A 70-year-old man presents with rapidly progressive dementia, myoclonus, and characteristic EEG changes (periodic sharp wave complexes). CSF 14-3-3 protein is positive, and RT-QuIC assay is positive. The pathological hallmark of this disease involves which molecular mechanism of neurodegeneration?
- A Misfolding of normal cellular prion protein (PrPC) into a protease-resistant beta-sheet-rich isoform (PrPSc) that templates further misfolding in a self-propagating chain reaction, causing spongiform vacuolation, neuronal loss, astrogliosis, and prion protein plaques ✓
- B TDP-43 protein aggregation in frontotemporal lobar degeneration (FTLD-TDP) causing RNA processing errors and ubiquitin-positive inclusions
- C Tau protein hyperphosphorylation forming neurofibrillary tangles in Alzheimer disease-type neurodegeneration
- D Alpha-synuclein aggregation into Lewy bodies causing Parkinson disease dementia with cortical Lewy bodies
Explanation
Creutzfeldt-Jakob disease (CJD) is a prion disease caused by the conformational conversion of cellular prion protein PrPC (alpha-helix-rich, protease-sensitive, GPI-anchored) into PrPSc (beta-sheet-rich, protease-resistant). PrPSc templates the misfolding of PrPC in an autocatalytic chain reaction — this is the 'protein-only' hypothesis of prion propagation. The resulting accumulation of PrPSc causes direct neurotoxicity, spongiform vacuolation of the neuropil, neuronal loss, reactive astrogliosis, and sometimes kuru-type amyloid plaques. RT-QuIC (real-time quaking-induced conversion) detects minute amounts of PrPSc in CSF by amplifying prion-seeded conversion, with high sensitivity and specificity. TDP-43, tau, and alpha-synuclein aggregation are mechanisms of FTLD/ALS, AD, and Lewy body diseases, respectively — distinct clinicopathological entities.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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Written and medically reviewed by the StethoPrep medical team.