Acta Neuropathologica

, Volume 113, Issue 1, pp 1–12 | Cite as

Assessing the cognitive impact of Alzheimer disease pathology and vascular burden in the aging brain: the Geneva experience

  • Panteleimon Giannakopoulos
  • Gabriel Gold
  • Enikö Kövari
  • Armin von Gunten
  • Anouk Imhof
  • Constantin Bouras
  • Patrick R. Hof
Review Article

Abstract

The progressive development of Alzheimer disease (AD)-related lesions, such as neurofibrillary tangles (NFT), amyloid deposits and synaptic loss, and the occurrence of microvascular and small macrovascular pathology within the cerebral cortex are conspicuous neuropathologic features of brain aging. Recent neuropathologic studies strongly suggested that the clinical diagnosis of dementia depends more on the severity and topography of pathological changes than on the presence of a qualitative marker. However, several methodological problems, such as selection biases, case–control design, density-based measures and masking effects, of concomitant pathologies persisted. In recent years, we performed several clinicopathologic studies using stereological counting of AD lesions. In order to define the cognitive impact of lacunes and microvascular lesions, we also analyzed pure vascular cases without substantial AD pathology. Our data revealed that total NFT numbers in the CA1 field, cortical microinfarcts and subcortical gray matter lacunes were the stronger determinants of dementia. In contrast, the contribution of periventricular and subcortical white matter demyelinations had a modest cognitive effect even in rare cases with isolated microvascular pathology. Importantly, in cases with pure AD pathology, more than 50% of Clinical Dementia Rating scale variability was not explained by NFT, amyloid deposits and neuronal loss in the hippocampal formation. In cases with microvascular pathology or lacunes, this percentage was even lower. The present review summarizes our data in this field and discusses their relevance within the theoretical framework of the functional neuropathology of brain aging and with particular reference to the current efforts to develop standardized neuropathological criteria for mixed dementia.

Keywords

Clinicopathological correlations Dementia Neurofibrillary tangles Neuropathology 

References

  1. 1.
    Arriagada PV, Marzloff K, Hyman BT (1992) Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 42:1681–1688PubMedGoogle Scholar
  2. 2.
    Ball MJ (1977) Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol (Berl) 37:111–118Google Scholar
  3. 3.
    Bancher C, Jellinger K, Lassmann H, Fischer P, Leblhuber F (1996) Correlations between mental state and quantitative neuropathology in the Vienna Longitudinal Study on Dementia. Eur Arch Psychiatry Clin Neurosci 246:137–146PubMedGoogle Scholar
  4. 4.
    Barcikowska M, Wisniewski HM, Bancher C, Grundke-Iqbal I (1989) About the presence of paired helical filaments in dystrophic neurites participating in the plaque formation. Acta Neuropathol (Berl) 78:225–231Google Scholar
  5. 5.
    Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, Wilson RS (2006) Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 66:1837–1844PubMedGoogle Scholar
  6. 6.
    Berg L, McKeel DW Jr, Miller JP, Storandt M, Rubin EH, Morris JC, Baty J, Coats M, Norton J, Goate AM, Price JL, Gearing M, Mirra SS, Saunders AM (1998) Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 55:326–335PubMedGoogle Scholar
  7. 7.
    Bierer LM, Hof PR, Purohit KP, Carlin L, Schmeidler J, Davis KL, Perl DP (1995) Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer’s disease. Arch Neurol 52:81–88PubMedGoogle Scholar
  8. 8.
    Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH (1994) Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital. Cereb Cortex 4:138–150PubMedGoogle Scholar
  9. 9.
    Bouras C, Hof PR, Morrison JH (1993) Neurofibrillary tangle densities in the hippocampal formation in a non-demented population define subgroups of patients with differential early pathologic changes. Neurosci Lett 153:131–135PubMedGoogle Scholar
  10. 10.
    Bouras C, Kövari E, Herrmann FR, Rivara CB, Bailey TL, von Gunten A, Hof PR, Giannakopoulos P (2006) Stereologic analysis of microvascular morphology in the elderly: Alzheimer disease pathology and cognitive status. J Neuropathol Exp Neurol 65:235–244PubMedGoogle Scholar
  11. 11.
    Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol (Berl) 112:388–403Google Scholar
  12. 12.
    Braak H, Braak E (1997) Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging 18:S85–S88PubMedGoogle Scholar
  13. 13.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 82:239–259Google Scholar
  14. 14.
    Braak H, Braak E (1997) Staging of Alzheimer-related cortical destruction. Int Psychogeriatr 9(Suppl 1):257–261 (discussion 269–272)Google Scholar
  15. 15.
    Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278 (discussion 278–284)Google Scholar
  16. 16.
    Braak H, Braak E, Bohl J (1993) Staging of Alzheimer-related cortical destruction. Eur Neurol 33:403–408PubMedGoogle Scholar
  17. 17.
    Bracco L, Campani D, Baratti E, Lippi A, Inzitari D, Pracucci G, Amaducci L (1993) Relation between MRI features and dementia in cerebrovascular disease patients with leukoaraiosis: a longitudinal study. J Neurol Sci 120:131–136PubMedGoogle Scholar
  18. 18.
    Bracco L, Piccini C, Moretti M, Mascalchi M, Sforza A, Nacmias B, Cellini E, Bagnoli S, Sorbi S (2005) Alzheimer’s disease: role of size and location of white matter changes in determining cognitive deficits. Dement Geriatr Cogn Disord 20:358–366PubMedGoogle Scholar
  19. 19.
    Bussière T, Friend PD, Sadeghi N, Wicinski B, Lin GI, Bouras C, Giannakopoulos P, Robakis NK, Morrison JH, Perl DP, Hof PR (2002) Stereologic assessment of the total cortical volume occupied by amyloid deposits and its relationship with cognitive status in aging and Alzheimer’s disease. Neuroscience 112:75–91PubMedGoogle Scholar
  20. 20.
    Callahan LM, Vaules WA, Coleman PD (2002) Progressive reduction of synaptophysin message in single neurons in Alzheimer disease. J Neuropathol Exp Neurol 61:384–395PubMedGoogle Scholar
  21. 21.
    Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, Masdeu J, Kawas C, Aronson M, Wolfson L (1988) Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer’s disease. Neurology 38:1682–1687PubMedGoogle Scholar
  22. 22.
    Cummings BJ, Pike CJ, Shankle R, Cotman CW (1996) Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer’s disease. Neurobiol Aging 17:921–933PubMedGoogle Scholar
  23. 23.
    Cummings JL (1993) Frontal-subcortical circuits and human behavior. Arch Neurol 50:873–880PubMedGoogle Scholar
  24. 24.
    Davis DG, Schmitt FA, Wekstein DR, Markesbery WR (1999) Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 58:376–388PubMedGoogle Scholar
  25. 25.
    Del Ser T, Bermejo F, Portera A, Arredondo JM, Bouras C, Constantinidis J (1990) Vascular dementia. A clinicopathological study. J Neurol Sci 96:1–17PubMedGoogle Scholar
  26. 26.
    Del Ser T, Hachinski V, Merskey H, Munoz DG (2005) Alzheimer’s disease with and without cerebral infarcts. J Neurol Sci 231:3–11PubMedGoogle Scholar
  27. 27.
    Delaere P, He Y, Fayet G, Duyckaerts C, Hauw JJ (1993) Beta A4 deposits are constant in the brain of the oldest old: an immunocytochemical study of 20 French centenarians. Neurobiol Aging 14:191–194PubMedGoogle Scholar
  28. 28.
    Derouesne C, Poirier J (1999) [Cerebral lacunae: still under debate]. Rev Neurol (Paris) 155:823–831Google Scholar
  29. 29.
    Desmond DW, Moroney JT, Sano M, Stern Y (2002) Incidence of dementia after ischemic stroke: results of a longitudinal study. Stroke 33:2254–2260PubMedGoogle Scholar
  30. 30.
    Dickson DW (1997) Neuropathological diagnosis of Alzheimer’s disease: a perspective from longitudinal clinicopathological studies. Neurobiol Aging 18:S21–S26PubMedGoogle Scholar
  31. 31.
    Dickson DW, Crystal HA, Bevona C, Honer W, Vincent I, Davies P (1995) Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging 16:285–298 (discussion 298–304)Google Scholar
  32. 32.
    Dickson DW, Crystal HA, Mattiace LA, Masur DM, Blau AD, Davies P, Yen SH, Aronson MK (1992) Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging 13:179–189PubMedGoogle Scholar
  33. 33.
    Duyckaerts C, Bennecib M, Grignon Y, Uchihara T, He Y, Piette F, Hauw JJ (1997) Modeling the relation between neurofibrillary tangles and intellectual status. Neurobiol Aging 18:267–273PubMedGoogle Scholar
  34. 34.
    Erkinjuntti T, Haltia M, Palo J, Sulkava R, Paetau A (1988) Accuracy of the clinical diagnosis of vascular dementia: a prospective clinical and post-mortem neuropathological study. J Neurol Neurosurg Psychiatry 51:1037–1044PubMedCrossRefGoogle Scholar
  35. 35.
    Esiri MM (2000) Which vascular lesions are of importance in vascular dementia? Ann N Y Acad Sci 903:239–243PubMedGoogle Scholar
  36. 36.
    Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD (1999) Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease [letter]. Lancet 354:919–920PubMedGoogle Scholar
  37. 37.
    Esiri MM, Wilcock GK, Morris JH (1997) Neuropathological assessment of the lesions of significance in vascular dementia. J Neurol Neurosurg Psychiatry 63:749–753PubMedGoogle Scholar
  38. 38.
    Farkas E, de Vos RA, Donka G, Jansen Steur EN, Mihaly A, Luiten PG (2006) Age-related microvascular degeneration in the human cerebral periventricular white matter. Acta Neuropathol (Berl) 111:150–157Google Scholar
  39. 39.
    Farkas E, Luiten PG (2001) Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol 64:575–611PubMedGoogle Scholar
  40. 40.
    Fernando MS, Ince PG (2004) Vascular pathologies and cognition in a population-based cohort of elderly people. J Neurol Sci 226:13–17PubMedGoogle Scholar
  41. 41.
    Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198PubMedGoogle Scholar
  42. 42.
    Garde E, Mortensen EL, Krabbe K, Rostrup E, Larsson HB (2000) Relation between age-related decline in intelligence and cerebral white-matter hyperintensities in healthy octogenarians: a longitudinal study. Lancet 356:628–634PubMedGoogle Scholar
  43. 43.
    Giannakopoulos P, Herrmann FR, Bussière T, Bouras C, Kövari E, Perl DP, Morrison JH, Gold G, Hof PR (2003) Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 60:1495–1500PubMedGoogle Scholar
  44. 44.
    Giannakopoulos P, Hof PR, Giannakopoulos AS, Buée-Scherrer V, Surini M, Delacourte A, Bouras C (1994) Dementia in the oldest–old: quantitative analysis of 12 cases from a psychiatric hospital. Dementia 5:348–356PubMedGoogle Scholar
  45. 45.
    Giannakopoulos P, Hof PR, Giannakopoulos AS, Herrmann FR, Michel JP, Bouras C (1995) Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of very old patients. Arch Neurol 52:1150–1159PubMedGoogle Scholar
  46. 46.
    Giannakopoulos P, Hof PR, Kövari E, Vallet PG, Bouras C (1996) Distinct patterns of neuronal loss and Alzheimer’s disease lesion distribution in elderly individuals older than 90 years. J Neuropathol Exp Neurol 55:1210–1220PubMedGoogle Scholar
  47. 47.
    Gold G, Kövari E, Corte G, Herrmann FR, Canuto A, Bussière T, Hof PR, Bouras C, Giannakopoulos P (2001) Clinical validity of a beta-protein deposition staging in brain aging and Alzheimer disease. J Neuropathol Exp Neurol 60:946–952PubMedGoogle Scholar
  48. 48.
    Gold G, Kövari E, Herrmann FR, Canuto A, Hof PR, Michel JP, Bouras C, Giannakopoulos P (2005) Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia. Stroke 36:1184–1188PubMedGoogle Scholar
  49. 49.
    Gómez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, Parisi JE, Hyman BT (1997) Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 41:17–24PubMedGoogle Scholar
  50. 50.
    Gómez-Isla T, Price JL, McKeel Jr DW, Morris JC, Growdon JH, Hyman BT (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16:4491–4500PubMedGoogle Scholar
  51. 51.
    Green MS, Kaye JA, Ball MJ (2000) The Oregon brain aging study: neuropathology accompanying healthy aging in the oldest old. Neurology 54:105–113PubMedGoogle Scholar
  52. 52.
    Grober E, Dickson D, Sliwinski MJ, Buschke H, Katz M, Crystal H, Lipton RB (1999) Memory and mental status correlates of modified Braak staging. Neurobiol Aging 20:573–579PubMedGoogle Scholar
  53. 53.
    Harding AJ, Halliday GM, Kril JJ (1998) Variation in hippocampal neuron number with age and brain volume. Cereb Cortex 8:710–718PubMedGoogle Scholar
  54. 54.
    Hof PR, Bierer LM, Perl DP, Delacourte A, Buée L, Bouras C, Morrison JH (1992) Evidence for early vulnerability of the medial and inferior aspects of the temporal lobe in an 82 year old patient with preclinical signs of dementia: regional and laminar distribution of neurofibrillary tangles and senile plaques. Arch Neurol 49:946–953PubMedGoogle Scholar
  55. 55.
    Hof PR, Bussière T, Gold G, Kövari E, Giannakopoulos P, Bouras C, Perl DP, Morrison JH (2003) Stereologic evidence for persistence of viable neurons in layer II of the entorhinal cortex and the CA1 field in Alzheimer disease. J Neuropathol Exp Neurol 62:55–67PubMedGoogle Scholar
  56. 56.
    Hubbard BM, Fenton GW, Anderson JM (1990) A quantitative histological study of early clinical and preclinical Alzheimer’s disease. Neuropathol Appl Neurobiol 16:111–121PubMedGoogle Scholar
  57. 57.
    Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140:566–572PubMedCrossRefGoogle Scholar
  58. 58.
    Hulette CM, Welsh-Bohmer KA, Murray MG, Saunders AM, Mash DC, McIntyre LM (1998) Neuropathological and neuropsychological changes in “normal” aging: evidence for preclinical Alzheimer disease in cognitively normal individuals. J Neuropathol Exp Neurol 57:1168–1174PubMedGoogle Scholar
  59. 59.
    Itoh Y, Yamada M, Suematsu N, Matsushita M, Otomo E (1998) An immunohistochemical study of centenarian brains: a comparison. J Neurol Sci 157:73–81PubMedGoogle Scholar
  60. 60.
    Jellinger KA (2005) Understanding the pathology of vascular cognitive impairment. J Neurol Sci 229–230:57–63PubMedGoogle Scholar
  61. 61.
    Jellinger KA, Attems J (2003) Incidence of cerebrovascular lesions in Alzheimer’s disease: a postmortem study. Acta Neuropathol (Berl) 105:14–17Google Scholar
  62. 62.
    Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, Renbing X, Peck A (1988) Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol 23:138–144PubMedGoogle Scholar
  63. 63.
    Knopman DS, Parisi JE, Salviati A, Floriach-Robert M, Boeve BF, Ivnik RJ, Smith GE, Dickson DW, Johnson KA, Petersen LE, McDonald WC, Braak H, Petersen RC (2003) Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 62:1087–1095PubMedGoogle Scholar
  64. 64.
    Kordower JH, Chu Y, Stebbins GT, DeKosky ST, Cochran EJ, Bennett D, Mufson EJ (2001) Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol 49:202–213PubMedGoogle Scholar
  65. 65.
    Kövari E, Gold G, Herrmann FR, Canuto A, Hof PR, Michel JP, Bouras C, Giannakopoulos P (2004) Cortical microinfarcts and demyelination significantly affect cognition in brain aging. Stroke 35:410–414PubMedGoogle Scholar
  66. 66.
    Kril JJ, Patel S, Harding AJ, Halliday GM (2002) Neuron loss from the hippocampus of Alzheimer’s disease exceeds extracellular neurofibrillary tangle formation. Acta Neuropathol (Berl) 103:370–376Google Scholar
  67. 67.
    Lee JH, Olichney JM, Hansen LA, Hofstetter CR, Thal LJ (2000) Small concomitant vascular lesions do not influence rates of cognitive decline in patients with alzheimer disease. Arch Neurol 57:1474–1479PubMedGoogle Scholar
  68. 68.
    Lewis DA, Campbell MJ, Terry RD, Morrison JH (1987) Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer’s disease: a quantitative study of visual and auditory cortices. J Neurosci 7:1799–1808PubMedGoogle Scholar
  69. 69.
    Leys D, Scheltens P, Vermersch P, Pruvo JP (1995) [Morphological imaging in the diagnosis of dementia. II. Vascular dementia]. Rev Med Interne 16:195–200PubMedCrossRefGoogle Scholar
  70. 70.
    Longstreth WT Jr, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, Enright PL, O’Leary D, Fried L (1996) Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. Stroke 27:1274–1282PubMedGoogle Scholar
  71. 71.
    Mackowiak-Cordoliani MA, Bombois S, Memin A, Henon H, Pasquier F (2005) Poststroke dementia in the elderly. Drugs Aging 22:483–493PubMedGoogle Scholar
  72. 72.
    Masliah E, Mallory M, Hansen L, DeTeresa R, Terry RD (1993) Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43:192–197PubMedGoogle Scholar
  73. 73.
    Morris JC, Storandt M, McKeel DW Jr, Rubin EH, Price JL, Grant EA, Berg L (1996) Cerebral amyloid deposition and diffuse plaques in “normal” aging: evidence for presymptomatic and very mild Alzheimer’s disease. Neurology 46:707–719PubMedGoogle Scholar
  74. 74.
    Mountjoy CQ, Roth M, Evans NJ, Evans HM (1983) Cortical neuronal counts in normal elderly controls and demented patients. Neurobiol Aging 4:1–11PubMedGoogle Scholar
  75. 75.
    Nagy Z, Esiri MM, Jobst KA, Morris JH, King EM, McDonald B, Joachim C, Litchfield S, Barnetson L, Smith AD (1997) The effects of additional pathology on the cognitive deficit in Alzheimer disease. J Neuropathol Exp Neurol 56:165–170PubMedGoogle Scholar
  76. 76.
    Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum JD (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283:1571–1577PubMedGoogle Scholar
  77. 77.
    Neuropathology Group of the Medical Research Council Cognitive Function, Ageing Study (MRC CFAS) (2001) Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet 357:169–175Google Scholar
  78. 78.
    Pearson RC, Esiri MM, Hiorns RW, Wilcock GK, Powell TP (1985) Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc Natl Acad Sci USA 82:4531–4534PubMedGoogle Scholar
  79. 79.
    Price JL, Davis PB, Morris JC, White DL (1991) The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging 12:295–312PubMedGoogle Scholar
  80. 80.
    Price JL, Ko AI, Wade MJ, Tsou SK, McKeel DW, Morris JC (2001) Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol 58:1395–1402PubMedGoogle Scholar
  81. 81.
    Price JL, Morris JC (1999) Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 45:358–368PubMedGoogle Scholar
  82. 82.
    Reed BR, Eberling JL, Mungas D, Weiner M, Jagust WJ (2001) Frontal lobe hypometabolism predicts cognitive decline in patients with lacunar infarcts. Arch Neurol 58:493–497PubMedGoogle Scholar
  83. 83.
    Riley KP, Snowdon DA, Desrosiers MF, Markesbery WR (2005) Early life linguistic ability, late life cognitive function, and neuropathology: findings from the Nun Study. Neurobiol Aging 26:341–347PubMedGoogle Scholar
  84. 84.
    Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC (2002) Subcortical ischaemic vascular dementia. Lancet Neurol 1:426–436PubMedGoogle Scholar
  85. 85.
    Samuel W, Masliah E, Hill LR, Butters N, Terry R (1994) Hippocampal connectivity and Alzheimer’s dementia: effects of synapse loss and tangle frequency in a two-component model. Neurology 44:2081–2088PubMedGoogle Scholar
  86. 86.
    Schmidt R, Schmidt H, Kapeller P, Lechner A, Fazekas F (2002) Evolution of white matter lesions. Cerebrovasc Dis 13:16–20PubMedGoogle Scholar
  87. 87.
    Schroeter ML, Bucheler MM, Preul C, Scheid R, Schmiedel O, Guthke T, von Cramon DY (2005) Spontaneous slow hemodynamic oscillations are impaired in cerebral microangiopathy. J Cereb Blood Flow Metab 25:1675–1684PubMedGoogle Scholar
  88. 88.
    Simic G, Kostovic I, Winblad B, Bogdanovic N (1997) Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease. J Comp Neurol 379:482–494PubMedGoogle Scholar
  89. 89.
    Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR (1997) Brain infarction and the clinical expression of Alzheimer disease. The nun study. JAMA 277:813–817PubMedGoogle Scholar
  90. 90.
    Tatemichi TK, Paik M, Bagiella E, Desmond DW, Stern Y, Sano M, Hauser WA, Mayeux R (1994) Risk of dementia after stroke in a hospitalized cohort: results of a longitudinal study. Neurology 44:1885–1891PubMedGoogle Scholar
  91. 91.
    Terry RD, Masliah E, Hansen LA (1994) Structural basis of the cognitive alterations in Alzheimer’s disease. In: Terry RD, Katzman R, Bick KL (eds) Alzheimer’s disease. Raven Press, New York, pp 179–196Google Scholar
  92. 92.
    Thal DR, Rüb U, Schultz C, Sassin I, Ghebremedhin E, Del Tredici K, Braak E, Braak H (2000) Sequence of Abeta-protein deposition in the human medial temporal lobe. J Neuropathol Exp Neurol 59:733–748PubMedGoogle Scholar
  93. 93.
    Tomlinson BE, Blessed G, Roth M (1968) Observations on the brains of non-demented old people. J Neurol Sci 7:331–356PubMedGoogle Scholar
  94. 94.
    Udaka F, Sawada H, Kameyama M (2002) White matter lesions and dementia: MRI-pathological correlation. Ann N Y Acad Sci 977:411–415PubMedCrossRefGoogle Scholar
  95. 95.
    Ulrich J (1985) Alzheimer changes in nondemented patients younger than sixty-five: possible early stages of Alzheimer’s disease and senile dementia of Alzheimer type. Ann Neurol 17:273–277PubMedGoogle Scholar
  96. 96.
    Uspenskaia O, Liebetrau M, Herms J, Danek A, Hamann GF (2004) Aging is associated with increased collagen type IV accumulation in the basal lamina of human cerebral microvessels. BMC Neurosci 5:37PubMedGoogle Scholar
  97. 97.
    van der Flier WM, van Straaten EC, Barkhof F, Verdelho A, Madureira S, Pantoni L, Inzitari D, Erkinjuntti T, Crisby M, Waldemar G, Schmidt R, Fazekas F, Scheltens P (2005) Small vessel disease and general cognitive function in nondisabled elderly: the LADIS study. Stroke 36:2116–2120PubMedGoogle Scholar
  98. 98.
    Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM (2003) Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 348:1215–1222PubMedGoogle Scholar
  99. 99.
    Vinters HV, Ellis WG, Zarow C, Zaias BW, Jagust WJ, Mack WJ, Chui HC (2000) Neuropathologic substrates of ischemic vascular dementia. J Neuropathol Exp Neurol 59:931–945PubMedGoogle Scholar
  100. 100.
    von Gunten A, Kövari E, Bussière T, Rivara CB, Gold G, Bouras C, Hof PR, Giannakopoulos P (2006) Cognitive impact of neuronal pathology in the entorhinal cortex and CA1 field in Alzheimer’s disease. Neurobiol Aging 27:270–277Google Scholar
  101. 101.
    von Gunten A, Kövari E, Rivara CB, Bouras C, Hof PR, Giannakopoulos P (2005) Stereologic analysis of hippocampal Alzheimer’s disease pathology in the oldest–old: evidence for sparing of the entorhinal cortex and CA1 field. Exp Neurol 193:198–206Google Scholar
  102. 102.
    Wen HM, Mok VC, Fan YH, Lam WW, Tang WK, Wong A, Huang RX, Wong KS (2004) Effect of white matter changes on cognitive impairment in patients with lacunar infarcts. Stroke 35:1826–1830PubMedGoogle Scholar
  103. 103.
    West MJ (1993) Regionally specific loss of neurons in the aging human hippocampus. Neurobiol Aging 14:287–293PubMedGoogle Scholar
  104. 104.
    West MJ, Coleman PD, Flood DG, Troncoso JC (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344:769–772PubMedGoogle Scholar
  105. 105.
    West MJ, Gundersen HJ (1990) Unbiased stereological estimation of the number of neurons in the human hippocampus. J Comp Neurol 296:1–22PubMedGoogle Scholar
  106. 106.
    Wilcock GK, Esiri MM (1982) Plaques, tangles and dementia. A quantitative study. J Neurol Sci 56:343–356PubMedGoogle Scholar
  107. 107.
    Wisniewski HM, Silverman W (1997) Diagnostic criteria for the neuropathological assessment of Alzheimer’s disease: current status and major issues. Neurobiol Aging 18:S43–S50PubMedGoogle Scholar
  108. 108.
    Ylikoski A, Erkinjuntti T, Raininko R, Sarna S, Sulkava R, Tilvis R (1995) White matter hyperintensities on MRI in the neurologically nondiseased elderly. Analysis of cohorts of consecutive subjects aged 55 to 85 years living at home. Stroke 26:1171–1177PubMedGoogle Scholar
  109. 109.
    Zekry D, Duyckaerts C, Moulias R, Belmin J, Geoffre C, Herrmann F, Hauw JJ (2002) Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol (Berl) 103:481–487Google Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Panteleimon Giannakopoulos
    • 1
    • 3
  • Gabriel Gold
    • 2
  • Enikö Kövari
    • 1
  • Armin von Gunten
    • 3
  • Anouk Imhof
    • 1
  • Constantin Bouras
    • 1
    • 4
  • Patrick R. Hof
    • 4
    • 5
  1. 1.Division of Geriatric Psychiatry, Department of PsychiatryUniversity of Geneva School of MedicineGenevaSwitzerland
  2. 2.Department of GeriatricsUniversity of Geneva School of MedicineGenevaSwitzerland
  3. 3.Division of Old Age PsychiatryUniversity of Lausanne School of MedicineLausanneSwitzerland
  4. 4.Department of NeuroscienceMount Sinai School of MedicineNew YorkUSA
  5. 5.Department of Geriatrics and Adult DevelopmentMount Sinai School of MedicineNew YorkUSA

Personalised recommendations