Advertisement
Research Article| Volume 283, ISSUE 1-2, P2-8, August 15, 2009

Improved detection of incipient vascular changes by a biotechnological platform combining post mortem MRI in situ with neuropathology

  • Lea Tenenholz Grinberg
    Correspondence
    Corresponding author. Morphological Brain Research Unit of the Psychiatric Clinic, Oberduerrbacher Str. 6, D-97080, Wuerzburg, Germany. Tel.: +49 931 201 76551.
    Affiliations
    Aging Brain Project, Department of Pathology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1353-01246903, Sao Paulo, SP, Brazil

    Instituto Israelita de Ensino e Pesquisa Albert Einstein, Av. Albert Einstein, 627-05651901, Sao Paulo, SP, Brazil

    Morphological Brain Research Unit, University of Wuerzburg, Josef-Schneider-Strasse 2, 97080,Wuerzburg, Germany
    Search for articles by this author
  • Edson Amaro Junior
    Affiliations
    Department of Radiology, University of Sao Paulo Medical School, Av. Dr. Enéas de Carvalho Aguiar, 255-05403.001, Sao Paulo, SP, Brazil
    Search for articles by this author
  • Alexandre Valotta da Silva
    Affiliations
    Department of Biosciences, Federal University of Sao Paulo, Av. Ana Costa 95 CEP 11060-001, Santos, Brazil
    Search for articles by this author
  • Rafael Emidio da Silva
    Affiliations
    Aging Brain Project, Department of Pathology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1353-01246903, Sao Paulo, SP, Brazil

    Instituto Israelita de Ensino e Pesquisa Albert Einstein, Av. Albert Einstein, 627-05651901, Sao Paulo, SP, Brazil
    Search for articles by this author
  • João Ricardo Sato
    Affiliations
    Center of Mathematics, Computation and Cognition — Federal University of ABC, Santo Andre, SP, Brazil
    Search for articles by this author
  • Denis Dionizio dos Santos
    Affiliations
    Aging Brain Project, Department of Pathology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1353-01246903, Sao Paulo, SP, Brazil
    Search for articles by this author
  • Silmara de Paula Pacheco
    Affiliations
    Aging Brain Project, Department of Pathology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1353-01246903, Sao Paulo, SP, Brazil
    Search for articles by this author
  • Renata Eloah de Lucena Ferretti
    Affiliations
    Aging Brain Project, Department of Pathology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1353-01246903, Sao Paulo, SP, Brazil
    Search for articles by this author
  • Renata Elaine Paraizo Leite
    Affiliations
    Aging Brain Project, Department of Pathology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1353-01246903, Sao Paulo, SP, Brazil
    Search for articles by this author
  • Carlos Augusto Pasqualucci
    Affiliations
    Aging Brain Project, Department of Pathology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1353-01246903, Sao Paulo, SP, Brazil

    Autopsy Service of Sao Paulo City, University of Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar 250-05403-000 Sao Paulo, SP, Brazil

    Department of Pathology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, 01246903, Sao Paulo, SP, Brazil
    Search for articles by this author
  • Stefan J. Teipel
    Affiliations
    Clinical Radiology, Ludwig-Maximilian University, Grosshadern, Marchioninistr. 15-81377,Munich, Germany
    Search for articles by this author
  • Wilhelm H. Flatz
    Affiliations
    Department of Psychiatry and Psychotherapy, University Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany
    Search for articles by this author
  • Brazilian Aging Brain Study Group
    Author Footnotes
    1 Brazilian Aging Brain Study Group, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1351-01246903, Sao Paulo, SP, Brazil.
  • Helmut Heinsen
    Affiliations
    Morphological Brain Research Unit, University of Wuerzburg, Josef-Schneider-Strasse 2, 97080,Wuerzburg, Germany
    Search for articles by this author
  • Author Footnotes
    1 Brazilian Aging Brain Study Group, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1351-01246903, Sao Paulo, SP, Brazil.
Published:March 16, 2009DOI:https://doi.org/10.1016/j.jns.2009.02.327

      Abstract

      The histopathological counterpart of white matter hyperintensities is a matter of debate. Methodological and ethical limitations have prevented this question to be elucidated.
      We want to introduce a protocol applying state-of-the-art methods in order to solve fundamental questions regarding the neuroimaging–neuropathological uncertainties comprising the most common white matter hyperintensities [WMHs] seen in aging. By this protocol, the correlation between signal features in in situ, post mortem MRI-derived methods, including DTI and MTR and quantitative and qualitative histopathology can be investigated. We are mainly interested in determining the precise neuroanatomical substrate of incipient WMHs. A major issue in this protocol is the exact co-registration of small lesion in a tridimensional coordinate system that compensates tissue deformations after histological processing.
      The protocol is based on four principles: post mortem MRI in situ performed in a short post mortem interval, minimal brain deformation during processing, thick serial histological sections and computer-assisted 3D reconstruction of the histological sections.
      This protocol will greatly facilitate a systematic study of the location, pathogenesis, clinical impact, prognosis and prevention of WMHs.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Gold G.
        • Kovari E.
        • Hof P.R.
        • Bouras C.
        • Giannakopoulos P.
        Sorting out the clinical consequences of ischemic lesions in brain aging: a clinicopathological approach.
        J Neurol Sci. 2007; 257: 17-22
        • O'Sullivan M.
        • Jones D.K.
        • Summers P.E.
        • Morris R.G.
        • Williams S.C.R.
        • Markus H.S.
        Evidence for cortical “disconnection” as a mechanism of age-related cognitive decline.
        Neurology. 2001; 57: 632-638
        • Breteler M.M.B.
        • van Swieten J.C.
        • Bots M.L.
        • Claus J.J.
        • Grobbee D.E.
        • van Gijn J.
        • et al.
        Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: the Rotterdam Study.
        Neurology. 1994; 44: 1246-1252
        • Schmidt R.
        • Fazekas F.
        • Offenbacher H.
        • Dusek T.
        • Zach E.
        • Reinhart B.
        • et al.
        Neuropsychologic correlates of MRI white matter hyperintensities: a study of 150 normal volunteers.
        Neurology. 1993; 43: 2490-2494
        • Ylikoski R.
        • Ylikoski A.
        • Erkinjuntti T.
        • Sulkava R.
        • Raininko R.
        • Tilvis R.
        White matter changes in healthy elderly persons correlate with attention and speed of mental processing.
        Arch Neurol. 1993; 50: 818-824
        • van der Flier W.M.
        • van Straaten E.C.
        • Barkhof F.
        • Verdelho A.
        • Madureira S.
        • Pantoni L.
        • et al.
        Small vessel disease and general cognitive function in nondisabled elderly: the LADIS study.
        Stroke. 2005; 36: 2116-2120
        • Longstreth W.T.
        • Manolio T.A.
        • Arnold A.
        • Burke G.L.
        • Bryan N.
        • Jungreis C.A.
        • et al.
        Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people: the cardiovascular health study.
        Stroke. 1996; 27: 1274-1282
        • Schmidt R.
        • Petrovic K.
        • Ropele S.
        • Enzinger C.
        • Fazekas F.
        Progression of leukoaraiosis and cognition.
        Stroke. 2007; 38: 2619-2625
        • Kalaria R.N.
        • Kenny R.A.
        • Ballard C.G.
        • Perry R.
        • Ince P.
        • Polvikoski T.
        Towards defining the neuropathological substrates of vascular dementia.
        J Neurol Sci. 2004; 226: 75-80
        • Munoz D.G.
        Small vessel disease: neuropathology.
        Int Psychogeriatr. 2003; : 67-69
        • Ljindgren A.
        • Roijer A.
        • Rudling O.
        • Norrving B.
        • Larsson E.-M.
        • Eskilsson J.
        • et al.
        Cerebral lesions on magnetic resonance imaging, heart disease, and vascular risk factors in subjects without stroke. A population-based study.
        Stroke. 1994; 25: 929-934
        • Pantoni L.
        • Garcia J.H.
        The significance of cerebral white matter abnormalities 100 years after Binswanger's report. A review.
        Stroke. 1995; 26: 1293-1301
        • Lazarus R.
        • Prettyman R.
        • Cherryman G.
        White matter lesions on magnetic resonance imaging and their relationship with vascular risk factors in memory clinic attenders.
        Int J Geriatr Psychiatry. 2005; 20: 274-279
        • Braffman B.H.
        • Zimmerman R.A.
        • Trojanowski J.Q.
        • Gonatas N.K.
        • Hickey W.F.
        • Schlaepfer W.W.
        • et al.
        pathologic correlation with gross and histopathology. 2. Hyperintense white-matter foci in the elderly.
        AJR. 1988; 151: 559-566
        • Murray A.D.
        • Staff R.T.
        • Shenkin S.D.
        • Deary I.J.
        • Starr J.M.
        • Whalley L.J.
        Brain white matter hyperintensities: relative importance of vascular risk factors in nondemented elderly people.
        Radiology. 2005; 237: 251-257
        • de Leeuw F.E.
        • de Groot J.C.
        • Bots M.L.
        • Witteman J.C.
        • Oudkerk M.
        • Hofman A.
        • et al.
        Carotid atherosclerosis and cerebral white matter lesions in a population based magnetic resonance imaging study.
        J Neurol. 2000; 247: 291-296
        • Sachdev P.
        • Wen W.
        • Chen X.
        • Brodaty H.
        Progression of white matter hyperintensities in elderly individuals over 3 years.
        Neurology. 2007; 68: 214-222
        • Hassan A.
        • Hunt B.J.
        • O'Sullivan M.
        • Parmar K.
        • Bamford J.M.
        • Briley D.
        • et al.
        Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis.
        Brain. 2003; 126: 424-432
        • Dashner R.A.
        • Chakeres D.W.
        • Kangarlu A.
        • Schmalbrock P.
        • Christoforidis G.A.
        • DePhilip R.M.
        MR imaging visualization of the cerebral microvasculature: a comparison of live and post mortem studies at 8 T.
        Am J Neuroradiol. 2003; 24: 1881-1884
        • Fazekas F.
        • Kleinert R.
        • Offenbacher H.
        • Schmidt R.
        • Kleinert G.
        • Payer F.
        • et al.
        Pathologic correlates of incidental MRI white matter signal hyperintensities.
        Neurology. 1993; 43: 1683-1689
        • van Swieten J.C.
        • van den Hout J.H.
        • van Ketel B.A.
        • Hijdra A.
        • Wokke J.H.
        • van Gijn J.
        Periventricular lesions in the white matter on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces.
        Brain. 1991; 114: 761-774
        • Chimowitz M.I.
        • Estes M.L.
        • Furlan A.J.
        • Awad I.A.
        Further observations on the pathology of subcortical lesions identified on magnetic resonance imaging.
        Arch Neurol. 1992; 49: 747-752
        • Inzitari D.
        Age-related white matter changes and cognitive impairment.
        Ann Neurol. 2000; 47: 141-143
        • Pantoni L.
        • Garcia J.H.
        Pathogenesis of leukoaraiosis: a review.
        Stroke. 1997; 28: 652-659
        • Pantoni L.
        • Garcia J.H.
        The significance of cerebral white matter abnormalities 100 years after Binswanger's report. A review.
        Stroke. 1995; 26: 1293-1301
        • Sze G.
        • De Armond S.J.
        • Brant-Zawadzki M.
        • Davis R.L.
        • Norman D.
        • Newton T.H.
        Foci of MRI signal [pseudo lesions] anterior to the frontal horns: histologic correlations of normal finding.
        AJR. 1986; 147: 331-337
        • Awad I.A.
        • Johnson P.C.
        • Spetzler R.F.
        • Hodak J.A.
        Incidental subcortical lesions identified on magnetic resonance in the elderly. II. Post mortem pathological correlations.
        Stroke. 1986; 17: 1090-1097
        • Scheltens P.
        • Barkhof F.
        • Leys D.
        • Wolters E.C.
        • Ravid R.
        • Kamphorst W.
        Histopathologic correlates of white matter changes on MRI in Alzheimer's disease and normal aging.
        Neurology. 1995; 45: 883-888
        • Tomimoto H.
        • Lin J.
        • Ihara M.
        • Ohtani R.
        • Matsuo A.
        • Miki Y.
        Subinsular vascular lesions: an analysis of 119 consecutive autopsied brains.
        Eur J Neurol. 2007; 14: 95-101
        • Scarpelli M.
        • Salvolini U.
        • Diamanti L.
        • Montironi R.
        • Chiaromoni L.
        • Maricotti M.
        MRI and pathological examination of post mortem brains: the problem of white matter high signal areas.
        Neuroradiology. 1994; 36: 393-398
        • Takao M.
        • Koto A.
        • Tanahashi N.
        • Fukuuchi Y.
        • Takagi M.
        • Morinaga S.
        Pathologic findings of silent, small hyperintense foci in the basal ganglia and thalamus on MRI.
        Neurology. 1999; 52: 666-668
        • Munoz D.G.
        • Dickson D.W.
        • Bergeron C.
        • Mackenzie I.R.A.
        • Delacourte A.
        • Zhukareva V.
        The neuropathology and biochemistry of frontotemporal dementia.
        Ann Neurol. 2003; 54: S24-S28
        • Matsusue E.
        • Sugihara S.
        • Fujii S.
        • Ohama E.
        • Kinoshita T.
        • Ogawa T.
        White matter changes in elderly people: MR–pathologic correlations.
        Magn Reson Med Sci. 2006; 5: 99-104
        • Marshall V.G.
        • Bradley W.G.J.
        • Marshall C.E.
        • Bhoopat T.
        • Rhodes R.H.
        Deep white matter infarction: correlation of MR imaging and histopathologic findings.
        Radiology. 1988; 167: 517-522
        • Moody D.M.
        • Thore C.R.
        • Anstrom J.A.
        • Challa V.R.
        • Langefeld C.D.
        • Brown W.R.
        Quantification of afferent vessels shows reduced brain vascular density in subjects with leukoaraiosis.
        Radiology. 2004; 233: 883-890
        • Grinberg L.T.
        • Ferretti R.E.
        • Farfel J.M.
        • Leite R.
        • Pasqualucci C.A.
        • Rosemberg S.
        • et al.
        Brain bank of the Brazilian aging brain study group — a milestone reached and more than 1,600 collected brains.
        Cell Tissue Bank. 2007; 8: 151-162
        • Grinberg L.T.
        • Amaro E.
        • Teipel S.J.
        • Santos D.D.
        • Pasqualucci C.A.
        • Leite R.E.P.
        • et al.
        Assessment of factors that confound MRI and neuropathological diagnosis of human post mortem brain tissue.
        Cell Tissue Bank. 2008; 9: 195-203
        • Heinsen H.
        • Arzberger T.
        • Schmitz C.
        Celloidin mounting (embedding without infiltration) — a new, simple and reliable method for producing serial sections of high thickness through complete human brains and its application to stereological and immunohistochemical investigations.
        J Chem Neuroanat. 2000; 20: 49-59
        • Grinberg L.T.
        • Heinsen H.
        Computer-assisted 3D reconstruction of the human basal forebrain complex.
        Dement Neuropsychol. 2007; 2: 140-146
        • Heinsen H.
        • Arzberger T.
        • Roggendorf W.
        • Mitrovic T.
        3D reconstruction of celloidin-mounted serial sections.
        Acta Neuropathol. 2004; 108: 374
        • Bendersky M.
        • Rugilo C.
        • Kochen S.
        • Schuster G.
        • Sica R.E.P.
        Magnetic resonance imaging identifies cytoarchitectonic subtypes of the normal human cerebral cortex.
        J Neurol Sci. 2003; 211: 75-80
        • Braffman B.H.
        • Zimmerman R.A.
        • Trojanowski J.Q.
        • Gonatas N.K.
        • Hickey W.F.
        • Schlaepfer W.W.
        • et al.
        pathologic correlation with gross and histopathology. 1. Lacunar infarction and Virchow–Robin spaces.
        AJR. 1988; 151: 551-558
        • Pfefferbaum A.
        • Sullivan E.V.
        • Adalsteinsson E.
        • Garrick T.
        • Harper C.
        Post mortem MR imaging of formalin-fixed human brain.
        Neuroimage. 2004; 21: 1585-1595
        • Boyko O.B.
        • Alston S.R.
        • Fuller G.N.
        • Hulette C.M.
        • Johnson G.A.
        • Burger P.C.
        Utility of post mortem magnetic resonance imaging in clinical neuropathology.
        Arch Pathol Lab Med. 1994; 118: 219-225
        • Tovi M.
        • Ericsson A.
        Measurements of T1 and T2 over time in formalin-fixed human whole-brain specimens.
        Acta Radiol. 1992; 33: 400-404
        • D'Arceuil H.
        • de Crespigny A.
        The effects of brain tissue decomposition on diffusion tensor imaging and tractography.
        Neuroimage. 2007; 36: 64-68
        • Kretschmann H.J.
        • Tafesse U.
        • Herrmann A.
        Different volume changes of cerebral cortex and white matter during histological preparation.
        Microsc Acta. 1982; 86: 13-24
        • Amunts K.
        • Schleicher A.
        • Burgel U.
        • Mohlberg H.
        • Uylings H.B.
        • Zilles K.
        Broca's region revisited: cytoarchitecture and intersubject variability.
        J Comp Neurol. 1999; 412: 319-341
        • Axer H.
        • Berks G.
        • Keyserlingk D.G.V.
        Visualization of nerve fiber orientation in gross histological sections of the human brain.
        Microsc Res Tech. 2000; 51: 481-492
        • Teipel S.J.
        • Flatz W.H.
        • Heinsen H.
        • Bokde A.L.
        • Schoenberg S.O.
        • Stockel S.
        • et al.
        Measurement of basal forebrain atrophy in Alzheimer's disease using MRI.
        Brain. 2005; 128: 2626-2644
        • Heinsen H.
        • Hampel H.
        • Teipel S.J.
        Nucleus subputaminalis: neglected part of the basal nucleus of Meynert — response to Boban et al: computer-assisted 3D reconstruction of the nucleus basalis complex, including the nucleus subputaminalis (Ayala's nucleus).
        Brain. 2006; 129: 1-4
        • Kreczmanski P.
        • Schmidt-Kastner R.
        • Heinsen H.
        • Steinbusch H.W.M.
        • Hof P.R.
        • Schmitz C.
        Stereological studies of capillary length density in the frontal cortex of schizophrenics.
        Acta Neuropathol. 2005; 109: 510-518
        • Burgel U.
        • Amunts K.
        • Hoemke L.
        • Mohlberg H.
        • Gilsbach J.M.
        • Zilles K.
        White matter fiber tracts of the human brain: three-dimensional mapping at microscopic resolution, topography and intersubject variability.
        Neuroimage. 2006; 29: 1092-1105
        • Grafton S.T.
        • Sumi S.M.
        • Stimac G.K.
        • Alvord E.C.
        • Shaw C.M.
        • Nochlin D.
        Comparison of post mortem magnetic resonance imaging and neuropathologic findings in the cerebral white matter.
        Arch Neurol. 1991; 48: 293-298
        • Bronge L.
        • Bogdanovic N.
        • Wahlund L.O.
        Post mortem MRI and histopathology of white matter changes in Alzheimer brains. A quantitative, comparative study.
        Dement Geriatr Cogn Disord. 2002; 13: 205-212