{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:55:17Z","timestamp":1781502917476,"version":"3.54.1"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Lower levels of several synaptic proteins in cerebrospinal fluid (CSF) have been associated with greater cognitive decline among older adults, but there is limited understanding of their associations with brain structure. This study is among the first to examine the cross-sectional relationship between levels of three synaptic proteins (VGF, NPTX2, and GluA4) with magnetic resonance imaging (MRI) measures of white matter microstructure and volumes, and with cognitive performance. We also examined whether relationships between synaptic protein levels and white matter measures are influenced by CSF Alzheimer\u2019s disease (AD) biomarker levels [ratio of p-tau\n                      <jats:sub>181<\/jats:sub>\n                      \/(A\u03b2\n                      <jats:sub>42<\/jats:sub>\n                      \/A\u03b2\n                      <jats:sub>40<\/jats:sub>\n                      )].\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Participants included 151 middle-aged and older adults without dementia (132 cognitively unimpaired, 19 mild cognitive impairment,\n                      <jats:italic>M<\/jats:italic>\n                      <jats:sub>age<\/jats:sub>\n                      \u202f=\u202f69.3\u202fyears). White matter volumes and microstructure [fractional anisotropy (FA), mean diffusivity (MD)], derived from MRI scans, were assessed in three regions: global cerebral, medial temporal lobe, and cerebellar peduncles.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In linear regression analyses, lower levels of NPTX2, VGF, and GluA4 were associated with lower FA and higher MD, even after accounting for CSF AD biomarker levels. Synaptic proteins were not associated with white matter volumes. Additionally, lower FA, higher MD, and lower VGF levels were associated with poorer executive function performance. An exploratory mediation analysis showed that cerebral white matter MD statistically mediated the relationship between VGF and executive performance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings provide preliminary, cross-sectional support that VGF may act on cognition via white matter microstructure. Together the results suggest that white matter microstructure may represent one pathway linking synaptic proteins levels to cognitive performance among older adults. Future research is needed to advance understanding of the specific mechanisms driving these relationships.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1851829","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:36:42Z","timestamp":1781501802000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Associations of cerebrospinal fluid measures of synaptic function with white matter microstructure and cognition in older adults"],"prefix":"10.3389","volume":"18","author":[{"given":"Elizabeth R.","family":"Paitel","sequence":"first","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Pettigrew","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhay","family":"Moghekar","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael I.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Johns Hopkins University","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreia V.","family":"Faria","sequence":"additional","affiliation":[{"name":"Department of Radiology, Johns Hopkins University","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn","family":"Albert","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan Hyun","family":"Na","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Worley","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Johns Hopkins School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Soldan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1093\/brain\/awp257","article-title":"Absolute diffusivities define the landscape of white matter degeneration in Alzheimer's disease","volume":"133","author":"Acosta-Cabronero","year":"2010","journal-title":"Brain"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1080\/14789450.2025.2584129","article-title":"Integrative analysis of proteomic and MRI data reveals protein associations with brain imaging features in Alzheimer\u2019s disease","volume":"22","author":"Afxenti","year":"2025","journal-title":"Expert Rev. 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