Brain white matter fiber bundles in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) have abnormalities not usually seen in unaffected subjects. Ideal algorithm of the localization-specific properties in white matter integrity might reveal the changes of tissue properties varying along each tract, while previous studies only detected the mean DTI parameters of each fiber. The aim of this study was to investigate whether these abnormalities of nerve fiber tracts are localized to specific regions of the tracts or spread throughout and to analyze which of the examined fiber tracts are involved in the early stages of Alzheimer's disease. In this study, we utilized VBA, TBSS as well as AFQ together to comprehensively investigate the white matter fiber impairment on 25 CE patients, 29 MCI patients and 34 normal control (NC) subjects. Two tract profiles, fractional anisotropy (FA) and mean diffusivity (MD), were extracted to evaluate the white matter integrity at 100 locations along each of 20 fiber tracts and then we validated the results with 27 CE patients, 21 MCI patients and 22 NC from the ADNI cohort. Also, we compare the AFQ with VBA and TBSS in our cohort. In comparison with NC, AD patients showed widespread FA reduction in 25% (5 /20) and MD increase in 65%(13/20) of the examined fiber tracts. The MCI patients showed a regional FA reduction in 5% (1/20) of the examined fiber tracts (right cingulum cingulate) and MD increase in 5%(1/20) of the examined fiber tracts (left arcuate fasciculus). Among these changed tracts, only the right cingulum cingulate showed widespread disruption of myelin or/and fiber axons in MCI and aggravated deterioration in AD, findings supported by FA/MD changes both by the mean and FA changes by point wise methods and TBSS. And the AFQ findings from ADNI cohort showed some similarity with our cohort, especially in the pointwise comparison of MD profiles between AD vs NC. Furthermore, the pattern of white matter abnormalities was different across neuronal fiber tracts; for example, the MCI and AD patients showed similar FA reduction in the middle part of the right cingulum cingulate, and the anterior part were not damaged. However, the left arcuate fasciculus showed MD elevation located at the temporal part of the fibers in the MCI patients and expanding to the temporal and middle part of the fibers in AD patients. So, the AFQ may be an alternative complementary method of VBA and TBSS, and may provide new insights into white matter degeneration in MCI and its association with AD.

Department of Geriatrics Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing China

Department of Neurology Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing China

Department of Neurology Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing China; Department of Radiology Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing China

Department of Radiology Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing China

International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic; Memory Clinic Department of Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Memory Clinic Department of Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

National Laboratory of Pattern Recognition Institute of Automation Chinese Academy of Sciences Beijing China

The Laboratory for Medical Electronics School of Biological Sciences and Medical Engineering Southeast University Nanjing China

See more in PubMed

Acosta-Cabronero J., Williams G.B., Pengas G., Nestor P.J. Absolute diffusivities define the landscape of white matter degeneration in Alzheimer's disease. Brain. 2010;133(2):529–539. PubMed

Alves G.S., Oertel Knochel V., Knochel C., Carvalho A.F., Pantel J., Engelhardt E. Integrating retrogenesis theory to Alzheimer's disease pathology: insight from DTI-TBSS investigation of the white matter microstructural integrity. Biomed. Res. Int. 2015;2015 PubMed PMC

Amlien I.K., Fjell A.M. Diffusion tensor imaging of white matter degeneration in Alzheimer's disease and mild cognitive impairment. Neuroscience. 2014;276:206–215. PubMed

Beaulieu C., Yeatman J.D., Dougherty R.F., Myall N.J., Wandell B.A., Feldman H.M. Tract profiles of white matter properties: automating fiber-tract quantification. PLoS One. 2012;7(11) PubMed PMC

Bosch B., Arenaza-Urquijo E.M., Rami L., Sala-Llonch R., Junqué C., Solé-Padullés C. Multiple DTI index analysis in normal aging, amnestic MCI and AD. Relationship with neuropsychological performance. Neurobiol. Aging. 2012;33(1):61–74. PubMed

Chao L.L., Decarli C., Kriger S., Truran D., Zhang Y., Laxamana J. Associations between white matter hyperintensities and beta amyloid on integrity of projection, association, and limbic fiber tracts measured with diffusion tensor MRI. PLoS One. 2013;8(6) PubMed PMC

Cui Z., Zhong S., Xu P., He Y., Gong G. PANDA: a pipeline toolbox for analyzing brain diffusion images. Front. Hum. Neurosci. 2013;7:42. PubMed PMC

Damoiseaux J.S., Smith S.M., Witter M.P., Sanz-Arigita E.J., Barkhof F., Scheltens P. White matter tract integrity in aging and Alzheimer's disease. Hum. Brain Mapp. 2009;30(4):1051–1059. PubMed PMC

Ebeling U., von Cramon D. Topography of the uncinate fascicle and adjacent temporal fiber tracts. Acta Neurochir. 1992;115(3–4):143–148. PubMed

Ferri C.P., Prince M., Brayne C., Brodaty H., Fratiglioni L., Ganguli M. Global prevalence of dementia: a Delphi consensus study. Lancet. 2006;366(9503):2112–2117. PubMed PMC

Furst A.J., Lal R.A. Amyloid-beta and glucose metabolism in Alzheimer's disease. J. Alzheimers Dis. 2011;26(Suppl. 3):105–116. PubMed

Gold B.T., Powell D.K., Andersen A.H., Smith C.D. Alterations in multiple measures of white matter integrity in normal women at high risk for Alzheimer's disease. NeuroImage. 2010;52(4):1487–1494. PubMed PMC

Hattori T., Yuasa T., Aoki S., Sato R., Sawaura H., Mori T. Altered microstructure in corticospinal tract in idiopathic normal pressure hydrocephalus: comparison with Alzheimer disease and Parkinson disease with dementia. AJNR Am. J. Neuroradiol. 2011;32(9):1681–1687. PubMed PMC

Honea R.A., Vidoni E., Harsha A., Burns J.M. Impact of APOE on the healthy aging brain: a voxel-based MRI and DTI study. J. Alzheimers Dis. 2009;18(3):553–564. PubMed PMC

Jenkinson M., Beckmann C.F., Behrens T.E., Woolrich M.W., Smith S.M. Fsl. Neuroimage. 2012;62(2):782–790. PubMed

Jin Y., Huang C., Daianu M., Zhan L., Dennis E.L., Reid R.I. 3D tract-specific local and global analysis of white matter integrity in Alzheimer's disease. Hum. Brain Mapp. 2017;38(3):1191–1207. PubMed PMC

Le Bihan D. Looking into the functional architecture of the brain with diffusion MRI. Nat. Rev. Neurosci. 2003;4(6):469–480. PubMed

Liu Y., Spulber G., Lehtimäki K.K., Könönen M., Hallikainen I., Gröhn H. Diffusion tensor imaging and tract-based spatial statistics in Alzheimer's disease and mild cognitive impairment. Neurobiol. Aging. 2011;32(9):1558–1571. PubMed

Medina D., Urresta F., Gabrieli J.D., Moseley M., Fleischman D., Bennett D.A. White matter changes in mild cognitive impairment and AD: a diffusion tensor imaging study. Neurobiol. Aging. 2006;27(5):663–672. PubMed

Molinuevo J.L., Ripolles P., Simo M., Llado A., Olives J., Balasa M. White matter changes in preclinical Alzheimer's disease: a magnetic resonance imaging-diffusion tensor imaging study on cognitively normal older people with positive amyloid beta protein 42 levels. Neurobiol. Aging. 2014;35(12):2671–2680. PubMed

Mufson E.J., Mahady L., Waters D., Counts S.E., Perez S.E., DeKosky S.T. Hippocampal plasticity during the progression of Alzheimer's disease. Neuroscience. 2015;309:51–67. PubMed PMC

Nestor P., Fryer T., Ikeda M., Hodges J. Retrosplenial cortex (BA 29/30) hypometabolism in mild cognitive impairment (prodromal Alzheimer's disease) Eur. J. Neurosci. 2003;18(9):2663–2667. PubMed

Nestor P.J., Fryer T.D., Smielewski P., Hodges J.R. Limbic hypometabolism in Alzheimer's disease and mild cognitive impairment. Ann. Neurol. 2003;54(3):343–351. PubMed

Nichols T.E., Holmes A.P. Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum. Brain Mapp. 2002;15(1):1–25. PubMed PMC

Nir T.M., Jahanshad N., Villalon-Reina J.E., Toga A.W., Jack C.R., Weiner M.W. Effectiveness of regional DTI measures in distinguishing Alzheimer's disease, MCI, and normal aging. NeuroImage. 2013;3:180–195. PubMed PMC

Persson J., Lind J., Larsson A., Ingvar M., Cruts M., Van Broeckhoven C. Altered brain white matter integrity in healthy carriers of the APOE ε4 allele a risk for AD? Neurology. 2006;66(7):1029–1033. PubMed

Petersen R.C. Mild cognitive impairment as a diagnostic entity. J. Intern. Med. 2004;256(3):183–194. PubMed

Rabe-Jablonska J., Bienkiewicz W. Anxiety disorders in the fourth edition of the classification of mental disorders prepared by the American Psychiatric Association: diagnostic and statistical manual of mental disorders (DMS-IV — options book) Psychiatr. Pol. 1994;28(2):255–268. PubMed

Smith C.D., Chebrolu H., Andersen A.H., Powell D.A., Lovell M.A., Xiong S. White matter diffusion alterations in normal women at risk of Alzheimer's disease. Neurobiol. Aging. 2010;31(7):1122–1131. PubMed PMC

Stricker N.H., Schweinsburg B., Delano-Wood L., Wierenga C.E., Bangen K.J., Haaland K. Decreased white matter integrity in late-myelinating fiber pathways in Alzheimer's disease supports retrogenesis. Neuroimage. 2009;45(1):10–16. PubMed PMC

Struyfs H., Van Hecke W., Veraart J., Sijbers J., Slaets S., De Belder M. Diffusion Kurtosis Imaging: a possible MRI biomarker for AD diagnosis. J. Alzheimer's Dis. 2015;48(4):937–948. PubMed PMC

Taoka T., Iwasaki S., Sakamoto M., Nakagawa H., Fukusumi A., Myochin K. Diffusion anisotropy and diffusivity of white matter tracts within the temporal stem in Alzheimer disease: evaluation of the “tract of interest” by diffusion tensor tractography. Am. J. Neuroradiol. 2006;27(5):1040–1045. PubMed PMC

J. M. Tsang, B. A. Wandell (2010). "Tract Alignment Errors Decrease Detection Power in Group Analyses of Diffusion Data With TBSS", In: Society for Neuroscience.).

Villain N., Desgranges B., Viader F., de la Sayette V., Mezenge F., Landeau B., Baron J.C., Eustache F., Chetelat G. Relationships between hippocampal atrophy, white matter disruption, and gray matter hypometabolism in Alzheimer's disease. J. Neurosci. 2008;28:6174–6181. PubMed PMC

Wakana S., Caprihan A., Panzenboeck M.M., Fallon J.H., Perry M., Gollub R.L. Reproducibility of quantitative tractography methods applied to cerebral white matter. Neuroimage. 2007;36(3):630–644. PubMed PMC

Wassermann D., Rathi Y., Bouix S., Kubicki M., Kikinis R., Shenton M. Information Processing in Medical Imaging. Springer; 2011. White matter bundle registration and population analysis based on Gaussian processes; pp. 320–332. PubMed PMC

Yasmin H., Nakata Y., Aoki S., Abe O., Sato N., Nemoto K. Diffusion abnormalities of the uncinate fasciculus in Alzheimer's disease: diffusion tensor tract-specific analysis using a new method to measure the core of the tract. Neuroradiology. 2008;50(4):293–299. PubMed

Yeatman J.D., Dougherty R.F., Rykhlevskaia E., Sherbondy A.J., Deutsch G.K., Wandell B.A. Anatomical properties of the arcuate fasciculus predict phonological and reading skills in children. J. Cogn. Neurosci. 2011;23(11):3304–3317. PubMed PMC

Yeatman J.D., Dougherty R.F., Myall N.J., Wandell B.A., Feldman H.M. Tract profiles of white matter properties: automating fiber-tract quantification. PLoS One. 2012;7(11) PubMed PMC

Zarei M., Damoiseaux J.S., Morgese C., Beckmann C.F., Smith S.M., Matthews P.M. Regional white matter integrity differentiates between vascular dementia and Alzheimer disease. Stroke. 2009;40(3):773–779. PubMed