Publications by authors named "Masayuki Sasaki"

352 Publications

Influences of radionuclides on left ventricular phase analysis of gated myocardial perfusion single-photon emission computed tomography images in ischemic heart disease.

Ann Nucl Med 2021 Apr 19. Epub 2021 Apr 19.

Department of Health Science, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Objective: Phase analysis is expected to improve the accuracy of myocardial ischemia diagnosis in conjunction with myocardial perfusion and wall motion imaging and quantification. Although previous studies have reported perfusion image disagreements in relation to radionuclides, a few reports have examined the influences of radionuclides on phase analysis. We evaluated the influences of different radionuclides on stress-induced left ventricular mechanical dyssynchrony by phase analysis using electrocardiogram (ECG)-gated myocardial perfusion single photon emission computed tomography (SPECT) (MPS) imaging in patients with ischemic heart disease (IHD).

Methods: A total of 202 patients with suspected or known IHD were investigated retrospectively. All the patients underwent coronary arteriography and were subsequently classified into the following groups: 43 patients without any coronary lesion (0VD), 71 patients with single-vessel disease (1VD), 59 patients with two-vessel disease (2VD), and 29 patients with three-vessel disease (3VD). Both stress and rest gated-MPS were performed using Tc-methoxyisobutylisonitrile (MIBI)/tetrofosmin (TF) in 118 patients and with TlCl in 84 patients. Phase analysis was performed to obtain the peak phase, phase standard deviation (SD), and bandwidth. Finally, we investigated potential differences between the phase analysis indices and the respective radionuclides used.

Results: The peak phase did not exhibit any significant differences in the numbers of affected branches in either Tc-MPS or Tl-MPS during stress or rest MPS. Furthermore, both the phase SD and bandwidth demonstrated a tendency to increase in patients with increased numbers of affected branches. A significant difference was observed in the stress MPS when Tc-MIBI/TF was used (p < 0.05), but no significant difference was observed in the stress MPS when TlCl was used. Both the phase SD and bandwidth of all patients in Tc-MPS during stress were significantly larger than those at rest (p < 0.05). Conversely, both the phase SD and bandwidth of all patients in Tl-MPS at stress was significantly smaller than that at rest (p < 0.05).

Conclusion: Phase analysis using Tc-MPS was considered to be useful for the detection of stress-induced left ventricular mechanical dyssynchrony, although it is necessary to be careful when using Tl-MPS.
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http://dx.doi.org/10.1007/s12149-021-01615-6DOI Listing
April 2021

AIF3 splicing switch triggers neurodegeneration.

Mol Neurodegener 2021 04 14;16(1):25. Epub 2021 Apr 14.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

Background: Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death once it is released from mitochondria and translocated to the nucleus under ischemic stroke or neurodegenerative diseases. Although alternative splicing regulation of AIF has been implicated, it remains unknown which AIF splicing isoform will be induced under pathological conditions and how it impacts mitochondrial functions and neurodegeneration in adult brain.

Methods: AIF splicing induction in brain was determined by multiple approaches including 5' RACE, Sanger sequencing, splicing-specific PCR assay and bottom-up proteomic analysis. The role of AIF splicing in mitochondria and neurodegeneration was determined by its biochemical properties, cell death analysis, morphological and functional alterations and animal behavior. Three animal models, including loss-of-function harlequin model, gain-of-function AIF3 knockin model and conditional inducible AIF splicing model established using either Cre-loxp recombination or CRISPR/Cas9 techniques, were applied to explore underlying mechanisms of AIF splicing-induced neurodegeneration.

Results: We identified a nature splicing AIF isoform lacking exons 2 and 3 named as AIF3. AIF3 was undetectable under physiological conditions but its expression was increased in mouse and human postmortem brain after stroke. AIF3 splicing in mouse brain caused enlarged ventricles and severe neurodegeneration in the forebrain regions. These AIF3 splicing mice died 2-4 months after birth. AIF3 splicing-triggered neurodegeneration involves both mitochondrial dysfunction and AIF3 nuclear translocation. We showed that AIF3 inhibited NADH oxidase activity, ATP production, oxygen consumption, and mitochondrial biogenesis. In addition, expression of AIF3 significantly increased chromatin condensation and nuclear shrinkage leading to neuronal cell death. However, loss-of-AIF alone in harlequin or gain-of-AIF3 alone in AIF3 knockin mice did not cause robust neurodegeneration as that observed in AIF3 splicing mice.

Conclusions: We identified AIF3 as a disease-inducible isoform and established AIF3 splicing mouse model. The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves mitochondrial dysfunction and AIF3 nuclear translocation resulting from the synergistic effect of loss-of-AIF and gain-of-AIF3. Our study provides a valuable tool to understand the role of AIF3 splicing in brain and a potential therapeutic target to prevent/delay the progress of neurodegenerative diseases.
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http://dx.doi.org/10.1186/s13024-021-00442-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048367PMC
April 2021

Improved accuracy of amyloid PET quantification with adaptive template-based anatomical standardization.

J Nucl Med Technol 2021 Apr 5. Epub 2021 Apr 5.

Kyushu University, Japan.

Amyloid positron emission tomography (PET) noninvasively visualizes amyloid-β (Aβ) accumulation in the brain. Visual binary reading is the standard method for interpreting amyloid PET, while objective quantitative evaluation is required in research and clinical trials. Anatomical standardization is important for quantitative analysis, and various standard templates are used for this purpose. To address the large differences in the radioactivity distribution between amyloid-positive and amyloid-negative participants, an adaptive template method has been proposed for the anatomical standardization of amyloid PET. In this study, we investigated the difference between the adaptive template method and the single template methods (use of a positive or a negative template) in amyloid PET quantitative evaluation, focusing on the accuracy in diagnosing Alzheimer's disease (AD). A total of 166 participants (58 normal controls (NCs), 62 participants with mild cognitive impairment (MCI), and 46 patients with AD) who underwent [C] Pittsburgh Compound B PET (C-PiB) through the Japanese Alzheimer's Disease Neuroimaging Initiative study were examined. For the anatomical standardization of C-PiB PET images, we applied three methods a positive template-based method, a negative template-based method, and adaptive template-based method. The positive template was created by averaged four patients with AD and seven patients with MCI PET images. Conversely, the negative template was created by averaged eight participants of NC PET images. In the adaptive template-based method, either of the templates was used on the basis of the similarity (normalized cross-correlation (NCC)) between the individual standardized image and the corresponding template. Empirical PiB-prone region-of-interest was used to evaluate specific regions where Aβ accumulates. The reference region was the cerebellar cortex, whereas the evaluated regions were the posterior cingulate gyrus and precuneus as well as the frontal, lateral temporal, lateral parietal, and occipital lobes. The mean cortical standardized uptake value ratio (mcSUVR) was calculated for quantitative evaluation. The NCCs of single template-based methods (the positive template or negative template) showed a significant difference between NC, MCI and AD ( < 0.05), whereas the NCC of the adaptive template-based method did not ( > 0.05). The mcSUVR exhibited significant differences between NC, MCI and AD in all methods ( < 0.05). The area under curve by receiver operating characteristic analysis between the positive group (MCI and AD) and NC was not significantly different in mcSUVR among all templates. With regard to diagnostic accuracy based on mcSUVR, the sensitivity of the negative and adaptive template-based methods was superior to that of the positive template-based method ( < 0.05); however, there was no significant difference in specificity between them. In the diagnostic accuracy for AD by amyloid PET quantitative evaluation, the adaptive template-based anatomical standardization method outperformed the single template-based methods.
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http://dx.doi.org/10.2967/jnmt.120.261701DOI Listing
April 2021

Whole genome sequencing of 45 Japanese patients with intellectual disability.

Am J Med Genet A 2021 05 24;185(5):1468-1480. Epub 2021 Feb 24.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.
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http://dx.doi.org/10.1002/ajmg.a.62138DOI Listing
May 2021

I metaiodobenzylguanidine (MIBG) uptake predicts early relapse of neuroblastoma using semi-quantitative SPECT/CT analysis.

Ann Nucl Med 2021 May 14;35(5):549-556. Epub 2021 Feb 14.

Department of Clinical Radiology, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan.

Objective: I metaiodobenzylguanidine (MIBG) scintigraphy is a useful tool for the diagnosis of neuroblastoma (NB). MIBG uptake is correlated with norepinephrine transporter expression; hence, it is expected that high-MIBG tumors would be more highly differentiated and have a better prognosis than those with lower expression. We have introduced a method of assessing MIBG accumulation semi-quantitatively using SPECT/CT fusion images. The purpose of this study was to evaluate the relationship of I MIBG uptake measured by semi-quantitative values of SPECT/CT and early relapse of NB.

Methods: We studied the cases of 11 patients (5 males and 6 females, age 5-65 months, median age 20 months) with histopathologically proven NB between April 2010 and March 2015. The early-relapse group was defined as patients who had relapsed within 3 years after the first I MIBG SPECT/CT exam. Other patients were classified as the delay-relapse group. Uptake of MIBG was evaluated using the count ratio of tumor and muscles. T/Mmax and T/Mmean were defined as follows: T/Mmax = max count of tumor/max count of muscle, T/Mmean = mean count of tumor/mean count of muscle.

Results: The average T/Mmean values of the early-relapse group and delay-relapse group were 2.65 ± 0.58 and 7.66 ± 2.68, respectively. The T/Mmean values of the early-relapse group were significantly lower than those of delay-relapse group (p < 0.05). The average T/Mmax of the early-relapse group and delay-relapse group were 8.86 ± 3.22 and 16.20 ± 1.97, respectively. There was no significant difference in T/Mmax values between the two groups.

Conclusions: Low I MIBG uptake using semi-quantitative SPECT/CT analysis was correlated with early relapse of NB.
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http://dx.doi.org/10.1007/s12149-021-01595-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079305PMC
May 2021

Clinical practice guidelines for high-resolution breast PET, 2019 edition.

Ann Nucl Med 2021 Mar 25;35(3):406-414. Epub 2021 Jan 25.

Health Insurance Committee, Japanese Society of Nuclear Medicine, Tokyo, Japan.

Breast positron emission tomography (PET) has had insurance coverage when performed with conventional whole-body PET in Japan since 2013. Together with whole-body PET, accurate examination of breast cancer and diagnosis of metastatic disease are possible, and are expected to contribute significantly to its treatment planning. To facilitate a safer, smoother, and more appropriate examination, the Japanese Society of Nuclear Medicine published the first edition of practice guidelines for high-resolution breast PET in 2013. Subsequently, new types of breast PET have been developed and their clinical usefulness clarified. Therefore, the guidelines for breast PET were revised in 2019. This article updates readers as to what is new in the second edition. This edition supports two different types of breast PET depending on the placement of the detector: the opposite-type (positron emission mammography; PEM) and the ring-shaped type (dedicated breast PET; dbPET), providing an overview of these scanners and appropriate imaging methods, their clinical applications, and future prospects. The name "dedicated breast PET" from the first edition is widely used to refer to ring-shaped type breast PET. In this edition, "breast PET" has been defined as a term that refers to both opposite- and ring-shaped devices. Up-to-date breast PET practice guidelines would help provide useful information for evidence-based breast imaging.
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http://dx.doi.org/10.1007/s12149-021-01582-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902575PMC
March 2021

Improvement of brain function after surgery in infants with posterior quadrant cortical dysplasia.

Clin Neurophysiol 2021 Feb 3;132(2):332-337. Epub 2020 Dec 3.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8551, Japan. Electronic address:

Objective: To reveal whether neurodevelopmental outcome of infants after epilepsy surgery can be quantitatively assessed by electroencephalography (EEG) functional connectivity analysis.

Methods: We enrolled 13 infants with posterior quadrant dysplasia aged <2 years who were treated using posterior quadrantectomy and 21 age-matched infants. EEG was performed both before and one year after surgery. Developmental quotient (DQ) was assessed both before and 3 years after surgery. The phase lag index (PLI) of three different pairs of electrodes in the nonsurgical hemisphere, i.e., the anterior short distance (ASD), posterior short distance (PSD), and long distance (LD) pairs, were calculated as indices of brain connectivity. The relationship between the PLI and DQ was evaluated.

Results: Overall, 77% infants experienced seizure freedom after surgery. The beta- and gamma- range PLI of PSD pairs increased preoperatively. All these pairs normalized postoperatively. Simple linear regression analysis revealed a significant relationship between the postoperative DQ and the postoperative beta-band PLI of ASD pairs.

Conclusion: Preoperative abnormal hyper-connectivity was normalized to the control level after surgery. The postoperative hyperconnectivity was associated with long-term neurodevelopmental improvement.

Significance: PLI quantifies neurodevelopmental improvements after posterior quadrantectomy.
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http://dx.doi.org/10.1016/j.clinph.2020.11.020DOI Listing
February 2021

Association between lack of functional connectivity of the frontal brain region and poor response inhibition in children with frontal lobe epilepsy.

Epilepsy Behav 2020 12 21;113:107561. Epub 2020 Nov 21.

Department of Developmental Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8553, Japan. Electronic address:

Purpose: We investigated the relationship between electroencephalographic (EEG) functional connectivity and executive function in children with frontal lobe epilepsy (FLE).

Methods: We enrolled 24 children with FLE (mean age, 11.0 years; 13 boys) and 22 sex-, age-, and intelligence-matched typically developing children (TDC) to undergo 19-channel EEG during light sleep. We estimated functional connectivity using the phase lag index (PLI) that captures the synchronization of EEG. We also performed continuous performance tests (CPTs) on the children and obtained questionnaire responses on attention deficit hyperactivity disorder and oppositional defiant disorder (ODD).

Results: The average gamma PLI was lower in the FLE group than in the TDC group, especially between long-distance frontoparietal pairs, between interhemispheric frontal pairs, and between interhemispheric parietotemporal pairs. Gamma PLIs with long-distance frontoparietal and interhemispheric frontal pairs were positively associated with inattention, ODD scores, omission error, and reaction time in the FLE group but not in the TDC group. Conversely, they were negatively associated with age, hyperactivity score, and commission error.

Conclusions: A lack of functional connectivity of the frontal brain regions in children with FLE was associated with poor response inhibition.
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http://dx.doi.org/10.1016/j.yebeh.2020.107561DOI Listing
December 2020

Clonazepam as an Effective Treatment for Epilepsy in a Female Patient with Mutation: Case Report.

Mol Syndromol 2020 Nov 1;11(4):232-237. Epub 2020 Sep 1.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.

The () gene is located in the X chromosome, and hemizygous mutations in cause X-linked intellectual disability in male patients. Female patients with heterozygous mutations in also show similar, but milder, intellectual disability. Most female patients demonstrate intractable epilepsy compared with male patients, and the treatment strategy for epilepsy is still uncertain. Thus far, 24 female patients with mutations have been reported. Of these 24 patients, 20 also have epilepsy. Until now, epilepsy has been controlled in only 2 of these female patients. We report a female patient with a heterozygous de novo mutation, NM_001008537.2:c.1123del (p.Glu375Argfs*21), in . The patient showed mild intellectual disability, facial dysmorphism, obesity, generalized tonic-clonic seizures, and nonconvulsive status epilepticus. Sodium valproate was effective but caused secondary amenorrhea. We successfully treated her epilepsy with clonazepam without side effects, indicating that clonazepam might be a good choice to treat epilepsy in patients with mutations.
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http://dx.doi.org/10.1159/000510172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675231PMC
November 2020

Hyperglycemic Crisis in Patients With Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS).

Pediatr Neurol 2021 01 30;114:1-4. Epub 2020 Sep 30.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Background: Diabetes mellitus is the most commonly encountered endocrinopathy in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which manifests as multisystemic organ failure. Whether the management of diabetes mellitus in MELAS requires special consideration is not fully clarified.

Methods: In this single-center study, we retrospectively reviewed the medical records of patients with MELAS to elucidate the clinical characteristics of MELAS-associated diabetes mellitus.

Results: Four patients among a total of 25 individuals with MELAS who were treated in the study institution developed diabetes mellitus. One patient had well-controlled diabetes mellitus, whereas the remaining three patients experienced hyperglycemic crisis as the first manifestation of diabetes mellitus. Two of the three patients were children aged four and six years. The hyperglycemic events occurred after surgery, infection, and status epilepticus, respectively. None of the three patients had diabetes mellitus previously based on randomly measured serum glucose levels that were within the normal range before the hyperglycemic crisis. Glycated hemoglobin levels measured during the hyperglycemic crisis indicated prediabetes in two patients and diabetes mellitus in one patient. Two patients recovered, whereas one patient died after developing multiorgan failure.

Conclusions: Fulminant-onset diabetes mellitus occurring in patients with MELAS underscore the importance of routine measurement for glycated hemoglobin and more intense evaluation of glucose intolerance regardless of the patient age and lack of symptoms. Clinicians should be aware of the potential acute onset of hyperglycemic crisis in patients with MELAS, especially in individuals with aggravating factors.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.09.013DOI Listing
January 2021

Evaluation of a Monte Carlo-based algorithm for the influence of totally implantable venous access ports in external radiation therapy.

Jpn J Radiol 2021 Apr 2;39(4):387-394. Epub 2020 Nov 2.

Division of Medical Quantum Science, Department of Health Sciences, Kyushu University Graduate School of Medical Sciences School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Purpose: This study aimed to assess whether a Monte Carlo (MC)-based algorithm reflects the influence of totally implantable venous access ports (TIVAPs) in external radiation therapy.

Materials And Methods: The present study comprised two steps: experimental measurements of depth doses and surface doses with and without TIVAPs and calculation with an MC-based algorithm.

Results: The TIVAP-associated maximum dose reduction compared with the dose at the same depths without TIVAPs was 7.8% at 4 MV, 6.9% at 6 MV, and 5.7% at 10 MV in measurement, and 7.4% at 4 MV, 6.6% at 6 MV, and 5.5% at 10 MV in calculation. Relative surface doses were higher with TIVAPs made of titanium, due to a higher fluence of backscattered electrons from the TIVAPs, than with plastic TIVAPs. There were no significant differences in the relative differences between the measured and calculated doses of the titanium TIVAP group and the plastic TIVAP group at 4 MV (p = 0.99), 6 MV (p = 0.67), and 10 MV (p = 0.54).

Conclusion: TIVAPs caused target dose reductions and dose increase near the TIVAP, especially when made of titanium. The influences are reflected in the MC-based algorithm.
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http://dx.doi.org/10.1007/s11604-020-01062-9DOI Listing
April 2021

CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury.

Nat Commun 2020 10 20;11(1):5237. Epub 2020 Oct 20.

Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, 21205, USA.

Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus of Hsc70-interacting protein (CHIP) is an important regulator of proteostasis in many cells, having E3-ligase and chaperone functions and often directing damaged proteins towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we report that CHIP-mediated protein turnover is markedly post-translationally enhanced by direct protein kinase G (PKG) phosphorylation at S20 (mouse, S19 human). This increases CHIP binding affinity to Hsc70, CHIP protein half-life, and consequent clearance of stress-induced ubiquitinated-insoluble proteins. PKG-mediated CHIP-pS20 or expressing CHIP-S20E (phosphomimetic) reduces ischemic proteo- and cytotoxicity, whereas a phospho-silenced CHIP-S20A amplifies both. In vivo, depressing PKG activity lowers CHIP-S20 phosphorylation and protein, exacerbating proteotoxicity and heart dysfunction after ischemic injury. CHIP-S20E knock-in mice better clear ubiquitinated proteins and are cardio-protected. PKG activation provides post-translational enhancement of protein quality control via CHIP.
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http://dx.doi.org/10.1038/s41467-020-18980-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575552PMC
October 2020

Development and evaluation of an automated quantification tool for amyloid PET images.

EJNMMI Phys 2020 Sep 29;7(1):59. Epub 2020 Sep 29.

Department of Medical Quantum Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: Quantitative evaluation of amyloid positron emission tomography (PET) with standardized uptake value ratio (SUVR) plays a key role in clinical studies of Alzheimer's disease (AD). We have proposed a PET-only (MR-free) amyloid quantification method, although some commercial software packages are required. The aim of this study was to develop an automated quantification tool for amyloid PET without using commercial software.

Methods: The quantification tool was created by combining four components: (1) anatomical standardization to positive and negative templates using NEUROSTAT stereo.exe; (2) similarity calculation between standardized images and respective templates based on normalized cross-correlation (selection of the image for SUVR measurement); (3) voxel value normalization by the mean value of reference regions (making an SUVR-scaled image); and (4) SUVR calculation based on pre-defined regions of interest (ROIs). We examined 166 subjects who underwent a [C] Pittsburgh compound-B PET scan through the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) study. SUVRs in five ROIs (frontal lobe, temporal lobe, parietal lobe, occipital lobe, and posterior cingulate cortex and precuneus) were calculated with the cerebellar cortex as the reference region. The SUVRs obtained by our tool were compared with manual step-by-step processing and the conventional PMOD-based method (PMOD Technologies, Switzerland).

Results: Compared with manual step-by-step processing, our developed automated quantification tool reduced processing time by 85%. The SUVRs obtained by the developed quantification tool were consistent with those obtained by manual processing. Compared with the conventional PMOD-based method, the developed quantification tool provided 1.5% lower SUVR values, on average. We determined that this bias is likely due to the difference in anatomical standardization methods.

Conclusions: We developed an automated quantification tool for amyloid PET images. Using this tool, SUVR values can be quickly measured without individual MRI and without commercial software. This quantification tool may be useful for clinical studies of AD.
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http://dx.doi.org/10.1186/s40658-020-00329-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524908PMC
September 2020

ATP1A3 variants and slowly progressive cerebellar ataxia without paroxysmal or episodic symptoms in children.

Dev Med Child Neurol 2021 01 7;63(1):111-115. Epub 2020 Sep 7.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

A heterogeneous spectrum of clinical manifestations caused by mutations in ATP1A3 have been previously described. Here we report two cases of infantile-onset cerebellar ataxia, due to two different ATP1A3 variants. Both patients showed slowly progressive cerebellar ataxia without paroxysmal or episodic symptoms. Brain magnetic resonance imaging revealed mild cerebellar cortical atrophy in both patients. Whole exome sequencing revealed a de novo heterozygous variant in ATP1A3 in both patients. One patient had the c.460A>G (p.Met154Val) variant, while the other carried the c.1050C>A (p.Asp350Lys) variant. This phenotype was characterized by a slowly progressive cerebellar ataxia since the infantile period, which has not been previously described in association with ATP1A3 variants or in ATP1A3-related clinical conditions. Our report contributes to extend the phenotypic spectrum of ATP1A3 mutations, showing paediatric slowly progressive cerebellar ataxia with mild cerebellar atrophy alone as an additional clinical presentation of ATP1A3-related neurological disorders.
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http://dx.doi.org/10.1111/dmcn.14666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754140PMC
January 2021

Postoperative improvement of executive function and adaptive behavior in children with intractable epilepsy.

Brain Dev 2021 Feb 29;43(2):280-287. Epub 2020 Aug 29.

Department of Developmental Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.

Introduction: An alteration in postoperative cognitive function varies according to the patients' background characteristics, such as etiology, focus, and seizure duration. Accurate prediction and assessment of postoperative cognitive function is difficult in each patient. Adaptive behavior could describe the typical performance of daily activities and represents the ability to translate cognitive potential into real-world skills. We examined the relationship between alterations of executive function (EF) and adaptive behavior in school children undergoing surgery for intractable epilepsy.

Methodology: We enrolled 31 children with focal resection or corpus callosotomy for intractable epilepsy [mean age at surgery, 12.5 years; 16 boys; mean intellectual quotient, 73.3]. We surveyed answered questionnaires on attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and adaptive behavior using the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II), and performed continuous performance tests (CPTs) on children pre- and postoperatively.

Result: ADHD and ASD symptoms improved after epilepsy surgery. The omission error (OE) in the CPT variable improved after epilepsy surgery, especially in children with a shorter preoperative period. Improved ASD symptoms led to an increased score of the coping skills subdomain. The reduced OE observed after surgery also increased the score of the community skills subdomain.

Conclusion: Improvement in EF and ASD symptoms resulted in better adaptive behavior postoperatively. These results were important for the pre- and postoperative evaluation and re-evaluation of children with epilepsy requiring special education and related services.
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http://dx.doi.org/10.1016/j.braindev.2020.08.005DOI Listing
February 2021

Cognitive and developmental outcomes after pediatric insular epilepsy surgery for focal cortical dysplasia.

J Neurosurg Pediatr 2020 Aug 7:1-9. Epub 2020 Aug 7.

Departments of1Neurosurgery and.

Objective: Cognitive risk associated with insular cortex resection is not well understood. The authors reviewed cognitive and developmental outcomes in pediatric patients who underwent resection of the epileptogenic zone involving the insula.

Methods: A review was conducted of 15 patients who underwent resective epilepsy surgery involving the insular cortex for focal cortical dysplasia, with a minimum follow-up of 12 months. The median age at surgery was 5.6 years (range 0.3-13.6 years). Developmental/intelligence quotient (DQ/IQ) scores were evaluated before surgery, within 4 months after surgery, and at 12 months or more after surgery. Repeated measures multivariate ANOVA was used to evaluate the effects on outcomes of the within-subject factor (time) and between-subject factors (resection side, anterior insular resection, seizure control, and antiepileptic drug [AED] reduction).

Results: The mean preoperative DQ/IQ score was 60.7 ± 22.8. Left-side resection and anterior insular resection were performed in 9 patients each. Favorable seizure control (International League Against Epilepsy class 1-3) was achieved in 8 patients. Postoperative motor deficits were observed in 9 patients (permanent in 6, transient in 3). Within-subject changes in DQ/IQ were not significantly affected by insular resection (p = 0.13). Postoperative changes in DQ/IQ were not significantly affected by surgical side, anterior insular resection, AED reduction, or seizure outcome. Only verbal function showed no significant changes before and after surgery and no significant effects of within-subject factors.

Conclusions: Resection involving the insula in children with impaired development or intelligence can be performed without significant reduction in DQ/IQ, but carries the risk of postoperative motor deficits.
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http://dx.doi.org/10.3171/2020.5.PEDS2058DOI Listing
August 2020

The cerebellar white matter lesions in dentatorubral-pallidoluysian atrophy.

J Neurol Sci 2020 Sep 16;416:117040. Epub 2020 Jul 16.

Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by a CAG nucleotide repeat expansion in atrophin 1. A previous report described cerebellar white matter lesions on magnetic resonance imaging (MRI) in elderly-onset DRPLA patients, but this finding has not been fully investigated in a total population of DRPLA patients, including juvenile or early-adult onset patients. Herein, we attempted to determine the frequency, distribution pattern, and features of the cerebellar white matter lesions in 30 consecutive DRPLA patients. We also assessed the relationships between the cerebellar white matter lesions and clinical parameters and other MRI findings. The cerebellar white matter lesions were found in 43% of the 30 DRPLA patients, and in 70% of the late adult-onset DRPLA patients. In approx. Two-thirds of the patients with cerebellar white matter lesions, the lesions were localized in the paravermal area (paravermal lesions). Multiple logistic regression analyses revealed that the Fazekas grade of 'cerebral' white matter lesions was independently associated with 'cerebellar' white matter lesions. In conclusion, cerebellar white matter lesions are one of the distinctive MRI features in DRPLA patients, especially in patients with older age at onset. Cerebellar white matter lesions, as well as cerebral white matter lesions, might originate from the disease process of DRPLA itself, and they often have a characteristic distribution of paravermal lesions.
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http://dx.doi.org/10.1016/j.jns.2020.117040DOI Listing
September 2020

Evaluating and comparing the image quality and quantification accuracy of SiPM-PET/CT and PMT-PET/CT.

Ann Nucl Med 2020 Oct 3;34(10):725-735. Epub 2020 Jul 3.

Department of Health Science, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Objective: The aim of this study was to evaluate the image quality and the quantification accuracy of Biograph Vision PET/CT scanner as a SiPM-PET in comparison to the conventional PMT-PET, Biograph mCT PET/CT scanner.

Methods: This study consisted of a phantom study and a retrospective clinical analysis where patients underwent F-FDG PET/CT in both PET systems. The body phantom of the NEMA IEC with 10-37 mm diameter spheres were filled with an F-FDG solution. The root mean square error (RMSE) of SUV, the detectability of 10-mm sphere, NEC, the background variability (N) and the contrast-noise-ratio (Q/N) were calculated based on the phantom analysis. We also examined the quality of the acquired clinical images using the NEC, NEC, SNR, SUV and SUV.

Results: In the phantom study on Vision scanner, RMSE was relatively lower when the iteration number was 2, 3 or 4. To satisfy a visual score of 1.5 and the reference range of Q/N, a 60-s or longer acquisition was required. Our clinical findings show that NEC averaged 17.4 ± 1.72 Mcounts/m in mCT and 29.1 ± 2.83 Mcounts/m in Vision. Furthermore, NEC averaged 0.29 ± 0.05 kcounts/cm in mCT and 0.53 ± 0.09 kcounts/cm in Vision, respectively, whereas SNR averaged 14.6 ± 3.77% in mCT and 21.3 ± 1.69% in Vision (P = 0.0156), respectively. Finally, SUV averaged 2.82 ± 0.28 and 2.55 ± 0.30, SUV ranged 1.6-17.6 and 1.9-22.9 in mCT and Vision, respectively.

Conclusion: SiPM-PET/CT provides superior image quality and quantification accuracy compared to PMT-PET/CT.
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http://dx.doi.org/10.1007/s12149-020-01496-1DOI Listing
October 2020

Feasibility study of a PET-only amyloid quantification method: a comparison with visual interpretation.

Ann Nucl Med 2020 Sep 13;34(9):629-635. Epub 2020 Jun 13.

Division of Medical Quantum Science, Department of Health Sciences, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Objective: Visual evaluation is the standard for amyloid positron emission tomography (PET) examination, though the result depends upon the physician's subjective review of the images. Therefore, it is expected that objective quantitative evaluation is useful for image interpretation. In this study, we examined the usefulness of the quantitative evaluation of amyloid PET using a PET-only quantification method in comparison with visual evaluation.

Methods: In this study we retrospectively investigated a total of 166 individuals, including 58 cognitively normal controls, 62 individuals with mild cognitive impairment, and 46 individuals with early Alzheimer's disease. They underwent C-Pittsburgh compound-B (PiB) PET examination through the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI). Amyloid accumulation in cerebral cortices was assessed using visual and quantitative methods. The quantitative evaluation was performed using the adaptive template method and empirically PiB-prone region of interest, and the standardized uptake value ratio (SUVR) in each area was obtained.

Results: Visual evaluation and SUVR were significantly correlated in the cerebral cortices (ρ = 0.85-0.87; p < 0.05). In visual evaluation, sensitivity, specificity, and accuracy were 78%, 76%, and 77%, respectively. Meanwhile, for quantitative evaluation, sensitivity, specificity, and accuracy were 77%, 79%, and 78% in mean cortical SUVR (mcSUVR) and 79%, 79%, and 79% in maximum SUVR (maxSUVR), respectively.

Conclusion: The PET-only quantification method provided a concordant result with visual evaluation and was considered useful for amyloid PET.
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http://dx.doi.org/10.1007/s12149-020-01486-3DOI Listing
September 2020

Accuracy of metabolic volume and total glycolysis among six threshold-based target segmentation algorithms.

Ann Nucl Med 2020 Aug 11;34(8):583-594. Epub 2020 Jun 11.

PET Imaging Center, Public Central Hospital of Matto Ishikawa, Hakusan, Japan.

Objective: This study aimed to evaluate the accuracy of six threshold-based segmentation methods with different target-to-background ratios (TBR), images with different voxel sizes and image noise, in measuring metabolic volume (MV) and total glycolysis (TG).

Methods: A standard body phantom consisting of six spheres (inner diameters of 37, 28, 22, 17, 13, and 10 mm) was filled with F-FDG solution. The background radioactivity level was 2.65 kBq/mL, and the TBRs were 4 and 8. PET data were acquired for 30 min with list mode. PET data for 30 and 3 min were reconstructed with a three-dimensional ordered subset expectation maximization algorithm plus time-of-flight information with images with 2 and 4 mm isotropic voxels. The six methods examined were absolute standardized uptake value (SUV) of 2.5 (SUV), 41%, 50%, adaptive 41%, and adaptive 50% thresholds of maximum SUV (Th, Th, ThA, and ThA, respectively); and the contrast-oriented algorithm (Th). Segmented MV and TG were compared with the actual inner volume and expressed as percentages (%MV and %TG, respectively). In addition, the segmented MV was converted to the diameter, and the differences of it from the reference diameter were compared among six methods.

Results: The Th method yielded the most accurate measurements of %MV and %TG; the difference between %MV or %TG and its reference were smaller than 10% in 30-min and 15% in 3-min images, but the segmented contour was almost the same as the reference diameter. Measurements with Th and Th were highly accurate for both %MV and %TG in the large spheres, and the adaptive threshold methods, including ThA, ThA, and Th were also highly accurate in the small spheres. The voxel sizes affected the accuracy of %MV and %TG with a TBR of 4 in any threshold-based methods.

Conclusions: Of the six threshold-based segmentation methods studied, Th was the most accurate method for evaluating MV and TG and had only minor dependence on TBRs and sphere size. The small voxel sizes improved the variation of the accuracy in low TBR.
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http://dx.doi.org/10.1007/s12149-020-01484-5DOI Listing
August 2020

13q13.3 microdeletion associated with apparently balanced translocation of 46,XX,t(7;13) suggests NBEA involvement.

Brain Dev 2020 Sep 4;42(8):581-586. Epub 2020 Jun 4.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, NCNP, Tokyo, Japan.

Background: Deletion of 13q13.3 is an extremely rare event.

Case: We report on a 25-month-old girl with neurodevelopmental disorder and intellectual disability. She had dysmorphic facies characterized by synophrys, long and narrow palpebral fissures; and a large, round face with small organs such as the eyes and mouth positioned near the center. She was hypotonic and had autism-like behaviors. Blood tests and brain MRI revealed no specific findings. However, G-banding chromosome analysis showed an apparently balanced translocation: 46,XX,t(7,13)(q11.23;q12.3). Both parents had normal karyotypes. Furthermore, her abnormal phenotype and chromosomal breakpoint lesion were suspected to be associated. Hence, we conducted array comparative genomic hybridization, which revealed a 3.2 Mb novel pathological microdeletion at 13q13.3 involving 17 genes including neurobeachin (NBEA), a neurodevelopment disorder gene. Furthermore, fluorescence in situ hybridization using probes adjacent to the microdeletion suggested a concomitant occurrence of the deletion and translocation as the structural basis of this rare genomic variant.

Conclusion: NBEA may have roles in her neurodevelopmental phenotypes, whereas other genes within the 13q13.3 microdeletion may contribute to her dysmorphic features.
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http://dx.doi.org/10.1016/j.braindev.2020.05.006DOI Listing
September 2020

Serial MRI alterations of pediatric patients with beta-propeller protein associated neurodegeneration (BPAN).

J Neuroradiol 2021 Mar 23;48(2):88-93. Epub 2020 Apr 23.

Department of Child Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan.

Background And Purpose: Beta-propeller protein-associated neurodegeneration (BPAN) is one subtype of neurodegeneration with brain iron accumulation. It is difficult to diagnose BPAN due to the non-specificity of their clinical findings and neuroimaging in early childhood. We experienced four pediatric patients with serial brain MRI and evaluated the alteration of the findings through their course.

Methods: We retrospectively reviewed the clinical findings and 21 MRI findings of the four patients with genetically confirmed pediatric BPAN. We also performed a quantitative MR assessment using the quantitative susceptibility mapping (QSM) values of the globus pallidus (GP), substantia nigra (SN), and deep cerebellar nuclei (DCN) compared to 10 age-matched disease controls.

Results: Only one patient was suspected of BPAN based on imaging findings before the genetic diagnosis was made. The other three patients could not be suspected until their Whole-exome sequencings (WES) done. In all four cases, no abnormal signals were noted in the GP and SN at the initial brain MRI, but hypointensities were observed after the ages of 4-7 years on T2-weighted images and after the ages of 2-7 years on susceptibility-weighted images. In three patients, T2 hyperintensity in the bilateral DCN was persistently observed throughout the observational period. Three patients showed transient T2 hyperintensity and swelling in the GP, SN and/or DCN during the episodes of pyrexia and seizures. The other findings included cerebral and cerebellar atrophy, thinning of the corpus callosum, and delayed myelination. The QSM values of the GP and SN were significantly higher in the patients compared to the controls (P=0.005, respectively), but that of the DCN did not differ significantly (P=0.16).

Conclusion: Brain MRI is a useful method to establish the early diagnosis of BPAN.
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http://dx.doi.org/10.1016/j.neurad.2020.04.002DOI Listing
March 2021

Adaptive behavior and its related factors in children with focal epilepsy.

Epilepsy Behav 2020 07 19;108:107092. Epub 2020 Apr 19.

Department of Developmental Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.

Objective: We aimed to clarify the strengths and weaknesses in adaptive behavior in children with focal epilepsy and show children-associated factors related to adaptive behavior.

Materials And Methods: Sixty-three children with focal epilepsy aged 5-18 years with intellectual quotient (IQ) ranging from 67 to 135 were enrolled in this study. Adaptive behavior was evaluated using the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II). The children performed continuous performance test and tests of reading, writing, and IQ; parents answered questionnaires regarding attention-deficit hyperactivity disorder and autism spectrum disorder (ASD). Participants were categorized into four groups based on IQ and adaptive behavior scores for statistical comparisons.

Results And Discussion: Children with low adaptive behavior were more likely to show a reduction in daily living skills, and those with both low adaptive behavior and IQ were more likely to show a reduction in daily living skills and communication. Lower adaptive behavior was related to more severe autistic symptoms, lower academic achievement in children with IQ > 85, and lower executive function in children with IQ ≤ 85. There was a qualitative difference of cognitive dysfunction in adaptive behavior between both groups.

Conclusions: There were differences in VABS-II domain and subdomain characteristics between children with focal epilepsy and those with ASD; however, it was more difficult for children with more severe ASD and coexisting focal epilepsy to show age-equivalent adaptive behavior.
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http://dx.doi.org/10.1016/j.yebeh.2020.107092DOI Listing
July 2020

Delineation of the nerve fiber bundles of the infant brain associated with aging using phase difference-enhanced imaging: a preliminary study.

Jpn J Radiol 2020 Aug 30;38(8):731-739. Epub 2020 Mar 30.

Department of Radiology, School of Medicine, Jichi Medical University, Tochigi, Japan.

Purpose: The purpose of this study was to evaluate the delineation of nerve fiber bundles in the brainstem and optic radiation in infants associated with aging on T1WI, T2WI, and phase difference-enhanced (PADRE) images.

Materials And Methods: We retrospectively reviewed 21 consecutive subjects < 2 years old who underwent brain MRI without abnormal imaging findings. Two neuroradiologists evaluated the eight nerve fiber bundles in the brainstem and optic radiation using a 3-point scale focused on the contrast to surrounding brain parenchyma. We also evaluated the signal ratio of the optic radiation to surrounding white matter on PADRE for each month age.

Results: T2WI was able to delineate nerve fiber bundles better than T1WI at 1 month old, and the images gradually became unclear with aging. On PADRE, almost all nerve fiber bundles were unclear or invisible at 1 month old but gradually became clearer with aging. There was a significant negative correlation between age and the signal ratio of the optic radiation to surrounding white matter.

Conclusions: The PADRE imaging was able to delineate the nerve fiber bundles in infants, and the delineation gradually became clearer with aging. The combination of PADRE, T1WI, and T2WI would be useful for evaluation of nerve fiber bundles in infants.
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http://dx.doi.org/10.1007/s11604-020-00955-zDOI Listing
August 2020

A novel pathogenic NFIX variant in a Malan syndrome patient associated with hindbrain overcrowding.

J Neurol Sci 2020 05 22;412:116758. Epub 2020 Feb 22.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan; Medical Genome Center, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2020.116758DOI Listing
May 2020

A case of CLCN2-related leukoencephalopathy with bright tree appearance during aseptic meningitis.

Brain Dev 2020 Jun 12;42(6):462-467. Epub 2020 Mar 12.

Department of Biochemistry, Hamamatsu University School of Medicine, Japan.

CLCN2-related leukoencephalopathy (CC2L) is a rare autosomal recessive disorder caused by variants in CLCN2. We report a boy whose brain MRI during an episode of aseptic meningitis at the age of 6 years revealed wide areas of restriction on diffusion-weighted images (DWI) in the cerebral subcortical white matter called bright tree appearance (BTA). In addition to the BTA, high intensity signals were also observed bilaterally in the posterior limbs of the internal capsules, cerebral peduncles, middle cerebellar peduncles, cerebellar white matter, and brain stem (longitudinal pontine bundle) along with low apparent diffusion coefficient values in the same areas. The BTA was transient, seen only during the acute phase of the aseptic meningitis. With the resolution of the infection, his meningitis symptoms completely resolved, but abnormal brain MRI findings remained, other than BTA, which disappeared. At age 13 years, whole exome sequencing revealed a homozygous variant (c.61dupC, p.(Leu21Profs*27)) of CLCN2. He had no intellectual disability or neurological abnormalities. The transient DWI high-intensity signals in the subcortical white matter and the T2 high-intensity signals in the white matter could reflect varying degrees of water imbalance in the extracellular space in myelin sheaths in CC2L.
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http://dx.doi.org/10.1016/j.braindev.2020.02.008DOI Listing
June 2020

Integrating science to find cures in child neurology.

Authors:
Masayuki Sasaki

Dev Med Child Neurol 2020 04;62(4):405

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http://dx.doi.org/10.1111/dmcn.14499DOI Listing
April 2020

Clinical features of inherited neuropathy with BSCL2 mutations in Japan.

J Peripher Nerv Syst 2020 06 12;25(2):125-131. Epub 2020 Mar 12.

Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene have been reported with different clinical phenotypes including Silver syndrome (SS)/spastic paraplegia 17 (SPG17), distal hereditary motor neuropathy type V (dHMN-V), and Charcot-Marie-Tooth (CMT) disease type 2. We screened 407 Japanese patients who were clinically suspected of having CMT by exome sequencing and searched mutations in BSCL2. As a result, we identified five patients with heterozygous mutations in BSCL2. We confirmed three cases of known mutations (p.N88S and p.S90L) and two cases of novel mutations (p.N88T and p.S141A). The clinical features of the cases with known mutations in Japan were similar to those previously reported in other countries. In particular, there were many cases with sensory disturbance. The case with p.N88T mutation showed severe phenotype such as early onset age and prominent vocal cord paresis. The case with p.S141A mutation showed characteristics of demyelinating neuropathy such as CMT disease type 1 by electrophysiological examination. In this article, we report the clinical features and spread of cases with BSCL2 mutation in a Japanese cohort.
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http://dx.doi.org/10.1111/jns.12369DOI Listing
June 2020

Left Ventricular End-Diastolic Diameter and Cardiac Mortality in Duchenne Muscular Dystrophy.

Neuropsychiatr Dis Treat 2020 16;16:171-178. Epub 2020 Jan 16.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.

Purpose: This study aimed to examine weather left ventricular end-diastolic diameter (LVDd) could predict mortality from heart failure in patients with Duchenne muscular dystrophy (DMD) receiving standard cardio-protective therapies.

Patients And Methods: One hundred thirty-three patients with DMD aged ≥10 years who underwent echocardiography from 2011 to 2015 were included in this study and retrospectively followed until August 2018. Patients were divided into two groups according to LVDd at initial echocardiography: ≤ 54 mm (Group 1: n=119) and ≥ 55 mm (Group 2: n=14). To identify factors other than LVDd that may affect heart failure-related mortality, Group 2 patients who developed no left atrial (LA) enlargement, moderate mitral regurgitation (MR), or pulmonary hypertension (PH) during the observation period (Group 2A: n=5) were compared with those who newly developed one or more of those complications (Group 2B: n=7). Clinical outcomes were all-cause mortality and mortality from heart failure.

Results: Mean observation period was 5.5±1.5 years in Group 1 and 4.4±1.9 years in Group 2. A total of 14 patients (10.5%) died, including 6 of 119 (5.0%) patients in Group 1 and 8 of 14 (57.1%) patients in Group 2 (p<0.001). Among these, 1 (0.8%) patient in Group 1 and 8 (57.1%) patients in Group 2 died from heart failure (p<0.001). Group 2B patients had shorter survival compared to Group 2A patients (p=0.006).

Conclusion: LVDd ≥ 55 mm is a predictive factor for mortality from heart failure in patients with DMD. Complications including LA enlargement, moderate MR, and PH were found to be predictive factors for mortality from heart failure in a short period.
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http://dx.doi.org/10.2147/NDT.S235166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972578PMC
January 2020

Altered MR imaging findings in a Japanese female child with PRUNE1-related disorder.

Brain Dev 2020 Mar 25;42(3):302-306. Epub 2019 Dec 25.

Department of Radiology, Jichi Medical University, School of Medicine, Japan.

Autosomal recessive PRUNE1 mutations on chromosome 1q21.3 are reported to cause a neurodevelopmental disorder with microcephaly, hypotonia, and variable brain malformations. Here, we report a Japanese case with a reported PRUNE1 mutation whose brain magnetic resonance imaging (MRI) showed specific imaging findings that have not been reported before. The patient was a 12-month-old girl, the first child of healthy and nonconsanguineous Japanese parents. She showed global developmental delay, intellectual disability, hypotonia, spastic quadriparesis, and hyperreflexia. Brain MRI showed cerebral and cerebellar atrophy, thin corpus callosum, white matter changes, and abnormal signal intensity of the brainstem, all of which were reported in the literature. In addition, we emphasize the three following imaging findings: a transient cerebral subcortical white matter lesion, atrophy of the midbrain and pontine tegmentum with a preserved pontine base, and abnormal signal intensity of the bilateral swelling putamina and medial portions of the thalami, which emerged after 4 years of age. The whole-exome sequencing (WES) analysis performed at the age of 4 years identified biallelic PRUNE1 variants, namely compound heterozygous mutations (c.[316G > A];[540 T > A],p.[Asp106Asn];[Cys180*]). Although the diagnosis of PRUNE1-related disorder requires WES, we think that these new characteristic MRI findings may help in the diagnosis of PRUNE1-related disorder.
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http://dx.doi.org/10.1016/j.braindev.2019.12.001DOI Listing
March 2020