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13 pages, 2141 KiB

Open AccessArticle

Phenotypic Heterogeneity of Variably Protease-Sensitive Prionopathy: A Report of Three Cases Carrying Different Genotypes at PRNP Codon 129

by Simone Baiardi, Angela Mammana, Marcello Rossi, Anna Ladogana, Benedetta Carlà, Pierluigi Gambetti, Sabina Capellari and Piero Parchi

Viruses 2022, 14(2), 367; https://doi.org/10.3390/v14020367 - 10 Feb 2022

Cited by 6 | Viewed by 2190

Abstract

Variably protease-sensitive prionopathy is an exceedingly rare, likely underestimated, sporadic prion disease that is characterized by heterogeneous and often non-specific clinical and pathological features posing diagnostic challenges. We report the results of a comprehensive analysis of three emblematic cases carrying different genotypes at [...] Read more.

Variably protease-sensitive prionopathy is an exceedingly rare, likely underestimated, sporadic prion disease that is characterized by heterogeneous and often non-specific clinical and pathological features posing diagnostic challenges. We report the results of a comprehensive analysis of three emblematic cases carrying different genotypes at the methionine (M)/valine (V) polymorphic codon 129 in the prion protein gene (PRNP). Clinical, biochemical, and neuropathological findings highlighted the prominent role of the host genetic background as a phenotypic modulator. In particular, the PRNP codon 129 showed a remarkable influence on the physicochemical properties of the pathological prion protein (PrP^Sc), especially on the sensitivity to proteinase K (PK) digestion (VV > MV > MM), which variably affected the three main fragments (i.e., of 19, 17, and 7 kDa, respectively) comprising the PrP^Sc profile after PK digestion and immunoblotting. This, in turn, correlated with significant differences in the ratio between the 19 kDa and the 7 kDa fragments which was highest in the MM case and lowest in the VV one. The relative amount of cerebral and cerebellar PrP mini-plaques immunohistochemistry showed a similar association with the codon 129 genotype (i.e., VV > MV > MM). Clinical manifestations and results of diagnostic investigations were non-specific, except for the detection of prion seeding activity by the real-time quaking-induced conversion assay in the only cerebrospinal fluid sample that we tested (from patient 129VV). Full article

(This article belongs to the Special Issue Prion Disease)

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14 pages, 2095 KiB

Open AccessArticle

Total and Phosphorylated Cerebrospinal Fluid Tau in the Differential Diagnosis of Sporadic Creutzfeldt-Jakob Disease and Rapidly Progressive Alzheimer’s Disease

by Peter Hermann, Philip Haller, Stefan Goebel, Timothy Bunck, Christian Schmidt, Jens Wiltfang and Inga Zerr

Viruses 2022, 14(2), 276; https://doi.org/10.3390/v14020276 - 28 Jan 2022

Cited by 14 | Viewed by 3310

Abstract

Background: CSF total-tau (t-tau) became a standard cerebrospinal fluid biomarker in Alzheimer’s disease (AD). In parallel, extremely elevated levels were observed in Creutzfeldt-Jakob disease (CJD). Therefore, tau is also considered as an alternative CJD biomarker, potentially complicating the interpretation of results. We investigated [...] Read more.

Background: CSF total-tau (t-tau) became a standard cerebrospinal fluid biomarker in Alzheimer’s disease (AD). In parallel, extremely elevated levels were observed in Creutzfeldt-Jakob disease (CJD). Therefore, tau is also considered as an alternative CJD biomarker, potentially complicating the interpretation of results. We investigated CSF t-tau and the t-tau/phosphorylated tau181 ratio in the differential diagnosis of sCJD and rapidly-progressive AD (rpAD). In addition, high t-tau concentrations and associated tau-ratios were explored in an unselected laboratory cohort. Methods: Retrospective analyses included n = 310 patients with CJD (n = 205), non-rpAD (n = 65), and rpAD (n = 40). The diagnostic accuracies of biomarkers were calculated and compared. Differential diagnoses were evaluated in patients from a neurochemistry laboratory with CSF t-tau >1250 pg/mL (n = 199 out of 7036). Results: CSF t-tau showed an AUC of 0.942 in the discrimination of sCJD from AD and 0.918 in the discrimination from rpAD. The tau ratio showed significantly higher AUCs (p < 0.001) of 0.992 versus non-rpAD and 0.990 versus rpAD. In the neurochemistry cohort, prion diseases accounted for only 25% of very high CSF t-tau values. High tau-ratios were observed in CJD, but also in non-neurodegenerative diseases. Conclusions: CSF t-tau is a reliable biomarker for sCJD, but false positive results may occur, especially in rpAD and acute encephalopathies. The t-tau/p-tau ratio may improve the diagnostic accuracy in centers where specific biomarkers are not available. Full article

(This article belongs to the Special Issue Prion Disease)

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11 pages, 902 KiB

Open AccessEditor’s ChoiceArticle

Histotype-Dependent Oligodendroglial PrP Pathology in Sporadic CJD: A Frequent Feature of the M2C “Strain”

by Ellen Gelpi, Sigrid Klotz, Nuria Vidal-Robau, Gerda Ricken, Günther Regelsberger, Thomas Ströbel, Ognian Kalev, Marlene Leoni, Herbert Budka and Gabor G. Kovacs

Viruses 2021, 13(9), 1796; https://doi.org/10.3390/v13091796 - 9 Sep 2021

Cited by 2 | Viewed by 2540

Abstract

In sporadic Creutzfeldt-Jakob disease, molecular subtypes are neuropathologically well identified by the lesioning profile and the immunohistochemical PrP^d deposition pattern in the grey matter (histotypes). While astrocytic PrP pathology has been reported in variant CJD and some less frequent histotypes (e.g., MV2K), [...] Read more.

In sporadic Creutzfeldt-Jakob disease, molecular subtypes are neuropathologically well identified by the lesioning profile and the immunohistochemical PrP^d deposition pattern in the grey matter (histotypes). While astrocytic PrP pathology has been reported in variant CJD and some less frequent histotypes (e.g., MV2K), oligodendroglial pathology has been rarely addressed. We assessed a series of sCJD cases with the aim to identify particular histotypes that could be more prone to harbor oligodendroglial PrP^d. Particularly, the MM2C phenotype, in both its more “pure” and its mixed MM1+2C or MV2K+2C forms, showed more frequent oligodendroglial PrP pathology in the underlying white matter than the more common MM1/MV1 and VV2 histotypes, and was more abundant in patients with a longer disease duration. We concluded that the MM2C strain was particularly prone to accumulate PrP^d in white matter oligodendrocytes. Full article

(This article belongs to the Special Issue Prion Disease)

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20 pages, 1970 KiB

Open AccessArticle

The Cellular Prion Protein Increases the Uptake and Toxicity of TDP-43 Fibrils

by Carlo Scialò, Luigi Celauro, Marco Zattoni, Thanh Hoa Tran, Edoardo Bistaffa, Fabio Moda, Robert Kammerer, Emanuele Buratti and Giuseppe Legname

Viruses 2021, 13(8), 1625; https://doi.org/10.3390/v13081625 - 17 Aug 2021

Cited by 17 | Viewed by 3658

Abstract

Cytoplasmic aggregation of the primarily nuclear TAR DNA-binding protein 43 (TDP-43) affects neurons in most amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal lobar degeneration (FTLD) cases. The cellular prion protein, PrP^C, has been recognized as a common receptor and [...] Read more.

Cytoplasmic aggregation of the primarily nuclear TAR DNA-binding protein 43 (TDP-43) affects neurons in most amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal lobar degeneration (FTLD) cases. The cellular prion protein, PrP^C, has been recognized as a common receptor and downstream effector of circulating neurotoxic species of several proteins involved in neurodegeneration. Here, capitalizing on our recently adapted TDP-43 real time quaking induced reaction, we set reproducible protocols to obtain standardized preparations of recombinant TDP-43 fibrils. We then exploited two different cellular systems (human SH-SY5Y and mouse N2a neuroblastoma cells) engineered to express low or high PrP^C levels to investigate the link between PrP^C expression on the cell surface and the internalization of TDP-43 fibrils. Fibril uptake was increased in cells overexpressing either human or mouse prion protein. Increased internalization was associated with detrimental consequences in all PrP-overexpressing cell lines but was milder in cells expressing the human form of the prion protein. As described for other amyloids, treatment with TDP-43 fibrils induced a reduction in the accumulation of the misfolded form of PrP^C, PrP^Sc, in cells chronically infected with prions. Our results expand the list of misfolded proteins whose uptake and detrimental effects are mediated by PrP^C, which encompass almost all pathological amyloids involved in neurodegeneration. Full article

(This article belongs to the Special Issue Prion Disease)

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11 pages, 9598 KiB

Open AccessCommunication

Preclinical Detection of Alpha-Synuclein Seeding Activity in the Colon of a Transgenic Mouse Model of Synucleinopathy by RT-QuIC

by Jung-Youn Han, Chaewon Shin and Young Pyo Choi

Viruses 2021, 13(5), 759; https://doi.org/10.3390/v13050759 - 26 Apr 2021

Cited by 6 | Viewed by 2736

Abstract

In synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy body (DLB), pathological alpha-synuclein (α-syn) aggregates are found in the gastrointestinal (GI) tract as well as in the brain. In this study, using real-time quaking-induced conversion (RT-QuIC), we investigated the presence of [...] Read more.

In synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy body (DLB), pathological alpha-synuclein (α-syn) aggregates are found in the gastrointestinal (GI) tract as well as in the brain. In this study, using real-time quaking-induced conversion (RT-QuIC), we investigated the presence of α-syn seeding activity in the brain and colon tissue of G2-3 transgenic mice expressing human A53T α-syn. Here we show that pathological α-syn aggregates with seeding activity were present in the colon of G2-3 mice as early as 3 months old, which is in the presymptomatic stage prior to the observation of any neurological abnormalities. In contrast, α-syn seeding activity was not detectable in 3 month-old mouse brains and only identified at 6 months of age in one of three mice. In the symptomatic stage of 12 months of age, RT-QuIC seeding activity was consistently detectable in both the brain and colon of G2-3 mice. Our results indicate that the RT-QuIC assay can presymptomatically detect pathological α-syn aggregates in the colon of G2-3 mice several months prior to their detection in brain tissue. Full article

(This article belongs to the Special Issue Prion Disease)

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Review

Jump to: Research, Other

11 pages, 783 KiB

Open AccessReview

THαβ Immunological Pathway as Protective Immune Response against Prion Diseases: An Insight for Prion Infection Therapy

by Adam Tsou, Po-Jui Chen, Kuo-Wang Tsai, Wan-Chung Hu and Kuo-Cheng Lu

Viruses 2022, 14(2), 408; https://doi.org/10.3390/v14020408 - 17 Feb 2022

Cited by 6 | Viewed by 3784

Abstract

Prion diseases, including Creutzfeldt–Jakob disease, are mediated by transmissible proteinaceous pathogens. Pathological changes indicative of neuro-degeneration have been observed in the brains of affected patients. Simultaneously, microglial activation, along with the upregulation of pro-inflammatory cytokines, including IL-1 or TNF-α, have also been observed [...] Read more.

Prion diseases, including Creutzfeldt–Jakob disease, are mediated by transmissible proteinaceous pathogens. Pathological changes indicative of neuro-degeneration have been observed in the brains of affected patients. Simultaneously, microglial activation, along with the upregulation of pro-inflammatory cytokines, including IL-1 or TNF-α, have also been observed in brain tissue of these patients. Consequently, pro-inflammatory cytokines are thought to be involved in the pathogenesis of these diseases. Accelerated prion infections have been seen in interleukin-10 knockout mice, and type 1 interferons have been found to be protective against these diseases. Since interleukin-10 and type 1 interferons are key mediators of the antiviral THαβ immunological pathway, protective host immunity against prion diseases may be regulated via THαβ immunity. Currently no effective treatment strategies exist for prion disease; however, drugs that target the regulation of IL-10, IFN-alpha, or IFN-β, and consequently modulate the THαβ immunological pathway, may prove to be effective therapeutic options. Full article

(This article belongs to the Special Issue Prion Disease)

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20 pages, 1003 KiB

Open AccessReview

Clinical Use of Improved Diagnostic Testing for Detection of Prion Disease

by Mark P. Figgie, Jr. and Brian S. Appleby

Viruses 2021, 13(5), 789; https://doi.org/10.3390/v13050789 - 28 Apr 2021

Cited by 18 | Viewed by 4722

Abstract

Prion diseases are difficult to recognize as many symptoms are shared among other neurologic pathologies and the full spectra of symptoms usually do not appear until late in the disease course. Additionally, many commonly used laboratory markers are non-specific to prion disease. The [...] Read more.

Prion diseases are difficult to recognize as many symptoms are shared among other neurologic pathologies and the full spectra of symptoms usually do not appear until late in the disease course. Additionally, many commonly used laboratory markers are non-specific to prion disease. The recent introduction of second-generation real time quaking induced conversion (RT-QuIC) has revolutionized pre-mortem diagnosis of prion disease due to its extremely high sensitivity and specificity. However, RT-QuIC does not provide prognostic data and has decreased diagnostic accuracy in some rarer, atypical prion diseases. The objective of this review is to provide an overview of the current clinical utility of fluid-based biomarkers, neurodiagnostic testing, and brain imaging in the diagnosis of prion disease and to suggest guidelines for their clinical use, with a focus on rarer prion diseases with atypical features. Recent advancements in laboratory-based testing and imaging criteria have shown improved diagnostic accuracy and prognostic potential in prion disease, but because these diagnostic tests are not sensitive in some prion disease subtypes and diagnostic test sensitivities are unknown in the event that CWD transmits to humans, it is important to continue investigations into the clinical utility of various testing modalities. Full article

(This article belongs to the Special Issue Prion Disease)

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Other

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7 pages, 988 KiB

Open AccessCase Report

The First Sporadic Creutzfeldt–Jakob Disease Case with a Rare Molecular Subtype VV1 and 1-Octapeptide Repeat Deletion in PRNP

by Aušrinė Areškevičiūtė, Eva Løbner Lund, Sabina Capellari, Piero Parchi and Christian Tersbøl Pinkowsky

Viruses 2021, 13(10), 2061; https://doi.org/10.3390/v13102061 - 14 Oct 2021

Cited by 1 | Viewed by 2454

Abstract

In the present manuscript, we report the clinical presentation and challenging diagnostic work-up of a sporadic Creutzfeldt–Jakob disease patient with confirmed VV1 subtype and heterozygous 1-octapeptide repeat deletion in the prion protein gene. The described patient was a 58-year-old woman. Interestingly, most of [...] Read more.

In the present manuscript, we report the clinical presentation and challenging diagnostic work-up of a sporadic Creutzfeldt–Jakob disease patient with confirmed VV1 subtype and heterozygous 1-octapeptide repeat deletion in the prion protein gene. The described patient was a 58-year-old woman. Interestingly, most of the reported patients with the VV1 subtype to date are men with an average age of 44 years at disease onset. The patient was observed clinically from symptoms onset until her death 22 months later. This report describes the patient’s insidious clinical evolution and the paraclinical examinations and pathology reports gathered at different time points of disease progression. Unfortunately, the absence of typical clinical and paraclinical features of classic sporadic Creutzfeldt–Jakob disease made the brain biopsy surgery necessary. This case report illustrates the diagnostic difficulties posed by the phenotypic heterogeneity of sporadic Creutzfeldt–Jakob disease and urges clinicians to consider this diagnosis even in patients who do not fulfil the typical clinical disease criteria. Furthermore, it highlights the need for real-time quaking-induced conversion method adaptation for detection of rare sporadic Creutzfeldt–Jakob disease subtypes with certain prion protein gene variants. Full article

(This article belongs to the Special Issue Prion Disease)

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6 pages, 856 KiB

Open AccessCase Report

Creutzfeldt–Jakob Disease with a Five-Year Clinical Course, Multicentric Cerebellar Prion Plaques and Prior History of Biopsy-Proven Primary Angiitis of the Central Nervous System: A Case for Iatrogenic Exposure?

by Kristina Jeon, Jeffrey T. Joseph, Gerard H. Jansen, Anne Peterson, J. David Knox and Valerie L. Sim

Viruses 2020, 12(12), 1411; https://doi.org/10.3390/v12121411 - 8 Dec 2020

Viewed by 2964

Abstract

Creutzfeldt–Jakob disease (CJD) is a rapidly progressive neurodegenerative disease that can arise spontaneously, genetically, or be acquired through iatrogenic exposure. Most patients die within a year of symptom onset. It is rare, affecting 1–2 per million per year, and the majority of cases [...] Read more.

Creutzfeldt–Jakob disease (CJD) is a rapidly progressive neurodegenerative disease that can arise spontaneously, genetically, or be acquired through iatrogenic exposure. Most patients die within a year of symptom onset. It is rare, affecting 1–2 per million per year, and the majority of cases are sporadic. Primary angiitis of the central nervous system (PACNS) is also rare, affecting 2.4 per million per year. We present a case of an unusually long clinical course of CJD, almost five years, which began with symptoms of apraxia. The patient had biopsy-proven PACNS 16 years prior to clinical presentation, and the site of biopsy was the left parietal lobe. Autopsy revealed multicentric prion plaques in the cerebellum, in the setting of normal genetic testing. The presence of plaques in the cerebellum, and prior neurosurgery, raises the possibility of iatrogenic exposure. We present the details of this case, including pathology from the original biopsy and final autopsy, as well as a review of relevant cases in the literature. Full article

(This article belongs to the Special Issue Prion Disease)

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