{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:49:49Z","timestamp":1790678989358,"version":"4.1.0"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T00:00:00Z","timestamp":1677024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014041","name":"Alzheimer\u2019s Disease Neuroimaging Initiative","doi-asserted-by":"publisher","award":["U01 AG024904"],"award-info":[{"award-number":["U01 AG024904"]}],"id":[{"id":"10.13039\/100014041","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Alzheimer\u2019s disease (AD) is indicated by a decrease in amyloid beta 42 (A\u03b242) level or the A\u03b242\/A\u03b240 ratio, and by increased levels of Tau with phosphorylated threonine at position 181 (pTau181) in cerebrospinal fluid (CSF) years before the onset of clinical symptoms. However, once only pTau181 is increased, cognitive decline in individuals with subjective or mild cognitive impairment is slowed compared to individuals with AD. Instead of a decrease in A\u03b242 levels, an increase in A\u03b242 was observed in these individuals, leading to the proposal to refer to them as nondemented subjects with increased pTau-levels and A\u03b2 surge with subtle cognitive deterioration (PASSED). In this study, we determined the longitudinal atrophy rates of AD, PASSED, and Biomarker-negative nondemented individuals of two independent cohorts to determine whether these groups can be distinguished by their longitudinal atrophy patterns or rates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Depending on their CSF-levels of pTau 181 (T), total Tau (tTau, N), A\u03b242 or ratio of A\u03b242\/A\u03b240 (A), 185 non-demented subjects from the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI) and 62 non-demented subjects from Erlangen AD cohort were assigned to an ATN group (A\u2013T\u2013N\u2013, A\u2013T+N\u00b1, A+T\u2013N\u00b1and A+T+N\u00b1) and underwent T1-weighted structural magnetic resonance imaging (sMRI). Longitudinal grey matter (GM) atrophy patterns were assessed with voxel-based morphometry (VBM) using the cat12 toolbox on spm12 (statistical parametric mapping) of MRI scans from individuals in the ADNI cohort with a mean follow-up of 2 and 5\u2009years, respectively. The annualized atrophy rate for individuals in the Erlangen cohort was determined using region of interest analysis (ROI) in terms of a confirmatory analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the A\u2013T+N\u00b1 group, VBM did not identify any brain region that showed greater longitudinal atrophy than the A+T+N\u00b1, A+T+N\u00b1 or biomarker negative control group. In contrast, marked longitudinal atrophy in the temporal lobe was evident in the A+T\u2013N\u00b1 group compared with A+T\u2013N\u00b1 \u2009and biomarker-negative subjects. The ROI in the angular gyrus identified by VBM analysis of the ADNI cohort did not discriminate better than the hippocampal volume and atrophy rate between AD and PASSED in the confirmatory analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In this study, nondemented subjects with PASSED did not show a unique longitudinal atrophy pattern in comparison to nondemented subjects with AD. The nonsignificant atrophy rate compared with controls suggests that increased pTau181-levels without concomitant amyloidopathy did not indicate a neurodegenerative disorder.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2023.1121500","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T08:54:56Z","timestamp":1677056096000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["PASSED: Brain atrophy in non-demented individuals in a long-term longitudinal study from two independent cohorts"],"prefix":"10.3389","volume":"15","author":[{"given":"Anna-Lena","family":"Haas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Olm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Utz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva-Maria","family":"Siegmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Spitzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Florvaag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel Alexander","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnd","family":"Doerfler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Lewczuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Kornhuber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Manuel","family":"Maler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo Jan","family":"Oberstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,22]]},"reference":[{"key":"ref1","author":"Aebi","year":"2002"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/BF02815140","article-title":"Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease?","volume":"26","author":"Blennow","year":"1995","journal-title":"Mol. Chem. Neuropathol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1016\/S1474-4422(16)30125-9","article-title":"Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer\u2019s disease pathophysiology (SNAP) or Alzheimer\u2019s disease pathology: a longitudinal study","volume":"15","author":"Burnham","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach","volume":"44","author":"Delong","year":"1988","journal-title":"Biometrics"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12713","article-title":"Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimer\u2019s disease pathophysiology","author":"Delvenne","year":"2022","journal-title":"Alzheimers Dement."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.dadm.2016.12.007","article-title":"Alzheimer\u2019s disease: the influence of age on clinical heterogeneity through the human brain connectome","volume":"6","author":"Dickerson","year":"2017","journal-title":"Alzheimers Dement (Amst.)"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/S1474-4422(14)70090-0","article-title":"Advancing research diagnostic criteria for Alzheimer\u2019s disease: the IWG-2 criteria","volume":"13","author":"Dubois","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.jalz.2016.02.002","article-title":"Preclinical Alzheimer\u2019s disease: definition, natural history, and diagnostic criteria","volume":"12","author":"Dubois","year":"2016","journal-title":"Alzheimers Dement."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"351","DOI":"10.2214\/ajr.149.2.351","article-title":"MR signal abnormalities at 1.5 T in Alzheimer\u2019s dementia and normal aging","volume":"149","author":"Fazekas","year":"1987","journal-title":"AJR Am. J. Roentgenol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1001\/archpsyc.61.1.95","article-title":"Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study","volume":"61","author":"Hampel","year":"2004","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13195-019-0485-0","article-title":"Advantages and disadvantages of the use of the CSF amyloid beta (Abeta) 42\/40 ratio in the diagnosis of Alzheimer\u2019s disease","volume":"11","author":"Hansson","year":"2019","journal-title":"Alzheimers Res. Ther."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA research framework: toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"","journal-title":"Alzheimers Dement."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA research framework: toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"","journal-title":"Alzheimers Dement."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/nrneurol.2015.251","article-title":"Suspected non-Alzheimer disease pathophysiology--concept and controversy","volume":"12","author":"Jack","year":"2016","journal-title":"Nat. Rev. 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Alzheimers Dis."},{"key":"ref18","article-title":"Region of interest analysis using an SPM toolbox [abstract]","author":"Matthew Brett","year":"2002"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","article-title":"The diagnosis of dementia due to Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Mckhann","year":"2011","journal-title":"Alzheimers Dement."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"4032","DOI":"10.1093\/brain\/awac297","article-title":"Amyloid-\u03b2 levels and cognitive trajectories in non-demented pTau181-positive subjects without amyloidopathy","volume":"145","author":"Oberstein","year":"2022","journal-title":"Brain"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"116189","DOI":"10.1016\/j.neuroimage.2019.116189","article-title":"Automated anatomical labelling atlas 3","volume":"206","author":"Rolls","year":"2020","journal-title":"NeuroImage"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1001\/jamaneurol.2016.5349","article-title":"Alzheimer disease signature neurodegeneration and APOE genotype in mild cognitive impairment with suspected non-Alzheimer disease pathophysiology","volume":"74","author":"Schreiber","year":"2017","journal-title":"JAMA Neurol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1002\/ana.21610","article-title":"Cerebrospinal fluid biomarker signature in Alzheimer\u2019s disease neuroimaging initiative subjects","volume":"65","author":"Shaw","year":"2009","journal-title":"Ann. 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