TY - JOUR
T1 - Potential diagnostic value of CSF metabolism-related proteins across the Alzheimer’s disease continuum
AU - Paciotti, Silvia
AU - Wojdała, Anna Lidia
AU - Bellomo, Giovanni
AU - Toja, Andrea
AU - Chipi, Elena
AU - Piersma, Sander R.
AU - Pham, Thang V.
AU - Gaetani, Lorenzo
AU - Jimenez, Connie R.
AU - Parnetti, Lucilla
AU - Chiasserini, Davide
N1 - Funding Information: This study was funded by the Associazione Italiana Ricerca Alzheimer Onlus (Airalzh), grant AGYR2020. Funding Information: SP was supported by Airalzh, grant AGYR2020. ALW is supported by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 86019 – MIRIADE. GB is supported by the Postdoctoral Fellowship for Basic Scientists grant of the Parkinson’s Foundation (Award ID: PF-PRF-934916). The authors thank Marta Ferrettini, Alfredo Megaro and Maya Petricciuolo for lab support. Funding Information: SP was supported by Airalzh, grant AGYR2020. ALW is supported by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 86019 – MIRIADE. GB is supported by the Postdoctoral Fellowship for Basic Scientists grant of the Parkinson’s Foundation (Award ID: PF-PRF-934916). The authors thank Marta Ferrettini, Alfredo Megaro and Maya Petricciuolo for lab support. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Background: Alzheimer’s disease (AD) cerebrospinal fluid (CSF) core biomarkers (Aβ42/40 ratio, p-tau, and t-tau) provide high diagnostic accuracy, even at the earliest stage of disease. However, these markers do not fully reflect the complex AD pathophysiology. Recent large scale CSF proteomic studies revealed several new AD candidate biomarkers related to metabolic pathways. In this study we measured the CSF levels of four metabolism-related proteins not directly linked to amyloid- and tau-pathways (i.e., pyruvate kinase, PKM; aldolase, ALDO; ubiquitin C-terminal hydrolase L1, UCHL1, and fatty acid-binding protein 3, FABP3) across the AD continuum. We aimed at validating the potential value of these proteins as new CSF biomarkers for AD and their possible involvement in AD pathogenesis, with specific interest on the preclinical phase of the disease. Methods: CSF PKM and ALDO activities were measured with specific enzyme assays while UCHL1 and FABP3 levels were measured with immunoassays in a cohort of patients composed as follows: preclinical AD (pre-AD, n = 19, cognitively unimpaired), mild cognitive impairment due to AD (MCI-AD, n = 50), dementia due to AD (ADdem, n = 45), and patients with frontotemporal dementia (FTD, n = 37). Individuals with MCI not due to AD (MCI, n = 30) and subjective cognitive decline (SCD, n = 52) with negative CSF AD-profile, were enrolled as control groups. Results: CSF UCHL1 and FABP3 levels, and PKM activity were significantly increased in AD patients, already at the pre-clinical stage. CSF PKM activity was also increased in FTD patients compared with control groups, being similar between AD and FTD patients. No difference was found in ALDO activity among the groups. UCHL1 showed good performance in discriminating early AD patients (pre-AD and MCI-AD) from controls (AUC ~ 0.83), as assessed by ROC analysis. Similar results were obtained for FABP3. Conversely, PKM provided the best performance when comparing FTD vs. MCI (AUC = 0.80). Combination of PKM, FABP3, and UCHL1 improved the diagnostic accuracy for the detection of patients within the AD continuum when compared with single biomarkers. Conclusions: Our study confirmed the potential role of UCHL1 and FABP3 as neurodegenerative biomarkers for AD. Furthermore, our results validated the increase of PKM activity in CSF of AD patients, already at the preclinical phase of the disease. Increased PKM activity was observed also in FTD patients, possibly underlining similar alterations in energy metabolism in AD and FTD.
AB - Background: Alzheimer’s disease (AD) cerebrospinal fluid (CSF) core biomarkers (Aβ42/40 ratio, p-tau, and t-tau) provide high diagnostic accuracy, even at the earliest stage of disease. However, these markers do not fully reflect the complex AD pathophysiology. Recent large scale CSF proteomic studies revealed several new AD candidate biomarkers related to metabolic pathways. In this study we measured the CSF levels of four metabolism-related proteins not directly linked to amyloid- and tau-pathways (i.e., pyruvate kinase, PKM; aldolase, ALDO; ubiquitin C-terminal hydrolase L1, UCHL1, and fatty acid-binding protein 3, FABP3) across the AD continuum. We aimed at validating the potential value of these proteins as new CSF biomarkers for AD and their possible involvement in AD pathogenesis, with specific interest on the preclinical phase of the disease. Methods: CSF PKM and ALDO activities were measured with specific enzyme assays while UCHL1 and FABP3 levels were measured with immunoassays in a cohort of patients composed as follows: preclinical AD (pre-AD, n = 19, cognitively unimpaired), mild cognitive impairment due to AD (MCI-AD, n = 50), dementia due to AD (ADdem, n = 45), and patients with frontotemporal dementia (FTD, n = 37). Individuals with MCI not due to AD (MCI, n = 30) and subjective cognitive decline (SCD, n = 52) with negative CSF AD-profile, were enrolled as control groups. Results: CSF UCHL1 and FABP3 levels, and PKM activity were significantly increased in AD patients, already at the pre-clinical stage. CSF PKM activity was also increased in FTD patients compared with control groups, being similar between AD and FTD patients. No difference was found in ALDO activity among the groups. UCHL1 showed good performance in discriminating early AD patients (pre-AD and MCI-AD) from controls (AUC ~ 0.83), as assessed by ROC analysis. Similar results were obtained for FABP3. Conversely, PKM provided the best performance when comparing FTD vs. MCI (AUC = 0.80). Combination of PKM, FABP3, and UCHL1 improved the diagnostic accuracy for the detection of patients within the AD continuum when compared with single biomarkers. Conclusions: Our study confirmed the potential role of UCHL1 and FABP3 as neurodegenerative biomarkers for AD. Furthermore, our results validated the increase of PKM activity in CSF of AD patients, already at the preclinical phase of the disease. Increased PKM activity was observed also in FTD patients, possibly underlining similar alterations in energy metabolism in AD and FTD.
KW - Aldolase
KW - Alzheimer’s disease
KW - Biomarkers
KW - Cerebrospinal fluid
KW - Fatty acid-binding protein 3
KW - Preclinical AD
KW - Pyruvate kinase
KW - Ubiquitin C-terminal hydrolase L1
UR - http://www.scopus.com/inward/record.url?scp=85164756080&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s13195-023-01269-8
DO - https://doi.org/10.1186/s13195-023-01269-8
M3 - Article
C2 - 37454217
SN - 1758-9193
VL - 15
JO - Alzheimer's Research and Therapy
JF - Alzheimer's Research and Therapy
IS - 1
M1 - 124
ER -