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

Alberto Rábano,Miguel Calero,María V Geijo,Ramón A Juste,Carmen Guerrero Márquez

doi:10.3390/biom11030413

Abstract

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.

Highlights

It is widely accepted that non prion neurodegenerative entities, like Alzheimer’s, Parkinson’s, or Huntington’s disease, share multiple features at a molecular, pathogenic, and neuropathological level with what we can still properly call human prion diseases (HPD) stricto sensu
Average intensity of involvement (Ai) was highest in sporadic Creutzfeldt-Jakob disease (sCJD) VV2, MV2K, MV2K + C, VV1, and iatrogenic CJD (iCJD) groups, and was significantly higher for sCJD VV2 compared to sCJD MM/MV1 (Mann–Whitney U test, p < 0.01) (Table 2)
Whereas this latter group displayed a wide range of variability, with more intense and diffuse changes observed in cases of the panencephalopathic type, Ai was uniformly high in the sCJD

Summary

Introduction

It is widely accepted that non prion neurodegenerative entities, like Alzheimer’s, Parkinson’s, or Huntington’s disease, share multiple features at a molecular, pathogenic, and neuropathological level with what we can still properly call human prion diseases (HPD) stricto sensu. HPD display, in a rather sharp way, phenotypic and pathogenic features that in other neurodegenerative diseases are somewhat blurred by associated factors of complexity. Certain molecular characteristics of the pathologic prion protein (PrPSc ) (“strain” features) are regularly associated with specific neuropathological and clinical disease phenotypes [6,7]. HPD may represent useful models for exploring two related factors that determine phenotypic variability in all neurodegenerative disorders: (i) differential vulnerability of specific cellular (both neuronal and glial) populations to pathogenic factors [8], and (ii) involvement of specific neural pathways that may facilitate the spread of pathology throughout the central nervous system [9]

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