{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:29:02Z","timestamp":1780108142740,"version":"3.54.0"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Malaysian Ministry of Education\/ Higher Education under the Fundamental Research Grant Scheme","award":["FRGS\/1\/2019\/SKK03\/UPM\/02\/4"],"award-info":[{"award-number":["FRGS\/1\/2019\/SKK03\/UPM\/02\/4"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Alzheimer\u2019s disease (AD) is a major neurocognitive disorder identified by memory loss and a significant cognitive decline based on previous level of performance in one or more cognitive domains that interferes in the independence of everyday activities. The accuracy of imaging helps to identify the neuropathological features that differentiate AD from its common precursor, mild cognitive impairment (MCI). Identification of early signs will aid in risk stratification of disease and ensures proper management is instituted to reduce the morbidity and mortality associated with AD. Magnetic resonance imaging (MRI) using structural MRI (sMRI), functional MRI (fMRI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (<jats:sup>1<\/jats:sup>H-MRS) performed alone is inadequate. Thus, the combination of multiparametric MRI is proposed to increase the accuracy of diagnosing MCI and AD when compared to elderly healthy controls.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>This protocol describes a non-interventional case control study. The AD and MCI patients and the healthy elderly controls will undergo multi-parametric MRI. The protocol consists of sMRI, fMRI, DTI, and single-voxel proton MRS sequences. An eco-planar imaging (EPI) will be used to perform resting-state fMRI sequence. The structural images will be analysed using Computational Anatomy Toolbox-12, functional images will be analysed using Statistical Parametric Mapping-12, DPABI (Data Processing &amp; Analysis for Brain Imaging), and Conn software, while DTI and <jats:sup>1<\/jats:sup>H-MRS will be analysed using the FSL (FMRIB\u2019s Software Library) and Tarquin respectively. Correlation of the MRI results and the data acquired from the APOE genotyping, neuropsychological evaluations (i.e. Montreal Cognitive Assessment [MoCA], and Mini\u2013Mental State Examination [MMSE] scores) will be performed. The imaging results will also be correlated with the sociodemographic factors. The diagnosis of AD and MCI will be standardized and based on the DSM-5 criteria and the neuropsychological scores.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Discussion<\/jats:title>\n<jats:p>The combination of sMRI, fMRI, DTI, and MRS sequences can provide information on the anatomical and functional changes in the brain such as regional grey matter volume atrophy, impaired functional connectivity among brain regions, and decreased metabolite levels specifically at the posterior cingulate cortex\/precuneus. The combination of multiparametric MRI sequences can be used to stratify the management of MCI and AD patients. Accurate imaging can decide on the frequency of follow-up at memory clinics and select classifiers for machine learning that may aid in the disease identification and prognostication. Reliable and consistent quantification, using standardised protocols, are crucial to establish an optimal diagnostic capability in the early detection of Alzheimer\u2019s disease.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0252883","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T17:54:15Z","timestamp":1632246855000},"page":"e0252883","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Multiparametric MRI for the improved diagnostic accuracy of Alzheimer\u2019s disease and mild cognitive impairment: Research protocol of a case-control study design"],"prefix":"10.1371","volume":"16","author":[{"given":"Albert Dayor","family":"Piersson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buhari","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subapriya","family":"Suppiah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mazlyfarina","family":"Mohamad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasyma Abu","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nur Farhayu","family":"Omar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd Izuan","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad Nazlim","family":"Yusoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Normala","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Iqbal","family":"Saripan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rizah Mazzuin","family":"Razali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,9,21]]},"reference":[{"key":"pone.0252883.ref001","unstructured":"Alzheimer\u2019s Disease International. World Alzheimer Report 2019: Attitudes to dementia. 2019 [cited 2019]. https:\/\/www.alzint.org\/u\/WorldAlzheimerReport2019.pdf."},{"key":"pone.0252883.ref002","unstructured":"Alzheimer\u2019s Disease International. World Alzheimer Report 2015 \u2013The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. 2014 [cited 2015] https:\/\/www.alzint.org\/u\/WorldAlzheimerReport2015.pdf."},{"key":"pone.0252883.ref003","unstructured":"Prince M, Comas-Herrera A, Knapp M, et al. World Alzheimer report 2016: improving healthcare for people living with dementia: coverage, quality and costs now and in the future. 2016 [cited 2016]. https:\/\/www.alzint.org\/u\/WorldAlzheimerReport2016.pdf."},{"issue":"5","key":"pone.0252883.ref004","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1093\/aje\/kwf074","article-title":"Risk factors for Alzheimer\u2019s disease: a prospective analysis from the Canadian Study of Health and Aging","volume":"156","author":"J Lindsay","year":"2002","journal-title":"Am J Epidemiol"},{"key":"pone.0252883.ref005","unstructured":"United Nations, Department of Economic and Social Affairs, Population Division. World population prospects: The 2015 Revision. 2015 [cited 2015]. http:\/\/esa.un.org\/unpd\/wpp\/DVD."},{"key":"pone.0252883.ref006","first-page":"4218756","article-title":"Identification of Neuroprotective Factors Associated with Successful Ageing and Risk of Cognitive Impairment among Malaysia Older Adults","volume":"2017","author":"H Lau","year":"2017","journal-title":"Curr Gerontol Geriatr Res"},{"issue":"Pt 10","key":"pone.0252883.ref007","doi-asserted-by":"crossref","first-page":"2814","DOI":"10.1093\/brain\/awv236","article-title":"The preclinical phase of the pathological process underlying sporadic Alzheimer\u2019s disease","volume":"138","author":"H Braak","year":"2015","journal-title":"Brain"},{"issue":"2","key":"pone.0252883.ref008","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s00401-014-1371-2","article-title":"Tau aggregation and its interplay with amyloid-\u03b2","volume":"129","author":"RM Nisbet","year":"2015","journal-title":"Acta Neuropathol"},{"issue":"9","key":"pone.0252883.ref009","doi-asserted-by":"crossref","first-page":"952","DOI":"10.2174\/1567205013666160314150501","article-title":"Molecular Basis of Familial and Sporadic Alzheimer\u2019s Disease","volume":"13","author":"J Dorszewska","year":"2016","journal-title":"Curr Alzheimer Res"},{"key":"pone.0252883.ref010","doi-asserted-by":"crossref","DOI":"10.1176\/appi.books.9780890425596","volume-title":"Diagnostic and statistical manual of mental disorders","author":"American Psychiatric Association","year":"2013","edition":"5"},{"issue":"1","key":"pone.0252883.ref011","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.archger.2011.03.015","article-title":"Prevalence of gender disparities and predictors affecting the occurrence of mild cognitive impairment (MCI)","volume":"54","author":"LK Lee","year":"2012","journal-title":"Arch Gerontol Geriatr"},{"key":"pone.0252883.ref012","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1186\/s12889-019-7508-4","article-title":"Incidence and predictors of mild cognitive impairment (MCI) within a multi-ethnic Asian populace: a community-based longitudinal study","volume":"19","author":"NM Hussin","year":"2019","journal-title":"BMC Public Health"},{"issue":"2","key":"pone.0252883.ref013","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.ijge.2013.07.002","article-title":"A Preliminary Randomized Controlled Trial of Multifaceted Educational Intervention for Mild Cognitive Impairment Among Elderly Malays in Kuala Lumpur","volume":"8","author":"SM Johari","year":"2014","journal-title":"International Journal of Gerontology"},{"key":"pone.0252883.ref014","doi-asserted-by":"crossref","first-page":"43","DOI":"10.2147\/CIA.S183425","article-title":"Relationships between dietary nutrients intake and lipid levels with functional MRI dorsolateral prefrontal cortex activation","volume":"14","author":"H Lau","year":"2018","journal-title":"Clin Interv Aging"},{"issue":"4","key":"pone.0252883.ref015","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1002\/jmri.26891","article-title":"Does traditional asian vegetables (ulam) consumption correlate with brain activity using fMRI? A study among aging adults from low-income households","volume":"51","author":"YX You","year":"2020","journal-title":"J Magn Reson Imaging"},{"key":"pone.0252883.ref016","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3390\/diagnostics9020065","article-title":"The Who, When, Why, and How of PET Amyloid Imaging in Management of Alzheimer\u2019s Disease\u2014Review of Literature and Interesting Images","volume":"9","author":"S Suppiah","year":"2019","journal-title":"Diagnostics"},{"issue":"1","key":"pone.0252883.ref017","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S1474-4422(09)70299-6","article-title":"Hypothetical model of dynamic biomarkers of the Alzheimer\u2019s pathological cascade","volume":"9","author":"CR Jack","year":"2010","journal-title":"Lancet Neurol"},{"issue":"3","key":"pone.0252883.ref018","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jalz.2011.03.003","article-title":"Toward defining the preclinical stages of Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"RA Sperling","year":"2011","journal-title":"Alzheimers Dement"},{"issue":"2","key":"pone.0252883.ref019","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1212\/WNL.0b013e3181e7ca82","article-title":"Serial MRI and CSF biomarkers in normal aging, MCI, and AD","volume":"75","author":"P Vemuri","year":"2010","journal-title":"Neurology"},{"issue":"3","key":"pone.0252883.ref020","first-page":"CD009628","article-title":"Structural magnetic resonance imaging for the early diagnosis of dementia due to Alzheimer\u2019s disease in people with mild cognitive impairment","volume":"3","author":"G Lombardi","year":"2020","journal-title":"Cochrane Database Syst 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coherence changes in the early stages of Alzheimer\u2019s disease: a combined structural and resting-state functional MRI study","volume":"35","author":"Y He","year":"2007","journal-title":"Neuroimage"},{"issue":"Suppl 3","key":"pone.0252883.ref025","doi-asserted-by":"crossref","first-page":"287","DOI":"10.3233\/JAD-2011-0007","article-title":"DTI analyses and clinical applications in Alzheimer\u2019s disease","volume":"26","author":"K Oishi","year":"2011","journal-title":"J Alzheimers Dis"},{"issue":"2","key":"pone.0252883.ref026","doi-asserted-by":"crossref","first-page":"455","DOI":"10.3233\/JAD-190446","article-title":"Multicenter Tract-Based Analysis of Microstructural Lesions within the Alzheimer\u2019s Disease Spectrum: Association with Amyloid Pathology and Diagnostic Usefulness","volume":"72","author":"SJ Teipel","year":"2019","journal-title":"J Alzheimers Dis"},{"key":"pone.0252883.ref027","first-page":"687","article-title":"Magnetic resonance spectroscopy in Alzheimer\u2019s disease","volume":"9","author":"J Graff-Radford","year":"2013","journal-title":"Neuropsychiatr Dis Treat"},{"key":"pone.0252883.ref028","article-title":"Cerebrospinal Fluid Amyloid Beta, Tau Levels, Apolipoprotein, and 1H-MRS Brain Metabolites in Alzheimer\u2019s Disease: A Systematic Review","author":"AD Piersson","year":"2020","journal-title":"Academic Radiology"},{"issue":"4","key":"pone.0252883.ref029","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.3233\/JAD-143225","article-title":"Magnetic Resonance Spectroscopy in Alzheimer\u2019s Disease: Systematic Review and Meta-Analysis","volume":"46","author":"H Wang","year":"2015","journal-title":"J Alzheimers Dis"},{"issue":"8","key":"pone.0252883.ref030","doi-asserted-by":"crossref","first-page":"e877","DOI":"10.1038\/tp.2016.140","article-title":"Whole-brain patterns of (1)H-magnetic resonance spectroscopy imaging in Alzheimer\u2019s disease and dementia with Lewy bodies","volume":"6","author":"L Su","year":"2016","journal-title":"Transl Psychiatry"},{"issue":"1","key":"pone.0252883.ref031","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/ejcts\/ezy169","article-title":"Statistical primer: sample size and power calculations-why, when and how?","volume":"54","author":"GL Hickey","year":"2018","journal-title":"Eur J Cardiothorac Surg"},{"issue":"10","key":"pone.0252883.ref032","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1002\/hbm.20324","article-title":"Altered functional connectivity in early Alzheimer\u2019s disease: a resting-state fMRI study","volume":"28","author":"K Wang","year":"2007","journal-title":"Hum Brain Mapp"},{"issue":"2","key":"pone.0252883.ref033","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1002\/mrm.27742","article-title":"Methodological consensus on clinical proton MRS of the brain: Review and recommendations","volume":"82","author":"M Wilson","year":"2019","journal-title":"Magn Reson Med"},{"key":"pone.0252883.ref034","volume-title":"Clinical MR Spectroscopy Techniques and Applications","author":"PB Barker","year":"2010"},{"key":"pone.0252883.ref035","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/978-1-4419-5864-8_3","volume-title":"MR Spectroscopy of Pediatric Brain Disorders","author":"S Bl\u00fcm","year":"2013"},{"key":"pone.0252883.ref036","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3233\/JAD-2010-1401","article-title":"Reduced cortical thickness in the posterior cingulate gyrus is characteristic of both typical and atypical Alzheimer\u2019s disease","volume":"20","author":"M Lehmann","year":"2010","journal-title":"J Alzheimers Dis"},{"key":"pone.0252883.ref037","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/ana.410420114","article-title":"Metabolic reduction in the posterior cingulate cortex in very early Alzheimer\u2019s disease","volume":"42","author":"S Minoshima","year":"1997","journal-title":"Ann Neurol"},{"key":"pone.0252883.ref038","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"H Braak","year":"1991","journal-title":"Acta Neuropathol"},{"key":"pone.0252883.ref039","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1212\/WNL.0b013e31822dc7e1","article-title":"Magnetic resonance spectroscopy, \u03b2-amyloid load, and cognition in a population-based sample of cognitively normal older adults","volume":"77","author":"KLV Kantarci","year":"2011","journal-title":"Neurology"},{"key":"pone.0252883.ref040","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.biopsych.2013.05.022","article-title":"APOE genotype modulates proton magnetic resonance spectroscopy metabolites in the aging brain","volume":"75","author":"JJ Gomar","year":"2013","journal-title":"Biol Psychiatry"},{"key":"pone.0252883.ref041","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1148\/radiol.13130531","article-title":"Clinical proton MR spectroscopy in central nervous system disorders","volume":"270","author":"G \u00d6z","year":"2014","journal-title":"Radiology"},{"key":"pone.0252883.ref042","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.neurobiolaging.2017.04.024","article-title":"White-matter integrity on DTI and the pathologic staging of Alzheimer\u2019s disease","volume":"56","author":"K Kantarci","year":"2017","journal-title":"Neurobiol Aging"},{"issue":"6","key":"pone.0252883.ref043","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1088\/1361-6560\/aa5dbe","article-title":"DTI measurements for Alzheimer\u2019s classification","volume":"62","author":"T Maggipinto","year":"2017","journal-title":"Phys Med Biol"},{"issue":"3","key":"pone.0252883.ref044","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s12021-016-9299-4","article-title":"DPABI: Data Processing & Analysis for (Resting-State) Brain Imaging","volume":"14","author":"CG Yan","year":"2016","journal-title":"Neuroinformatics"},{"issue":"3","key":"pone.0252883.ref045","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1089\/brain.2012.0073","article-title":"Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks","volume":"2","author":"S Whitfield-Gabrieli","year":"2012","journal-title":"Brain Connect"},{"issue":"1","key":"pone.0252883.ref046","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13195-019-0575-z","article-title":"Changes in gray matter volume and functional connectivity in dementia with Lewy bodies compared to Alzheimer\u2019s disease and normal aging: implications for fluctuations","volume":"12","author":"E 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