Diagnosis of Human Prion Disease Using Real-Time Quaking-Induced Conversion Testing of Olfactory Mucosa and Cerebrospinal Fluid Samples

Bongianni, Matilde; Orrú, Christina D.; Groveman, Bradley R.; Sacchetto, Luca; Fiorini, Michele; Tonoli, Giovanni; Triva, Giorgio; Capaldi, Stefano; Testi, Silvia; Ferrari, Sergio; Cagnin, Annachiara; Ladogana, Anna; Poleggi, Anna; Colaizzo, Elisa; Tiple, Dorina; Vaianella, Luana; Castriciano, Santina; Marchioni, Daniele; Hughson, Andrew G.; Imperiale, Daniele; Cattaruzza, Tatiana; Fabrizi, Gian Maria; Pocchiari, Maurizio; Monaco, Salvatore; Caughey, Byron; Zanusso, Gianluigi

doi:10.1001/jamaneurol.2016.4614

Cited by 180 publications

(166 citation statements)

References 30 publications

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“…We consider this a finding indicative of PrP infection because the present case had short disease duration and the olfactory bulb contained postmitotic tissue. In support of this hypothesis, there have been several reports showing that PrP Sc could be detected in the olfactory mucosa . The olfactory bulb is connected to the olfactory mucosa through the olfactory nerve and the latter is in contact with the external environment.…”

Section: Discussionmentioning

confidence: 79%

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Autopsied case of sporadic Creutzfeldt–Jakob disease classified as MM1+2C‐type

et al. 2019

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We encountered an autopsy case of sporadic Creutzfeldt‐Jakob disease (CJD) pathologically classified as MM1+2C‐type, where Western blot analysis of prion protein (PrP) mainly showed type‐1 scrapie PrP (PrPSc) but also, partially, mixed type‐2 PrPSc. A Japanese woman complained of visual disorder at the age of 86 years and then showed disorientation and memory disturbances. Magnetic resonance imaging (MRI) showed cerebral cortical hyperintensity on diffusion‐weighted images. The patient died 2 months after the onset of symptoms; her condition did not reach the akinetic mutism state and periodic sharp‐wave complexes on electroencephalography and myoclonus were not recognized. The brain weighed 1100 g and neuropathological examination showed extensive fine vacuole‐type spongiform changes in the cerebral cortex. In some cortical regions, large confluent vacuole‐type spongiform changes were also present. Gliosis and hypertrophic astrocytosis were generally mild, and tissue rarefaction of the neuropil and neuronal loss were not apparent. PrP immunostaining showed diffuse synaptic‐type PrP deposition in the cerebral gray matter, but some regions with large confluent vacuoles showed perivacuolar‐type deposition. We speculated, based on the clinicopathological findings and previous reports, that most MM1‐type sporadic CJD cases may be associated with type‐2 PrPSc, at least partially, within certain regions of the cerebrum.

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Section: Discussionmentioning

confidence: 79%

“…In support of this hypothesis, there have been several reports showing that PrP Sc could be detected in the olfactory mucosa. 12 The olfactory bulb is connected to the olfactory mucosa through the olfactory nerve and the latter is in contact with the external environment. The olfactory bulb may be a possible route of PrP infection in sCJD.…”

Section: Discussionmentioning

confidence: 99%

Autopsied case of sporadic Creutzfeldt–Jakob disease classified as MM1+2C‐type

et al. 2019

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“…Protein 14‐3‐3 was positive in 6 of 12 tested patients (50%). Real‐time quaking‐induced conversion (RT‐QuIC) test results for GSS were only reported in a few articles and appeared to have a sensitivity up to 75 to 78% …”

Section: Characteristics Of Our Reported 7 Cases Compared To Previousmentioning

confidence: 99%

Clinical Variability in P102L Gerstmann–Sträussler–Scheinker Syndrome

Tesař

Matěj

Kukal

et al. 2019

Annals of Neurology

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Gerstmann–Sträussler–Scheinker syndrome (GSS) with the P102L mutation is a rare genetic prion disease caused by a pathogenic mutation at codon 102 in the prion protein gene. Cluster analysis encompassing data from 7 Czech patients and 87 published cases suggests the existence of 4 clinical phenotypes (typical GSS, GSS with areflexia and paresthesia, pure dementia GSS, and Creutzfeldt–Jakob disease–like GSS); GSS may be more common than previously estimated. In making a clinical diagnosis or progression estimates of GSS, magnetic resonance imaging and real‐time quaking‐induced conversion may be helpful, but the results should be evaluated with respect to the overall clinical context. ANN NEUROL 2019;86:643–652

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“…Such testing can provide intra vitam diagnoses that can be virtually 100% sensitive and specific [2, 34]. We and others have recently described α-synuclein RT-QuIC and closely related assays for the CSF-based early diagnosis of Parkinson disease (PD) and Lewy body dementia (LBD) [11, 18, 41].…”

Section: Introductionmentioning

confidence: 99%

Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease

Kraus¹,

Saijo²,

Metrick³

et al. 2018

Acta Neuropathol

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Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) involve the abnormal accumulation in the brain of filaments composed of both three-repeat (3R) and four-repeat (4R) (3R/4R) tau isoforms. To probe the molecular basis for AD’s tau filament propagation and to improve detection of tau aggregates as potential biomarkers, we have exploited the seeded polymerization growth mechanism of tau filaments to develop a highly selective and ultrasensitive cell-free tau seed amplification assay optimized for AD (AD real-time quaking-induced conversion or AD RT-QuIC). The reaction is based on the ability of AD tau aggregates to seed the formation of amyloid fibrils made of certain recombinant tau fragments. AD RT-QuIC detected seeding activity in AD (n = 16) brains at dilutions as extreme as 107–1010-fold, but was 102–106-fold less responsive when seeded with brain from most cases of other types of tauopathy with comparable loads of predominant 3R or 4R tau aggregates. For example, AD brains had average seeding activities that were orders of magnitude higher than Pick disease brains with predominant 3R tau deposits, but the opposite was true using our previously described Pick-optimized tau RT-QuIC assay. CTE brains (n = 2) had seed concentrations comparable to the weakest of the AD specimens, and higher than 3 of 4 specimens with 3R/4R primary age-related tauopathy. AD seeds shared properties with the tau filaments found in AD brains, as AD seeds were sarkosyl-insoluble, protease resistant, and reactive with tau antibodies. Moreover, AD RT-QuIC detected as little as 16 fg of pure synthetic tau fibrils. The distinctive seeding activity exhibited by AD and CTE tau filaments compared to other types of tauopathies in these seeded polymerization reactions provides a mechanistic basis for their consistent propagation as specific conformers in patients with 3R/4R tau diseases. Importantly, AD RT-QuIC also provides rapid ultrasensitive quantitation of 3R/4R tau-seeding activity as a biomarker.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1947-3) contains supplementary material, which is available to authorized users.

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Diagnosis of Human Prion Disease Using Real-Time Quaking-Induced Conversion Testing of Olfactory Mucosa and Cerebrospinal Fluid Samples

Cited by 180 publications

References 30 publications

Autopsied case of sporadic Creutzfeldt–Jakob disease classified as MM1+2C‐type

Autopsied case of sporadic Creutzfeldt–Jakob disease classified as MM1+2C‐type

Clinical Variability in P102L Gerstmann–Sträussler–Scheinker Syndrome

Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease

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