{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:49:37Z","timestamp":1785408577511,"version":"3.56.0"},"reference-count":26,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health & Welfare, Republic of Korea","award":["HI22C0667"],"award-info":[{"award-number":["HI22C0667"]}]},{"name":"Soonchunhyang University Research Fund"},{"id":[{"id":"https:\/\/ror.org\/03qjsrb10","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background and Objectives: To quantify behavioral complexity in probable Alzheimer\u2019s disease (AD), compare complexity phenotypes, and determine whether behavioral complexity provides clinically meaningful information beyond total neuropsychiatric burden. We also explored whether global amyloid extent and lobar amyloid topography added explanatory value. Methods: In this cross-sectional retrospective study, we analyzed 245 psychotropic drug-na\u00efve patients with probable AD, positive 18F-FC119S amyloid positron emission tomography (PET), and complete neuropsychiatric, cognitive, functional, and regional PET data. Behavioral complexity was derived from 12 Korean Neuropsychiatric Inventory domains using symptom count, normalized Shannon entropy of the frequency \u00d7 severity profile, and a composite index. Patients were classified into tertiles. Multivariable regression and burden-stratified analyses examined associations with cognition, dementia severity, function, and amyloid measures. Results: Higher behavioral complexity was associated with lower Korean Mini-Mental State Examination (K-MMSE) scores and higher Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS) stages. In multivariable analysis, higher CDR, higher GDS, and lower Barthel Index independently predicted greater complexity, whereas amyloid extent did not. After adjustment for total neuropsychiatric burden, higher CDR remained independently associated with the composite complexity index and normalized entropy, while amyloid extent remained non-significant. Complexity-related clinical differences were most evident in the lowest burden stratum and attenuated at higher burden levels. Regional amyloid analyses yielded only selective signals. Conclusions: Behavioral complexity is a clinically meaningful neuropsychiatric phenotype in AD. Although strongly related to total neuropsychiatric burden, it is not fully reducible to it, with its clearest independent association seen for global dementia severity, particularly at lower overall burden.<\/jats:p>","DOI":"10.3390\/brainsci16070659","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T07:57:24Z","timestamp":1782287844000},"page":"659","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Behavioral Complexity in Alzheimer\u2019s Disease: A Diversity-Based Analysis of Neuropsychiatric Symptoms"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2448-2599","authenticated-orcid":false,"given":"YoungSoon","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurology, Soonchunhyang University College of Medicine, Cheonan Hospital, Cheonan 31151, Chungcheongnam-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4195-8971","authenticated-orcid":false,"given":"Yong Tae","family":"Kwak","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hyoja Geriatric Hospital, Yongin 17089, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.jalz.2011.05.2410","article-title":"Neuropsychiatric symptoms in Alzheimer\u2019s disease","volume":"7","author":"Lyketsos","year":"2011","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"h369","DOI":"10.1136\/bmj.h369","article-title":"Assessment and management of behavioral and psychological symptoms of dementia","volume":"350","author":"Kales","year":"2015","journal-title":"BMJ"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.mam.2015.05.005","article-title":"Neuropsychiatric symptoms in Alzheimer\u2019s disease: What might be associated brain circuits?","volume":"43\u201344","author":"Rosenberg","year":"2015","journal-title":"Mol. Asp. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1159\/000067972","article-title":"Behavioral problems in dementia: A factor analysis of the Neuropsychiatric Inventory","volume":"15","author":"Aalten","year":"2003","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1002\/gps.448","article-title":"Neuropsychiatric disturbance in Alzheimer\u2019s disease clusters into three groups: The Cache County Study","volume":"16","author":"Lyketsos","year":"2001","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.eurpsy.2004.09.031","article-title":"Grouping for behavioral and psychological symptoms in dementia: Clinical and biological aspects. Consensus paper of the European Alzheimer Disease Consortium","volume":"20","author":"Robert","year":"2005","journal-title":"Eur. Psychiatry"},{"key":"ref_7","first-page":"1157","article-title":"Grouping and trajectories of the neuropsychiatric symptoms in patients with Alzheimer\u2019s disease, Part I: Symptom clusters","volume":"22","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"87","DOI":"10.12779\/dnd.2012.11.3.87","article-title":"Clinical characteristics of behavioral and psychological symptoms in patients with drug-na\u00efve Alzheimer\u2019s disease","volume":"11","author":"Kwak","year":"2012","journal-title":"Dement. Neurocogn. Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1177\/13872877251411433","article-title":"Neuropsychiatric signs and symptoms clusters and regional amyloid on 18F-FC119S PET in Alzheimer\u2019s disease","volume":"109","author":"Yang","year":"2026","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s13195-023-01279-6","article-title":"Network analysis of neuropsychiatric symptoms in Alzheimer\u2019s disease","volume":"15","author":"Goodwin","year":"2023","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1212\/WNL.44.12.2308","article-title":"The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia","volume":"44","author":"Cummings","year":"1994","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1177\/0891988719882102","article-title":"The Neuropsychiatric Inventory: Development and applications","volume":"33","author":"Cummings","year":"2020","journal-title":"J. Geriatr. Psychiatry Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"379\u2013423, 623\u2013656","DOI":"10.1002\/j.1538-7305.1948.tb01338.x","article-title":"A mathematical theory of communication","volume":"27","author":"Shannon","year":"1948","journal-title":"Bell Syst. Tech. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1097\/NNR.0b013e3182741948","article-title":"Composite variables: When and how","volume":"62","author":"Song","year":"2013","journal-title":"Nurs. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/nn.2583","article-title":"Amyloid-beta-induced neuronal dysfunction in Alzheimer\u2019s disease: From synapses toward neural networks","volume":"13","author":"Palop","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40035-021-00270-1","article-title":"The role of pathological tau in synaptic dysfunction in Alzheimer\u2019s diseases","volume":"10","author":"Wu","year":"2021","journal-title":"Transl. Neurodegener."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1196\/annals.1440.011","article-title":"The brain\u2019s default network: Anatomy, function, and relevance to disease","volume":"1124","author":"Buckner","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1523\/JNEUROSCI.5587-06.2007","article-title":"Dissociable intrinsic connectivity networks for salience processing and executive control","volume":"27","author":"Seeley","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.neuron.2009.03.024","article-title":"Neurodegenerative diseases target large-scale human brain networks","volume":"62","author":"Seeley","year":"2009","journal-title":"Neuron"},{"key":"ref_20","doi-asserted-by":"crossref","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":"Alzheimer\u2019s Dement."},{"key":"ref_21","doi-asserted-by":"crossref","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":"2018","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3988\/jcn.2020.16.1.131","article-title":"Clinical usefulness of 18F-FC119S positron-emission tomography as an auxiliary diagnostic method for dementia: An open-label, single-dose, evaluator-blind clinical trial","volume":"16","author":"Lee","year":"2020","journal-title":"J. Clin. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"260","DOI":"10.3988\/jcn.2022.0207","article-title":"Comparison between 18F-florapronol and 18F-florbetaben imaging in patients with cognitive impairment","volume":"19","author":"Baik","year":"2023","journal-title":"J. Clin. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e70169","DOI":"10.1002\/gps.70169","article-title":"Natural evolution and heterogeneity of neuropsychiatric symptoms across neurocognitive disorders: A systematic review and meta-analysis of longitudinal studies","volume":"40","author":"Skoda","year":"2025","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tascone, L.S., Payne, M.E., MacFall, J., Azevedo, D., de Castro, C.C., Steffens, D.C., Krishnan, K.R.R., Busatto, G.F., and Balthazar, M.L.F. (2017). Cortical brain volume abnormalities associated with few or multiple neuropsychiatric symptoms in Alzheimer\u2019s disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0177169"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.neurobiolaging.2024.09.009","article-title":"Modeling the progression of neuropsychiatric symptoms in Alzheimer\u2019s disease with PET-based Braak staging","volume":"144","author":"Macedo","year":"2024","journal-title":"Neurobiol. Aging"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/7\/659\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T09:22:25Z","timestamp":1782292945000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/7\/659"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,23]]},"references-count":26,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["brainsci16070659"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16070659","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,23]]}}}