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1.
J Neuroimmunol ; 334: 577003, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306854

RESUMO

Olivary hypertrophy (OH) is the secondary degeneration of the inferior olivary nucleus (ION). It is observed one month after the onset of a primary lesion within the dento-rubro-olivary pathway and is usually associated with oculopalatal tremors. Here, we report two unique cases with rare autoimmune diseases leading to OH development with progressive cerebellar ataxia, both of which improved with steroid treatment. The first patient was a 59-year-old man with slowly progressive dysarthria and ataxic gait without palatal tremor. Anti-N-methyl-d-aspartate (NMDA) receptor antibody was positive in the CSF, supporting a diagnosis of anti-NMDA receptor encephalitis. The second patient was a 56-year-old man who developed dysarthria, ataxia, gait disturbance, and palatal tremor. He was diagnosed with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), based on presence of a punctate contrast-enhancing lesion in the middle cerebellar peduncle, pons, and cerebellum on magnetic resonance imaging (MRI). Brain MRI in both patients demonstrated high signal intensity regions in the bilateral IONs. Semi-quantitative volume analysis of MRI revealed significant reduction in ION volume after steroid treatment and accordingly cerebellar ataxia was improved in both cases. Clinical and radiological features of the two cases were unique, indicating potential novel etiologies in the pathophysiology of OH associated with cerebellar ataxia.

2.
PLoS One ; 14(7): e0219619, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291358

RESUMO

Virtual three-dimensional (3D) surface models of autopsied human brain hemispheres were constructed by integrating multiple two-dimensional (2D) photographs. To avoid gravity-dependent deformity, formalin-fixed hemispheres were placed on non-refractile, transparent acrylic plates, which allowed us to take 2D photographs from various different angles. Photogrammetric calculations using software (ReCap Pro cloud service, Autodesk, San Rafael, CA, USA) allowed us calculate the 3D surface of each brain hemisphere. Virtual brain models could be moved and rotated freely to allow smooth, seamless views from different angles and different magnifications. When viewing rotating 3D models on 2D screens, 3D aspects of the models were enhanced using motion parallax. Comparison of different brains using this method allowed us to identify disease-specific patterns of macroscopic atrophy, that were not apparent in conventional 2D photographs. For example, we observed frontal lobe atrophy in a progressive supranuclear palsy brain, and even more subtle atrophy in the superior temporal gyrus in amyotrophic lateral sclerosis-frontotemporal lobar degeneration. Thus, our method facilities recognition of gyral atrophy. In addition, it provides a much more powerful and suitable way of visualizing the overall appearance of the brain as a three-dimensional structure. Comparison of normal and diseased brains will allow us to associate different macroscopic changes in the brain to clinical manifestations of various diseases.

3.
Intern Med ; 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31243232

RESUMO

Objective Cryptococcal meningoencephalitis (CM) causes significant morbidity and mortality in HIV-negative and HIV-positive populations. White matter lesions (WMLs) have been reported in both populations of CM patients; however, the mechanisms underlying WML formation remain unknown. We herein report the relationship between the intrathecal immune response and the development of WMLs in HIV-negative patients with CM. Methods Eleven consecutive HIV-negative patients with CM who presented at one of three emergency hospitals in Japan from April 2001 to March 2018 were enrolled. For all patients, we retrospectively assessed the relationships between clinical and laboratory information and the presence of WMLs. Results At presentation, 6 patients had WMLs on magnetic resonance imaging (MRI). The cerebrospinal fluid immunoglobulin G (CSF IgG) index was significantly higher in the patients with WMLs than in those without WMLs (mean, 1.34 vs. 0.70, p=0.017). The time from the symptom onset to initial neuroimaging was also significantly longer in the patients with WMLs than in those without WMLs (median, 31.5 vs. 7.0 days; p=0.008). The clinical outcome was comparable among the patients with and without WMLs. Conclusion In HIV-negative patients with CM, a persistent, aberrant immune response to Cryptococcus, such as intrathecal IgG synthesis, may induce WML formation.

4.
Stroke ; 50(7): 1751-1757, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31233392

RESUMO

Background and Purpose- We aimed to evaluate the effect of chronic hypertension on acute leptomeningeal collateral flow in patients with large-vessel ischemic stroke using digital subtraction angiography, which is the gold standard for the assessment of collateral circulation. Methods- Of the consecutive ischemic stroke patients from October 2011 to December 2017 seen in our institution, patients with acute occlusion of the M1 segment of the middle cerebral artery confirmed on initial digital subtraction angiography were enrolled. Chronic hypertension was defined as its documentation before the index stroke or as the administration of antihypertensive medications before onset. Angiographic leptomeningeal collateral flow was evaluated according to the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology Collateral Flow Grading System and dichotomized the findings into excellent (grade 3-4) or poor (grade 0-2) collateral status for analysis. Results- Of the 3759 consecutive ischemic stroke patients, 100 patients were analyzed. Thirty-nine patients (39%) had poor collateral status. Patients with poor collateral status were older, more frequently male, and had chronic hypertension more frequently, shorter time from onset to angiography, and higher admission systolic blood pressure than those with excellent collateral status. Multivariable logistic analysis with prespecified covariates showed a significantly positive association between chronic hypertension and poor collateral status (odds ratio, 2.80; 95% CI, 1.08-7.70; P=0.034). This association was independent of admission systolic blood pressure. The proportion of patients with poor collateral status increased in a stepwise manner in patients without chronic hypertension, hypertensive patients with premorbid antihypertensive medications, and hypertensive patients without antihypertensive medications ( P for trend <0.001). Conclusions- Our data suggest that chronic hypertension has a detrimental effect on acute leptomeningeal collateral flow in patients with cerebral large-vessel occlusion. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02251665.

5.
Nucleic Acids Res ; 47(14): 7321-7332, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31214713

RESUMO

AntimiR is an antisense oligonucleotide that has been developed to silence microRNA (miRNA) for the treatment of intractable diseases. Enhancement of its in vivo efficacy and improvement of its toxicity are highly desirable but remain challenging. We here design heteroduplex oligonucleotide (HDO)-antimiR as a new technology comprising an antimiR and its complementary RNA. HDO-antimiR binds targeted miRNA in vivo more efficiently by 12-fold than the parent single-stranded antimiR. HDO-antimiR also produced enhanced phenotypic effects in mice with upregulated expression of miRNA-targeting messenger RNAs. In addition, we demonstrated that the enhanced potency of HDO-antimiR was not explained by its bio-stability or delivery to the targeted cell, but reflected an improved intracellular potency. Our findings provide new insights into biology of miRNA silencing by double-stranded oligonucleotides and support the in vivo potential of this technology based on a new class of for the treatment of miRNA-related diseases.

6.
Neuropathology ; 39(4): 294-306, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31155757

RESUMO

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder caused by opportunistic infection of JC polyomavirus (JCV). Today, increased attention has been focused on PML development in multiple sclerosis (MS) patients under disease-modifying therapies (DMT). Although in the acquired immunodeficiency syndrome (AIDS) era, PML was thought to be a rapidly progressive disease with poor prognosis, drug-associated PML is relatively slow in progress, and a favorable outcome may be expected with early diagnosis. However, early PML diagnosis on magnetic resonance imaging (MRI) is frequently difficult, and JCV DNA copy number in cerebrospinal fluid (CSF) is usually low. To facilitate early PML diagnosis on MRI, the pre-mortem images were compared with neuropathology of the post-mortem brain, and underlying pathology corresponding to the MRI findings was evaluated. As a result, PML lesions of the autopsied brain were divided into three parts, based on the disease extension patterns: (A) Progressive white matter lesion in the right frontoparietal lobe including the precentral gyrus. Huge demyelinated lesions were formed with fusions of numerous small lesions. (B) Central lesion including deep gray matters, such as the putamen and thalamus. The left thalamic lesion was contiguous with the pontine tegmentum. (C) Infratentorial lesion of brainstem and cerebellum. Demyelination in the pontine basilar region and in cerebellar white matter was contiguous via middle cerebellar peduncles (MCPs). In addition, (D) satellite lesions were scattered all over the brain. These observations indicate that PML lesions likely evolve with three steps in a tract-dependent manner: (1) initiation; (2) extension/expansion of demyelinating lesions; and (3) fusion. Understanding of the PML disease evolution patterns would enable confident early diagnosis on MRI, which is essential for favorable prognosis with good functional outcome.

7.
Neurobiol Dis ; 130: 104516, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31229688

RESUMO

Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

8.
Sci Rep ; 9(1): 7567, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31110191

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. A characteristic pathological feature of PD is cytoplasmic accumulation of α-synuclein (SNCA) protein. Multiplication of the SNCA gene in familial PD and pathological accumulation of SNCA protein during progression of sporadic PD suggest that increased SNCA protein levels increase the risk of PD. Thus, reducing SNCA expression levels could delay PD onset or modify the disease course. For efficient knock down, we designed and synthesized an amido-bridged nucleic acids (AmNA)-modified antisense oligonucleotide (ASO) that targeted SNCA with improved stability and cellular uptake in vivo. AmNA-ASO efficiently downregulated SNCA at both the mRNA and protein level in vitro and in vivo. Notably, AmNA-ASO was efficiently delivered into the mouse brain by intracerebroventricular injection without the aid of additional chemicals. Furthermore, administration of AmNA-ASO ameliorated neurological defects in PD model mice expressing human wild type SNCA. Taken together, these findings suggest that AmNA-ASO is a promising therapeutic strategy for SNCA-associated pathology in PD.

9.
Parkinsonism Relat Disord ; 65: 238-242, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31105016

RESUMO

INTRODUCTION: Spinocerebellar ataxia (SCA) type 34, a form of autosomal dominantly inherited ataxia, has recently been associated with mutations in the ELOVL4 gene. However, a genetic study of the prevalence of SCA34 in an ataxia cohort has never been reported. METHODS: We performed a mutation screening of ELOVL4 in a cohort of 153 undiagnosed index ataxia patients, selected after excluding for common SCA types, in a series of 506 Japanese index ataxia patients. RESULTS: Heterozygous mutation c.698C > T (p.T233M) was detected in an index patient with multisystem neurodegeneration including ataxia and erythrokeratodermia skin lesions, an archetypal skin phenotype in SCA34. The patient's father also presented with ataxia but not skin lesions. Although this mutation has been recently reported in a single English-Canadian patient, the present study confirms its cosegregation with the ataxia phenotype in the Japanese kindred. Brain magnetic resonance imaging (MRI) of the patient and his father revealed marked pontine and cerebellar atrophy as well as the hot cross bun sign, that is common in cerebellar type of multiple system atrophy and was also described in SCA34 patients harboring two other mutations: p.L168F and p.W246G. CONCLUSION: This represents the first genetic study of the prevalence of SCA34 in an ataxia cohort and demonstrates its low prevalence (0.2%) in ataxia patients. The broad SCA34 clinical spectrum suggests variable multisystem neurodegeneration. Clinicians should be aware of this rare disease entity, particularly if erythrokeratodermia or the hot cross bun sign in MRI are present in undiagnosed degenerative ataxia patients.

10.
Am J Hum Genet ; 104(5): 925-935, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982609

RESUMO

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.

11.
Neurol Med Chir (Tokyo) ; 59(5): 176-183, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30996153

RESUMO

Tumefactive multiple sclerosis (tumefactive MS) is an atypical variant of MS characterized by a large isolated demyelinating lesion. Because tumefactive MS mimics high grade astrocytoma clinically and radiologically, it is difficult to distinguish between the two using only traditional diagnostic modalities, such as routine magnetic resonance imaging. [11C] methionine positron emission tomography (MET PET) has been known as a useful diagnostic tool for glioma. However, it has not been established as a diagnostic tool for tumefactive MS yet. Therefore, the objective of this study was to evaluate the performance of MET PET in differentiating tumefactive MS from high grade astrocytoma. We studied patients with tumefactive MS [six patients (three men, three women), 7 lesions] and 77 patients with astrocytoma (World Health Organization grade II: 13 patients, grade III: 28 patients, and grade IV: 36 patients), and we compared MET uptake of tumefactive demyelinating lesions and astrocytoma. For MET PET analysis, Lesion/Normal region ratios (L/N ratios) were calculated and compared between tumefactive demyelinating lesions and astrocytoma. On MET PET, the L mean/N ratio of tumefactive MS was 1.18 ± 0.50, which was significantly lower than that of high-grade glioma (astrocytoma grade III: 1.95 ± 0.62, P = 0.006; grade IV: 2.35 ± 0.54, P <0.0001). The L maximum (L max)/N ratio of tumefactive demyelinating lesion was also significantly lower than that of high grade astrocytoma (tumefactive MS: 1.89 ± 0.55; astrocytoma grade III: 3.37 ± 1.36, P = 0.0232; astrocytoma grade IV: 4.35 ± 1.30, P <0.0001). In conclusion, MET PET can help differentiate tumefactive MS from high grade astrocytoma.

13.
Eur Neurol ; 81(1-2): 13-18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31013498

RESUMO

BACKGROUND: Caudate nucleus atrophy is a well-known neuroimaging feature of Huntington's disease (HD). Some researchers have reported a decrease in the volume of the striatum on magnetic resonance images (MRIs) even in the presymptomatic stage of the disease. Despite the many neuroimaging studies on HD, the optimal method for measuring the caudate nucleus area on MRIs and the most effective cutoff values for diagnosing HD remain unclear. OBJECTIVES AND METHODS: To define suitable imaging sequences and cutoff values for HD, we measured the area of the head of the caudate nucleus (HCN) in 11 patients with HD, 22 age- and sex-matched individuals without neurodegenerative disorders in the central nervous system, 22 sex-matched patients with Alzheimer's disease, 22 sex-matched patients with Parkinson's disease, and 7 patients with dentatorubral-pallidoluysian atrophy. RESULTS: On T2-weighted images (T2WIs), we found significantly reduced HCN area at the rostral level in individuals with HD relative to those of the individuals in the other groups. A significant inverse correlation (ρ = -0.61, p = 0.046) was observed between the HD duration and HCN area at the rostral slice level on T2WIs. The cutoff value for distinguishing patients with HD from healthy individuals and those with other neurodegenerative diseases was 85 mm2 at the rostral level on T2WIs (100% sensitivity and specificity). CONCLUSIONS: This cutoff value can be applied clinically to evaluate brain atrophy in HD. Our method is advantageous because it is simple and can be implemented easily in daily clinical practice.

14.
Intern Med ; 58(12): 1775-1779, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30799339

RESUMO

Encephalopathy is a rare side effect of cephalosporin treatment. We herein present a case of encephalopathy induced by ceftriaxone, a third-generation cephalosporin, in a patient with renal failure. An 86-year-old woman on maintenance hemodialysis received ceftriaxone for Helicobacter cinaedi bacteremia. Her mental status deteriorated during antibiotic treatment, and an electroencephalogram revealed triphasic waves predominantly in the frontal area. Her consciousness improved after the discontinuation of the antibiotic due to the suspicion of ceftriaxone-induced encephalopathy. This is the first reported case of encephalopathy associated with high plasma and cerebrospinal fluid ceftriaxone concentrations, and provides significant evidence for a causal relationship between the administration of ceftriaxone and the onset of encephalopathy.


Assuntos
Antibacterianos/efeitos adversos , Encefalopatias/induzido quimicamente , Ceftriaxona/efeitos adversos , Diálise Renal/efeitos adversos , Idoso de 80 Anos ou mais , Antibacterianos/sangue , Antibacterianos/líquido cefalorraquidiano , Bacteriemia/tratamento farmacológico , Ceftriaxona/sangue , Ceftriaxona/líquido cefalorraquidiano , Eletroencefalografia , Feminino , Infecções por Helicobacter/tratamento farmacológico , Humanos
15.
Artigo em Inglês | MEDLINE | ID: mdl-30663497

RESUMO

Properties of cationic peptides bearing amino or guanidino groups with various side chain lengths that bind to double stranded RNAs (dsRNAs) were investigated. Peptides with shorter side chain lengths effectively bound to dsRNAs (12mers) increasing their thermal stability. NMR measurements suggested that the cationic peptide binds to the inner side of the major groove of dsRNA. These peptides also increased the thermal stability of siRNA and effectively protected from RNase A digestion. On the other hand, both peptides containing amino groups and guanidine groups did not disturb RNAi activity.


Assuntos
Peptídeos/química , Interferência de RNA , RNA Interferente Pequeno/química , Ribonucleases/química , Aminas/química , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Cátions , Linhagem Celular Tumoral , Guanidinas/química , Humanos , Peptídeos/metabolismo , Transição de Fase , Estabilidade de RNA , RNA de Cadeia Dupla/química , RNA de Cadeia Dupla/metabolismo , RNA Interferente Pequeno/metabolismo , Ribonucleases/metabolismo , Termodinâmica
16.
J Clin Neurosci ; 62: 226-228, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30612916

RESUMO

Progressive multifocal leukoencephalopathy (PML) is caused by John Cunningham (JC) virus in immunocompromized patients such as those with human immunodeficiency virus (HIV) infection, hematological malignancy, autoimmune disorder, and immunodeficiency disorder as well as those undergoing chemotherapy or immunosuppressive therapy. No effective treatments have been established for PML, which commonly causes severe neurological sequelae. We describe the first case of PML in a patient without HIV infection who exhibited remarkable improvement following acute pyelonephritis with Escherichia coli bacteremia.


Assuntos
Hospedeiro Imunocomprometido , Leucoencefalopatia Multifocal Progressiva/imunologia , Pielonefrite/complicações , Adulto , Anemia Hemolítica Autoimune/complicações , Bacteriemia/complicações , Feminino , Humanos , Neoplasias Pulmonares/complicações , Linfoma de Zona Marginal Tipo Células B/complicações
17.
Arch Biochem Biophys ; 663: 120-128, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30629958

RESUMO

BACKGROUND: Vitamin C (l-ascorbic acid, VC) and vitamin E (α-tocopherol, VE) play important physiological roles as endogenous antioxidants in many tissues and organs. However, their roles in the brain remain entirely elusive. We established senescence marker protein 30 (SMP30)/α-tocopherol transfer protein (αTTP) double knockout (DKO) mice as a novel VC and VE double-deficiency model and examined the effect of VC and VE double-deficiency on brain functions. METHODS: DKO and wild-type (WT) mice were divided into the following two groups: mice in the CE (+) group were supplied with sufficient amounts of VC and VE and mice in the CE (-) group were deficient in both VC and VE. After 8 weeks of CE (+) or CE (-) treatments, a battery of behavioral experiments was conducted to analyze cognitive functions, including memory, through the Morris water maze and Pavlovian fear conditioning tasks. RESULTS: The plasma VC and VE levels in DKO-CE (-) mice and VE level in WT-CE (-) mice were almost completely depleted after 8 weeks of the deficient treatment. The behavioral study revealed that the general behaviors, including locomotor activity and anxiety level, were not influenced by the CE (-) treatment in DKO and WT mice. However, in the Pavlovian fear conditioning task, DKO-CE (-) mice showed impaired conditioned fear memory compared with that of DKO-CE (+) mice. Furthermore, increased mRNA expression was observed in inflammatory-related genes, such as IL-6, TNFα, F4/80, and Mcp-1, in the hippocampus of DKO-CE (-) mice. CONCLUSIONS: The findings of this study provide evidence that VC and VE deficiency led to impaired conditioned fear memory possibly caused by neuroinflammation in the brain.

18.
J Neurol ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30511098

RESUMO

OBJECTIVE: In the present study, we analyzed the inflammatory profiles of brain tissues obtained from patients with progressive multifocal leukoencephalopathy (PML) due to John Cunningham (JC) virus infection to identify potential prognostic factors. METHODS: The study included seven patients (two men, five women) who had been pathologically diagnosed with PML, and all of whom were HIV negative. Fixed brain samples were analyzed via hematoxylin and eosin (HE) staining and Klüver-Barrera (KB) staining. We then performed immunohistochemistry (IHC) specific to JC virus capsid proteins (VP1 and VP2/3) and lymphocyte surface markers (CD4, CD8, CD138, and PD-1). RESULTS: The mean age at onset was 53.4, while the mean duration until biopsy/autopsy was 4.7 months. Four patients were included in the good prognosis (GP) group, while three were included in the poor prognosis (PP) group. Pathological analysis revealed a significantly larger number of CD4-positive T-cell infiltrations (P = .029) in the GP group, along with a preserved CD4:CD8 ratio. Larger numbers of CD138-positive plasma cells were also observed in the GP group (P = .029) than in the PP group. Linear regression analyses revealed a significant association between the numbers of CD138-positive plasma cells and PD-1-positive cells (R2 = 0.80). CONCLUSIONS: Viral loads in the cerebrospinal fluid, a controlled inflammatory response mediated by CD4- and CD8-positive T cells, and plasma cells are associated with PML prognosis. Our findings further indicate that regulatory plasma cells may regulate inflammatory T-cell activity via a PD-1/PD-L1 immuno-checkpoint pathway, thereby protecting the uninfected brain from excessive immune-mediated damage during an active JC virus infection.

20.
Prion ; 12(5-6): 315-319, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30394185

RESUMO

Although colocalization of amyloid ß (Aß) with prion protein (PrP) in the kuru plaque has previously been observed in the brain of prion diseases patients, the participating Aß species has not been identified. Here, we present an immunohistochemical assessment of the brain and spinal cord of a 69-year-old Japanese female patient with Gerstmann-Sträussler-Scheinker disease with a P105L mutation on the PRNP gene (GSS-P105L). Immunohistochemical assessment of serial brain sections was performed using anti-PrP and -Aß antibodies in the hippocampus, frontal and occipital lobes. She died 69 years after a 21-year clinical course. Immunohistochemistorical examination revealed that ~50% of the kuru plaques in the cerebrum were colocalized with Aß, and Aß42 was predominantly observed to be colocalized with PrP-plaques. The Aß deposition patterns were unique, and distinct from diffuse plaques observed in the normal aging brain or Alzheimer's disease brain. The spinal cord exhibited degeneration in the lateral corticospinal tract, posterior horn, and fasciculus gracilis. We have demonstrated for the first time that Aß42, rather than Aß40, is the main Aß component associated with PrP-plaques, and also the degeneration of the fasciculus gracilis in the spinal cord in GSS-P105L, which could be associated with specific clinical features of GSS-P105L.

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