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The cholinergic efferent network from the medial septal nucleus to the hippocampus is crucial for learning and memory. This study aimed to clarify whether hippocampal cholinergic neurostimulating peptide (HCNP) has a rescue function in the cholinergic dysfunction of HCNP precursor protein (HCNP-pp) conditional knockout (cKO). Chemically synthesized HCNP or a vehicle were continuously administered into the cerebral ventricle of HCNP-pp cKO mice and littermate floxed (control) mice for two weeks via osmotic pumps. We immunohistochemically measured the cholinergic axon volume in the stratum oriens and functionally evaluated the local field potential in the CA1. Furthermore, choline acetyltransferase (ChAT) and nerve growth factor (NGF) receptor (TrkA and p75NTR) abundances were quantified in wild-type (WT) mice administered HCNP or the vehicle. As a result, HCNP administration morphologically increased the cholinergic axonal volume and electrophysiological theta power in HCNP-pp cKO and control mice. Following the administration of HCNP to WT mice, TrkA and p75NTR levels also decreased significantly. These data suggest that extrinsic HCNP may compensate for the reduced cholinergic axonal volume and theta power in HCNP-pp cKO mice. HCNP may function complementarily to NGF in the cholinergic network in vivo. HCNP may represent a therapeutic candidate for neurological diseases with cholinergic dysfunction, e.g., Alzheimer’s disease and Lewy body dementia.

Cholinergic neural activation from the medial septal nucleus to hippocampus plays a crucial role in episodic memory as a regulating system for glutamatergic neural activation in the hippocampus. As a candidate regulating factor for acetylcholine synthesis in the medial septal nucleus, hippocampal cholinergic neurostimulating peptide (HCNP) was purified from the soluble fraction of young adult rat hippocampus. HCNP is released from its precursor protein (HCNP-pp), also referred to as phosphatidylethanolamine-binding protein 1. We recently reported that HCNP-pp conditional knockout (KO) mice, in which the HCNP-pp gene was knocked out at 3 months of age by tamoxifen injection, display no significant behavioral abnormalities, whereas HCNP-pp KO mice have a diminished cholinergic projection to CA1 and a decreased of theta activity in CA1. In this study, to address whether HCNP-pp reduction in early life is associated with behavioral changes, we evaluated the behavior of HCNP-pp KO mice in which HCNP-pp was downregulated from an early phase (postnatal days 14-28). As unexpected, HCNP-pp KO mice had no behavioral deficits. However, a significant positive correlation between HCNP-pp and gamma-aminobutyric acid A (GABAA) receptor α3 subunit mRNA expression was found in individuals. This finding suggests involvement of HCNP-pp in regulating GABAA receptor α3 gene expression.

The cholinergic efferent network from the medial septal nucleus to the hippocampus plays an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP), which induces acetylcholine (Ach) synthesis in the medial septal nuclei of an explant culture system, was purified from the soluble fraction of postnatal rat hippocampus. HCNP is processed from the N-terminal region of a 186-amino acid, 21-kDa HCNP precursor protein, also known as Raf kinase inhibitory protein and phosphatidylethanolamine-binding protein 1. Here, we confirmed direct reduction of Ach release in the hippocampus of freely moving HCNP-pp knockout mice under an arousal state by the microdialysis method. The levels of vesicular acetylcholine transporter were also decreased in the hippocampus of these mice in comparison with those in control mice, suggesting there was decreased incorporation of Ach into the synaptic vesicle. These results potently indicate that HCNP may be a cholinergic regulator in the septo-hippocampal network.

Although several studies have demonstrated correlation between white matter hyperintensities (WMH) and impairment of executive functions, the underlying anatomical-functional relationships are not fully understood. The present study sought to investigate the correlations between the volume of WMH and medial temporal lobe atrophy (MTA) using quantitative magnetic resonance image (MRI) and a variety of executive function assessments. A total of 91 patients ranging in age from 58 to 90 years with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or early phase AD were recruited from the outpatient clinic at the Department of Neurology of Nagoya City University Hospital. We administered neuropsychological batteries evaluating verbal memory, orientation, spatial ability, sustained attention, and a variety of executive functions, including verbal fluency, flexibility, inhibition, and working memory. Quantitative MRI analyses were performed using Dr. View/Linux software and a voxel-based specific regional analysis system. Significant correlations were observed between WMH, as well as MTA, and some executive function scores. Regression analysis revealed that MTA was the strongest predictor of flexibility and verbal fluency. These findings provide new insight into the relationship between quantitative MRI analyses and various types of executive dysfunction in elderly people with MCI due to AD and/or early phase AD. When cognitive function is examined in elderly patients with MCI due to AD or early phase AD, it is important to consider the involvement of WMH and MTA, which is indicative of AD pathology in cognitive dysfunction, particularly executive function.

Cholinergic neural activation from the medial septal nucleus to hippocampus plays a crucial role in episodic memory as a regulating system for glutamatergic neural activation in the hippocampus. As a candidate regulating factor for acetylcholine synthesis in the medial septal nucleus, hippocampal cholinergic neurostimulating peptide (HCNP) was purified from the soluble fraction of young adult rat hippocampus. HCNP is released from its precursor protein (HCNP-pp), also referred to as phosphatidylethanolamine-binding protein 1. We recently reported that HCNP-pp conditional knockout (KO) mice, in which the HCNP-pp gene was knocked out at 3 months of age by tamoxifen injection, display no significant behavioral abnormalities, whereas HCNP-pp KO mice have a diminished cholinergic projection to CA1 and a decreased of theta activity in CA1. In this study, to address whether HCNP-pp reduction in early life is associated with behavioral changes, we evaluated the behavior of HCNP-pp KO mice in which HCNP-pp was downregulated from an early phase (postnatal days 14-28). As unexpected, HCNP-pp KO mice had no behavioral deficits. However, a significant positive correlation between HCNP-pp and gamma-aminobutyric acid A (GABA

Background Cross-sensitivity of rash has been reported between various antiepileptic drugs (AEDs). However, few studies have determined the frequency and management of cross-sensitivity in patients with super-refractory status epilepticus (SRSE). Aims of the study To examine the optimal AED for treating SRSE with cross-sensitivity. Methods We performed a retrospective review of adult patients with SRSE treated at Nagoya City University Hospital, in which we investigated the frequency of cross-sensitivity among patients with SRSE and their clinical and medical profiles. Results We identified 10 adult patients with SRSE, 5 of whom had cross-sensitivity. Stiripentol (STP) was administered when previously used AEDs had demonstrated cross-sensitivity and failed to control seizures. After initiation of STP, the dose of general anaesthetics was reduced, and status epilepticus (SE) eventually ceased with co-administered AEDs without additional adverse effects. The mean time to SE cessation after initiation of STP was 30.8 days (range, 18-46 days), mean duration of general anaesthesia was 101.2 days (range, 74-128 days), and mean number of AEDs was 9.0 (range, 6-11). Conclusions This study suggests that cross-sensitivity between AEDs is common in adults with SRSE and that STP may be useful for treating SRSE with cross-sensitivity.

令和元年度

Non-dystrophic myotonias are caused by mutations of either the skeletal muscle chloride (CLCN1) or sodium channel (SCN4A) gene. They exhibit several distinct phenotypes, including myotonia congenita, paramyotonia congenita and sodium channel myotonia, and a genotype-phenotype correlation has been established. However, there are atypical cases that do not fit with the standard classification. We report a case of 27-year-old male who had non-dystrophic myotonia with periodic paralysis and two heterozygous mutations, E950K in CLCN1 and F1290L in SCN4A. His mother, who exhibited myotonia without paralytic attack, only harbored E950K, and no mutations were identified in his asymptomatic father. Therefore, the E950K mutation was presumed to be pathogenic, although it was reported as an extremely rare genetic variant. The proband experienced paralytic attacks that lasted for weeks and were less likely to be caused by CLCN1 mutation alone. Functional analysis of the F1290L mutant channel heterologously expressed in cultured cells revealed enhanced activation inducing membrane hyperexcitability. We therefore propose that the two mutations had additive effects on membrane excitability that resulted in more prominent myotonia in the proband. Our case stresses the value of performing genetic analysis of both CLCN1 and SCN4A genes for myotonic patients with an atypical phenotype.

Introduction The accurate diagnosis of isolated anterior cerebral artery dissection (iACA-D) is made difficult by the spatial resolution on conventional magnetic resonance imaging (MRI) techniques including time-of-flight magnetic resonance angiography that is too limited to detect minute arterial wall abnormalities. Recent advances in high-resolution vessel wall imaging (HRVWI), which can detect intramural hematomas (IMH), have improved the noninvasive diagnostic accuracy of iACA-D. However, despite the risk of overlooking minute IMH and aneurysmal dilations especially at the early disease stage, the utility of T1-weighted and T2-weighted HRVWI at each disease stage (i.e., acute, early subacute, late subacute and chronic) has not been evaluated thoroughly enough. This prompted us to undertake the present study to determine the diagnostic value of chronological changes of IMHs on T1-weighted HRVWI and arterial dilations on T2-weighted HRVWI to achieve the earliest possible and most accurate diagnosis of iACA-D. Methods In addition to six patients with iACA-D, five previously reported iACA-D patients from three institutions for whom reliable information on HRVWI and its examination date was available were enrolled in this study. IMHs on T1-weighted HRVWI and aneurysmal dilations on T2-weighted HRVWI and their chronological changes were visually evaluated. Results Either or both of IMHs on T1-weighted HRVWI and aneurysmal dilations on T2-weighted HRVWI were detected in all our six patients and the five previously reported ones. The disease stage showed a notable influence on the degree of their visualization. In contrast to IMHs which are regarded as the gold standard for the diagnosis of intracranial dissections, aneurysmal dilations were identified in 80% of cases even at the acute stage, reaching 100% at the early subacute stage. Despite the excellent detection rate of IMHs at the late subacute stage (100%), their detectability is poor at the acute and early subacute stages (0 and 40%, respectively). Conclusion The results of this study highlighted the importance of aneurysmal dilations on T2-weighted HRVWI as a diagnostic marker to raise suspicion of iACA-D at the acute and early subacute stages, and similarly IMHs on T1-weighted HRVWI to confirm the diagnosis of iACA-D at the late subacute stage. These stage-dependent detectability changes in IMHs and aneurysmal dilations make an understanding of the chronological changes of these abnormal imaging findings mandatory to achieve an early and accurate diagnosis of iACA-D.

A 46-year-old woman presenting to the Department of Hematology with swelling of the mandibular lymph nodes was diagnosed with angioimmunoblastic T-cell lymphoma (AITL) in June 2013. The patient went into complete remission in December 2013 with chemotherapy; however, she was re-evaluated because of mental confusion during May 2014. In addition to the memory disturbances, elevated cerebrospinal fluid cell count and protein were noted. Fluid attenuated inversion recovery cranial magnetic resonance imaging revealed multiple hyperintense areas in both the mammillary bodies and thalamus accompanied by contrast-enhancing in some areas. The diagnosis of recurrent AITL was made based on the brain biopsy. AITL recurrence in the cranium should be considered in patients exhibiting central nervous system symptoms although such recurrences have not been reported previously.

We report the case of a 72-year-old male who presented with the complaints of muscular pain and weakness. The patient showed marked eosinophilia, elevated levels of myogenic enzymes and pathological abnormalities including eosinophil infiltration obtained from the muscle biopsy. Based on these findings, the patient was diagnosed with eosinophilic myositis. During follow-up, left ventricular wall motion abnormalities with transient electrocardiographic abnormalities were identified; these were believed to be concurrent with eosinophilic myocarditis. Further, notable complications included cardiogenic cerebral embolism. Eosinophilic myositis has been found to cause a wide spectrum of complications. Our findings indicate that in cases of suspected eosinophilic myositis, it is crucial to identify myocarditis immediately and to select an anticoagulant therapy to prevent cerebral embolism.

Background An accurate diagnosis of isolated posterior inferior cerebellar artery dissection (iPICA-D) is difficult due to the limitation of spatial resolution on conventional magnetic resonance imaging (MRI) techniques to detect subtle vessel wall abnormalities. The recent development of MRI techniques, including high-resolution vessel wall imaging (HRVWI), has resulted in the improved diagnostic accuracy and efficiency of iPICA-D. In fact, T1-weighted HRVWI, which can reveal intramural hematomas in the posterior inferior cerebellar artery (PICA), is useful for the diagnosis of iPICA-D. However, the utility of T2-weighted HRVWI has not been previously reported. The aim of this study was to investigate the diagnostic utility of T1- and T2-weighted HRVWI for the diagnosis of iPICA-D. Methods We retrospectively evaluated MRI findings including intramural hematomas, dilations, and chronological changes in 4 patients with iPICA-D admitted to our hospital and related facility from January 2015 to August 2016. In addition to T1-weighted HRVWI, T2-weighted HRVWI was performed on isovoxel three-dimensional (3D) fast spin-echo or 3D sampling perfection with application-optimized contrast using different flip-angle evolution. We also reviewed cases of nonhemorrhagic iPICA-D with ischemic onset in which the MRI findings were described. Results In all 4 patients, in addition to the intramural hematomas on T1-weighted HRVWI, T2-weighted HRVWI clearly showed the fusiform dilation of the external diameter of the PICA. T2-weighted HRVWI was more useful than other techniques, including T1-weighted HRVWI, for the evaluation of arterial shape changes. Conclusions Like T1-weighted HRVWI, T2-weighted HRVWI is useful for the diagnosis and assessment of chronological changes in vessel wall abnormalities during the follow-up period.

We herein describe a 45-year-old man with posterior neck pain and severe dysphagia secondary to retropharyngeal calcific tendinitis. Brain stem infarction as a result of vertebral artery dissection was suspected, but head magnetic resonance imaging showed no acute ischemic lesion. Sagittal T2-weighted neck magnetic resonance imaging showed a retropharyngeal fluid collection from C2 to C8, and neck computed tomography showed calcification at the tendon of the longus colli muscle. Based on these characteristic imaging findings, retropharyngeal calcific tendinitis was diagnosed. Neurologists should remember that retropharyngeal calcific tendinitis can cause neck pain and severe dysphagia, and mimic brain stem infarction as a result of vertebral artery dissection.