Serum anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder presenting as acute eosinophilic encephalomyelitis.

We report the case of a 57-year-old man with neuromyelitis optica spectrum disorder (NMOSD) presenting as acute eosinophilic encephalomyelitis. Magnetic resonance imaging revealed central nervous system lesions typical of NMOSD and anti-aquaporin-4 antibodies in the serum were identified; however, eosinophilia was evident in the cerebrospinal fluid (CSF) at the early stage of the disease. The number of eosinophils in the CSF decreased subsequently. Although activation of eosinophils is known to be an important factor in the development of NMOSD lesions, prominent eosinophilia in the CSF at the early stage of the disease has never been reported in patients with NMOSD.

Time-series analysis: variation of anti-acetylcholine receptor antibody titer in myasthenia gravis is related to incidence of Mycoplasma pneumoniae and influenza virus infections.

Objectives The exacerbating factors of myasthenia gravis (MG) are unknown. However, it has been speculated that infections may play a role in disease progression. Methods We calculated the adjusted anti-acetylcholine receptor antibody (Adj-AChR-Ab) titers (range, 0-1) in 58 MG patients between 2006 and 2012. We determined the relationship between Adj-AChR-Ab titer and infection incidence. Results A cross-correlation function (CCF) analysis of Adj-AChR-Ab titer and incidence of Mycoplasma pneumoniae (M. pneumoniae) (r = 0.449, P < 0.0001) and influenza virus (r = 0.411, P < 0.001) infections indicated significant correlations. MG with thymoma was highly correlated with M. pneumoniae infection (r = 0.798, P < 0.0001). The relative risk for Adj-AChR-Ab titer was 1.407 for M. pneumoniae (95% CI, 1.193-1.661 for an increase in one infected patient per monitoring point) and 1.158 for influenza (95% CI, 1.071-1.253 for 100 infected patients). Conclusion Variation of Adj-AChR-Ab titer is significantly influenced by the presence of M. pneumoniae and influenza virus infections.

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with lateral medullary syndrome: case report and literature review.

BACKGROUND: Only one case of syndrome of inappropriate secretion of antidiuretic hormone with lateral medullary syndrome has been reported so far. We report a case of lateral medullary syndrome showing syndrome of inappropriate secretion of antidiuretic hormone and analyze the pathomechanism underlying its clinical features. CASE PRESENTATION: A 67-year-old man was admitted to our hospital for dizziness, dysarthria, and dysphagia. He was diagnosed with lateral medullary syndrome based on the neurological examination and brain magnetic resonance imaging. Horner syndrome was absent. Asymptomatic hyponatremia appeared 9 days after admission and the patient was diagnosed with syndrome of inappropriate secretion of antidiuretic hormone. Fluid restriction and intravenous furosemide injection improved the hyponatremia. CONCLUSION: Lateral medullary syndrome could be associated with syndrome of inappropriate secretion of antidiuretic hormone.

Effect of cognitive and aerobic training intervention on older adults with mild or no cognitive impairment: a derivative study of the nakajima project.

BACKGROUND: An increasing elderly population in Japan requires effective cognitive intervention programs for dementia. This study demonstrates the effectiveness of such programs for older adults. METHODS: The participants were local community-dwelling non-demented older adults and adults with mild cognitive impairment who underwent executive function and group aerobic training. In addition, a non-intervention group participated in activity sessions involving handicraft, Skutt ball matches, and cooking. The four criteria for assessment were cognitive function, instrumental activities of daily living, human relationships, and physical function. RESULTS: The participants in both intervention groups showed a significant improvement in their memory function compared with the non-intervention group. CONCLUSION: Early rehabilitation intervention using executive function and aerobic training programs may improve memory.

Glucose metabolism and gray-matter concentration in apolipoprotein E ε4 positive normal subjects.

Apolipoprotein E (ApoE) ε4 is known as a genetic risk factor for Alzheimer's disease (AD). This study investigated the prevalence of imaging abnormalities suggestive of AD in cognitively normal ApoE ε4 carriers using (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and voxel-based morphometry (VBM). Forty-five cognitive normal ApoE ε4 allele carriers and 45 noncarriers underwent both FDG positron emission tomography and magnetic resonance imaging (MRI). A total of 90 normal database sets were generated for the individual 45 ε4 carriers and 45 noncarriers. Mean z-scores in the predefined AD-specific regions of interest (ROI) were calculated for each ε4 carrier and noncarrier using the individually defined normal database. The prevalence of AD-like hypometabolism and atrophy in the ε4 carriers was 8.9% and 17.7%, respectively, and did not differ significantly from those in the noncarriers (8.9%, 8.8%). The majority of ε4 carriers showed preserved FDG uptake or gray matter concentration.

Posterior cingulate atrophy and metabolic decline in early stage Alzheimer's disease.

To test the hypothesis that Alzheimer's disease (AD) patients with posterior cingulate/precuneus (PCP) atrophy would be a distinct disease form in view of metabolic decline. Eighty-one AD patients underwent (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and structural magnetic resonance imaging (MRI). Positron emission tomography and voxel-based morphometry (VBM) Z-score maps were generated for the individual patients using age-specific normal databases. The patients were classified into 3 groups based on atrophic patterns (no-Hipp-PCP, atrophy in neither hippocampus nor PCP; Hipp, hippocampal atrophy; PCP, PCP atrophy). There were 16 patients classified as no-Hipp-PCP, 55 as Hipp, and 10 as PCP. The Mini Mental State Examination (MMSE) score was similar among the groups. The greater FDG decline than atrophy was observed in all groups, including the no-Hipp-PCP. The PCP group was younger, and was associated with a greater degree of FDG decline in PCP than the others. There are diverse atrophic patterns in a spectrum of AD. In particular, a subset of patients show PCP atrophy, which is associated with greater metabolic burden.

Effect of an age-mismatched and sex-mismatched normal database on the diagnostic performance of ¹8F-FDG PET for Alzheimer's disease: the Ishikawa Brain Imaging Study.

OBJECTIVES: ¹8F-FDG PET with voxel-based statistical image analysis plays an important role in the diagnosis of Alzheimer's disease (AD). However, the effect of an age-matched and sex-matched or mismatched normal database (NDB) on the diagnostic performance of ¹8F-FDG PET has not yet been investigated systematically. The aim of this study was to determine whether an age-matched and sex-matched NDB is necessary for the detection of AD using ¹8F-FDG PET. METHODS: We generated 11 NDB sets for ¹8F-FDG PET, including six age-specific NDB sets consisting of participants ranging in age from 20 to 70 years, one age-non-specific NDB set, one age-matched NDB set, two sex-specific NDB sets, each consisting of 20 men or 20 women, and one sex-matched NDB set. The average z-scores in predefined AD-specific regions of interest of the PET images were calculated using those NDB sets and a receiver-operating characteristic analysis was carried out to assess the diagnostic performance of ¹8F-FDG PET to discriminate 46 patients with AD from 50 normal controls. RESULTS: There was no significant difference in each area under the receiver-operating characteristic curve using either age-matched/mismatched NDB sets or sex-matched/mismatched NDB sets. CONCLUSION: The diagnostic performance of ¹8F-FDG PET was rather insensitive to differences in age or sex in the NDB, indicating that exact age-matched or sex-matched NDB may not be essential for discriminating patients with AD from normal participants using ¹8F-FDG PET.

A comparison of the diagnostic sensitivity of MRI, CBF-SPECT, FDG-PET and cerebrospinal fluid biomarkers for detecting Alzheimer's disease in a memory clinic.

BACKGROUND/AIM: Magnetic resonance imaging (MRI), cerebral blood flow single photon emission computed tomography (CBF-SPECT), fluorodeoxyglucose-positron emission tomography (FDG-PET) and cerebrospinal fluid (CSF) biomarkers are used for the diagnosis of Alzheimer's disease (AD). We aimed to reveal the relative sensitivity of these tools in a memory clinic setting. METHODS: In 207 patients with probable AD in our memory clinic, medial temporal lobe atrophy on MRI, hypoperfusion/hypometabolism of the parietotemporal lobe and posterior cingulate gyrus in ethylcysteinate dimer-CBF-SPECT/FDG-PET, and abnormalities of CSF amyloid ß-protein 1-42, total tau and phosphorylated tau were evaluated as findings characteristic of AD. RESULTS: The AD findings were observed in 77.4% of all AD patients with MRI, 81.6% with CBF-SPECT, 93.1% with FDG-PET and 94.0% with CSF biomarkers. At the stage of Clinical Dementia Rating (CDR) 0.5, CSF biomarkers were the most sensitive (90.0%); at the stage of CDR 1, FDG-PET (96.7%) and CSF biomarkers (95.5%) were highly sensitive. At the stage of CDR 2, all tools showed high positive percentages. CONCLUSION: The diagnosis of AD was most often supported by CSF biomarkers and FDG-PET at the early stage of dementia (CDR 1) and by CSF biomarkers at the earlier stage (CDR 0.5).

Epidemiology of familial amyloid polyneuropathy in Japan: Identification of a novel endemic focus.

BACKGROUND: Familial amyloid polyneuropathy (FAP) is distributed worldwide with several endemic foci including two major foci in Japan. OBJECTIVE: To elucidate a nationwide epidemiology of FAP in Japan. DESIGN, SETTING, AND PATIENTS: (i) We analyzed the data of FAP patients registered by the Ministry of Health, Labour, and Welfare, Japan, during 2003-2005. (ii) As Ishikawa prefecture was found to be a novel endemic focus, we examined 27 FAP patients in Ishikawa to characterize their clinical and genetic features in comparison with other endemic foci. RESULTS: (i) The prevalence of familial amyloidosis in Japan was estimated to be 0.87-1.1 per 1,000,000 persons. Nagano prefecture had the highest prevalence (11-15.5), followed by Kumamoto (10.1-10.3), and then Ishikawa (3.5-4.2). (ii) All the FAP patients in Ishikawa had transthyretin (TTR) type FAP; all the families had a TTR Val30Met mutation except one family with a Leu58Arg mutation. FAP with Val30Met mutation in Ishikawa was characterized by late onset, high penetrance, and moderate autonomic dysfunction. CONCLUSIONS: Ishikawa prefecture is the third endemic focus of FAP in Japan. FAP with TTR Val30Met mutation in Japan can be classified to (i) early-onset and endemic (Nagano and Kumamoto), (ii) late-onset and endemic (Ishikawa), and (iii) late-onset and non-endemic types.

Effect of sample size for normal database on diagnostic performance of brain FDG PET for the detection of Alzheimer's disease using automated image analysis.

OBJECTIVE: To investigate the relationship between the sample size for a normal database (NDB) and diagnostic performance of FDG PET using three-dimensional stereotactic surface projection for the detection of Alzheimer's disease. METHODS: We generated nine NDB sets consisting of 4, 6, 8, 10, 20, 30, 40, 50 and 60 normal subjects. In order to assess the diagnostic performance using these NDBs to distinguish Alzheimer's disease patients from normal subjects, we recruited 52 patients with probable Alzheimer's disease (25 males, 27 females; mean age, 66.8+/-8.1 years) and 50 normal subjects (24 males, 26 females; mean age, 65.7+/-9.4 years). A receiver operating characteristic (ROC) analysis was performed for comparison of diagnostic accuracy among NDB sets. RESULTS: Small NDBs (n< or =10) yielded poor quality of mean and SD images as compared with large NDBs (n> or =20). The ROC curves of the smaller group varied inconsistently, whereas those of the larger group were nearly superimposable. The area under the ROC curve (AUC) of the NDBs with sample size 6 (0.911) or 8 (0.929) was significantly smaller than that of the largest NDB (n=60, 0.956). The AUCs of the larger group did not fall below 0.950, whereas AUCs of the smaller subgroup never exceeded 0.950. CONCLUSIONS: Our data indicate that the sample size for an NDB affects the diagnostic performance of FDG PET using automated statistical approach, and that inclusion of at least 10 subjects is recommended, and 20 seems to be preferable for generating NDBs, although even a small NDB may provide clinically relevant results.

Cerebrospinal fluid/serum IgG index is correlated with medial temporal lobe atrophy in Alzheimer's disease.

BACKGROUND/AIM: Intrathecal inflammation has been suggested to play an important role in the pathogenesis of Alzheimer's disease (AD). However, there is little clinical evidence in support of this hypothesis in AD patients. We previously reported that the blood-brain barrier permeability represented by the cerebrospinal fluid/serum albumin ratio correlates with medial temporal lobe atrophy (MTA) in AD. The aim of this study was to elucidate the relationship between intrathecal inflammation and the severity of AD. METHODS: We investigated the correlations between the cerebrospinal fluid/serum IgG index and the indices of AD severity, including Clinical Dementia Rating and Mini-Mental State Examination, and MTA on magnetic resonance imaging in 42 AD patients. Further, the number of apolipoprotein E isoforms and the blood-brain barrier permeability were also examined for the correlation with the IgG index. RESULTS: The IgG index showed a positive correlation with the severity of MTA but not with the other parameters examined. CONCLUSION: Our results suggest that intrathecal inflammation increases in association with the severity of MTA in AD.

Partial volume effect-corrected FDG PET and grey matter volume loss in patients with mild Alzheimer's disease.

PURPOSE: Although( 18)F-fluorodeoxyglucose (FDG) PET is an established imaging technique to assess brain glucose utilisation, accurate measurement of tracer concentration is confounded by the presence of partial volume effect (PVE) due to the limited spatial resolution of PET, which is particularly true in atrophic brains such as those encountered in patients with Alzheimer's disease (AD). Our aim was to investigate the effects of PVE correction on FDG PET in conjunction with voxel-based morphometry (VBM) in patients with mild AD. METHODS: Thirty-nine AD patients and 73 controls underwent FDG PET and MRI. The PVE-corrected grey matter PET images were obtained using an MRI-based three-compartment method. Additionally, the results of PET were compared with grey matter loss detected by VBM. RESULTS: Before PVE correction, reduced FDG uptake was observed in posterior cingulate gyri (PCG) and parieto-temporal lobes (PTL) in AD patients, which persisted after PVE correction. Notably, PVE correction revealed relatively preserved FDG uptake in hippocampal areas, despite the grey matter loss in medial temporal lobe (MTL) revealed by VBM. CONCLUSION: FDG uptake in PCG and PTL is reduced in AD regardless of whether or not PVE correction is applied, supporting the notion that the reduced FDG uptake in these areas is not the result of atrophy. Furthermore, FDG uptake by grey matter tissue in the MTL, including hippocampal areas, is relatively preserved, suggesting that compensatory mechanisms may play a role in patients with mild AD.

Blood-brain barrier permeability correlates with medial temporal lobe atrophy but not with amyloid-beta protein transport across the blood-brain barrier in Alzheimer's disease.

BACKGROUND/AIMS: Alterations in the blood-brain barrier (BBB) may play an important role in the pathogenesis and treatment of Alzheimer's disease (AD). We investigated BBB disturbance and its influence on the equilibrium of amyloid-beta protein (Abeta) between plasma and cerebrospinal fluid (CSF) in AD patients. METHODS: We analyzed albumin ratio as a marker of the BBB permeability and correlated it with the severity of dementia, brain atrophy on MRI, apolipoprotein E isoform, CSF levels of total tau, CSF and plasma levels of Abeta 1-40 (Abeta40) and 1-42 (Abeta42), and CSF/plasma ratios of Abeta40 and Abeta42 in 42 AD patients. RESULTS: The albumin ratio was positively correlated with the severity of medial temporal lobe atrophy but not with the other parameters including CSF/plasma ratios of Abeta40 or Abeta42. CONCLUSION: Our results suggest that progression of medial temporal lobe atrophy is associated with increased BBB permeability and that the transport of Abeta across the BBB is not influenced by the BBB alteration in AD.

Blood-borne factors inhibit Alzheimer's beta-amyloid fibril formation in vitro.

Soluble amyloid beta-protein (Abeta) does not aggregate to beta-amyloid fibrils (fAbeta) in the brain of normal humans. We recently found that the cerebrospinal fluid (CSF) from non-Alzheimer's disease (AD) subjects inhibited the formation of fAbeta(1-40) and fAbeta(1-42) more strongly than that from AD subjects, although the CSF obtained from both groups inhibited the fAbetas formation in vitro. Here, we examined the influence of plasma obtained from AD, non-AD and healthy control (CTL) subjects on the formation of fAbeta(1-40) and fAbeta(1-42) in vitro. Although the plasma obtained from all groups inhibited the formation of fAbeta(1-40) and fAbeta(1-42), the plasma from non-AD and CTL subjects inhibited the formation of fAbetas more strongly than that from AD subjects. These results indicate that the plasma as well as CSF in AD would provide a molecular environment favorable for fAbeta formation, suggesting a decrease of specific inhibitory factors and/or increase of specific accelerating factors.

Immunoglobulin light-chain (AL) amyloidosis with myasthenic symptoms and echocardiographic features of dilated cardiomyopathy.

Myasthenic symptoms and the echocardiographic findings of dilated cardiomyopathy are very rare in primary AL amyloidosis. We report a 59-year-old man with dyspnea on effort and weakness after exercise. His electrocardiogram showed ischemic heart disease and echocardiography indicated dilated cardiomyopathy. Muscle biopsy revealed amyloidosis with deposits of lambda light chain-derived amyloid within the vessel wall. Treatment with PGE1 resulted in improvement of the myasthenic symptoms. This patient indicates that myasthenic symptoms and dilated cardiomyopathy would be a unique syndrome associated with systemic AL amyloidosis involving mainly the small vessels, i.e., AL amyloid angiopathy, in the skeletal muscles and myocardium vessels.

Cerebrospinal fluid of Alzheimer patients promotes beta-amyloid fibril formation in vitro.

Cerebral deposition of amyloid beta-peptide (Abeta) is an invariant feature of Alzheimer's disease (AD). To answer why soluble Abeta does not aggregate to beta-amyloid fibrils (fAbeta) in the brain of normal humans, we examined the influence of cerebrospinal fluid (CSF) obtained from AD and non-AD patients on the formation of fAbeta(1-40) and fAbeta(1-42) in vitro, by using fluorescence spectroscopy with thioflavin T and electron microscopy. Although the CSF obtained from both groups inhibited the formation of both fAbeta(1-40) and fAbeta(1-42), the CSF from non-AD patients inhibited the formation of fAbetas more strongly than that from AD patients. In AD patients, the final levels of fAbetas formation showed a significant negative correlation with the Abeta(1-42) level in CSF. These results indicate that fAbeta deposition in the brain of AD may be enhanced by the decrease of specific inhibitory factors and/or by the increase of specific accelerating factors in CSF.