123I-MIBG myocardial scintigraphy for the diagnosis of DLB: a multicentre 3-year follow-up study.

BACKGROUND AND PURPOSE: We previously reported the usefulness of iodine-123 metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy for differentiation of dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) in a cross-sectional multicentre study. The aim of this study was, by using reassessed diagnosis after 3-year follow-up, to evaluate the diagnostic accuracy of 123I-MIBG scintigraphy in differentiation of probable DLB from probable AD. METHODS: We undertook 3-year follow-up of 133 patients with probable or possible DLB or probable AD who had undergone 123I-MIBG myocardial scintigraphy at baseline. An independent consensus panel made final diagnosis at 3-year follow-up. Based on the final diagnosis, we re-evaluated the diagnostic accuracy of 123I-MIBG scintigraphy performed at baseline. RESULTS: Sixty-five patients completed 3-year follow-up assessment. The final diagnoses were probable DLB (n=30), possible DLB (n=3) and probably AD (n=31), and depression (n=1). With a receiver operating characteristic curve analysis of heart-to-mediastinum (H/M) ratios for differentiating probable DLB from probable AD, the sensitivity/specificity were 0.77/0.94 for early images using 2.51 as the threshold of early H/M ratio, and 0.77/0.97 for delayed images using 2.20 as the threshold of delayed H/M ratio. Five of six patients who were diagnosed with possible DLB at baseline and with probable DLB at follow-up had low H/M ratio at baseline. CONCLUSIONS: Our follow-up study confirmed high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy at baseline and the clinical diagnosis of probable DLB at 3-year follow-up. Its diagnostic usefulness in early stage of DLB was suggested. TRIAL REGISTRATION NUMBER: UMIN00003419.

Differences in Dementia Beliefs between Non-Demented Public Screeners and In-Home Screeners and Their Potential Impact on Future Dementia Screening Intention: The Nakajima Study.

In many cohort studies of dementia, while differences in sociodemographic characters between responders and non-responders of dementia screening have been reported, differences in dementia beliefs have been relatively less known. The aims of this study were to clarify dementia beliefs and to explore potential impacts on an intention to attend a future dementia screening in public screeners and in-home screeners, respectively. We performed a cross-sectional population-based study using a question about an intention to attend a future dementia screening and a questionnaire on dementia beliefs. Subjects were all residents aged 65 years or older in the north area of Nakajima, Japan (n = 385). All subjects were asked to attend a public dementia screening first. An in-home dementia screening was subsequently conducted in subjects with non-responders to a public screening. The questionnaire consisted of four dementia beliefs: "perceived susceptibility," "perceived severity," "perceived barriers," and "perceived benefits." Public screeners significantly expressed an intention to attend a future dementia screening more than in-home screeners (p = 0.002). In in-home screeners, low "perceived severity" were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 0.51 (0.32-0.80)]. In both public and in-home screeners, high "perceived benefits" were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 2.13 (1.46-3.10); adjusted OR (95% CI) = 2.56 (1.22-5.35), respectively]. It is necessary to reduce "perceived severity" among in-home screeners to increase dementia screening participants.

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.

Multiple sclerosis showing elevation of adenosine deaminase levels in the cerebrospinal fluid.

An 80-year-old man developed dysarthria, quadriplegia, sensory disturbance and ataxia in all limbs. Brain and spinal magnetic resonance imaging (MRI) revealed multiple enhanced lesions. Cerebrospinal fluid (CSF) levels of adenosine deaminase (ADA) remarkably elevated. Tuberculosis DNA was not detected, and tuberculosis was not cultured either in the CSF. Brain biopsy revealed the inflammatory demyelinating lesions. With the diagnosis of multiple sclerosis, corticosteroid therapy resulted in rapid improvement of his symptoms and MRI abnormalities. CSF levels of ADA also decreased. Multiple sclerosis should be included in differential diagnosis of disorders with ADA elevation in the CSF.

Cerebral Amyloid Angiopathy-Related Microbleeds and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) commonly accompanies cerebral amyloid angiopathy (CAA). OBJECTIVE: We aimed to reveal associations between CAA-related brain microbleeds and cerebrospinal fluid (CSF) markers in AD patients. METHODS: Patients with probable AD (n = 88) from consecutive patients in our memory clinic were evaluated for patient demographics, vascular risk factors, neuropsychological tests, apolipoprotein E phenotype, MRI including T2*-weighted image and fluid attenuated inversion recovery sequence, and CSF amyloid and tau markers. RESULTS: The 88 patients with AD included 15 with microbleeds only in cortical/subcortical regions (cortical microbleeds) that could be CAA-related, 16 with microbleeds only in deep locations (deep microbleeds), 3 with microbleeds in both cortical and deep locations (mixed microbleeds), and 54 without microbleeds. The CSF levels of amyloid ß-protein 1-40 (Aß40) and amyloid ß-protein 1-42 (Aß42) were significantly lower in patients with cortical microbleeds than in those without microbleeds (p = 0.001 and p = 0.027, respectively). The result remained unchanged after adjustment for age, sex, apolipoprotein E E4 presence, and leukoaraiosis. CONCLUSIONS: CAA-related cortical microbleeds would be associated with lower CSF levels of Aß40 and Aß42 in AD, reflecting the deposition of both Aß40 and Aß42 in the cerebrovasculature.

Cerebral Amyloid Angiopathy-Related Microbleeds Correlate with Glucose Metabolism and Brain Volume in Alzheimer's Disease.

BACKGROUND: Microbleeds (MBs) are frequently observed in Alzheimer's disease (AD); however, the relevance to AD pathophysiology has not been elucidated. OBJECTIVES: We investigated correlation of MBs, especially cerebral amyloid angiopathy (CAA)-related MBs with cognitive function, gray matter volume, and glucose metabolism in AD. METHODS: We performed magnetic resonance imaging including T2*-weighted imaging sequence for 206 patients with AD. Among them, 158 AD patients with no focal brain lesions except for MBs were investigated with cognitive tests, voxel-based morphometry, and 18F-fluorodeoxyglucose positron emission tomography in a cross-sectional observational study. RESULTS: Of the 158 patients with no hemorrhagic and/or ischemic stroke lesions except for MBs, 27 patients had MBs, in which 17 patients showed CAA-related MBs that located only in cortex/subcortex (CAA-related MBs), and 10 patients showed CAA-unrelated MBs that located in deep regions regardless of the presence of MBs in cortical/subcortical regions. There were slightly but significant differences in cognitive functions between the patients without MBs, those with CAA-related MBs, and those with CAA-unrelated MBs. MBs were recognized frequently in the occipital lobe in the patients with CAA-related MBs. The patients with CAA-related MBs showed gray matter atrophy in the temporal lobe and cerebellum, and glucose hypometabolism in the temporal lobe compared with those without MBs. CONCLUSIONS: Our results indicate that MBs, particularly CAA-related MBs would cause gray matter atrophy and glucose hypometabolism in AD.

Diagnostic accuracy of 123I-meta-iodobenzylguanidine myocardial scintigraphy in dementia with Lewy bodies: a multicenter study.

BACKGROUND AND PURPOSE: Dementia with Lewy bodies (DLB) needs to be distinguished from Alzheimer's disease (AD) because of important differences in patient management and outcome. Severe cardiac sympathetic degeneration occurs in DLB, but not in AD, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the diagnostic accuracy, in the ante-mortem differentiation of probable DLB from probable AD, of cardiac imaging with the ligand 123I-meta-iodobenzylguanidine (MIBG) which binds to the noradrenaline reuptake site, in the first multicenter study. METHODS: We performed a multicenter study in which we used 123I-MIBG scans to assess 133 patients with clinical diagnoses of probable (n = 61) or possible (n = 26) DLB or probable AD (n = 46) established by a consensus panel. Three readers, unaware of the clinical diagnosis, classified the images as either normal or abnormal by visual inspection. The heart-to-mediastinum ratios of 123I-MIBG uptake were also calculated using an automated region-of-interest based system. RESULTS: Using the heart-to-mediastinum ratio calculated with the automated system, the sensitivity was 68.9% and the specificity was 89.1% to differentiate probable DLB from probable AD in both early and delayed images. By visual assessment, the sensitivity and specificity were 68.9% and 87.0%, respectively. In a subpopulation of patients with mild dementia (MMSE ≥ 22, n = 47), the sensitivity and specificity were 77.4% and 93.8%, respectively, with the delayed heart-to-mediastinum ratio. CONCLUSIONS: Our first multicenter study confirmed the high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from AD, especially in patients with mild dementia.

Agraphia of Kanji (Chinese characters): an early symptom of sporadic Creutzfeldt-Jakob disease in a Japanese patient: a case report.

INTRODUCTION: Slowly progressive cognitive decline is the most frequent initial manifestation in MM2-cortical-type sporadic Creutzfeldt-Jakob disease. Agraphia has never been noted in patients with this type of sporadic Creutzfeldt-Jakob disease, however, we report the case of a Japanese patient with sporadic Creutzfeldt-Jakob disease in whom agraphia of Kanji was an initial cardinal symptom. CASE PRESENTATION: A 59-year-old right-handed Japanese woman complained of agraphia of Kanji (Chinese characters) as an initial symptom. A neurological examination revealed mild word-finding difficulty, constructive disturbance, hyperreflexia in her jaw and lower limbs, and bilateral extensor plantar reflexes. An examination of her cerebrospinal fluid revealed increased levels of 14-3-3 and total tau proteins, and abnormal conformation of the proteinase K-resistant prion protein. Diffusion-weighted magnetic resonance imaging showed diffuse hyperintensity in bilateral cerebral cortices. Single-photon emission computed tomography scans revealed hypoperfusion in the left temporal lobe, bilateral parietal and occipital lobes. An analysis of the prion protein gene demonstrated no mutation with homozygous for methionine at the codon 129. We diagnosed our patient with sporadic Creutzfeldt-Jakob disease. Although a histological examination was not performed, it was assumed that our patient could be the MM2-cortical type according to the clinical findings and the elevated levels of 14-3-3 protein in her cerebrospinal fluid. The left posterior inferior temporal area, which was affected in our patient as a hypoperfusion area, is associated with selecting and recalling Kanji characters. CONCLUSIONS: Focal signs as an early symptom and hypoperfusion areas in sporadic Creutzfeldt-Jakob disease are critical to recognize initial brain lesions damaged by the proteinase K-resistant prion protein accumulation.

Efficacy of diflunisal on autonomic dysfunction of late-onset familial amyloid polyneuropathy (TTR Val30Met) in a Japanese endemic area.

OBJECTIVE: To evaluate the long-term efficacy and safety of diflunisal in late-onset familial amyloid polyneuropathy (FAP) in a Japanese endemic area. METHODS: Consecutive six FAP patients (mean age: 65.8 ± 7.3 years) with a transthyretin (TTR) Val30Met mutation from an endemic area of late-onset FAP were prospectively recruited to an open label study with oral diflunisal (250 mg twice a day). We evaluated clinical symptoms, Kumamoto FAP score, modified body mass index (mBMI), Medical Research Council sum score, nerve conduction studies (NCS), electrocardiogram (ECG), ECG Holter monitor test, echocardiography, and (123)iodine-metaiodobenzylguanidine ((123)I-MIBG) myocardial scintigraphy. RESULTS: One patient ceased to take diflunisal because of hematuria which was reversible. The other five patients were treated with diflunisal for 3-5 (4.4 ± 0.9 years) years. Autonomic symptoms (orthostatic hypotension and gastrointestinal symptoms) disappeared after treatment in two of the four patients with the symptoms. Delayed heart to mediastinum ratio on (123)I-MIBG imaging, a marker of cardiac postganglionic sympathetic nerve function, increased during the three-year treatment. mBMI was maintained through observation period. While, motor and sensory symptoms, Kumamoto FAP scores, and data on NCS gradually deteriorated. CONCLUSION: Diflunisal might be effective especially for autonomic dysfunction in late-onset FAP with a TTR Val30Met mutation.

Consumption of green tea, but not black tea or coffee, is associated with reduced risk of cognitive decline.

Our objective was to determine whether the consumption of green tea, coffee, or black tea influences the incidence of dementia and mild cognitive impairment (MCI) in older people. We conducted a population-based prospective study with Japanese residents aged >60 years from Nakajima, Japan (the Nakajima Project). Participants received an evaluation of cognitive function and blood tests. The consumption of green tea, coffee, and black tea was also evaluated at baseline. Of 723 participants with normal cognitive function at a baseline survey (2007-2008), 490 completed the follow up survey in 2011-2013. The incidence of dementia during the follow-up period (mean ± SD: 4.9 ± 0.9 years) was 5.3%, and that of MCI was 13.1%. The multiple-adjusted odds ratio for the incidence of overall cognitive decline (dementia or MCI) was 0.32 (95% CI: 0.16-0.64) among individuals who consumed green tea every day and 0.47 (95% CI: 0.25-0.86) among those who consumed green tea 1-6 days per week compared with individuals who did not consume green tea at all. The multiple-adjusted odds ratio for the incidence of dementia was 0.26 (95% CI: 0.06-1.06) among individuals who consumed green tea every day compared with those who did not consume green tea at all. No association was found between coffee or black tea consumption and the incidence of dementia or MCI. Our results indicate that green tea consumption is significantly associated with reduced risk of cognitive decline, even after adjustment for possible confounding factors.

Myasthenia gravis: predictive factors associated with the synchronized elevation of anti-acetylcholine receptor antibody titer in Kanazawa, Japan.

For a brief period, an increased incidence of elevated anti-acetylcholine receptor antibody titer was observed in patients with myasthenia gravis (MG) in Kanazawa, Japan. The purpose of this study was to examine the predictive factors associated with this antibody titer elevation. Decreased odds of titer elevation were seen in patients with early-onset MG than in those with late-onset MG. In patients with non-thymoma-related MG, thymectomy prevented the antibody titer elevation. Our data suggest that late-onset MG may have a different immunogenic response and the thymus might play an immunoregulatory role against extrinsic factors in some types of MG.

Differences in the prevalence of dementia and mild cognitive impairment and cognitive functions between early and delayed responders in a community-based study of the elderly.

Significant differences exist in demographic characteristics between responders and non-responders in population-based studies on mental health and cognitive status, but much less is known regarding differences in the prevalence of dementia and cognitive dysfunction between them. Here we compared the prevalence of dementia and mild cognitive impairment between early responders of a mass brain function examination and delayed responders (non-responders of the mass brain function examination) in a survey of elderly Japanese citizens (≥65 years) to evaluate non-responder bias. All residents in an area of Nakajima, Japan, were considered as potential candidates (n = 783). Participants of a mass brain function examination were considered as "early responders." The cognitive functions of delayed responders were assessed by home visits. To assess the correlation between sociodemographic characteristics and cognitive functions, the early and delayed responders completed the same questionnaires and neuropsychological tests. Delayed responders (n = 320) were significantly older and less educated than the early responders (n = 307). The delayed responders also exhibited a higher frequency of dementia and mild cognitive impairment than the early responders, even when the groups were restricted to the age group 65-89 years. Our results suggest that population-based studies likely underestimate the prevalence of dementia and mild cognitive impairment, especially if the participation rate is low.

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).