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Pre-dementia Memory Impairment is Associated with White Matter Tract Affection

  • Ramune Grambaite (a1) (a2), Ivar Reinvang (a3), Per Selnes (a1) (a4), Anders M. Fjell (a3) (a5), Kristine B. Walhovd (a3) (a5), Vidar Stenset (a1) (a4) (a6) and Tormod Fladby (a1) (a4)...

Mild cognitive impairment (MCI), especially amnestic, often represents pre-dementia Alzheimer’s disease, characterized by medial temporal lobe atrophy, while white matter (WM) alterations are insufficiently described. We analyze both cortical morphometric and WM diffusivity differences in amnestic versus non-amnestic subtypes and ask if memory and WM tract affection are related independently of cortical atrophy. Forty-nine patients from a university-hospital based memory clinic with a score of 3 on the Global Deterioration Scale aged 43–77 years (45% female) were included. Two neuropsychologists have classified cases as amnestic (aMCI), non-amnestic (naMCI), or less advanced (laMCI), not satisfying criteria for aMCI/naMCI. Diffusion tensor imaging (DTI) WM tract and morphometric data of the temporal-parietal memory network were compared among patient subtypes and related to story, word list, and visual memory. WM radial and mean diffusivity (DR and MD), underlying the entorhinal cortex, were higher in aMCI compared with laMCI. WM DR and MD, underlying the entorhinal, parahippocampal, and middle temporal cortex, explained unique variance in word list and story memory, and this was not due to secondary effects of cortical thinning. DTI may thus potentially aid diagnosis in early disease stages. (JINS, 2011, 17, 000–000)

Corresponding author
Correspondence and reprint requests to: Ramune Grambaite, Department of Neurology, Akershus University Hospital, Sykehusveien 25, NO-1478 Lørenskog, Norway. E-mail:
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Andersson, J.L.R., Jenkinson, M., Smith, S. (2007). Non-linear registration, aka Spatial normalisation. FMRIB Technical Report TR07JA2 from
Auer, S., Reisberg, B. (1997). The GDS/FAST staging system. International Psychogeriatrics/IPA, 9(Suppl 1), 167171.
Bickel, H., Mosch, E., Seigerschmidt, E., Siemen, M., Forstl, H. (2006). Prevalence and persistence of mild cognitive impairment among elderly patients in general hospitals. Dementia and Geriatric Cognitive Disorders, 21, 242250.
Bosch, B., Arenaza-Urquijo, E.M., Rami, L., Sala-Llonch, R., Junque, C., Sole-Padulles, C., Bartrés-Faz, D. (2010). Multiple DTI index analysis in normal aging, amnestic MCI and AD. Relationship with neuropsychological performance. Neurobiology of Aging, [Epub ahead of print].
Braak, H., Braak, E. (1996). Evolution of the neuropathology of Alzheimer’s disease. Acta Neurologica Scandinavica. Supplementum, 165, 312.
Buckner, R.L., Wheeler, M.E. (2001). The cognitive neuroscience of remembering. Nature Reviews. Neuroscience, 2, 624634.
Charlton, R.A., Barrick, T.R., McIntyre, D.J., Shen, Y., O’Sullivan, M., Howe, F.A., Markus, H.S. (2006). White matter damage on diffusion tensor imaging correlates with age-related cognitive decline. Neurology, 66, 217222.
Chetelat, G., Desgranges, B., de la Sayette, V., Viader, F., Berkouk, K., Landeau, B., Eustache, F. (2003). Dissociating atrophy and hypometabolism impact on episodic memory in mild cognitive impairment. Brain, 126, 19551967.
Cohen, C.K. (1988). Statistical power analysis for the behavioral sciences. Hillsdale, NJ: Erlbaum.
Concha, L., Livy, D.J., Beaulieu, C., Wheatley, B.M., Gross, D.W. (2010). In vivo diffusion tensor imaging and histopathology of the fimbria-fornix in temporal lobe epilepsy. The Journal of Neuroscience, 30, 9961002.
De Santi, S., de Leon, M.J., Rusinek, H., Convit, A., Tarshish, C.Y., Roche, A., Fowler, J. (2001). Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiology of Aging, 22, 529539.
Delis, D.C., Kaplan, E., Kramer, J.H. (2001). Delis and Kaplan D-KEFS Executive Functions System: Examiner’s manual. San Antonio, TX: The Psychological Corporation.
Desikan, R.S., Ségonne, F., Fischl, B., Quinn, B.T., Dickerson, B.C., Blacker, D., Killiany, R.J. (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage, 31, 968980.
Dubois, B., Feldman, H.H., Jacova, C., Dekosky, S.T., Barberger-Gateau, P., Cummings, J., Scheltens, P. (2007). Research criteria for the diagnosis of Alzheimer’s disease: Revising the NINCDS-ADRDA criteria. Lancet Neurology, 6, 734746.
Edman, A., Mahnfeldt, M., Wallin, A. (2001). Inter-rater reliability of the STEP protocol. Journal of Geriatric Psychiatry and Neurology, 14, 140144.
Fellgiebel, A., Muller, M.J., Wille, P., Dellani, P.R., Scheurich, A., Schmidt, L.G., Stoeter, P. (2005). Color-coded diffusion-tensor-imaging of posterior cingulate fiber tracts in mild cognitive impairment. Neurobiology of Aging, 26, 11931198.
Fischer, P., Jungwirth, S., Zehetmayer, S., Weissgram, S., Hoenigschnabl, S., Gelpi, E., Tragl, K.H. (2007). Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology, 68, 288291.
Fischl, B., Salat, D.H., Busa, E., Albert, M., Dieterich, M., Haselgrove, C., Dale, A.M. (2002). Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain. Neuron, 33, 341355.
Fischl, B., van der Kouwe, A., Destrieux, C., Halgren, E., Segonne, F., Salat, D.H., Dale, A.M. (2004). Automatically parcellating the human cerebral cortex. Cerebral Cortex, 14, 1122.
Fjell, A.M., Amlien, I.K., Westlye, L.T., Stenset, V., Fladby, T., Skinningsrud, A., Walhovd, K.B. (2010). CSF biomarker pathology correlates with a medial temporo-parietal network affected by very mild to moderate Alzheimer’s disease but not a fronto-striatal network affected by healthy aging. Neuroimage, 49, 18201830.
Fjell, A.M., Walhovd, K.B., Amlien, I., Bjornerud, A., Reinvang, I., Gjerstad, L., Fladby, T. (2008). Morphometric changes in the episodic memory network and tau pathologic features correlate with memory performance in patients with mild cognitive impairment. AJNR. American Journal of Neuroradiology, 29, 11831189.
Fjell, A.M., Westlye, L.T., Greve, D.N., Fischl, B., Benner, T., van der Kouwe, A.J., Walhovd, K.B. (2008). The relationship between diffusion tensor imaging and volumetry as measures of white matter properties. Neuroimage, 42, 16541668.
Folstein, M.F., Folstein, S.E., McHugh, P.R. (1975). “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189198.
Grambaite, R., Stenset, V., Reinvang, I., Walhovd, K.B., Fjell, A.M., Fladby, T. (2010). White matter diffusivity predicts memory in patients with subjective and mild cognitive impairment and normal CSF total tau levels. Journal of the International Neuropsychological Society, 16, 5869.
Huang, J., Friedland, R.P., Auchus, A.P. (2007). Diffusion tensor imaging of normal-appearing white matter in mild cognitive impairment and early Alzheimer disease: Preliminary evidence of axonal degeneration in the temporal lobe. AJNR. American journal of neuroradiology, 28, 19431948.
Jack, C.R.J., Lowe, V.J., Senjem, M.L., Weigand, S.D., Kemp, B.J., Shiung, M.M., Petersen, R.C. (2008). 11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment. Brain, 131, 665680.
Jack, C.R.J., Petersen, R.C., Xu, Y.C., O’Brien, P.C., Smith, G.E., Ivnik, R.J., Kokmen, E. (1999). Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology, 52, 13971403.
Jack, C.R.J., Shiung, M.M., Gunter, J.L., O’Brien, P.C., Weigand, S.D., Knopman, D.S., Petersen, R.C. (2004). Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD. Neurology, 62, 591600.
Jak, A.J., Bangen, K.J., Wierenga, C.E., Delano-Wood, L., Corey-Bloom, J., Bondi, M.W. (2009). Contributions of neuropsychology and neuroimaging to understanding clinical subtypes of mild cognitive impairment. International Review of Neurobiology, 84, 81103.
Jak, A.J., Bondi, M.W., Delano-Wood, L., Wierenga, C., Corey-Bloom, J., Salmon, D.P., Delis, D.C. (2009). Quantification of five neuropsychological approaches to defining mild cognitive impairment. The American Journal of Geriatric Psychiatry, 17, 368375.
Jenkinson, M., Smith, S. (2001). A global optimisation method for robust affine registration of brain images. Medical Image Analysis, 5, 143156.
Kaplan, E.F., Goodglass, H., Weintraub, S. (1983). The Boston Naming Test (2nd ed.). Philadelphia: Lea & Febiger.
Karas, G., Sluimer, J., Goekoop, R., van der Flier, W., Rombouts, S.A., Vrenken, H., Barkhof, F. (2008). Amnestic mild cognitive impairment: Structural MR imaging findings predictive of conversion to Alzheimer disease. AJNR. American Journal of Neuroradiology, 29, 944949.
Kiernan, R.J., Mueller, J., Langston, J.W., Van Dyke, C. (1987). The Neurobehavioral Cognitive Status Examination: A brief but quantitative approach to cognitive assessment. Annals of Internal Medicine, 107, 481485.
Le Bihan, D., Mangin, J.F., Poupon, C., Clark, C.A., Pappata, S., Molko, N., Chabriat, H. (2001). Diffusion tensor imaging: Concepts and applications. Journal of Magnetic Resonance Imaging, 13, 534546.
Liu, Y., Spulber, G., Lehtimaki, K.K., Kononen, M., Hallikainen, I., Grohn, H., Soininen, H. (2009). Diffusion tensor imaging and Tract-Based Spatial Statistics in Alzheimer’s disease and mild cognitive impairment. Neurobiology of Aging, [Epub ahead of print].
Medina, D., DeToledo-Morrell, L., Urresta, F., Gabrieli, J.D., Moseley, M., Fleischman, D., Stebbins, G.T. (2006). White matter changes in mild cognitive impairment and AD: A diffusion tensor imaging study. Neurobiology of Aging, 27, 663672.
Meyers, J.E., Meyers, K.R. (1995). Rey complex figure test and recognition trial. Lutz, FL: Psychological Assessment Resources.
Morris, J.C. (1993). The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology, 43, 24122414.
Nordlund, A., Rolstad, S., Klang, O., Edman, A., Hansen, S., Wallin, A. (2010). Two year outcome of MCI subtypes and aetiologies in the Goteborg MCI study. Journal of Neurology, Neurosurgery, and Psychiatry, 81, 541546.
Paus, T. (2009). Growth of white matter in the adolescent brain: Myelin or axon? Brain and Cognition, 72, 2635.
Petersen, R.C. (2003). Conceptual overview. In R.C. Petersen (Ed.), Mild cognitive impairment: Aging to Alzheimer’s disease pp. (114). New York: Oxford University Press.
Petersen, R.C. (2004). Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine, 256, 183194.
Petersen, R.C., Parisi, J.E., Dickson, D.W., Johnson, K.A., Knopman, D.S., Boeve, B.F., Kokmen, E. (2006). Neuropathologic features of amnestic mild cognitive impairment. Archives of Neurology, 63, 665672.
Petersen, R.C., Roberts, R.O., Knopman, D.S., Boeve, B.F., Geda, Y.E., Ivnik, R.J., Jack, C.R. Jr. (2009). Mild cognitive impairment: Ten years later. Archives of Neurology, 66, 14471455.
Petersen, R.C., Smith, G.E., Waring, S.C., Ivnik, R.J., Tangalos, E.G., Kokmen, E. (1999). Mild cognitive impairment: Clinical characterization and outcome. Archives of Neurology, 56, 303308.
Pievani, M., Agosta, F., Pagani, E., Canu, E., Sala, S., Absinta, M., Filippi, M. (2010). Assessment of white matter tract damage in mild cognitive impairment and Alzheimer’s disease. Human Brain Mapping, [Epub ahead of print].
Reisberg, B., Ferris, S.H., de Leon, M.J., Crook, T. (1988). Global Deterioration Scale (GDS). Psychopharmacology Bulletin, 24, 661663.
Rogalski, E.J., Murphy, C.M., deToledo-Morrell, L., Shah, R.C., Moseley, M.E., Bammer, R., Stebbins, G.T. (2009). Changes in parahippocampal white matter integrity in amnestic mild cognitive impairment: A diffusion tensor imaging study. Behavioural Neurology, 21, 5161.
Rose, S.E., McMahon, K.L., Janke, A.L., O’Dowd, B., de Zubicaray, G., Strudwick, M.W., Chalk, J.B. (2006). Diffusion indices on magnetic resonance imaging and neuropsychological performance in amnestic mild cognitive impairment. Journal of Neurology, Neurosurgery, and Psychiatry, 77, 11221128.
Rountree, S.D., Waring, S.C., Chan, W.C., Lupo, P.J., Darby, E.J., Doody, R.S. (2007). Importance of subtle amnestic and nonamnestic deficits in mild cognitive impairment: Prognosis and conversion to dementia. Dementia and Geriatric Cognitive Disorders, 24, 476482.
Royall, D.R., Mahurin, R.K., Gray, K.F. (1992). Bedside assessment of executive cognitive impairment: The executive interview. Journal of the American Geriatrics Society, 40, 12211226.
Rueckert, D., Sonoda, L.I., Hayes, C., Hill, D.L., Leach, M.O., Hawkes, D.J. (1999). Nonrigid registration using free-form deformations: Application to breast MR images. IEEE Transactions on Medical Imaging, 18, 712721.
Salat, D.H., Tuch, D.S., van der Kouwe, A.J., Greve, D.N., Pappu, V., Lee, S.Y., Rosas, H.D. (2010). White matter pathology isolates the hippocampal formation in Alzheimer’s disease. Neurobiology of Aging, 31, 244256.
Schmidt, M. (1996). Rey auditory and verbal learning test. A handbook. Los Angeles, CA: Western Psychological Services.
Schneider, J.A., Arvanitakis, Z., Leurgans, S.E., Bennett, D.A. (2009). The neuropathology of probable Alzheimer disease and mild cognitive impairment. Annals of Neurology, 66, 200208.
Smith, S.M. (2002). Fast robust automated brain extraction. Human Brain Mapping, 17, 143155.
Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E., Behrens, T.E. (2006). Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data. Neuroimage, 31, 14871505.
Smith, S.M., Jenkinson, M., Woolrich, M.W., Beckmann, C.F., Behrens, T.E., Johansen-Berg, H., Matthews, P.M. (2004). Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage, 23(Suppl 1), S208S219.
Snowdon, D.A., Greiner, L.H., Mortimer, J.A., Riley, K.P., Greiner, P.A., Markesbery, W.R. (1997). Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA, 277, 813817.
Song, S.K., Sun, S.W., Ju, W.K., Lin, S.J., Cross, A.H., Neufeld, A.H. (2003). Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage, 20, 17141722.
Song, S.K., Yoshino, J., Le, T.Q., Lin, S.J., Sun, S.W., Cross, A.H., Armstrong, R.C. (2005). Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage, 26, 132140.
Spreen, O., Strauss, E.A. (1998). A compendium of neuropsychological tests, second edition: Administration, norms and commentary. New York: Oxford University Press.
Stebbins, G.T., Murphy, C.M. (2009). Diffusion tensor imaging in Alzheimer’s disease and mild cognitive impairment. Behavioural Neurology, 21, 3949.
Stenset, V., Bjornerud, A., Fjell, A.M., Walhovd, K.B., Hofoss, D., Due-Tonnessen, P., Fladby, T. (2009). Cingulum fiber diffusivity and CSF T-tau in patients with subjective and mild cognitive impairment. Neurobiology of Aging, [Epub ahead of print].
Stenset, V., Grambaite, R., Reinvang, I., Hessen, E., Cappelen, T., Bjornerud, A., Fladby, T. (2007). Diaschisis after thalamic stroke: A comparison of metabolic and structural changes in a patient with amnesic syndrome. Acta Neurologica Scandinavica. Supplementum, 187, 6871.
Stenset, V., Hofoss, D., Johnsen, L., Skinningsrud, A., Berstad, A.E., Negaard, A., Fladby, T. (2008). White matter lesion severity is associated with reduced cognitive performances in patients with normal CSF Abeta42 levels. Acta Neurologica Scandinavica, 118, 373378.
Stenset, V., Johnsen, L., Kocot, D., Negaard, A., Skinningsrud, A., Gulbrandsen, P., Fladby, T. (2006). Associations between white matter lesions, cerebrovascular risk factors, and low CSF Abeta42. Neurology, 67, 830833.
Wagner, A.D., Shannon, B.J., Kahn, I., Buckner, R.L. (2005). Parietal lobe contributions to episodic memory retrieval. Trends in Cognitive Sciences, 9, 445453.
Walhovd, K.B., Fjell, A.M., Amlien, I., Grambaite, R., Stenset, V., Bjornerud, A., Fladby, T. (2009). Multimodal imaging in mild cognitive impairment: Metabolism, morphometry and diffusion of the temporal-parietal memory network. Neuroimage, 45, 215223.
Wallin, A., Edman, A., Blennow, K., Gottfries, C.G., Karlsson, I., Regland, B., Sjögren, M. (1996). Stepwise comparative status analysis (STEP): A tool for identification of regional brain syndromes in dementia. Journal of Geriatric Psychiatry and Neurology, 9, 185199.
Wang, L., Goldstein, F.C., Veledar, E., Levey, A.I., Lah, J.J., Meltzer, C.C., Mao, H. (2009). Alterations in cortical thickness and white matter integrity in mild cognitive impairment measured by whole-brain cortical thickness mapping and diffusion tensor imaging. AJNR. American Journal of Neuroradiology, 30, 893899.
Wechsler, D. (1987). Wechsler memory scale-revised. New York: Psychological Corporation.
Wechsler, D. (1999). Wechsler Abbreviated scale of intelligence (WASI). San Antonio, TX: The Psychological Corporation.
Wechsler, D. (2003). Wechsler adult intelligence scale—third edition: manual. San Antonio, TX: The Psychological Corporation.
Whitwell, J.L., Jack, C.R. Jr., Przybelski, S.A., Parisi, J.E., Senjem, M.L., Boeve, B.F., Josephs, K.A. (2009). Temporoparietal atrophy: A marker of AD pathology independent of clinical diagnosis. Neurobiology of Aging, [Epub ahead of print].
Whitwell, J.L., Petersen, R.C., Negash, S., Weigand, S.D., Kantarci, K., Ivnik, R.J., Jack, C.R. Jr. (2007). Patterns of atrophy differ among specific subtypes of mild cognitive impairment. Archives of Neurology, 64, 11301138.
Whitwell, J.L., Przybelski, S.A., Weigand, S.D., Knopman, D.S., Boeve, B.F., Petersen, R.C., Jack, C.R. Jr. (2007). 3D maps from multiple MRI illustrate changing atrophy patterns as subjects progress from mild cognitive impairment to Alzheimer’s disease. Brain, 130, 17771786.
Whitwell, J.L., Shiung, M.M., Przybelski, S.A., Weigand, S.D., Knopman, D.S., Boeve, B.F., Jack, C.R. Jr. (2008). MRI patterns of atrophy associated with progression to AD in amnestic mild cognitive impairment. Neurology, 70, 512520.
Wisdom, N.M., Callahan, J.L., Hawkins, K.A. (2009). The effects of apolipoprotein E on non-impaired cognitive functioning: A meta-analysis. Neurobiology of Aging, [Epub ahead of print].
Woolrich, M.W., Jbabdi, S., Patenaude, B., Chappell, M., Makni, S., Behrens, T., Smith, S.M. (2009). Bayesian analysis of neuroimaging data in FSL. Neuroimage, 45, S173S186.
World Medical Association. Declaration of Helsinki (1991). Law, Medicine & Health Care, 19, 264–265.
Yaffe, K., Petersen, R.C., Lindquist, K., Kramer, J., Miller, B. (2006). Subtype of mild cognitive impairment and progression to dementia and death. Dementia and Geriatric Cognitive Disorders, 22, 312319.
Zhang, Y., Schuff, N., Jahng, G.H., Bayne, W., Mori, S., Schad, L., Weiner, M.W. (2007). Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease. Neurology, 68, 1319.
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