Disturbances in the
ubiquitin-
proteasome system seem to play a role in neurodegenerative
dementias (
NDs). Previous studies documented an increase of cerebrospinal fluid (CSF) free monoubiquitin in
Alzheimer's disease (AD) and
Creutzfeldt-Jakob disease (CJD). However, to date, no study explored this
biomarker across the heterogeneous spectrum of
prion disease. Using a liquid chromatography-multiple reaction monitoring mass spectrometry, we investigated CSF free monoubiquitin in controls (n = 28) and in cases with
prion disease (n = 84), AD (n = 38), and
frontotemporal dementia (FTD) (
n = 30). Furthermore, in CJD subtypes, we evaluated by immunohistochemistry (IHC) the relative extent of brain
ubiquitin deposits.
Prion disease and, to a lesser extent, AD subjects showed increased levels of CSF free monoubiquitin, whereas FTD cases had median
protein values similar to controls. The
biomarker showed a good to optimal accuracy in the differential diagnosis between
NDs and, most interestingly, between AD and FTD. After stratification, according to molecular subtypes,
sporadic CJD VV2 demonstrated significantly higher levels of CSF
ubiquitin and more numerous brain
ubiquitin deposits at IHC in comparison to the typical and most prevalent MM(V)1 subtype. Moreover, CSF
ubiquitin correlated with
biomarkers of neurodegeneration and
astrogliosis in
NDs, and was associated with disease stage but not with survival in
prion disease. The differential increase of CSF free monoubiquitin in
prion disease subtypes and AD may reflect common, though disease and time-specific, phenomena related to neurodegeneration, such as neuritic damage, dysfunctional proteostasis, and
neuroinflammation.