysis of disease-related genes].

Laminopathy, caused by mutations in the LMNA gene, include a variety of diseases, such as Emery-Dreifuss muscular dystrophy. A Japanese woman developed progressive muscle weakness, muscle atrophy and joint contractures of upper and lower limbs after the age of two years old. She had restrictive respiratory dysfunction, and developed both supraventricular and ventricular arrhythmias after the fourth decade of life. At 55 years old, she had tracheostomy, required mechanical ventilation and was implanted with the implantable cardioverter defibrillator. The serum level of creatine kinase was within normal range. Electromyography showed polyphasic or large motor unit potentials and reduced interference pattern, while relatively normal recruitment. The exome analysis of disease-related genes revealed a heterozygous pathogenic variant c.1072G>A (p.E358K) in the LMNA gene, which contributed to the diagnosis of laminopathy.

Synchronous double primary cancers of the extrahepatic bile duct: A case report and literature review.

BACKGROUND: Double cancers of the biliary tract system are rare. Most of these cancers are synchronous double cancers of the gall bladder and bile duct, associated with pancreaticobiliary maljunction (PBM). Synchronous double cancers of the extrahepatic bile duct without PBM are especially rare, and only 4 cases have been reported. CASE PRESENTATION: A 78-year-old woman was admitted to our hospital for examination of hyperbilirubinemia and liver dysfunction. Contrast-enhanced abdominal computed tomography, Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography revealed 2 stenotic regions in the common bile duct: at its junction with the cystic duct and in the distal bile duct. No findings suggested PBM, such as a markedly long common channel. The diagnosis based on endoscopic brush cytology from both stricture portions was adenocarcinoma. The patient had a pylorus-preserving pancreaticoduodenectomy with regional lymph node resection. Macroscopically, there were 2 stenotic regions at the cystic duct junction and in the distal bile duct. Microscopically, the tumor at the junction of the cystic duct was a well-to-moderately differentiated adenocarcinoma. On the other hand, the tumor of the distal bile duct was a poorly differentiated adenocarcinoma. There was no evidence of communication between these 2 cancers. CONCLUSION: Double cancers of the extrahepatic bile duct without PBM are very rare. Therefore, an accurate diagnosis prior to surgery is necessary. Furthermore, this rare condition seems to be associated with a poor prognosis.

Relationship between white matter lesions and regional cerebral blood flow changes during longitudinal follow up in Alzheimer's disease.

AIM: The aim of the present study was to evaluate the relationship between baseline white matter lesions (WML) and changes in regional cerebral blood flow during longitudinal follow up of patients with Alzheimer's disease (AD). METHODS: A total of 38 patients with AD were included in the study (16 men, 22 women; mean age 77.8 years). All patients were evaluated using the Mini-Mental State Examination and brain perfusion single-photon emission computed tomography at baseline with an approximately 2-year follow up. The patients were divided into two subgroups according to the presence of WML on magnetic resonance imaging. Single-photon emission computed tomography data were analyzed using a voxel-by-voxel group analysis with Statistical Parametric Mapping 8 and region of interest analysis using FineSRT. Changes in Mini-Mental State Examination scores and regional cerebral blood flow were analyzed using the Wilcoxon signed-rank test. RESULTS: Mean Mini-Mental State Examination scores in AD patients with WML significantly decreased from 19.4 ± 4.8 to 15.5 ± 6.5 (P = 0.003). Statistical Parametric Mapping 8 and FineSRT analysis showed more severe and widespread regional cerebral blood flow reduction, mainly in the frontal and mesial temporal regions in AD patients with WML compared with those without WML. CONCLUSION: Baseline WML could predict a rapid progression of cognitive and brain functional impairment during longitudinal follow up in AD. Geriatr Gerontol Int 2016; 16: 836-842.

Evaluation of regional cerebral blood flow in Alzheimer's disease patients with subclinical hypothyroidism.

BACKGROUND: This study examined regional cerebral blood flow (rCBF) in Alzheimer's disease (AD) patients with and without subclinical hypothyroidism (SCH). METHODS: Eleven AD patients with SCH and 141 AD patients without SCH underwent brain perfusion single photon emission computed tomography (SPECT). The SPECT data were analyzed by statistical parametric mapping (SPM8) and FineSRT. RESULTS: AD patients with SCH showed a significantly decreased rCBF mainly in the temporal lobe and thalamus, whereas those without SCH showed a significantly decreased rCBF in the parietotemporal lobe and cingulate gyrus as well as the frontal lobe. CONCLUSION: Our findings suggest that SCH may affect cerebral perfusion in regions associated with the memory function.

Creutzfeldt-Jakob Disease with a prion protein gene codon 180 mutation presenting asymmetric cortical high-intensity on magnetic resonance imaging.

Here we report a genetically confirmed case of Creutzfeldt-Jakob disease with a prion protein gene codon 180 mutation presenting atypical magnetic resonance imaging findings. The present case exhibited an acute onset and lateralized neurologic signs, and progressive cognitive impairment. No myoclonus or periodic synchronous discharges on electroencephalography were observed. Diffusion-weighted images revealed areas of high signal intensity in the right frontal and temporal cortices at onset that extended to the whole cortex and basal ganglia of the right cerebral hemisphere at 3 months. Although the cerebrospinal fluid (CSF) was initially negative for neuron specific enolase, tau protein, 14-3-3 protein, and abnormal prion protein, the CSF was positive for these brain-derived proteins at 3 months after onset.

Evaluation of the regional cerebral blood flow changes during long-term donepezil therapy in patients with Alzheimer's disease using 3DSRT.

BACKGROUND: We attempt to evaluate objectively the regional cerebral blood flow (rCBF) changes during long-term donepezil therapy and the relationship between the clinical response and rCBF change in patients with Alzheimer's disease (AD). PATIENTS AND METHODS: Thirty-one patients with mild-to-moderate AD (11 men, 20 female; mean age, 76.2 ± 6.7 years) were treated with donepezil and underwent brain perfusion single-photon emission computed tomography (SPECT) twice with an interval of 24.5 ± 4.2 months. The rCBF was calculated using 3-dimensional stereotaxic region of interest template, a fully automated each region of interest technique. We compared the differences in rCBF between baseline and follow-up SPECT studies. Moreover, all patients were divided into stabilized (n = 14) and nonstabilized subgroups (n = 17) based on Mini-Mental State Examination (MMSE) score changes and the changes in rCBF were compared between two subgroups. RESULTS: The mean MMSE score significantly decreased from 20.7 ± 4.6 at baseline to 16.5 ± 6.5 after 2 years. The mean rCBF significantly decreased in the widespread brain regions between the baseline and follow-up SPECT studies. The nonstabilized subgroup showed a significant decrease in rCBF of the parietal and temporal segments compared to the stabilized subgroup. CONCLUSION: The progression of cognitive deterioration may be related to rCBF affected by the neuropathologic changes of AD.

Brain perfusion differences in parkinsonian disorders.

We aimed to objectively examine the brain perfusion differences between PD, Parkinson variant of multiple system atrophy, and progressive supranuclear palsy. (99m) Tc ethylcysteinate dimer single-photon emission CT (SPECT) was performed in 28 patients with PD, 12 with Parkinson variant of multiple system atrophy, 19 with progressive supranuclear palsy, and 17 age- and sex-matched control subjects. A voxel-by-voxel group analysis, using statistical parametric mapping 8, was performed to detect the differences of regional cerebral blood flow among three diseases and control groups. Regional cerebral blood flow was measured using the noninvasive Patlak plot method and calculated using a fully automated region of interest technique. Progressive supranuclear palsy showed decreased regional cerebral blood flow in the cingulate gyrus and thalamus, whereas Parkinson variant of multiple system atrophy showed decreased regional cerebral blood flow in the cerebellum, compared with other patients and controls. Regional cerebral blood flow in the thalamus could be used to discriminate progressive supranuclear palsy from other diseases and control subjects with high sensitivity. These findings suggest that parkinsonian disorders, such as PD, Parkinson variant of multiple system atrophy, and progressive supranuclear palsy show a distinct SPECT pattern in the frontal cortex, thalamus, and cerebellum. Moreover, the measurements of regional cerebral blood flow in the thalamus and cerebellum may be helpful in screening for the differential diagnosis of parkinsonian syndrome.

Relationship between thyroid hormone levels and regional cerebral blood flow in Alzheimer disease.

Subclinical thyroid disease and even variations in thyroid function within the normal range is associated with cognitive function and a risk of Alzheimer disease (AD). Several studies reported the effect of thyroid hormones on cerebral blood flow. The aim of this study was to objectively evaluate regional cerebral blood flow (rCBF) in association with thyroid hormone levels within the normal range in patients with AD. Serum thyroid-stimulating hormone (TSH), free T3, and free T4 levels were measured in 62 patients with AD (23 men and 39 women; age 56 to 91 y; mean age 77.3 y) and 27 control subjects (9 men and 18 women; age 61 to 93 y; mean age 75.8 y). The 99mTc ethylcysteinate dimer single photon emission computed tomography was performed in all subjects. The rCBF in the region of interest was measured by the noninvasive Patlak plot method and calculated using FineSRT, which is a fully automated region of interest technique. No significant correlation was found between thyroid hormone levels and Mini-Mental State Examination scores or global CBF values. Serum levels of TSH, but not free T3 or free T4, were significantly inversely correlated with rCBF in the middle and inferior temporal regions of right cerebral hemisphere in patients with AD. Control subjects showed no significant correlation between thyroid hormone levels and rCBF. Although these findings of a regional relationship must be considers preliminary, this study proposed the hypothesis that altered TSH levels within the normal range may be related to brain perfusion in right temporal region.

Evaluation of the effects of thyrotropin releasing hormone (TRH) therapy on regional cerebral blood flow in the cerebellar variant of multiple system atrophy using 3DSRT.

BACKGROUND: Thyrotropin releasing hormone (TRH) improves cerebellar ataxia and cerebellar perfusion in patients with spinocerebellar degeneration. It is not known whether TRH therapy can improve the cerebellar regional cerebral blood flow (rCBF) or not in patients with cerebellar variant of multiple-system atrophy (MSA-C). PATIENTS AND METHODS: Seven patients with MSA-C received TRH intravenously (2 mg/day) for 14 days. Clinical efficacy was assessed using the International Cooperative Ataxia Rating Scale (ICARS) and brain perfusion single photon emission-computed tomography was performed before and after therapy. The rCBF in each region of interest (ROI) was calculated using 3DSRT, a fully automated the ROI technique. RESULTS: The ICARS scores slightly improved in 6 of the 7 patients after TRH therapy, but this was not statistically significant. After TRH therapy, the cerebellar rCBF reduced in the 6 of 7 patients and the mean rCBF in cerebellum also significantly decreased (P=0.029, paired t-test), whereas the rCBF in the precentral segment tend to increase (P=0.048, paired t-test). CONCLUSION: TRH therapy may be less effective on cerebellar ataxia and cerebellar rCBF in MSA-C. The 3DSRT program may be useful for the evaluation of the efficacy of TRH therapy on cerebral blood flow.

Clinical significance of the highly sensitive fucosylated fraction of α-fetoprotein in patients with chronic liver disease.

BACKGROUND AND AIM: The purpose of the present study was to investigate the clinical significance of the highly sensitive fucosylated fraction of α-fetoprotein (hs-AFP-L3) in patients with chronic liver disease (CLD) and low serum α-fetoprotein (AFP) concentration. METHODS: A total of 241 patients being treated at our institute with CLD and low serum AFP concentration (3-10 ng/mL) were investigated retrospectively. We measured total AFP and the percentage of AFP-L3 using a µTAS Wako i30 device. The possible presence of hepatocellular carcinoma (HCC) was thoroughly investigated by various examinations carried out from 1 month before to 1 month after measurements. In addition, hs-AFP-L3 elevated and non-elevated groups, divided by the cut-off value based on a receiver-operator characteristic (ROC) curve, were followed for possible future development of HCC. RESULTS: hs-AFP-L3 was above the detectable range in 60 patients (24.9%). Among those AFP-L3 positive cases, 20 (33.3%) were found to be HCC prevalent, whereas HCC was found in just 16 patients (8.8%) with undetectable hs-AFP-L3 levels. We determined the cut-off value of hs-AFP-L3%, which shows the proportion of AFP L3 in total AFP, to be 5.75%. During the follow-up period, HCC was newly detected in six patients (22.2%) in the hs-AFP-L3% elevated group and in 10 (5.6%) in the non-elevated group. Analysis using the Kaplan-Meier method showed the HCC-free rate of the hs-AFP-L3% elevated group was significantly lower than that of the non-elevated group (P=0.0038). Independent predicting variants were female sex (P=0.0024) and hs-AFP-L3% elevation (P=0.0036). CONCLUSION: Our results suggest hs-AFP-L3 level is a useful tumor marker for HCC in patients with CLD and low serum AFP concentration.

A sub-centimeter HCC with bright loop appearance diagnosed by contrast-enhanced ultrasonography.

Detection of a hepatocellular carcinoma (HCC) in the early stage is critical, as clinical stage influences treatment selection and patient prognosis. Carcinogenetic development of an HCC is a multi-step process, and a differential diagnosis between a dysplastic nodule and a well-differentiated HCC is often difficult. A bright loop appearance is a significant finding that indicates disappearance of fatty deposition in the central area of the nodule during the progression toward HCC, however such a finding is rare in cases of sub-centimeter-sized HCCs. We encountered a case of HCC that developed a bright loop appearance on ultrasound (US) without enlargement approximately 2 years after diagnosis as a dysplastic nodule. Moreover, the hypoechoic area in the center of the nodule showed an HCC pattern in contrast enhanced US with Sonazoid™. Vascularity in the nodule could not be observed on dynamic contrast-enhanced CT or Gd-EOB-DTPA-enhanced MRI. When a change in the intranodular echo pattern is observed in sub-centimeter-sized nodules, examination of intranodular vascularity by contrast-enhanced US is important to evaluate borderline lesions.

Evaluation of regional cerebral blood flow in cerebellar variant of multiple system atrophy using FineSRT.

OBJECTIVES: In the present study, we compared the patterns of regional cerebral blood flow (rCBF) between cerebellar variant of multiple system atrophy (MSA-C) and the late-onset cortical cerebellar ataxia (LCCA) using FineSRT. PATIENTS AND METHODS: We performed (99m)Tc ethylcysteinate dimer (ECD) single-photon emission computed tomography in 11 patients with MSA-C (mean age 65.7 years), 7 patients with LCCA (mean age 62.0 years), and 12 age-matched healthy controls (mean age 64.1 years). The rCBF in the region of interest (ROI) was measured by the noninvasive Patlak plot method and calculated using FineSRT, which is a fully automated the ROI technique. RESULTS: All patients with MSA-C had various degrees of atrophy in the brainstem and middle cerebellar peduncles and 4 of 11 patients showed a clear 'hot cross bun' sign in pontine base on T2-weighted MR images. All patients with LCCA showed the various degrees of atrophy in cerebellum without brainstem. FineSRT revealed the significantly decreased rCBF in the caudate tail, fusiform, lingual, cerebellum, midbrain, and pons in MSA-C group compared with controls. Moreover, MSA-C group showed significantly decreased rCBF in the pons compared with LCCA group. CONCLUSION: We suggest that a widespread brain involvement is present in patients with MSA-C and the decreased rCBF in the pons may support the differential diagnosis between MSA-C and LCCA.

A dose-up of ursodeoxycholic acid decreases transaminases in hepatitis C patients.

AIM: To examine whether a dose-up to 900 mg of ursodeoxycholic acid (UDCA) decreases transaminases in hepatitis C patients. METHODS: From January to December 2007, patients with chronic hepatitis C or compensated liver cirrhosis with hepatitis C virus (HCV) (43-80 years old) showing positive serum HCV-RNA who had already taken 600 mg/d of UDCA were recruited into this study. Blood parameters were examined at 4, 8 and 24 wk after increasing the dose of oral UDCA from 600 to 900 mg/d. RESULTS: Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) levels were significantly decreased following the administration of 900 mg/d as compared to 600 mg/d. The decrease in ALT from immediately before the dose-up of UDCA to 8 wk after the dose-up was 14.3 IU/L, while that for AST was 10.5 IU/L and for GGT was 9.8 IU/L. Platelet count tended to increase after the dose-up of UDCA, although it did not show a statistically significant level (P = 0.05). Minor adverse events were observed in 3 cases, although no drop-outs from the study occurred. CONCLUSION: Oral administration of 900 mg/d of UDCA was more effective than 600 mg/d for reducing ALT, AST, and GGT levels in patients with HCV-related chronic liver disease.

Evaluation of the effect of thyrotropin releasing hormone (TRH) on regional cerebral blood flow in spinocerebellar degeneration using 3DSRT.

Thyrotropin releasing hormone (TRH) therapy improves cerebellar ataxia in patients with spinocerebellar degeneration (SCD). We investigated the effect of TRH on regional cerebral blood flow (rCBF) using the fully automated region of interest (ROI) technique, 3DSRT. Ten patients with SCD received TRH intravenously (2 mg/day) for 14 days and underwent brain perfusion single photon emission computed tomography before and after therapy. Clinical efficacy was assessed using the International Cooperative Ataxia Rating Scale (ICARS). The rCBF in each ROI was measured using the noninvasive Patlak plot method and calculated using 3DSRT. TRH significantly improved the ICARS scores and increased rCBF in the callosomarginal segment and cerebellum. Cerebellar rCBF increased in 4 of 5 patients with improved ICARS scores and in 3 of 5 patients without improved ICARS scores after TRH therapy. The correlation between the change in cerebellar rCBF and the improved ICARS score, however, was not significant. These findings indicate that TRH therapy may increase cerebellar rCBF in some patients with cerebellar forms of SCD and that 3DSRT may be useful for evaluating the efficacy of TRH for increasing CBF. The beneficial effects of TRH may be due to increased cerebellar rCBF or the increased rCBF may be a secondary effect of TRH therapy.

Monofocal large inflammatory demyelinating lesion, mimicking brain glioma.

Here we report two cases of pathologically confirmed tumor-like demyelinating lesions. In comparison with common primary demyelinating diseases, our cases demonstrated atypical radiologic features, such as a large monofocal lesion with mild brain edema, and open ring-like or focal enhancement on magnetic resonance images, suggesting brain tumors. The clinical manifestations included focal neurologic signs due to the lesions, monophasic episodes without relapse over a long follow-up period, and efficacy of oral corticosteroid therapy. Histological analysis of brain biopsy specimens showed the inflammatory demyelination and preserved axons without tumor cells. The present cases suggest the importance of considering inflammatory demyelinating disease in the different diagnosis of monofocal tumor-like lesion.

[A case of hematomyelia caused by coagulation--fibrinolysis abnormality accompanied with colon cancer and its metastasis].

A 76-year-old woman developed weakness and sensory loss in the lower limbs and urinary disturbance in four days. She had a history of operation for the ascending colon cancer and lung metastasis one year ago. Neurological examination revealed flaccid paraplegia, absent Achilles tendon reflex, severe disturbance of superficial and deep sensation below the L3 level, and vesicorectal abnormality. Magnetic resonance imaging (MRI) studies showed an intramedullary T1-iso, T2-low lesion with Gd-DTPA contrast enhancement in conus medullaris at LI level. The laboratory examination revealed the elevated level of serum FDP. D-dimer and TAT. She was diagnosed as hematomyelia, which may be caused by the activation of coagulation and fibrinolysis system. We suggested that the ascending colon cancer and lung metastasis may contribute to the coagulation-fibrinolysis abnormality.