Medial Temporal Lobe Involvement in Human Prion Diseases: Implications for the Study of Focal Non Prion Neurodegenerative Pathology

Human prion and non-prion neurodegenerative diseases share pathogenic mechanisms and neuropathological features. The lesion profile of a particular entity results from specific involvement of vulnerable neuron populations and connectivity circuits by a pathogenic protein isoform with strain-like properties. The lesion profile of the medial temporal lobe (MTL) was studied in postmortem tissue of 143 patients with human prion disease (HPD) including sporadic, genetic, and acquired forms. Most cases (90%) were classified according to PrPres type and/or PRNP codon 129 status, in addition to a full neuropathological profile. Mixed histotypes represented 29.4% of total sporadic Creutzfeldt-Jakob disease (sCJD) cases. An intensity score of involvement including spongiosis and astrogliosis was determined for the amygdala, presubiculum, subiculum, entorhinal cortex, CA1 to CA4 sectors of the hippocampal cortex, and dentate gyrus. Connectivity hubs within the MTL presented the highest scores. Diverse lesion profiles were obtained for different types and subtypes of HPD. Impact of mixed PrPres types on the MTL lesion profile was higher for sCJDMV2K cases than in other histotypes. Differences between MTL profiles was globally consistent with current evidence on specific strains in HPD. These results may be relevant for the analysis of possible strain effects in focal non-prion neurodegenerative conditions limited to the MTL.

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Human Prion Diseases

Escourolle and Poirier's Manual of Basic Neuropathology ◽

10.1093/med/9780199929054.003.0006 ◽

2013 ◽

pp. 149-160

Author(s):

James W. Ironside ◽

Matthew P. Frosch ◽

Bernardino Ghetti

Keyword(s):

Prion Diseases ◽

Neuronal Loss ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Pituitary Hormone ◽

Human Pituitary ◽

Spongiform Encephalopathies ◽

Jakob Disease ◽

Prnp Codon ◽

Codon 129

This chapter describes and illustrates the neuropathology of prion diseases, also known as transmissible spongiform encephalopathies. These diseases are characterized pathologically by varying combinations of spongiform change, neuronal loss, reactive gliosis, and prion protein (PrP) deposition. The morphologic pattern depends on the etiology of the disease and the genotype of the patient. Different clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (CJD) have been described depending on the PRNP codon 129 genotype and the PrP isotype. A novel form known as variably protease-sensitive prionopathy has been recently identified. Familial prion diseases include familial CJD, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Over 40 different PRNP mutations have been identified. Acquired prion diseases include Kuru; iatrogenic CJD, particularly in recipients of contaminated human pituitary hormone, and variant CJD, which seems closely related to bovine spongiform encephalopathy.

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Perception and the Medial Temporal Lobe: Evaluating the Current Evidence

Neuron ◽

10.1016/j.neuron.2009.03.002 ◽

2009 ◽

Vol 61 (6) ◽

pp. 964

Author(s):

Wendy A. Suzuki

Keyword(s):

Temporal Lobe ◽

Medial Temporal Lobe ◽

Current Evidence

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Molecular Characterization of the Danish Prion Diseases Cohort With Special Emphasis on Rare and Unique Cases

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlz089 ◽

2019 ◽

Vol 78 (11) ◽

pp. 980-992 ◽

Cited By ~ 2

Author(s):

Aušrinė Areškevičiūtė ◽

Helle Broholm ◽

Linea C Melchior ◽

Anna Bartoletti-Stella ◽

Piero Parchi ◽

...

Keyword(s):

Molecular Characterization ◽

Prion Disease ◽

Prion Diseases ◽

The Past ◽

Disease Biology ◽

Fresh Frozen ◽

Jakob Disease ◽

Disease Subtypes ◽

Codon 129

Abstract The purpose of this study was to perform an updated reclassification of all definite prion disease cases with available fresh-frozen samples referred to the Danish Reference Center over the past 40 years, putting a special emphasis on the molecular characterization of novel disease subtypes. Investigation of the Danish prion diseases cohort revealed rare sporadic Creutzfeldt-Jakob disease cases with mixed subtypes and subtypes with previously uncharacterized white matter plaques, a new case of sporadic fatal insomnia, and 3 novel mutations, including 2 large octapeptide repeat insertions, and a point mutation in the prion protein gene. The evaluation of methionine and valine distribution at codon 129 among the prion disease patients in the cohort revealed the increased prevalence of methionine homozygotes compared to the general population. This observation was in line with the prevalence reported in other Caucasian prion disease cohort studies. Reclassification of the old prion diseases cohort revealed unique cases, the molecular characterization of which improves prion diseases classification, diagnostic accuracy, genetic counseling of affected families, and the understanding of disease biology.

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Cerebrospinal Fluid Biomarker-Based Diagnosis of Sporadic Creutzfeldt-Jakob Disease: A Validation Study for Previously Established Cutoffs

Dementia and Geriatric Cognitive Disorders ◽

10.1159/000454802 ◽

2017 ◽

Vol 43 (1-2) ◽

pp. 71-80 ◽

Cited By ~ 12

Author(s):

Franc Llorens ◽

André Karch ◽

Ewa Golanska ◽

Matthias Schmitz ◽

Peter Lange ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Negative Correlation ◽

Disease Duration ◽

Population Sample ◽

Clinical Accuracy ◽

Jakob Disease ◽

And Control ◽

Fluid Biomarker ◽

Prnp Codon ◽

Codon 129

Background: Several biomarkers have been proposed to discriminate sporadic Creutzfeldt-Jakob disease (sCJD) from other dementias and control cases. However, their clinical accuracy depends on the PRNP codon 129 genotype, leaving it unclear how well established markers behave in untested conditions. Methods: We analyzed 14-3-3, tau, p-tau levels, and the p-tau/tau ratio in a population sample collected from Polish hospitals including nondementia, dementia, and definite sCJD cases and validated their parameters according to previously established cutoffs. Additionally, the correlation between biomarkers and disease duration as well as the influence of the PRNP129 polymorphism are reported. Results: The tau levels and p-tau/tau ratios differed considerably between sCJD and clinically characterized non-CJD cases (p < 0.001). p-tau was only elevated in sCJD when compared to cases without dementia (p < 0.05). Tau and the p-tau/tau ratio showed a sensitivity of 95 and 100%, respectively, in detecting sCJD cases. A negative correlation between tau levels and disease duration, but not the timing of lumbar puncture was observed. Conclusion: The present findings confirmed the value of the p-tau/tau ratio as a robust sCJD biomarker and suggest a role for tau as prognostic marker.

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