A researcher is studying autopsy findings in patients diagnosed with neurodegenerative disorders. In some of the brain specimens, a neuronal protein that primarily exists in an alpha-helical secondary structure is found to be in a beta-sheet conformation. The altered protein is resistant to protease and has accumulated in large quantities within the cells. Further investigation shows that the abnormal isoform can perpetually induce the same conformational change within normally folded proteins. Which of the following histopathological changes are most likely present in the brains of these patients?

Question

A researcher is studying autopsy findings in patients diagnosed with neurodegenerative disorders.  In some of the brain specimens, a neuronal protein that primarily exists in an alpha-helical secondary structure is found to be in a beta-sheet conformation.  The altered protein is resistant to protease and has accumulated in large quantities within the cells.  Further investigation shows that the abnormal isoform can perpetually induce the same conformational change within normally folded proteins.  Which of the following histopathological changes are most likely present in the brains of these patients?

Quizplus · Accepted Answer

11ec160b_39da_4572_9249_cd28a785525c_MD0001_00 Prion diseases are progressive neurodegenerative disorders caused by accumulation of an abnormally folded protein within the brain. Prion diseases are seen in both humans (eg, Creutzfeldt-Jacob, fatal familial insomnia, Kuru) and animals (eg, scrapie, bovine spongiform encephalopathy) and may be transmitted between species with ingestion of tainted meat (eg, variant Creutzfeldt-Jacob). Prion proteins are found in both neuronal and non-neuronal brain cells and normally exist in an alpha-helical structure (PrP^c). Prion disease occurs after a domain in this protein undergoes a conformation change from an alpha helix into beta-pleated sheet isoform (PrP^Sc [scrapie]), which confers the ability to induce similar conformational changes in other proteins. This beta sheet conformation is resistant to proteases and forms long, highly neurotoxic fibrils, which accumulate intracellularly in neurons and form extracellular deposits. On microscopy, there is spongiform degeneration of the gray matter, which is characterized by formation of microscopic vacuoles within the neuronal processes. Neuronal loss, reactive gliosis, and cystic expansion of vacuoles occur as the disease progresses. Extracellular prion accumulations (Kuru plaques) are also frequently present and stain positive with Congo-red and periodic acid-Schiff stains. (Choice A) Discrete, demyelinated plaques and gliosis are seen in multiple sclerosis, in which autoreactive T lymphocytes, microglia, and plasma cells react to antigens in myelin. (Choice B) Progressive multifocal leukoencephalopathy is a demyelinating disease caused by reactivation of the JC virus; intranuclear inclusions within oligodendrocytes and large, bizarre astrocytes are typical findings. (Choice C) Microglial nodules form when cells of microglia surround a neuron and phagocytize it. These structures, along with multinucleated giant cells, are characteristic of viral infections of the CNS. They are found in HIV-associated encephalopathy. (Choice D) Neurofibrillary tangles and neuritic plaques are seen in Alzheimer disease. Hyperphosphorylation of tau protein results in neurofibrillary tangles, and decreased clearance of amyloid-beta results in senile plaques. However, these proteins cannot induce similar conformational changes in normal proteins. Educational objective: Prion diseases are rapidly progressive neurodegenerative disorders caused by the accumulation of an abnormally folded protein within the brain. Prion proteins are normally found in an alpha helix form; a conformation change into a beta-sheet form confers resistance to proteases and can trigger similar conformational changes in other normally folded proteins. Characteristic microscopic findings include spongiform degeneration of the gray matter with vacuolization of neurons, gliosis, and cyst formation.

A Researcher Is Studying Autopsy Findings in Patients Diagnosed with Neurodegenerative