A 57-year-old man is hospitalized for aspiration pneumonia. The patient was healthy and worked as an engineer without difficulty until about 4 months ago. Since that time, he has developed severe confusion, mood changes, and memory impairment and had to take medical leave from work. The patient is now completely dependent on his wife for toileting, feeding, and general self-care. Physical examination shows disorientation and sporadic, jerky extremity movements. During hospitalization, the patient lapses into a coma and dies. Postmortem examination of his brain shows widespread atrophy of the cerebral cortex and cerebellum. Histologic analysis of the patient's brain tissue would most likely show accumulation of which of the following?
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This previously healthy patient developed rapidly progressive dementia associated with myoclonus (eg, involuntary, jerky extremity movements) and brain atrophy (due to widespread neuronal loss). These findings are consistent with Creutzfeldt-Jakob disease (CJD), a rapidly fatal transmissible spongiform encephalopathy caused by prions.
Prion protein (PrP) is found in both neuronal and nonneuronal brain cells and normally exist in an alpha-helical structure (PrPC). Prion disease occurs after a domain in this protein undergoes a conformational change from an alpha helix into a beta pleated sheet isoform (PrPSC), 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 that 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. This leads to widespread neuronal loss and reactive gliosis without associated inflammation. This may be evident on imaging or gross pathology as widespread atrophy involving both the cerebrum and cerebellum (in contrast to many other neurodegenerative diseases that spare the cerebellum).
(Choice A) Cytoplasmic inclusions of alpha-synuclein are characteristic of dementia with Lewy bodies, which is characterized by visual hallucinations, parkinsonism, cognitive fluctuations, and REM sleep disorder.
(Choice B) Deposition of beta-amyloid occurs in Alzheimer dementia, which commonly presents with early and prominent memory impairment with language deficits and spatial disorientation. It is characterized by a slow (years to decades) decline in function until death.
(Choice C) Phosphorylated tau forms paired helical filaments that create intracellular neurofibrillary tangles. This is seen in both Alzheimer disease as well as frontotemporal dementia. Although memory impairment and behavioral changes can occur in these diseases, this patient's myoclonus and rapid progression leading to death are more consistent with CJD.
(Choice E) Prion diseases are the only known diseases that are transmissible by protein. Prion isoforms do not contain nucleic acids. Although HIV (an RNA virus) can cause dementia, it typically causes mild, subacute cognitive impairment without myoclonus.
Educational objective:
Creutzfeldt-Jakob disease is a prion disease characterized by rapidly progressive dementia, myoclonus, and death within a year of symptom onset. It is caused by the accumulation of an abnormally folded (ie, beta pleated sheet) protein that is resistant to proteases and can trigger similar conformational changes in other normally folded proteins.