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Cerebrospinal fluid NPTX2 changes and relationship with regional brain metabolism metrics across mild cognitive impairment due to Alzheimer's disease

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Abstract

Background

Neuronal pentraxin-2 (NPTX2), crucial for synaptic functioning, declines in cerebrospinal fluid (CSF) as cognition deteriorates. The variations of CSF NPTX2 across mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and its association with brain metabolism remain elusive, albeit relevant for patient stratification and pathophysiological insights.

Methods

We retrospectively analyzed 49 MCI-AD patients grouped by time until dementia (EMCI, n = 34 progressing within 2 years; LMCI, n = 15 progressing later/stable at follow-up). We analyzed demographic variables, cognitive status (MMSE score), and CSF NPTX2 levels using a commercial ELISA assay in EMCI, LMCI, and a control group of age-/sex-matched individuals with other non-dementing disorders (OND). Using [18F]FDG PET scans for voxel-based analysis, we explored correlations between regional brain metabolism metrics and CSF NPTX2 levels in MCI-AD patients, accounting for age.

Results

Baseline and follow-up MMSE scores were lower in LMCI than EMCI (p value = 0.006 and p < 0.001). EMCI exhibited significantly higher CSF NPTX2 values than both LMCI (p = 0.028) and OND (p = 0.006). We found a significant positive correlation between NPTX2 values and metabolism of bilateral precuneus in MCI-AD patients (p < 0.005 at voxel level, p < 0.05 with family-wise error correction at the cluster level).

Conclusions

Higher CSF NPTX2 in EMCI compared to controls and LMCI suggests compensatory synaptic responses to initial AD pathology. Disease progression sees these mechanisms overwhelmed, lowering CSF NPTX2 approaching dementia. Positive CSF NPTX2 correlation with precuneus glucose metabolism links to AD-related metabolic changes across MCI course. These findings posit CSF NPTX2 as a promising biomarker for both AD staging and progression risk stratification.

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Data availability

Data are available on reasonable request from the corresponding author.

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Acknowledgements

This work was developed within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016). The authors are thankful to Davide Visigalli for his technical assistance in the sample pre-analysis and biobanking work.

Funding

This work was partially supported by a grant from the Italian Ministry of Health to IRCCS Ospedale Policlinico San Martino [Fondi per la Ricerca Corrente, and Italian Neuroscience network (RIN)], by #NEXTGENERATIONEU (NGEU) and partially funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)—A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022).

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Authors and Affiliations

  1. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy

    Federico Massa, Caterina Martinuzzo, Virginia Pelagotti, Wendy Kreshpa, Pietro Mattioli, Beatrice Orso, Andrea Brugnolo, Nicola Girtler, Dario Arnaldi, Antonio Uccelli & Matteo Pardini

  2. IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Federico Massa, Pietro Mattioli, Andrea Brugnolo, Nicola Girtler, Tiziana Vigo, Dario Arnaldi, Antonio Uccelli, Silvia Morbelli & Matteo Pardini

  3. Department of Neurology, Ulm University Hospital, Ulm, Germany

    Nerea Gómez de San José

  4. Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany

    Samir Abu-Rumeileh, Lorenzo Barba & Markus Otto

  5. Neurology Unit, ASL 1 Hospital, Imperia, Italy

    Carlo Serrati

  6. Department of Health Science (DISSAL), University of Genoa, Genoa, Italy

    Silvia Morbelli

  7. National Institute of Nuclear Physics (INFN), Genoa Section, Genoa, Italy

    Andrea Chincarini

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  1. Federico Massa
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Corresponding author

Correspondence to Federico Massa.

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Conflict of interest

F Massa has received speaker honorarium from Roche Diagnostic Spa, Gómez de San José N is a part-time employer at Proteintech, S Abu-Rumeileh S received research support from the Medical Faculty of Martin-Luther-University Halle-Wittenberg (Clinician Scientist-Program No. CS22/06), D Arnaldi received fees from Fidia, Bruno, Italfarmaco, Idorsia for lectures and board participation; A Uccelli, received grants (to his Institution) from FISM, Biogen, Roche, Alexion, Merck Serono; participated on a Data Safety Monitoring Board or Advisory Board (to his Institution) for BD, Biogen, Iqvia, Sanofi, Roche, Alexion, Bristol Myers Squibb; S Morbelli has received speaker Honoraria from G.E. Healthcare; Otto M received fees for advisory board meetings from Roche, Biogen, Grifols, and Axon; M Pardini receives research support from Novartis and Nutricia, received fees from Novartis, Merck. The other authors have nothing to disclose.

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This research involves human participants and was approved by the regional ethical committee (ref:PNRR-POC-2022–12376726). Informed consent was obtained from all participants. Anonymized data published per hospital rules for retrospective data collected during the clinical routine. All procedures followed the 1964 Helsinki Declaration and its later amendments.

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Massa, F., Martinuzzo, C., Gómez de San José, N. et al. Cerebrospinal fluid NPTX2 changes and relationship with regional brain metabolism metrics across mild cognitive impairment due to Alzheimer's disease. J Neurol 271, 1999–2009 (2024). https://doi.org/10.1007/s00415-023-12154-7

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