Junji Komatsu

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.

Inclusion body myopathy with paget disease of bone and frontotemporal dementia associated with a novel G156s mutation in the VCP gene

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

BACKGROUND Alzheimers 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 β-protein 1-40 (Aβ40) and amyloid β-protein 1-42 (Aβ42) 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 Aβ40 and Aβ42 in AD, reflecting the deposition of both Aβ40 and Aβ42 in the cerebrovasculature.

Creutzfeldt-Jakob disease associated with a V203I homozygous mutation in the prion protein gene

We report a Japanese patient with Creutzfeldt-Jakob disease (CJD) with a V203I homozygous mutation of the prion protein gene (PRNP). A 73-year-old woman developed rapidly progressive gait disturbance and cognitive dysfunction. Four months after the onset, she entered a state of an akinetic mutism. Gene analysis revealed a homozygous V203I mutation in the PRNP. Familial CJD with a V203I mutation is rare, and all previously reported cases had a heterozygous mutation showing manifestations similar to those of typical sporadic CJD. Although genetic prion diseases with homozygous PRNP mutations often present with an earlier onset and more rapid clinical course than those with heterozygous mutations, no difference was found in clinical phenotype between our homozygous case and reported heterozygous cases.

123 I-Metaiodobenzylguanidine Myocardial Scintigraphy in Dementia with Lewy Bodies

Differential diagnosis of dementia with Lewy bodies (DLB) from Alzheimer’s disease (AD) and other dementias is essential for better management. Metaiodobenzylguanidine (MIBG) is a physiological analogue of norepinephrine, and 123I-MIBG myocardial scintigraphy has been used as a noninvasive tool for estimating myocardial sympathetic nerve damage due to various disorders such as heart and neurologic diseases. Degeneration of the cardiac sympathetic nerves is a neuropathological feature of Lewy body diseases including Parkinson’s disease and DLB. Multiple single-center studies, including ours, reported very high sensitivity and specificity of 123I-MIBG myocardial scintigraphy for the differential diagnosis of DLB from AD and other dementias; further, our first multicenter study of DLB with the standardized technique [1] substantiated the high diagnostic accuracy of 123I-MIBG myocardial scintigraphy, which was comparable to that of 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) SPECT multicenter study [2]. In the current version of the consensus diagnostic criteria for DLB [3], 123I-FP-CIT SPECT was listed as one of the suggestive features of DLB, whereas 123I-MIBG myocardial scintigraphy was listed as one of the supportive features. As 123I-MIBG myocardial scintigraphy has been proved to have high diagnostic specificity, it is recommended to upgrade the abnormal MIBG myocardial scintigraphy to one of the suggestive features of DLB.

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.

Optimization of DARTEL Settings for the Detection of Alzheimer Disease

BACKGROUND AND PURPOSE: Although Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) has been introduced as an alternative to conventional voxel-based morphometry, there are scant data available regarding the optimal image-processing settings. The aim of this study was to optimize image-processing and ROI settings for the diagnosis of Alzheimer disease using DARTEL. MATERIALS AND METHODS: Between May 2002 and August 2014, we selected 158 patients with Alzheimer disease and 198 age-matched healthy subjects; 158 healthy subjects served as the control group against the patients with Alzheimer disease, and the remaining 40 served as the healthy data base. Structural MR images were obtained in all the participants and were processed using DARTEL-based voxel-based morphometry with a variety of settings. These included modulated or nonmodulated, nonsmoothed or smoothed settings with a 4-, 8-, 12-, 16-, or 20-mm kernel size. A z score was calculated for each ROI, and univariate and multivariate logistic regression analyses were performed to determine the optimal ROI settings for each dataset. The optimal settings were defined as those demonstrating the highest χ2 test statistics in the multivariate logistic regression analyses. Finally, using the optimal settings, we obtained receiver operating characteristic curves. The models were verified using 10-fold cross-validation. RESULTS: The optimal settings were obtained using the hippocampus and precuneus as ROIs without modulation and smoothing. The average area under the curve was 0.845 (95% confidence interval, 0.788–0.902). CONCLUSIONS: We recommend using the precuneus and hippocampus as ROIs without modulation and smoothing for DARTEL-based voxel-based morphometry as a tool for diagnosing Alzheimer disease.

Long spinal cord lesions in a patient with pathologically proven multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. We report the case of a 50-year-old man who presented with progressive gait ataxia. Brain magnetic resonance imaging (MRI) on fluid-attenuated inversion recovery revealed a hyperintense lesion in the right temporal white matter. The spinal cord showed a long hyperintense lesion between the vertebral levels C6 and L1 on T2-weighted MRI. Biopsied tissues from the brain lesion demonstrated features of inflammatory demyelination with preservation of astrocytes, consistent with typical MS. This is the first reported case of pathologically proven MS with longitudinally extensive spinal cord lesions.

ASSOCIATIONS BETWEEN CEREBRAL AMYLOID ANGIOPATHY-RELATED MICROBLEEDS AND CEREBROSPINAL FLUID BIOMARKERS IN ALZHEIMER'S DISEASE

P1-248 ASSOCIATIONS BETWEEN CEREBRAL AMYLOID ANGIOPATHY-RELATED MICROBLEEDS AND CEREBROSPINAL FLUID BIOMARKERS IN ALZHEIMER’S DISEASE Moeko Shinohara, Junji Komatsu, Miharu Samuraki, IchiroMatsunari, Tokuhei Ikeda, Kenji Sakai, Tsuyoshi Hamaguchi, Kenjiro Ono, Hiroyuki Nakamura, Masahito Yamada, Kanazawa University, Kanazawa, Japan; Saitama Medical University, Saitama, Japan; Showa University, Tokyo, Japan. Contact e-mail: m-nohara@med.kanazawa-u.ac.jp