An Overview of Primary Dementias as Clinicopathological Entities

Arash Salardini, MD


Semin Neurol. 2019;39(2):153-166. 

In This Article

Prion Disease

• Neuropathology: Misfolded prions are proteinaceous infectious particles which cause several devastating neurodegenerative diseases, including Creutzfeldt–Jakob disease (CJD), fatal familial insomnia (FFI), Gerstmann–Straussler–Scheinker (GSS) syndrome, kuru, variably protease-sensitive prionopathy, and variant CJD (vCJD). Prions are normal parts of neuronal cell surface. Misfolded prions replicate and interact with normal prion protein to cause them to misfold, causing damage and spreading throughout the brain. The disease progresses over a few months after its first symptoms, leading to death. Most prion disease is sporadic, followed by those caused by genetic and infectious transmission.[60]

• Clinical phenotypes:[61]

   – CJD: Sporadic CJD (sCJD) is the most common form of prion disease, and presents with cognitive symptoms, pyramidal and extrapyramidal motor symptoms, ataxia, myoclonus, and psychiatric comorbidities. Infrequently there is a prodrome of psychological or constitutional symptoms such as anxiety, depression, apathy, sleep problems, and feeling unwell. The phenotype of the disease is partially determined by polymorphism at codon 129 which can either be valine or methionine. Familial CJD presents very similarly but may have a slower course.

   – vCJD: This is a prion disease which is caused by eating of contaminated meat from livestock stricken with bovine spongiform encephalopathy. vCJD progresses more slowly and can have a psychiatric prodrome.

   – Other prion diseases: FFI, now referred to as fatal insomnia because sporadic forms are also known, presents with sympathetic hyperarousal with insomnia, dysautonomia, cognitive problems, and eventually death. GSS is a difficult disease to diagnose because of its prolonged course. It is associated with cerebellar or extrapyramidal symptoms. There is considerable variability in the natural history of the disease, but it is generally slow and may progress over 10 to 20 years.

• Biomarkers: Several classic test findings are described in prion disease, including periodic sharp-wave complexes at 1 to 2 Hz. More reliable is the MRI findings especially the demonstration of diffusion restriction (DWI MRI) along the cortical ribbon (ribboning), thalamus, and basal ganglia. CSF testing now relies on 14–3-3 protein and total tau. When the test is positive, the test is double checked with CSF real-time quaking-induced conversion (RT-QuIC) test which is highly sensitive and specific. Brain biopsy confirms the diagnosis postmortem. vCJD can be diagnosed, during life, by performing a tonsil biopsy (vCJD gets into the lymphatic system)[62] (see Figure 8).

Figure 8.

(A) This shows a DWI image with increased cortical signal suggesting cortical cytotoxic edema or cortical ribboning in a patient suspected of having CJD. Uncharacteristically there are no basal ganglionic or thalamic changes. (B) This shows a DWI image with increased caudate and mesial thalamic (hockey stick) increased signal. In this case there is little evidence of cortical ribboning. CJD, Creutzfeldt–Jakob disease; DWI, diffusion-weighted imaging.

• Treatment: There is no treatment for CJD. Autopsy of the brain may be organized with the National Prion Disease Pathology Surveillance Center situated in Case Western University.