Dataset Information

Amyloid- and FDG-PET in sporadic Creutzfeldt-Jakob disease: Correlation with pathological prion protein in neuropathology.

ABSTRACT:

Introduction

The role of positron emission tomography (PET) in Creutzfeldt-Jakob disease is less defined than in other neurodegenerative diseases. We studied the correlation between the uptake of ¹⁸F-florbetaben and ¹⁸F-fluorodeoxyglucose with pathological prion protein deposition in histopathology in a case.

Methods

A patient with 80 y old with a rapid neurological deterioration with a confirmed diagnosis of CJD was studied. PET and MRI studies were performed between 13-20 d before the death. A region of interest analysis was performed using Statistical Parametric Mapping.

Results

MRI showed atrophy with no other alterations. FDG-PET showed extensive areas of hypometabolism including left frontoparietal lobes as well as bilateral thalamus. Correlation between uptake of ¹⁸F-florbetaben and pathological prion protein deposition was r = 0.786 (p < 0.05). Otherwise, correlation between uptake of ¹⁸F-FDG and pathological prion protein was r = 0.357 (p = 0.385). Immunohistochemistry with ?-amyloid did not show amyloid deposition or neuritic plaques.

Conclusions

Our study supports the use of FDG-PET in the assessment of CJD. FDG-PET may be especially useful in cases of suspected CJD and negative MRI. Furthermore, this case report provides more evidence about the behavioral of amyloid tracers, and the possibility of a low-affinity binding to other non-amyloid proteins, such as the pathological prion protein, is discussed.

SUBMITTER: Matias-Guiu JA

PROVIDER: S-EPMC5480385 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Amyloid- and FDG-PET in sporadic Creutzfeldt-Jakob disease: Correlation with pathological prion protein in neuropathology.

Matías-Guiu Jordi A JA Guerrero-Márquez Carmen C Cabrera-Martín María Nieves MN Gómez-Pinedo Ulises U Romeral María M Mayo Diego D Porta-Etessam Jesús J Moreno-Ramos Teresa T Carreras José Luis JL Matías-Guiu Jorge J

Prion 20170516 3

<h4>Introduction</h4>The role of positron emission tomography (PET) in Creutzfeldt-Jakob disease is less defined than in other neurodegenerative diseases. We studied the correlation between the uptake of <sup>18</sup>F-florbetaben and <sup>18</sup>F-fluorodeoxyglucose with pathological prion protein deposition in histopathology in a case.<h4>Methods</h4>A patient with 80 y old with a rapid neurological deterioration with a confirmed diagnosis of CJD was studied. PET and MRI studies were performe ...[more]

PMID: 28509609

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Project description:BackgroundPrion diseases are a group of invariably fatal neurodegenerative disorders affecting humans and a wide range of mammals. An essential part of the infectious agent, termed the prion, is composed of an abnormal isoform (PrPSc) of a host-encoded normal cellular protein (PrPC). The conversion of PrPC to PrPSc is thought to play a crucial role in the development of prion diseases and leads to PrPSc deposition, mainly in the central nervous system. Sporadic Creutzfeldt-Jakob disease (sCJD), the most common form of human prion disease, presents with a marked clinical heterogeneity. This diversity is accompanied by a molecular signature which can be defined by histological, biochemical, and genetic means. The molecular classification of sCJD is an important tool to aid in the understanding of underlying disease mechanisms and the development of therapy protocols. Comparability of classifications is hampered by disparity of applied methods and inter-observer variability.Methods and findingsTo overcome these difficulties, we developed a new quantification protocol for PrPSc by using internal standards on each Western blot, which allows for generation and direct comparison of individual PrPSc profiles. By studying PrPSc profiles and PrPSc type expression within nine defined central nervous system areas of 50 patients with sCJD, we were able to show distinct PrPSc distribution patterns in diverse subtypes of sCJD. Furthermore, we were able to demonstrate the co-existence of more than one PrPSc type in individuals with sCJD in about 20% of all patients and in more than 50% of patients heterozygous for a polymorphism on codon 129 of the gene encoding the prion protein (PRNP).ConclusionPrPSc profiling represents a valuable tool for the molecular classification of human prion diseases and has important implications for their diagnosis by brain biopsy. Our results show that the co-existence of more than one PrPSc type might be influenced by genetic and brain region-specific determinants. These findings provide valuable insights into the generation of distinct PrPSc types.

Project description:Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common prion disease in humans and has been iatrogenically transmitted through corneal graft transplantation. Approximately 40% of sCJD patients develop visual or oculomotor symptoms and may seek ophthalmological consultation. Here we used the highly sensitive real-time quaking-induced conversion (RT-QuIC) assay to measure postmortem prion seeding activities in cornea, lens, ocular fluid, retina, choroid, sclera, optic nerve, and extraocular muscle in the largest series of sCJD patient eyes studied by any assay to date. We detected prion seeding activity in 100% of sCJD eyes, representing three common sCJD subtypes, with levels varying by up to 4 log-fold among individuals. The retina consistently showed the highest seed levels, which in some cases were only slightly lower than brain. Within the retina, prion deposits were detected by immunohistochemistry (IHC) in the retinal outer plexiform layer in most sCJD cases, and in some eyes the inner plexiform layer, consistent with synaptic prion deposition. Prions were not detected by IHC in any other eye region. With RT-QuIC, prion seed levels generally declined in eye tissues with increased distance from the brain, and yet all corneas had prion seeds detectable. Prion seeds were also present in the optic nerve, extraocular muscle, choroid, lens, vitreous, and sclera. Collectively, these results reveal that sCJD patients accumulate prion seeds throughout the eye, indicating the potential diagnostic utility as well as a possible biohazard.IMPORTANCE Cases of iatrogenic prion disease have been reported from corneal transplants, yet the distribution and levels of prions throughout the eye remain unknown. This study probes the occurrence, level, and distribution of prions in the eyes of patients with sporadic Creutzfeldt-Jakob disease (sCJD). We tested the largest series of prion-infected eyes reported to date using an ultrasensitive technique to establish the prion seed levels in eight regions of the eye. All 11 cases had detectable prion seeds in the eye, and in some cases, the seed levels in the retina approached those in brain. In most cases, prion deposits could also be seen by immunohistochemical staining of retinal tissue; other ocular tissues were negative. Our results have implications for estimating the risk for iatrogenic transmission of sCJD as well as for the development of antemortem diagnostic tests for prion diseases.

Project description:ImportanceCreutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder associated with the accumulation of infectious abnormal prion protein through a mechanism of templated misfolding. A recent report has described the detection of abnormal prion protein in the urine of patients with variant CJD (vCJD) using protein misfolding by cyclic amplification, which was apparently absent in the more common sporadic form of CJD (sCJD). A noninvasive diagnostic test could improve early diagnosis of sCJD and, by screening donations, mitigate the potential risks of prion transmission through human urine-derived pharmaceuticals. Here, we describe the adaptation of the direct detection assay, developed originally as a blood test for vCJD, for the detection of disease-associated prion protein in urine samples from patients with sCJD.ObjectiveTo determine the feasibility of sCJD diagnosis by adaptation of an established vCJD diagnostic blood test to urine.Design, setting, and participantsThis retrospective, cross-sectional study included anonymized urine samples from healthy nonneurological control individuals (n = 91), patients with non-prion neurodegenerative diseases (n = 34), and patients with prion disease (n = 37) of which 20 had sCJD. Urine samples obtained during the Medical Research Council PRION-1 Trial, the National Prion Monitoring Cohort Study, and/or referred to the National Prion Clinic or Dementia Research Centre at the National Hospital for Neurology and Neurosurgery in the United Kingdom.Main outcomes and measuresPresence of sCJD infection determined by an assay that captures, enriches, and detects disease-associated prion protein isoforms.ResultsA total of 162 samples were analyzed, composed of 91 normal control individuals (51 male, 33 female, and 7 not recorded), 34 neurological disease control individuals (19 male and 15 female), and 37 with prion disease (22 male and 15 female). The assay's specificity for prion disease was 100% (95% CI, 97%-100%), with no false-positive reactions from 125 control individuals, including 34 from a range of neurodegenerative diseases. In contrast to a previous study, which used a different method, sensitivity to vCJD infection was low (7.7%; 95% CI, 0.2%-36%), with only 1 of 13 patients with positive test results, while sensitivity to sCJD was unexpectedly high at 40% (95% CI, 19%-64%).Conclusions and relevanceWe determined 40% of sCJD urine sample results as positive. To our knowledge, this is the first demonstration of an assay that can detect sCJD infection in urine or any target analyte outside of the central nervous system. Urine detection could allow the development of rapid, molecular diagnostics for sCJD and has implications for other neurodegenerative diseases where disease-related assemblies of misfolded proteins might also be present in urine.

Dataset Information

Amyloid- and FDG-PET in sporadic Creutzfeldt-Jakob disease: Correlation with pathological prion protein in neuropathology.

Introduction

Methods

Results

Conclusions

Publications

Amyloid- and FDG-PET in sporadic Creutzfeldt-Jakob disease: Correlation with pathological prion protein in neuropathology.

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