Induction of Genes Expressed in Endothelial Cells of the Corpus Callosum in the Chronic Cerebral Hypoperfusion Rat Model.

BACKGROUND: Cerebrovascular white matter lesions (WMLs) are associated with cognitive impairment in patients with subcortical vascular dementia. We performed a comprehensive gene expression analysis to elucidate genes associated with WML development in a chronic cerebral hypoperfusion rat model. METHODS: Brains of rats with bilateral carotid ligation (2VO, n = 10) and sham-operated rats (n = 5-10/group) were removed on days 1, 7, or 28 after surgery. Total RNA isolated from the corpus callosum was evaluated by microarray analysis and quantitative reverse transcription-polymerase chain reaction. RESULTS: On days 7 and 28, WMLs exhibited histologic changes. On day 7, 16 genes were differentially expressed between groups. mRNA levels of Ptprb, Kcnj8, Crispld2, Bcl6b, and Gja5 were differentially expressed in 2VO rats on day 7, but then returned to normal, whereas mRNA levels of Vwf and Trappc6a were upregulated after day 7. Immunohistochemistry showed that GJA5 and vWF were detected in endothelial cells, KCNJ8 in endothelial cells and astrocytes, CRISPLD2 in neurons and astrocytes, and TRAPPC6A in neurons. CONCLUSION: Our findings indicate novel genes that may be associated with WML development in the chronic cerebral hypoperfusion rat model, and suggest an important role of neurovascular dysfunction in the pathophysiology.

Thomsen disease with ptosis and abnormal MR findings.

Myotonia congenita is a non-dystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction caused by a mutation in the gene encoding skeletal muscle chloride channel-1 (CLCN1). We encountered a case of Thomsen disease with ptosis. A short tau inversion recovery MR imaging demonstrated high-intensity lesions in the levator palpebrae superioris muscles. Molecular genetic testing revealed a heterozygosity for the c.1439C>A (p.P480H) mutation in the CLCN1 gene. The expression level of ClC-1 was significantly reduced on the sarcolemma of the biceps brachii muscle from the patient, compared with that from healthy volunteer. Functional analysis of the p.P480H mutation is required for further elucidating the pathogenesis of Thomsen disease.

Angiopoietin-2 expression in patients with an acute exacerbation of idiopathic interstitial pneumonias.

BACKGROUND AND OBJECTIVE: We hypothesized that increased pulmonary vascular permeability may play a role in the pathogenesis of an acute exacerbation of the idiopathic interstitial pneumonias (AE-IIPs). Angiopoietin-2 (Ang-2) promotes endothelial activation, destabilization, and inflammation. The purpose of this study was to examine whether Ang-2 expression was associated with the pathogenesis of AE-IIPs. METHODS: Twenty-three patients with AE-IIP patients, 18 acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients, 37 idiopathic pulmonary fibrosis (IPF) patients, and 33 healthy volunteers (HVs) were enrolled. The serum level of Ang-2 was measured by an enzyme-linked immunosorbent assay. RESULTS: The serum levels of Ang-2 were higher in AE-IIPs and ALI/ARDS patients than in IPF patients and HVs; the BALF levels of Ang-2 were also higher than in IPF patients. There was a positive correlation between the serum level of Ang-2 and the CRP in patients with AE-IIP patients, whereas a significant positive correlation was found between the serum Ang-2 level and the CRP or SOFA scores of the ALI/ARDS patients. Although the baseline Ang-2 level was not related to survival, the Ang-2 levels significantly declined in survivors during treatment, while they did not change in non-survivors. CONCLUSIONS: Increased pulmonary vascular permeability and inflammation due to Ang-2 may play a role in the pathogenesis of AE-IIPs.

Brain perfusion SPECT in limbic encephalitis associated with autoantibody against the glutamate receptor epsilon 2.

OBJECTIVES: The aim of this study was to elucidate the single-photon emission computed tomography (SPECT) pattern at the acute stage of disease in non-herpetic limbic encephalitis (NHLE) patients associated with the N-methyl-D-aspartate-type glutamate receptor epsilon 2 (GluR ϵ2) autoantibody using Z-score imaging system (eZIS) analyses. METHODS: Brain magnetic resonance imaging (MRI) and brain perfusion SPECT using technetium-99 ethyl cysteinate dimer ((99m)Tc-ECD) were performed in eight patients with NHLE (5 men and 3 women; mean age 48.8±22 years) within 20days after clinical onset. RESULTS: All patients had various clinical limbic-associated symptoms and no evidence of herpes simplex infection or systemic malignancies. Two of eight patients showed abnormally hyperintense lesions on diffusion-weighted images and significant hyperperfusion in ipsilateral cerebral cortex on eZIS analysis, whereas other patients showed normal MRI findings and significant hypoperfusion in one or both sides of the limbic and paralimbic areas. CONCLUSION: We suggest that (99m)Tc-ECD SPECT study using eZIS analyses may be helpful to detect the neuronal dysfunction, particularly in NHLE patients without abnormal MRI findings.

Hard metal lung disease successfully treated with inhaled corticosteroids.

We herein report a case of hard metal lung disease that was successfully treated with inhaled corticosteroids. A 46-year-old man was admitted to our hospital due to coughing and an abnormal shadow on a chest radiograph. He had worked as a hard metal tool sharpener for five years. Chest computed tomography scans showed centrilobular micronodules and areas of ground-glass opacity in the bilateral lung fields. Video-associated lung biopsy specimens revealed bronchocentric interstitial pneumonia and cellular bronchiolitis. A high-energy dispersion X-ray microanalysis detected tungsten. The patient was diagnosed with hard metal lung disease. Inhaled corticosteroid therapy (800 µg of ciclesonide hydrofluoroalkane daily) resolved the patient's symptoms, elevated KL-6 level, abnormal areas of chest opacity and obstructive, restrictive and diffusion impairments.

Relationship between White Matter Lesions and Progression of Cognitive Decline in Alzheimer's Disease.

BACKGROUND: This study examined the relationship between baseline white matter lesions (WMLs) and the progression of cognitive decline in patients with late-onset Alzheimer's disease (AD). METHODS: Fifty-six patients with AD were included in the study (23 men, 33 women; mean age, 77.8 years). All subjects were treated with acetylcholinesterase inhibitors and followed up for approximately 1 year. The Mini-Mental State Examination (MMSE) score was assessed at least twice to evaluate the progressive cognitive impairment. All subjects underwent brain MRI at baseline and were divided into WMLs(-), mild WMLs(+), and moderate WMLs(+) groups based on WML severity. Changes in MMSE scores between baseline and follow-up were analyzed using the Wilcoxon signed-rank test. RESULTS: MMSE scores at baseline did not differ significantly among the three groups (p = 0.1658), whereas MMSE scores at the follow-up evaluation were significantly lower in the moderate WMLs(+) group than in the WMLs(-) group (p = 0.0257). The mean MMSE scores remained above baseline values during the approximately 1-year follow-up in the WMLs(-) group, whereas they were decreased in the mild and moderate WMLs(+) groups. Moreover, the frequency of improvement in patients from the WMLs(-) group tended to be higher than that in patients from the WMLs(+) groups. CONCLUSION: Baseline WMLs may be associated with the heterogeneous progression of cognitive decline in patients with AD.

Incidence of myeloperoxidase anti-neutrophil cytoplasmic antibody positivity and microscopic polyangitis in the course of idiopathic pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis is a manifestation of microscopic polyangitis (MPA), and often precedes the detection of MPA. The prevalence and sequence of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) and MPA in patients initially diagnosed with idiopathic pulmonary fibrosis (IPF) have not been precisely elucidated. METHODS: We enrolled 61 consecutive patients with IPF and measured the MPO-ANCA titers at initial presentation and during the follow-up period. Clinical, radiologic and histologic features of MPO-ANCA-positive cases were examined. RESULTS: Of 61 patients, 3 (4.9%) had positive MPO-ANCA titers at the initial presentation of IPF. During the disease course, MPO-ANCA-positive conversion occurred in 6 patients and the prevalence of ANCA increased to 14.8%. Among the nine patients positive for MPO-ANCA, two patients developed MPA during follow-up. Histologic features of MPO-ANCA-positive pulmonary fibrosis were compatible with the usual interstitial pneumonia pattern in which alveolar hemorrhage and capillaritis were not observed. The patients with MPO-ANCA-positive conversion showed increased percentages of bronchoalveolar lavage eosinophils and more frequent complication of pulmonary emphysema compared to those with MPO-ANCA-negative IPF. CONCLUSIONS: The findings of the present study demonstrated that patients with an initial diagnosis of IPF occasionally acquire MPO-ANCA, which develops to MPA during the disease course of IPF. The presence of pulmonary eosinophilia and low attenuation areas on computed tomography scans might be predictive of MPO-ANCA positive conversion.

[Central nervous system involvement of sarcoidosis: diagnosis and management].

Sarcoidosis is a multisystem inflammatory granulomatous disease that affects the central nervous system (CNS). CNS Involvement occurs in a relatively small number of patients with sarcoidosis but is potentially serious manifestation. Diagnostic criteria usually include histologic identification of a noncaseating epithelioid granuloma, supportive laboratory or neuroimaging tests or both, and a compatible clinical course. Diagnostic criteria proposed by "The Diagnosis Guideline for Sarcoidosis in Japan -2006" can distinguish definite, probable, and possible neurosarcoidosis, and may be now commonly used. Patients with a definite or probable diagnosis of CNS sarcoidosis should start treatment promptly. The pharmacologic regimens for the treatment of neurosarcoidosis are not standardized since no prospective, randomized, controlled trials have been performed in the World. Corticosteroids, however, are typically the first line or therapy and approximately half of patients have substantial benefit. For patients who are refractory to or intolerant of corticosteroid therapy, second-line agents include azathioprine, methotrexate, cyclosporine, cyclophosphamide, and mycophenolate mofetil (MMF). Treatment regimens vary in term of doing, maintenance, and tapering. Radiotherapy or neurosurgical treatment is indicated when medications fail or when life-threatening emergences, such as severe hydrocephalus and elevated intracranial pressure, arise. The combination of infliximab, an anti-TNF-alpha neutralizing antibody, and MMF has recently been used to treat neurosarcoidosis. Treatment option will likely evolve as well-designed studies are undertaken.

Effect of white matter lesions on brain perfusion in Alzheimer's disease.

BACKGROUND: This study examined the effect of white matter lesions (WMLs) on regional cerebral blood flow (rCBF) in patients with Alzheimer's disease (AD). METHODS: Ninety-eight patients with AD were included in the study (40 men and 58 women; mean age, 78.1 years). Cognitive function was assessed using the Mini-Mental State Examination. Brain magnetic resonance imaging (MRI) and (99m)Tc ethyl cysteinate dimer single photon emission computed tomography were performed in all subjects. AD patients were divided into two subgroups according to the presence of WMLs on MRI. A voxel-by-voxel group analysis using Statistical Parametric Mapping 8 was used to detect the differences in rCBF between the two groups. RESULTS: Fifty-seven of 98 AD patients (58%) showed mild to moderate WMLs on MRI. The prevalence of hypertension was significantly higher in AD patients with WMLs than in those without WMLs. AD patients with WMLs exhibited a significantly decreased rCBF in the anterior cingulate gyrus and insula, compared to AD patients without WMLs. CONCLUSION: We suggest that WMLs might influence brain regions associated with the limbic system in patients with AD.

Incidentally discovered primary malignant melanoma of the trachea.

Primary malignant melanoma of the trachea is extremely rare. We report here the first case of primary tracheal malignant melanoma in the asymptomatic stage. Incidentally, this 73-year-old man was found to have a flat tumor at the upper trachea on chest computed tomography scans. The tumor was surgically resected with end-to-end anastomosis and was diagnosed to be primary malignant melanoma of the trachea. Four months after the surgical resection, cervical lymph node metastasis was found. Despite the resection of metastatic lymph nodes and six courses of chemotherapy, he died of cachexia approximately two years after the discovery of the tracheal tumor.

Heterozygous UDP-GlcNAc 2-epimerase and N-acetylmannosamine kinase domain mutations in the GNE gene result in a less severe GNE myopathy phenotype compared to homozygous N-acetylmannosamine kinase domain mutations.

BACKGROUND: Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy, also called distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy (HIBM), is a rare, progressive autosomal recessive disorder caused by mutations in the GNE gene. Here, we examined the relationship between genotype and clinical phenotype in participants with GNE myopathy. METHODS: Participants with GNE myopathy were asked to complete a questionnaire regarding medical history and current symptoms. RESULTS: A total of 71 participants with genetically confirmed GNE myopathy (27 males and 44 females; mean age, 43.1±13.0 (mean±SD) years) completed the questionnaire. Initial symptoms (e.g., foot drop and lower limb weakness) appeared at a mean age of 24.8±8.3 years. Among the 71 participants, 11 (15.5%) had the ability to walk, with a median time to loss of ambulation of 17.0±2.1 years after disease onset. Participants with a homozygous mutation (p.V572L) in the N-acetylmannosamine kinase domain (KD/KD participants) had an earlier disease onset compared to compound heterozygous participants with mutations in the uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase and N-acetylmannosamine kinase domains (ED/KD participants; 26.3±7.3 vs. 21.2±11.1 years, respectively). KD/KD participants were more frequently non-ambulatory compared to ED/KD participants at the time of survey (80% vs. 50%). Data were verified using medical records available from 17 outpatient participants. CONCLUSIONS: Homozygous KD/KD participants exhibited a more severe phenotype compared to heterozygous ED/KD participants.

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.

[A case of neurosarcoidosis with swelling and gadolinium enhancement of spinal nerve roots on magnetic resonance imaging].

An 80-year-old woman was admitted to our hospital because of developed sense of constriction in the trunk and gradually progressive numbness and muscle weakness in the upper and lower extremities. Cerebrospinal fluid analysis showed increased cell count and protein level. Gadolinium enhanced magnetic resonance imaging (MRI) of spine showed the enhancement and swelling of bilateral nerve root in the cervical and lumbar segments. Although chest computed tomography showed neither bilateral hilar lymphoadenopathy nor lung lesions and serum angiotensin converting enzyme and lysozyme (ACE) were normal, tuberculin skin test was negative and cell count and CD4/CD8 elevated in bronchoalveolar lavage fluid. Biopsy specimen of scalene lymph node showed noncaseating granuloma. The patient was treated with oral predonisolone, which improved her symptoms and abnormalities on MRI. It is important to consider neurosarcoidosis in the differential diagnosis of polyradiculopathy with swelling and gadolinium enhancement of spinal nerve roots.

[A case of limbic encephalitis repeated aphasic status epilepticus with periodic lateralized epileptiform discharges].

We report a case of limbic encephalitis repeated aphasic status epilepticus with periodic lateralized epileptiform discharges (PLEDs). A 51-year-old man developed convulsions, psychiatric symptoms such as anxiety, phobia and ease of anger, and Wernicke's aphasia. Analysis of the cerebrospinal fluid (CSF) showed increase of leukocyte count (148/microl, mononuclear cells). Brain magnetic resonance imaging (MRI) showed hyperintensity lesions in the left medial temporal area and basal frontal area on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. The electroencephalography (EEG) showed PLEDs over the left hemisphere, occurring at intervals of 0.5-1 Hz. Although his limbic symptoms improved, Wernicke's aphasia occurred periodically with PLEDs appearance. After the administration of antiepileptic drugs, his language performance improved, and PLEDs were completely disappeared. We diagnosed him limbic encephalitis with non-convulsive repeated aphasic status epilepticus with periodic lateralized epileptiform discharges. Aphasic status epilepticus should be considered in the patients with limbic encephalitis, and careful evaluation of aphasia and EEG should be necessary to diagnose of aphasic status epilepticus.

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.