Genome‐wide association studies demonstrated that polymorphisms in the CD33/sialic acid‐binding immunoglobulin‐like lectin 3 gene are associated with late‐onset Alzheimer's disease (AD). CD33 is ...expressed on myeloid immune cells and mediates inhibitory signaling through protein tyrosine phosphatases, but the exact function of CD33 in microglia is still unknown. Here, we analyzed CD33 knockout human THP1 macrophages and human induced pluripotent stem cell‐derived microglia for immunoreceptor tyrosine‐based activation motif pathway activation, cytokine transcription, phagocytosis, and phagocytosis‐associated oxidative burst. Transcriptome analysis of the macrophage lines showed that knockout of CD33 as well as knockdown of the CD33 signaling‐associated protein tyrosine phosphatase, nonreceptor type 6 (PTPN6) led to constitutive activation of inflammation‐related pathways. Moreover, deletion of CD33 or expression of Exon 2‐deleted CD33 (CD33ΔE2/CD33m) led to increased phosphorylation of the kinases spleen tyrosine kinase (SYK) and extracellular signal‐regulated kinase 1 and 2 (ERK1 and 2). Transcript analysis by quantitative real‐time polymerase chain reaction confirmed increased levels of interleukin (IL) 1B, IL8, and IL10 after knockout of CD33 in macrophages and microglia. In addition, upregulation of the gene transcripts of the AD‐associated phosphatase INPP5D was observed after knockout of CD33. Functional analysis of macrophages and microglia showed that phagocytosis of aggregated amyloid‐β1‐42 and bacterial particles were increased after knockout of CD33 or CD33ΔE2 expression and knockdown of PTPN6. Furthermore, the phagocytic oxidative burst during uptake of amyloid‐β1‐42 or bacterial particles was increased after CD33 knockout but not in CD33ΔE2‐expressing microglia. In summary, deletion of CD33 or expression of CD33ΔE2 in human macrophages and microglia resulted in putative beneficial phagocytosis of amyloid β1‐42, but potentially detrimental oxidative burst and inflammation, which was absent in CD33ΔE2‐expressing microglia.
Main points
Ablation of the myeloid receptor CD33 in human macrophages and microglia causes increased activation of the SYK/ERK1/2 signaling axis, phagocytosis, phagocytic oxidative burst and inflammation.
Pathogenic variants in Gap Junction Protein Beta 1 (GJB1) cause X-linked Charcot-Marie-Tooth (CMT) disease type 1 (CMTX1), which is a common hereditary motor and sensory neuropathy. A 45-year-old man ...presented with progressive muscle weakness, atrophy, sensory disturbance of all limbs from childhood, and visual field defects in both eyes at 40 years old. A segregation analysis revealed a novel variant, c.173C>A (p.P58H), in the GJB1 gene. Patients with variants at codon 58 in GJB1 showed clinically varied phenotypes, ranging from demyelinating neuropathy to cerebellar ataxia. This patient may represent one of the various clinical phenotypes of GJB1 variants.
Neurologic manifestations of long COVID NOZAKI, Ichiro; ONO, Kenjiro
Japanese Journal of Thrombosis and Hemostasis,
2022, Volume:
33, Issue:
4
Journal Article
Background
Acute disseminated encephalomyelitis (ADEM) followed by optic neuritis (ADEM-ON) is characterized by the following features: early onset, monophasic or multiphasic ADEM followed by one or ...more episodes of ON, and the presence of serum anti-myelin oligodendrocyte glycoprotein (MOG) antibodies.
Case report
We report a case of ADEM-ON without anti-MOG antibodies in a 78-year-old woman. The patient developed acute-onset neurological findings and was diagnosed with ADEM. She was treated with intravenous methylprednisolone (IVMP), and oral corticosteroids. Her clinical symptoms and MRI findings subsequently improved. Left optic neuritis emerged 6 months later, and we made a diagnosis of ADEM-ON. A brain biopsy performed during the acute phase of ADEM showed perivascular infiltration of macrophages with demyelination.
Conclusion
The majority of the reported ADEM-ON cases are pediatric cases with serum anti-MOG antibodies, but our patient was the elderly, without anti-MOG antibodies. Moreover, the pathological features of our case were similar to those observed in patients with typical ADEM and in patients with anti-MOG antibody-positive ADEM. Although ADEM-ON is related to the presence of anti-MOG antibodies, factors other than anti-MOG antibodies could contribute to the development of ADEM-ON.
We herein report a 44-year-old Japanese man with hereditary transthyretin amyloidosis (ATTRv amyloidosis) harboring the variant Leu58Arg (p.Leu78Arg) in TTR in whom we conducted an observational ...study with liver transplantation (LT) and transthyretin (TTR) stabilizers (tafamidis and diflunisal) for 9 years. This patient showed gradual deterioration of sensory, motor, and autonomic neuropathy symptoms after LT. Furthermore, cardiac amyloidosis gradually developed. Although the present case showed deterioration of the symptoms after disease-modifying treatments, LT might be suitable in patients with the same variant if they are young and in good condition due to a long survival after LT.
To elucidate the extension patterns of the hyperintense areas on diffusion-weighted magnetic resonance imaging (DW-MRI) in patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD).
...We collected the DW-MRI of dCJD cases identified by the CJD Surveillance Committee in Japan, between April 1999 and February 2018. The dCJD cases were classified into non-plaque and plaque-types. The relationship among the abnormal signals, the pathological classification, and the sites of grafting were analyzed.
We collected DW-MRI of 11 patients with dCJD, all of whom were methionine homozygous at codon 129 of the prion protein gene. The age at onset was 41 (26–76) median (range) years, the age at dural grafting was 19 (10–53) years, and the incubation period was 22 (16–29) years. Eight dCJD cases were classified as non-plaque-type and three cases were plaque-type. Five of the non-plaque-type cases and all the plaque-type cases were pathologically confirmed. Brain DW-MRI was performed 3 (1−22) months after the onset. Most of the non-plaque-type cases showed brighter hyperintensity in the cerebral cortex and basal ganglia on the side of dural grafting. Subsequent DW-MRI showed widespread hyperintense lesions in the brain. Regarding the plaque-type cases, initial scans showed hyperintensity in the basal ganglia and the thalamus in one patient. Another patient's lesion was confined to the basal ganglia. The third patient showed no abnormalities seven months post-onset; however, serial images showed a hyperintensity confined to the thalamus.
Non-plaque and plaque-types demonstrated different patterns of propagation of distinct prion strains.
•We examined DW-MRI of dura mater graft-associated Creutzfeldt-Jakob disease.•Non-plaque-type cases showed brighter signals in the brain on the side of grafting.•Plaque-type tended to show abnormalities confined to thalamus and basal ganglia.•Non-plaque and plaque-types showed distinct propagation pattern of prion protein.
•We report a case of therapy-refractory anti-NMDA receptor antibody encephalitis.•The patient recovered three years after ventilation and multidisciplinary therapy.•The response to rituximab may be ...delayed during a prolonged clinical course.
A national system for surveillance of prion diseases (PrDs) was established in Japan in April 1999. Here, we analyzed the relationships among prion protein gene (PRNP) mutations and the clinical ...features, cerebrospinal fluid (CSF) markers, and pathological characteristics of the major genotypes of genetic PrDs (gPrDs). We retrospectively analyzed age at onset and disease duration; the concentrations and incidences of 14-3-3 protein, tau protein, and abnormal prion protein (PrP(Sc)) in the CSF of 309 gPrD patients with P102L, P105L, E200K, V180I, or M232R mutations; and brain pathology in 32 autopsied patients. Three clinical phenotypes were seen: rapidly progressive Creutzfeldt-Jakob disease (CJD), which included 100% of E200K cases, 70% of M232R, and 21% of P102L; slowly progressive CJD, which included 100% of V180I and 30% of M232R; and Gerstmann-Sträussler-Scheinker disease, which included 100% of P105L and 79% of P102L. PrP(Sc) was detected in the CSF of more than 80% of patients with E200K, M232R, or P102L mutations but in only 39% of patients with V180I. V180I was accompanied by weak PrP immunoreactivity in the brain. Patients negative for PrP(Sc) in the CSF were older at disease onset than positive patients. Patients with mutations associated with high 14-3-3 protein levels in the CSF typically had synaptic deposition of PrP in the brain and a rapid course of disease. The presence of small PrP protein fragments in brain homogenates was not correlated with other clinicopathological features. Positivity for PrP(Sc) in the CSF may reflect the pathological process before or at disease onset, or abnormality in the secretion or metabolism of PrP(Sc). The amount of 14-3-3 protein in the CSF likely indicates the severity of the pathological process and accompanying neuronal damage. These characteristic features of the CSF in cases of gPrD will likely facilitate accurate diagnosis and clinicopathological study of the various disease subtypes.
We herein describe the case of an 81-year-old Japanese woman with neuroleptic malignant syndrome that occurred 36 days after the initiation of combination therapy with tiapride (75 mg/day) and ...tetrabenazine (12.5 mg/day) for Huntington's disease. The patient had been treated with tiapride or tetrabenazine alone without any adverse effects before the administration of the combination therapy. She also had advanced breast cancer when the combination therapy was initiated. To the best of our knowledge, the occurrence of neuroleptic malignant syndrome due to combination therapy with tetrabenazine and tiapride has not been previously reported. Tetrabenazine should be administered very carefully in combination with other neuroleptic drugs, particularly in patients with a worsening general condition.
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