Abstract
Objective: The underlying mechanisms of mild behavioral impairment (MBI), a marker for cognitive impairment and dementia, have remained unclear especially in a multiethnic Asian population. The study aimed to examine whether baseline Alzheimer disease biomarkers, including plasma neurofilament light (NfL) chain, phosphorylated tau-181 (p-tau181), and the p-tau181-to-amyloid-β42 (p-tau181/Aβ42) ratio, could predict MBI incidence in dementia-free Asian older adults.
Methods: Participants were recruited from the community and memory clinics from August 2010 to April 2022. All participants underwent cognitive, neuropsychiatric, and clinical assessments annually and neuroimaging scans biennially at baseline and over a maximum of 5 years. Neuropsychiatric symptoms (NPS) and incident MBI were examined using Neuropsychiatric Inventory. Plasma NfL, p-tau181, and Aβ42 were measured using single molecule array assays. Neuroimaging measures of hippocampal volume (HV) and white matter hyperintensities (WMH) were obtained.
Results: A total of 305 dementia-free participants were included (age 72.1 ± 7.8 years, 52.5% female, 27.9% no cognitive impairment). Among 248 MBI-free participants at baseline, 55 (25.3%) participants developed incident MBI in 5 years. Higher baseline p-tau181, p-tau181/Aβ42 ratio, and NfL were predictive of increased NPS severity longitudinally and MBI incidence (P < .05). Higher p-tau181 levels (hazard ratio [HR] [95% CI], 2.40 [1.00–5.75], P = .05) were independently associated with an increased likelihood of incident MBI after accounting for incident dementia and plasma NfL. This relationship remained significant when controlling for HV and WMH (HR [95% CI], 2.69 [1.08–6.70], P = .03).
Conclusions: Our findings highlighted the relationship between amyloid burden and neuroaxonal degeneration with neurobehavioral changes in multiethnic Asian older adults with underlying mixed pathology.
J Clin Psychiatry 2025;86(1):24m15558
Author affiliations are listed at the end of this article.
Continue Reading...
Did you know members enjoy unlimited free PDF downloads as part of their subscription? Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.
References (37)
- Lyketsos CG, Lopez O, Jones B, et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive Impairment: results from the Cardiovascular Health Study. JAMA. 2002;288(12):1475–1483. PubMed CrossRef
- Xu X, Ang SL, Hilal S, et al. Association of neuropsychiatric symptoms and sub-syndromes with cognitive impairment in community-dwelling Asian elderly. Int Psychogeriatr. 2015;27(11):1839–1847. PubMed CrossRef
- Martin E, Velayudhan L. Neuropsychiatric symptoms in mild cognitive impairment: a literature review. Dement Geriatr Cogn Disord. 2020;49(2):146–155. PubMed CrossRef
- Mortby ME, Ismail Z, Anstey KJ. Prevalence estimates of mild behavioral impairment in a population-based sample of pre-dementia states and cognitively healthy older adults. Int Psychogeriatr. 2018;30(2):221–232. PubMed CrossRef
- Ismail Z, Smith EE, Geda Y, et al. Neuropsychiatric symptoms as early manifestations of emergent dementia: provisional diagnostic criteria for mild behavioral impairment. Alzheimers Dement. 2016;12(2):195–202. CrossRef
- Kan CN, Cano J, Zhao X, et al. Prevalence, clinical correlates, cognitive trajectories, and dementia risk associated with mild behavioral impairment in Asians. J Clin Psychiatry. 2022;83(3):21m14105. PubMed CrossRef
- Creese B, Ismail Z. Mild behavioral impairment: measurement and clinical correlates of a novel marker of preclinical Alzheimer’s disease. Alzheimers Res Ther. 2022;14(1):2. PubMed CrossRef
- Pan Y, Shea YF, Li S, et al. Prevalence of mild behavioural impairment: a systematic review and meta-analysis. Psychogeriatrics. 2021;21(1):100–111.
- Johansson M, Stomrud E, Insel PS, et al. Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer’s disease. Transl Psychiatry. 2021;11(1):76. PubMed CrossRef
- Lussier FZ, Pascoal TA, Chamoun M, et al. Mild behavioral impairment is associated with β-amyloid but not tau or neurodegeneration in cognitively intact elderly individuals. Alzheimers Dement. 2020;16(1):192–199. PubMed CrossRef
- Chong JR, Ashton NJ, Karikari TK, et al. Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer’s disease: a focused review on recent advances. J Neurol Neurosurg Psychiatry. 2021;92(11):1231–1241. PubMed CrossRef
- Ashton NJ, Schöll M, Heurling K, et al. Update on biomarkers for amyloid pathology in Alzheimer’s disease. Biomark Med. 2018;12(7):799–812. PubMed CrossRef
- Janelidze S, Mattsson N, Palmqvist S, et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med. 2020;26(3):379–386. PubMed CrossRef
- Moscoso A, Grothe MJ, Ashton NJ, et al. Longitudinal associations of blood phosphorylated Tau181 and neurofilament light chain with neurodegeneration in Alzheimer disease. JAMA Neurol. 2021;78(4):396–406. PubMed CrossRef
- Smirnov DS, Ashton NJ, Blennow K, et al. Plasma biomarkers for Alzheimer’s Disease in relation to neuropathology and cognitive change. Acta Neuropathol. 2022;143(4):487–503. PubMed CrossRef
- Ghahremani M, Wang M, Chen HY, et al. Plasma phosphorylated tau at threonine 181 and neuropsychiatric symptoms in preclinical and prodromal Alzheimer disease. Neurology. 2023;100(7):e683–e693. PubMed CrossRef
- Naude JP, Gill S, Hu S, et al. Plasma neurofilament light: a marker of neurodegeneration in mild behavioral impairment. J Alzheimers Dis. 2020;76(3):1017–1027. CrossRef
- Miao R, Chen HY, Gill S, et al. Plasma β-amyloid in mild behavioural impairment - neuropsychiatric symptoms on the Alzheimer’s continuum. J Geriatr Psychiatry Neurol. 2022;35(3):434–441.
- Babulal GM, Quiroz YT, Albensi BC, et al. Perspectives on ethnic and racial disparities in alzheimer’s disease and related dementias: update and areas of immediate need. Alzheimers Dement. 2019;15(2):292–312. PubMed CrossRef
- Schindler SE, Karikari TK, Ashton NJ, et al. Effect of race on prediction of brain amyloidosis by plasma Aβ42/Aβ40, phosphorylated tau, and neurofilament light. Neurology. 2022;99(3):e245–e257. PubMed CrossRef
- Chen C, Homma A, Mok VCT, et al. Alzheimer’s disease with cerebrovascular disease: current status in the Asia-Pacific region. J Intern Med. 2016;280(4):359–374. PubMed CrossRef
- Chong JR, Ashton NJ, Karikari TK, et al. Plasma P-Tau181 to Aβ42 ratio is associated with brain amyloid burden and hippocampal atrophy in an Asian cohort of Alzheimer’s disease patients with concomitant cerebrovascular disease. Alzheimers Dement. 2021;17(10):1649–1662.
- Hilal S, Chai YL, Ikram MK, et al. Markers of cardiac dysfunction in cognitive impairment and dementia. Medicine (Baltimore). 2015;94(1):e297. PubMed CrossRef
- Xu X, Chan YH, Chan QL, et al. Global cerebrovascular burden and long-term clinical outcomes in Asian elderly across the spectrum of cognitive impairment. Int Psychogeriatr. 2018;30(9):1355–1363. PubMed CrossRef
- Chai YL, Hilal S, Chong JPC, et al. Growth differentiation factor-15 and white matter hyperintensities in cognitive impairment and dementia. Medicine (Baltimore). 2016;95(33):e4566. PubMed CrossRef
- Xu X, Chan QL, Hilal S, et al. The diagnostic utility of the NINDS-CSN neuropsychological battery in memory clinics. Dement Geriatr Cogn Dis Extra. 2016;6(2):276–282. PubMed CrossRef
- Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology. 1997;48(5 suppl 6):S10–S16. PubMed CrossRef
- Chong JR, Hilal S, Ashton NJ, et al. Brain atrophy and white matter hyperintensities are independently associated with plasma neurofilament light chain in an Asian cohort of cognitively impaired patients with concomitant cerebral small vessel disease. Alzheimers Dement. 2023;15(1):e12396. PubMed
- Chia RSL, Minta K, Wu LY, et al. Serum brevican as a biomarker of cerebrovascular disease in an elderly cognitively impaired cohort. Biomolecules. 2024;14(1):75. CrossRef
- Kapeller P, Barber R, Vermeulen RJ, et al. Visual rating of age-related white matter changes on magnetic resonance imaging: scale comparison, interrater agreement, and correlations with quantitative measurements. Stroke. 2003;34(2):441–445. PubMed CrossRef
- Rabl M, Clark C, Dayon L, et al. Blood plasma protein profiles of neuropsychiatric symptoms and related cognitive decline in older people. J Neurochem. 2023;164(2):242–254. PubMed CrossRef
- Johansson M, Stomrud E, Johansson PM, et al. Development of apathy, anxiety, and depression in cognitively unimpaired older adults: effects of Alzheimer’s disease pathology and cognitive decline. Biol Psychiatry. 2022;92(1):34–43. PubMed CrossRef
- Mattsson N, Andreasson U, Zetterberg H, et al. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 2017;74(5):557–566. PubMed CrossRef
- Gaetani L, Blennow K, Calabresi P, et al. Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry. 2019;90(8):870–881. PubMed CrossRef
- Ashton NJ, Janelidze S, Al Khleifat A, et al. A multicentre validation study of the diagnostic value of plasma neurofilament light. Nat Commun. 2021;12(1):3400. PubMed CrossRef
- Ismail Z, Leon R, Creese B, et al. Optimizing detection of Alzheimer’s disease in mild cognitive impairment: a 4-year biomarker study of mild behavioral impairment in ADNI and MEMENTO. Mol Neurodegener. 2023;18(1):50. PubMed CrossRef
- Fowler CJ, Stoops E, Rainey-Smith SR, et al. Plasma p-tau181/Aβ1-42 ratio predicts Aβ-PET status and correlates with CSF-p-tau181/Aβ1-42 and future cognitive decline. Alzheimers Dement. 2022;14(1):e12375. PubMed
Please sign in or purchase this PDF for $40.
Save
Share
Cite
Already a member? Login
