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1.
Acta Neuropathol ; 148(1): 53, 2024 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-39400557

RESUMEN

Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.


Asunto(s)
Tronco Encefálico , Moléculas de Adhesión Celular Neuronal , Tauopatías , Proteínas tau , Humanos , Tauopatías/patología , Tauopatías/inmunología , Persona de Mediana Edad , Tronco Encefálico/patología , Tronco Encefálico/metabolismo , Tronco Encefálico/inmunología , Masculino , Femenino , Anciano , Anciano de 80 o más Años , Proteínas tau/metabolismo , Proteínas tau/inmunología , Moléculas de Adhesión Celular Neuronal/metabolismo , Moléculas de Adhesión Celular Neuronal/inmunología , Adulto , Autoanticuerpos/inmunología , Proteínas de Unión al ADN/metabolismo
2.
Neuropathology ; 44(1): 59-67, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37357975

RESUMEN

Erdheim-Chester disease is a non-Langerhans cell histiocytosis syndrome characterised by histiocytic infiltration of different organs and systems in the body. Erdheim-Chester disease with isolated central nervous system (CNS) involvement causes diagnostic difficulties due to the absence of systemic findings and may result in misdiagnosis and inaccurate treatment choices. The case discussed in this report exemplifies how challenging it is to diagnose Erdheim-Chester disease with isolated CNS involvement. This case, which presented with progressive pyramidocerebellar syndrome, was clinically and radiologically resistant to all immunosuppressive and immunomodulatory treatments administered. The presence of false negative results in repeated histopathological investigations and the absence of evidence for systemic disease hindered the diagnosis and treatment work-up. In this study, we reviewed and discussed the prominent features of the presented case in light of the relevant literature.


Asunto(s)
Enfermedad de Erdheim-Chester , Humanos , Enfermedad de Erdheim-Chester/diagnóstico por imagen , Enfermedad de Erdheim-Chester/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Inmunosupresores
3.
Eur J Neurol ; 28(3): 1009-1015, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33131137

RESUMEN

BACKGROUND: The C9orf72 hexanucleotide expansion mutation is the most common cause of genetic frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and combined FTD-ALS. Its underlying neuropathology combines TDP-43 pathology and dipeptide repeat protein (DPR) deposits and may also associate with other neurodegeneration-associated protein aggregates. Herein we present a unique combination of C9orf72 mutation with sporadic Creutzfeldt-Jakob disease (CJD) in a 74-year-old patient with rapidly progressive dementia. METHODS: Detailed neuropathological examination including immunohistochemistry for several proteinopathies. Genetic analysis was conducted by repeat primed polymerase chain reaction (PCR). Furthermore, we analyzed additional C9orf72 mutation carriers for prion-protein (PrP) deposits in brain tissue and screened the cerebellar cortex of other CJD cases for p62/DPR neuronal inclusions to assess the frequency of combined pathologies. RESULTS: Postmortem brain examination of a patient with a rapidly progressive neurological deterioration of 8 months' duration confirmed the diagnosis of CJD. She harbored valine homozygosity at PRNP codon 129. In addition, a frontotemporal lobar degeneration (FTLD)-pattern with TDP-43 protein aggregates and p62+/C9RANT+ positive inclusions along with a high degree of Alzheimer-related pathology (A3B3C3) were identified. The suspected C9orf72 expansion mutation was confirmed by repeat-primed PCR. Screening of 13 C9orf72 cases showed no pathological PrP aggregates and screening of 100 CJD cases revealed no other C9orf72 expansion mutation carriers. CONCLUSION: A combination of a C9orf72 expansion mutation-related FTLD with sporadic CJD in the same patient is rare. While the rarity of both diseases makes this concurrence most likely to be coincidental, questions regarding a potential link between these two neurodegenerative pathologies deserve further studies.


Asunto(s)
Esclerosis Amiotrófica Lateral , Síndrome de Creutzfeldt-Jakob , Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Anciano , Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Síndrome de Creutzfeldt-Jakob/genética , Expansión de las Repeticiones de ADN/genética , Proteínas de Unión al ADN/genética , Femenino , Demencia Frontotemporal/genética , Degeneración Lobar Frontotemporal/genética , Humanos , Mutación
4.
Neuropathology ; 40(4): 358-366, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32483828

RESUMEN

Metabolic/hepatic encephalopathy is neuropathologically characterized by the presence of Alzheimer type II astrocytes (AA II) with large and clear nuclear morphology. To date, there is no good immunohistochemical marker to better identify these cells. Here, we assessed cases of hepatic encephalopathy of different etiologies by immunohistochemistry using an anti-p62 antibody. We observed peripheral or diffuse nuclear staining of variable intensity in AA II in all cases but not in normal controls or reactive astrocytes. We conclude that p62 is a useful immunohistochemical marker for the identification of AA II and may be helpful for the neuropathological diagnosis of metabolic/hepatic encephalopathy in difficult or equivocal cases.


Asunto(s)
Astrocitos/patología , Biomarcadores/metabolismo , Encefalopatía Hepática/patología , Proteínas de Unión al ARN/análisis , Adolescente , Anciano , Anticuerpos Monoclonales , Autofagia , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad
5.
PLoS Pathog ; 13(5): e1006294, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28467504

RESUMEN

[This corrects the article DOI: 10.1371/journal.ppat.1002350.].

6.
Ann Neurol ; 79(3): 404-18, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26874214

RESUMEN

OBJECTIVE: Symptomatic infections of the central nervous system (CNS) with JC polyomavirus (JCV) usually occur as a result of immunocompromise and manifest as progressive multifocal leukoencephalopathy (PML) or granule cell neuronopathy (GCN). After immune reconstitution, some of these cases may show long-term persistence of JCV and delayed clinical improvement despite inflammation. METHODS: We followed 4 patients with multiple sclerosis, who developed natalizumab-associated PML or GCN with regard to JC viral load and JCV-specific T-cell responses in the CNS. All of them experienced immune reconstitution inflammatory syndrome (IRIS), but in 2 cases JCV persisted > 21 months after IRIS accompanied by delayed clinical improvement. RESULTS: Persistence of JCV was associated with a lack of JCV VP1-specific T-cell responses during immune reconstitution in 1 of the patients. Detailed analysis of the brain infiltrate in another patient with neuronal persistence of JCV revealed strong infiltration of CD8(+) T cells and clonal expansion of activated CD8(+) effector T cells with a CD4(dim) CD8(+) phenotype, both exhibiting exquisite specificity for conserved epitopes of JCV large T antigen. However, clearance of JCV was not efficient, because mutations in the major capsid protein VP1 caused reduced CD4(+) T-cell responses against the identified JCV variant and subsequently resulted in a decline of CD8(+) T-cell responses after IRIS. INTERPRETATION: Our findings suggest that efficient CD4(+) T-cell recognition of neurotropic JCV variants is crucial to support CD8(+) T cells in combating JCV infection of the CNS.


Asunto(s)
Evasión Inmune/inmunología , Síndrome Inflamatorio de Reconstitución Inmune/inmunología , Virus JC/fisiología , Leucoencefalopatía Multifocal Progresiva/inmunología , Leucoencefalopatía Multifocal Progresiva/virología , Esclerosis Múltiple/inmunología , Adulto , Encéfalo/inmunología , Encéfalo/virología , Femenino , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/virología , Virus JC/clasificación , Virus JC/genética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/virología
7.
Neuropathology ; 37(4): 293-305, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28261874

RESUMEN

Senescence accelerated mice P8 (SAMP8) show significant age-related deteriorations in memory and learning ability in accordance with early onset and rapid advancement of senescence. Brains of SAMP8 mice reveal an age-associated increase of PAS-positive granular structures in the hippocampal formation and astrogliosis in the brain stem and hippocampus. A spongy degeneration in the brain stem appears at 1 month of age and reaches a maximum at 4-8 months. In addition, clusters of activated microglia also appear around the vacuoles in the brain stem. ß/A4(Aß) protein-like immunoreactive granular structures are observed in various regions and increase in number markedly with age. Other age-associated histological changes include cortical atrophy, neuronal cell loss in locus coeruleus and lateral tegmental nuclei, intraneuronal accumulation of lipopigments in Purkinje cells and eosinophilic inclusion bodies in thalamic neurons. A blood-brain barrier dysfunction and astrogliosis are also prominent with advancing age in the hippocampus. These changes are generally similar to the pathomorphology of aging human brains and characterized by their association with some specific glioneuronal reactions. As for the hallmarks of Alzheimer brains, tau morphology has not yet been confirmed regardless of the age-related increase in phosphorylated tau in SAMP8 mice brains, but early age-related Aß deposition in the hippocampus has recently been published. SAMP8 mice are, therefore, not only a senescence-accelerated model but also a promising model for Alzheimer's disease and other cognitive disorders.


Asunto(s)
Envejecimiento/patología , Encéfalo/patología , Demencia/patología , Modelos Animales de Enfermedad , Animales , Ratones , Ratones Mutantes
8.
PLoS Pathog ; 10(12): e1004531, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25502554

RESUMEN

Prion infections cause neurodegeneration, which often goes along with oxidative stress. However, the cellular source of reactive oxygen species (ROS) and their pathogenetic significance are unclear. Here we analyzed the contribution of NOX2, a prominent NADPH oxidase, to prion diseases. We found that NOX2 is markedly upregulated in microglia within affected brain regions of patients with Creutzfeldt-Jakob disease (CJD). Similarly, NOX2 expression was upregulated in prion-inoculated mouse brains and in murine cerebellar organotypic cultured slices (COCS). We then removed microglia from COCS using a ganciclovir-dependent lineage ablation strategy. NOX2 became undetectable in ganciclovir-treated COCS, confirming its microglial origin. Upon challenge with prions, NOX2-deficient mice showed delayed onset of motor deficits and a modest, but significant prolongation of survival. Dihydroethidium assays demonstrated a conspicuous ROS burst at the terminal stage of disease in wild-type mice, but not in NOX2-ablated mice. Interestingly, the improved motor performance in NOX2 deficient mice was already measurable at earlier stages of the disease, between 13 and 16 weeks post-inoculation. We conclude that NOX2 is a major source of ROS in prion diseases and can affect prion pathogenesis.


Asunto(s)
Síndrome de Creutzfeldt-Jakob/fisiopatología , Glicoproteínas de Membrana/fisiología , NADPH Oxidasas/fisiología , Enfermedades por Prión/fisiopatología , Priones/fisiología , Animales , Estudios de Casos y Controles , Proliferación Celular , Cerebelo/metabolismo , Cerebelo/patología , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patología , Modelos Animales de Enfermedad , Femenino , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Humanos , Masculino , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , Microglía/patología , NADPH Oxidasa 2 , NADPH Oxidasas/deficiencia , NADPH Oxidasas/genética , Enfermedades por Prión/metabolismo , Enfermedades por Prión/patología , Especies Reactivas de Oxígeno/metabolismo
9.
Acta Neuropathol ; 131(6): 911-23, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27016065

RESUMEN

Deposition of amyloid-ß (Aß) in the brain parenchyma and vessels is one of the hallmarks of Alzheimer disease (AD). Recent observations of Aß deposition in iatrogenic Creutzfeldt-Jakob disease (iCJD) after dural grafting or treatment with pituitary extracts raised concerns whether Aß is capable of transmitting disease as seen in prion diseases by the disease-associated prion protein. To address this issue, we re-sampled and re-evaluated archival material, including the grafted dura mater of two cases with iCJD (28 and 33-years-old) without mutations in the AßPP, PSEN1 and PSEN2 genes, and carrying ε3/ε3 alleles of the APOE gene. In addition, we evaluated 84 dura mater samples obtained at autopsy (mean age 84.9 ± 0.3) in the community-based VITA study for the presence of Aß deposition. We show that the dura mater may harbor Aß deposits (13 %) in the form of cerebral amyloid angiopathy or amorphous aggregates. In both iCJD cases, the grafted dura mater had accumulated Aß. The morphology and distribution pattern of cerebral Aß deposition together with the lack of tau pathology distinguishes the Aß proteinopathy in iCJD from AD, from that seen in young individuals without cognitive decline carrying one or two APOE4 alleles, and from that related to traumatic brain injury. Our novel findings of Aß deposits in the dura mater, including the grafted dura, and the distinct cerebral Aß distribution in iCJD support the seeding properties of Aß. However, in contrast to prion diseases, our study suggests that such Aß seeding is unable to reproduce the full clinicopathological phenotype of AD.


Asunto(s)
Enfermedad de Alzheimer/patología , Angiopatía Amiloide Cerebral/patología , Síndrome de Creutzfeldt-Jakob/patología , Duramadre/patología , Enfermedades por Prión/patología , Adulto , Enfermedad de Alzheimer/diagnóstico , Precursor de Proteína beta-Amiloide/metabolismo , Autopsia , Encéfalo/patología , Angiopatía Amiloide Cerebral/diagnóstico , Síndrome de Creutzfeldt-Jakob/diagnóstico , Femenino , Humanos , Enfermedades por Prión/diagnóstico , Enfermedades por Prión/metabolismo
10.
Acta Neuropathol ; 132(4): 531-43, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27358064

RESUMEN

We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define "definite", "probable" and "possible" diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A "definite" diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a "probable" diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB1*1001 and HLA-DQB1*0501 alleles. A "possible" diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder.


Asunto(s)
Encéfalo/inmunología , Moléculas de Adhesión Celular Neuronal/metabolismo , Tauopatías/diagnóstico , Tauopatías/inmunología , Proteínas tau/metabolismo , Anciano , Encéfalo/patología , Moléculas de Adhesión Celular Neuronal/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas/inmunología , Neuronas/patología , Tauopatías/patología
11.
Acta Neuropathol ; 131(1): 87-102, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26659578

RESUMEN

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.


Asunto(s)
Envejecimiento , Astrocitos/citología , Encéfalo/patología , Tauopatías/patología , Proteínas tau/metabolismo , Animales , Encéfalo/metabolismo , Humanos , Neuroglía/patología , Tauopatías/metabolismo
12.
Neurobiol Dis ; 69: 76-92, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24878508

RESUMEN

Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and multiple system atrophy are characterized by the deposition of disease-associated α-synuclein. In the present study we 1) examined the molecular specificity of the novel anti-α-synuclein 5G4 antibody; 2) evaluated immunoreactivity patterns and their correlation in human brain tissue with micro- and astrogliosis in 57 cases with PD or DLB; and 3) performed a systematic immunoelectron microscopical mapping of subcellular localizations. 5G4 strongly binds to the high molecular weight fraction of ß-sheet rich oligomers, while no binding to primarily disordered oligomers or monomers was observed. We show novel localizations of disease-associated α-synuclein including perivascular macrophages, ependyma and cranial nerves. α-Synuclein immunoreactive neuropil dots and thin threads associate more with glial reaction than Lewy bodies alone. Astrocytic α-synuclein is an important component of the pathology. Furthermore, we document ultrastructurally the pathway of processing of disease-associated α-synuclein within neurons and astroglial cells. Interaction of mitochondria and disease-associated α-synuclein plays a key role in the molecular-structural cytopathogenesis of disorders with Lewy bodies. We conclude that 1) the 5G4 antibody has strong selectivity for ß-sheet rich α-synuclein oligomers; 2) Lewy bodies themselves are not the most relevant morphological substrate that evokes tissue lesioning; 3) both neurons and astrocytes internalize disease-associated α-synuclein in the human brain, suggesting prion-like cell-to-cell spread of α-synuclein by uptake from surrounding structures, as shown previously in experimental observations.


Asunto(s)
Astrocitos/metabolismo , Encéfalo/metabolismo , Espacio Intracelular/metabolismo , Neuronas/metabolismo , alfa-Sinucleína/metabolismo , Anciano , Anciano de 80 o más Años , Anticuerpos/metabolismo , Espacio Extracelular/metabolismo , Femenino , Gliosis/metabolismo , Humanos , Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/metabolismo , Masculino , Microglía/metabolismo , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Estructura Secundaria de Proteína , alfa-Sinucleína/genética , alfa-Sinucleína/inmunología
13.
Ann Neurol ; 74(4): 622-6, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23868420

RESUMEN

Progressive multifocal leukoencephalopathy is the most common clinical presentation of JC virus (JCV)-associated central nervous system (CNS) disease and has emerged as a major safety concern in multiple sclerosis patients treated with the monoclonal antibody natalizumab. Here we report clinical, radiological, and histological findings of a case of cerebellar granule cell neuronopathy (GCN), a JCV-associated CNS disease, so far unreported amongst patients treated with natalizumab. GCN should be considered as a JCV CNS manifestation in patients with newly developed, progressive cerebellar signs under natalizumab treatment, especially in cases where cerebellar atrophy can be visualized by magnetic resonance imaging.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Inflamatorio de Reconstitución Inmune/etiología , Virus JC/fisiología , Leucoencefalopatía Multifocal Progresiva/complicaciones , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Degeneraciones Espinocerebelosas/etiología , Adulto , Antígenos CD/metabolismo , Encéfalo/patología , Encéfalo/virología , Femenino , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/patología , Síndrome Inflamatorio de Reconstitución Inmune/virología , Imagen por Resonancia Magnética , Natalizumab , Degeneraciones Espinocerebelosas/tratamiento farmacológico
14.
Ideggyogy Sz ; 67(3-4): 135-9, 2014 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-26118258

RESUMEN

Identification of etiological connections among virtually distinct diseases in a patient may be sometimes challenging. We report a unique case with two B cell malignancies and an inflammatory leukoencephalopathy. Three days prior to admission, the elderly male patient developed fatigue, headaches, recurrent vomiting, memory disturbances, depression and somnolence. Clinical, laboratory and imaging evaluations as well as post mortem histological studies were performed. Simultaneous presence of primary central nervous system B cell lymphoma, temporal lobe inflammatory leukoencephalopathy and multiple (smoldering) myeloma, was revealed by the detailed work up in the treatment-naïve patient. Based on recent data from genomic studies, we propose that a sequential evolution of molecular pathology lead to the co-occurrence of multiple myeloma and primary central nervous system B cell lymphoma in this patient, and interpret the development of the temporal lobe leukoencephalopathy as a likely paraneoplastic complication of smoldering myeloma.


Asunto(s)
Neoplasias Encefálicas , Leucoencefalopatías , Linfoma de Células B , Mieloma Múltiple , Lóbulo Temporal , Anciano , Antígenos CD20/análisis , Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/diagnóstico , Antígenos CD8/análisis , Linfocitos T CD8-positivos/inmunología , Resultado Fatal , Humanos , Inmunohistoquímica , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inflamación , Leucoencefalopatías/complicaciones , Leucoencefalopatías/diagnóstico , Linfoma de Células B/complicaciones , Linfoma de Células B/diagnóstico , Imagen por Resonancia Magnética , Masculino , Mieloma Múltiple/complicaciones , Mieloma Múltiple/diagnóstico , Síndromes Paraneoplásicos , Sepsis/etiología , Lóbulo Temporal/química , Lóbulo Temporal/patología
15.
PLoS One ; 19(7): e0304528, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39079175

RESUMEN

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.


Asunto(s)
Edad de Inicio , Síndrome de Creutzfeldt-Jakob , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patología , Anciano , Persona de Mediana Edad , Femenino , Masculino , Fenotipo , Genotipo
16.
J Neurosci ; 32(21): 7345-55, 2012 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-22623680

RESUMEN

The transmissible agent of prion disease consists of prion protein (PrP) in ß-sheet-rich state (PrP(Sc)) that can replicate its conformation according to a template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide accurately reproduces that of the PrP(Sc) template. Here, three conformationally distinct amyloid states were prepared in vitro using Syrian hamster recombinant PrP (rPrP) in the absence of cellular cofactors. Surprisingly, no signs of prion infection were found in Syrian hamsters inoculated with rPrP fibrils that resembled PrP(Sc), whereas an alternative amyloid state, with a folding pattern different from that of PrP(Sc), induced a pathogenic process that led to transmissible prion disease. An atypical proteinase K-resistant, transmissible PrP form that resembled the structure of the amyloid seeds was observed during a clinically silent stage before authentic PrP(Sc) emerged. The dynamics between the two forms suggest that atypical proteinase K-resistant PrP (PrPres) gave rise to PrP(Sc). While no PrP(Sc) was found in preparations of fibrils using protein misfolding cyclic amplification with beads (PMCAb), rPrP fibrils gave rise to atypical PrPres in modified PMCAb, suggesting that atypical PrPres was the first product of PrP(C) misfolding triggered by fibrils. The current work demonstrates that a new mechanism responsible for prion diseases different from the PrP(Sc)-templated or spontaneous conversion of PrP(C) into PrP(Sc) exists. This study provides compelling evidence that noninfectious amyloids with a structure different from that of PrP(Sc) could lead to transmissible prion disease. This work has numerous implications for understanding the etiology of prion and other neurodegenerative diseases.


Asunto(s)
Enfermedades por Prión/transmisión , Priones/metabolismo , Pliegue de Proteína , Amiloide/metabolismo , Animales , Encéfalo/enzimología , Encéfalo/metabolismo , Encéfalo/patología , Cricetinae , Endopeptidasa K/metabolismo , Masculino , Enfermedades por Prión/enzimología , Enfermedades por Prión/patología , Conformación Proteica , Proteínas Recombinantes/metabolismo
17.
J Biol Chem ; 287(36): 30205-14, 2012 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-22807452

RESUMEN

Transmission of prions to a new host is frequently accompanied by strain adaptation, a phenomenon that involves reduction of the incubation period, a change in neuropathological features and, sometimes, tissue tropism. Here we show that a strain of synthetic origin (SSLOW), although serially transmitted within the same species, displayed the key attributes of the strain adaptation process. At least four serial passages were required to stabilize the strain-specific SSLOW phenotype. The biological titration of SSLOW revealed a correlation between clinical signs and accumulation of PrP(Sc) in brains of animals inoculated with high doses (10(-1)-10(-5) diluted brain material), but dissociation between the two processes at low dose inocula (10(-6)-10(-8) diluted brain material). At low doses, several asymptomatic animals harbored large amounts of PrP(Sc) comparable with those seen in the brains of terminally ill animals, whereas one clinically ill animal had very little, if any, PrP(Sc). In summary, the current study illustrates that the phenomenon of prion strain adaptation is more common than generally thought and could be observed upon serial transmission without changing the host species. When PrP(Sc) is seeded by recombinant PrP structures different from that of authentic PrP(Sc), PrP(Sc) properties continued to evolve for as long as four serial passages.


Asunto(s)
Encéfalo/metabolismo , Proteínas PrPSc/metabolismo , Proteínas PrPSc/patogenicidad , Enfermedades por Prión/metabolismo , Animales , Encéfalo/patología , Cricetinae , Enfermedades por Prión/patología , Enfermedades por Prión/transmisión , Estabilidad Proteica
18.
PLoS Pathog ; 7(12): e1002419, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22144901

RESUMEN

The transmissible agent of prion disease consists of a prion protein in its abnormal, ß-sheet rich state (PrP(Sc)), which is capable of replicating itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a PrP(Sc) template. Here we report that authentic PrP(Sc) and transmissible prion disease can be generated de novo in wild type animals by recombinant PrP (rPrP) amyloid fibrils, which are structurally different from PrP(Sc) and lack any detectable PrP(Sc) particles. When induced by rPrP fibrils, a long silent stage that involved two serial passages preceded development of the clinical disease. Once emerged, the prion disease was characterized by unique clinical, neuropathological, and biochemical features. The long silent stage to the disease was accompanied by significant transformation in neuropathological properties and biochemical features of the proteinase K-resistant PrP material (PrPres) before authentic PrP(Sc) evolved. The current work illustrates that transmissible prion diseases can be induced by PrP structures different from that of authentic PrP(Sc) and suggests that a new mechanism different from the classical templating exists. This new mechanism designated as "deformed templating" postulates that a change in the PrP folding pattern from the one present in rPrP fibrils to an alternative specific for PrP(Sc) can occur. The current work provides important new insight into the mechanisms underlying genesis of the transmissible protein states and has numerous implications for understanding the etiology of neurodegenerative diseases.


Asunto(s)
Amiloide/metabolismo , Proteínas PrPSc/metabolismo , Proteínas PrPSc/patogenicidad , Enfermedades por Prión/metabolismo , Enfermedades por Prión/transmisión , Pliegue de Proteína , Amiloide/genética , Animales , Cricetinae , Mesocricetus , Proteínas PrPSc/genética , Enfermedades por Prión/genética , Enfermedades por Prión/patología , Estructura Secundaria de Proteína
19.
PLoS Pathog ; 7(11): e1002350, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22072968

RESUMEN

Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5-6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments.


Asunto(s)
Síndrome de Creutzfeldt-Jakob , Modelos Animales de Enfermedad , Priones/genética , Animales , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patología , Síndrome de Creutzfeldt-Jakob/transmisión , Progresión de la Enfermedad , Humanos , Ratones , Ratones Transgénicos , Proteínas Recombinantes de Fusión/metabolismo
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