Neuropathological and genetic characteristics of a post-mortem series of cases with dementia with Lewy bodies clinically suspected of Creutzfeldt-Jakob's disease

Parkinsonism Relat Disord. 2019 Jun;63:162-168. doi: 10.1016/j.parkreldis.2019.02.011. Epub 2019 Feb 13.


Introduction: The disease course of dementia with Lewy bodies (DLB) can be rapidly progressive, clinically resembling Creutzfeldt-Jakob's disease (CJD). To better understand factors contributing to this rapidly progressive disease course, we describe load and distribution of neuropathology, and the presence of possible disease-associated genetic defects in a post-mortem series of DLB cases clinically suspected of CJD.

Methods: We included pathologically confirmed DLB cases with a disease duration of 3.5 years or less from the Dutch Surveillance Center for Prion Diseases, collected between 1998 and 2014. Lewy body disease (LBD) and Alzheimer's disease (AD)-related pathology were staged and semi-quantitatively scored in selected brain regions. Whole exome sequencing analysis of known disease-associated genes, copy number analysis, APOE ε genotyping and C9orf72 repeat expansion analysis were performed to identify defects in genes with a well-established involvement in Parkinson's disease or AD.

Results: Diffuse LBD was present in nine cases, transitional LBD in six cases and brainstem-predominant LBD in one case. Neocortical alpha-synuclein load was significantly higher in cases with intermediate-to-high than in cases with low-to-none AD-related pathology (p = 0.007). We found two GBA variants (p.D140H and p.E326K) in one patient and two heterozygous rare variants of unknown significance in SORL1 in two patients.

Conclusion: A high load of neocortical alpha-synuclein pathology was present in most, but not all DLB cases. Additional burden from presence of concomitant pathologies, synergistic effects and specific genetic defects in the known disease-associated genes may have contributed to the rapid disease progression.

Keywords: Alpha-synuclein pathology; Autopsy; GBA; Rapidly progressive dementia.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Creutzfeldt-Jakob Syndrome / diagnosis
  • Creutzfeldt-Jakob Syndrome / genetics*
  • Creutzfeldt-Jakob Syndrome / metabolism
  • Creutzfeldt-Jakob Syndrome / pathology*
  • Diagnosis
  • Disease Progression*
  • Exome Sequencing
  • Female
  • Glucosylceramidase / metabolism
  • Humans
  • LDL-Receptor Related Proteins / metabolism
  • Lewy Body Disease / diagnosis
  • Lewy Body Disease / genetics*
  • Lewy Body Disease / metabolism
  • Lewy Body Disease / pathology*
  • Male
  • Membrane Transport Proteins / metabolism
  • Neocortex / metabolism
  • Neocortex / pathology*
  • alpha-Synuclein / metabolism*


  • LDL-Receptor Related Proteins
  • Membrane Transport Proteins
  • SNCA protein, human
  • SORL1 protein, human
  • alpha-Synuclein
  • GBA protein, human
  • Glucosylceramidase