DOI: 10.1002/alz.072577 ISSN: 1552-5260

Blood and CSF proteome alterations, and regional brain volumetry patterns associated with neuropsychiatric symptoms in a memory clinic cohort

Miriam Rabl, Christopher Clark, Jonas Richiardi, Bénédicte Maréchal, Gene L. Bowman, Loic Dayon, Julius Popp
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Neuropsychiatric symptoms (NPS) are common in older people, may precede cognitive decline, and are associated with worse long‐term prognosis. However, the underlying pathophysiology remains unclear. Therefore, our main objective was to examine systemic and central nervous system (CNS) protein signatures and regional brain volumetry patterns related to NPS as indicators of pathophysiological mechanisms that may have diagnostic or therapeutic implications.


We included older subjects with normal cognition or cognitive impairment (mild cognitive impairment and mild dementia) participating in a longitudinal memory clinic study. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI‐Q). CSF biomarkers of Alzheimer’s disease (AD) were quantified in all participants. We performed untargeted proteomics in plasma and CSF, as well as MRI volumetry using the MorphoBox research application to ascertain regional brain volumes, both at baseline, and assessed their associations with NPS. Pathway enrichment analysis was used to identify systemic and CNS pathway alterations associated with regional brain volumes and NPS.


The strongest correlations between regional brain volumes and NPS severity were found for white matter (WM) right temporal lobe (r = ‐0.41), third ventricle (r = 0.40), WM frontal lobe (r = ‐0.38) and right hippocampus (r = ‐0.38) (all p<0.001). Most regional brain volumes correlated with NPS severity after considering the presence of AD pathology, defined according to CSF AD biomarkers. Twenty‐four out of 282 plasma proteins and 67 out of 605 CSF proteins were altered in relation to NPS. Pathway enrichment analysis revealed brain region‐specific proteomic alterations associated with NPS (Fig.1). The most common pathway alterations were immune reaction, hemostasis, and protein metabolism.


Older adults with NPS have region‐specific differences in brain volumes, particularly in white matter that are accompanied by systemic and CNS signatures related to immune activation, hemostasis, and protein metabolism. These findings show the potential of combining untargeted proteomics and MRI volumetry to detect pathophysiological changes related to NPS.

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