CSF and blood Kallikrein-8: a promising early biomarker for Alzheimer’s disease

Abstract

ObjectiveThere is still an urgent need for supportive minimally invasive and cost-effective biomarkers for early diagnosis of Alzheimer’s disease (AD). Previous work in our lab has identified Kallikrein-8 (KLK8) as a potential candidate since it shows an excessive increase in human brain in preclinical disease stages. The aim of this study was to evaluate the diagnostic performance of cerebrospinal fluid (CSF) and blood KLK8 for AD and mild cognitive impairment (MCI) due to AD.MethodsIn this multi-centre trans-sectional study, clinical and laboratory data as well as CSF and/or blood serum samples of 237 participants, including 98 patients with mild AD, 21 with MCI due to AD and 118 controls were collected. CSF and/or serum KLK8 levels were analysed by ELISA. The diagnostic accuracy of KLK8 in CSF and blood was determined using receiver operating characteristic (ROC) analyses and compared with that of CSF core biomarkers Aβ42, P-tau and T-tau.ResultsThe diagnostic accuracy of CSF KLK8 was as good as that of core CSF biomarkers for AD (area under the curve (AUC)=0.89) and in case of MCI (AUC=0.97) even superior to CSF Aβ42. Blood KLK8 was a similarly strong discriminator for MCI (AUC=0.94) but slightly weaker for AD (AUC=0.83).ConclusionsThis is the first study to demonstrate the potential clinical utility of blood and CSF KLK8 as a biomarker for incipient AD. Future prospective validation studies are warranted.

Genetic knockdown of Klk8 has sex‐specific multi‐targeted therapeutic effects on Alzheimer’s pathology in mice

“…26 In this pilot cross-sectional study, the diagnostic performance of CSF and blood KLK8 was relatively comparable and in the case of MCI, in part, even superior to that of the established CSF core biomarkers Aβ 42 , phospho-tau and total tau. 26 Intriguingly, short-term inhibition of pathologically elevated KLK8 in transgenic CRND8 (TgCRND8) mice for four weeks was capable of attenuating various pathological features of AD (i.e. Aβ pathology, tau hyper-phosphorylation, neurovascular dysfunction, disturbances in autophagy and microglial Aβ phagocytosis, deficits in structural neuroplasticity, anxiety and cognitive decline), whereas in wildtype mice with normal physiological KLK8 levels, KLK8 inhibition exhibited no effects or slightly deteriorating effects on few parameters.…”

“…Interestingly, cerebral KLK8 levels were, regardless of Alzheimer’s pathology, higher in women or female mice as compared to male individuals 25 . KLK8 elevation is not only detectable in the brain but also in the blood and cerebrospinal fluid (CSF) of patients with early AD and even stronger with mild cognitive impairment (MCI) 26 . In this pilot cross‐sectional study, the diagnostic performance of CSF and blood KLK8 was relatively comparable and in the case of MCI, in part, even superior to that of the established CSF core biomarkers Aβ 42 , phospho‐tau and total tau 26 .…”

Neuropsin in mental health

“…However, the endoprotease and molecular machinery responsible for neuropsin activation remains to be characterized and it is possible that post-translational regulation of neuropsin may be the dominating molecular mechanism of activity regulation in the mature brain. Interestingly, KLK8 expression measured in blood as well as cerebrospinal fluid is a promising early biomarker for AD as well as mild cognitive impairment due to AD [67]. Blood KLK8 levels have, furthermore, successfully been established as a biomarker for cancer diagnosis [68].…”

Extracellular Vesicles: Novel Roles in Neurological Disorders

“…However, as a reliable specimen, CSF is not easily available, and lumbar puncture can induce surgical trauma. Consequently, compared with CSF, peripheral blood may be an ideal source for the diagnosis of neurodegenerative diseases [ 67 ].…”

“…However, as a reliable specimen, CSF is not easily available, and lumbar puncture can induce surgical trauma. Consequently, compared with CSF, peripheral blood may be an ideal source for the diagnosis of neurodegenerative diseases [67]. BBB, formed by tight junction of brain endothelial cells and coverage of pericytes, astrocyte end feet, and capillary basement membrane, is a selective biological barrier between the blood and neuronal tissue.…”