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Neuropsychology Review

Erschienen in:

01.03.2008

Neuropsychological Contributions to the Early Identification of Alzheimer’s Disease

verfasst von: Mark W. Bondi, Amy J. Jak, Lisa Delano-Wood, Mark W. Jacobson, Dean C. Delis, David P. Salmon

Erschienen in: Neuropsychology Review | Ausgabe 1/2008

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Abstract

A wealth of evidence demonstrates that a prodromal period of Alzheimer’s disease (AD) exists for some years prior to the appearance of significant cognitive and functional declines required for the clinical diagnosis. This prodromal period of decline is characterized by a number of different neuropsychological and brain changes, and reliable identification of individuals prior to the development of significant clinical symptoms remains a top priority of research. In this review we provide an overview of those neuropsychological changes. In particular, we examine specific domains of cognition that appear to be negatively affected during the prodromal period of AD, and we review newer analytic strategies designed to examine cognitive asymmetries or discrepancies between higher-order cognitive functions versus fundamental skills. Finally, we provide a critical examination of the clinical concept of Mild Cognitive Impairment and offer suggestions for an increased focus on the impact of cerebrovascular disease (CVD) and CVD risk during the prodromal period of AD.

Albert, M., Blacker, D., Moss, M. B., Tanzi, R., & McArdle, J. J. (2007). Longitudinal change in cognitive performance among individuals with mild cognitive impairment. Neuropsychology, 21, 158–169.PubMedCrossRef

Albert, M. S., Moss, M. B., Tanzi, R., & Jones, K. (2001). Preclinical prediction of AD using neuropsychological tests. Journal of the International Neuropsychological Society, 7, 631–639.PubMedCrossRef

Alladi, S., Arnold, R., Mitchell, J., Nestor, P. J., & Hodges, J. R. (2006). Mild cognitive impairment: applicability of research criteria in a memory clinic and characterization of cognitive profile. Psychological Medicine, 36(4), 1–9.CrossRef

Allen, J. S., Bruss, J., & Damasio, H. (2005). The aging brain: the cognitive reserve hypothesis and hominid evolution. American journal of human biology, 17(6), 673–689.PubMedCrossRef

Alzheimer, A. (1907). Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fuÉr Psychiatrie und psychisch-gerichtliche Medizin, 64, 146–148.

Andrews-Hanna, J. R., Snyder, A. Z., Vincent, J. L., et al. (2007). Disruption of large-scale brain systems in advanced aging. Neuron, 56, 924–935.PubMedCrossRef

Arnaiz, E., Jelic, V., Almkvist, O., et al. (2001). Impaired cerebral glucose metabolism and cognitive functioning predict deterioration in mild cognitive impairment. Neuroreport, 12, 851–855.PubMedCrossRef

Bachman, D. L., Wolf, P. A., Linn, R., Knoefel, J. E., Cobb, J. L., Belanger, A. J., et al. (1992). Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham study. Neurology, 42, 115–119.PubMed

Bachman, D. L., Wolf, P. A., Linn, R., Knoefel, J. E., Cobb, J. L., Belanger, A. J., et al. (1993). Incidence of dementia and probable Alzheimer’s disease in a general population: The Framingham study. Neurology, 43, 515–519.PubMed

Bäckman, L., Small, B. J., & Fratiglioni, L. (2001). Stability of the preclinical episodic memory deficit in Alzheimer’s disease. Brain, 124, 96–102.PubMedCrossRef

Bäckman, L., Jones, S., Berger, A., Laukka, E. J., & Small, B. J. (2005). Cognitive impairment in preclinical Alzheimer’s disease: A meta-analysis. Neuropsychology, 19, 520–531.PubMedCrossRef

Bangen, K. J., Restom, K., Liu, T. T., Jak, A. J., Perthen, J. E., Wierenga, C. E., et al. (2007). Differential age effects on cerebral blood flow and BOLD response to encoding: Associations with cognition and stroke risk. Neurobiology of Aging (in press) DOI 10.1016/j.neurobiolaging.2007.11.012.

Barber, R., Gholkar, A., Scheltens, P., et al. (2000). MRI volumetric correlates of white matter lesions in dementia with Lewy bodies and Alzheimer’s disease. International Journal of Geriatric Psychiatry, 15(10), 911–916.PubMedCrossRef

Barnes, D. E., Yaffe, K., Satariano, W. A., & Tager, I. B. (2003). A longitudinal study of cardiorespiratory fitness and cognitive function in healthy older adults. Journal of the American Geriatrics Society, 51(4), 459–465.PubMedCrossRef

Bennett, D. A., Schneider, J. A., Arvanitakis, Z., Kelly, J. F., Aggarwal, N. T., Shah, R. C., et al. (2006). Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology, 66(12), 1837–1844.PubMedCrossRef

Bickel, H., Mösch, E., Seigerschmidt, E., Siemen, M., & Förstl, H. (2006). Prevalence and persistence of mild cognitive impairment among elderly patients in general hospitals. Dementia and Geriatric Cognitive Disorders, 21(4), 242–250.PubMedCrossRef

Bigler, E. D., Tate, D. F., Miller, M. J., et al. (2002). Dementia, asymmetry of temporal lobe structures, and Apolipoprotein E genotype: Relationships to cerebral atrophy and neuropsychological impairment. Journal of the International Neuropsychological Society, 8, 925–933.PubMedCrossRef

Blessed, G., Tomlinson, B. E., & Roth, M. (1968). The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. British journal of psychiatry, 114, 797–811.PubMedCrossRef

Bondi, M. W., Houston, W. W., Eyler, L. T., & Brown, G. G. (2005). FMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer’s disease. Neurology, 64, 501–508.PubMed

Bondi, M. W., Houston, W. S., Salmon, D. P., Corey-Bloom, J., Katzman, R., Thal, L. J., et al. (2003). Neuropsychological deficits associated with Alzheimer’s disease in the very old: Discrepancies in raw vs. standardized scores. Journal of the International Neuropsychological Society, 9, 783–795.PubMedCrossRef

Bondi, M. W., Monsch, A. U., Galasko, D., Butters, N., Salmon, D. P., & Delis, D. C. (1994). Preclinical cognitive markers of dementia of the Alzheimer type. Neuropsychology, 8, 374–384.CrossRef

Bondi, M. W., Salmon, D. P., Galasko, D., Thomas, R. G., & Thal, L. J. (1999). Neuropsychological function and apolipoprotein E genotype in the preclinical detection of Alzheimer's disease. Psychology & Aging, 14, 295–303.CrossRef

Bondi, M. W., Salmon, D. P., Monsch, A. U., Galasko, D., Butters, N., Klauber, M. R., et al. (1995). Episodic memory changes are associated with the ApoE-e4 allele in nondemented older adults. Neurology, 45, 2203–2206.PubMed

Bookheimer, S. Y., Strojwas, M. H., Cohen, M. S., Saunders, A. M., Pericak-Vance, M. A., Mazziotta, J. C., et al. (2000). Patterns of brain activation in people at risk for Alzheimer’s disease. New England journal of medicine, 343, 450–456.PubMedCrossRef

Borenstein, A. R., Copenhaver, C. I., & Mortimer, J. A. (2006). Early-life risk factors for Alzheimer disease. Alzheimer disease and associated disorders, 20, 63–72.PubMedCrossRef

Bowler, J. (2003). Epidemiology: Identifying vascular cognitive impairment. International psychogeriatrics, 15(Suppl1), 115–122.PubMedCrossRef

Bowler, J. V., & Hachinski, V. (2003). Vascular Cognitive Impairment. Oxford, UK: Oxford University Press.

Braak, H., & Braak, E. (1991). Neuropathological staging of Alzheimer-related changes. Acta Neuropathologica, 82, 239–259.PubMedCrossRef

Braak, H., & Braak, E. (1995). Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging, 16, 15–31.

Braak, H., Braak, E., Bohl, J., & Bratzke, H. (1998). Evolution of Alzheimer’s disease related cortical lesions. Journal of neural transmission, (Supplement), 54, 97–106.

Breteler, M. M. (1998). Epidemiological evidence of a connection between Alzheimer’s disease and vascular dementia. Neurobiol Aging, 19(Suppl 4), S150.

Breteler, M. M. (2000). Vascular involvement in cognitive decline and dementia: epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Annals of the New York Academy of Sciences, 903, 457–465.PubMedCrossRef

Brewer, J. B., & Moghekar, A. (2002). Imaging the medial temporal lobe: exploring new dimensions. Trends in cognitive sciences, 6, 217–223.PubMedCrossRef

Brookmeyer, R., Gray, S., & Kawas, C. (1998). Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. American journal of public health, 88(9), 1337–1342.PubMedCrossRef

Bugiani, O., Constantinidis, J., Ghetti, B., Bouras, C., & Tagliavini, F. (1991). Asymmetrical cerebral atrophy in Alzheimer’s disease. Clinical Neuropathology, 10, 55–60.PubMed

Busse, A., Hensel, A., Guhne, U., Angermeyer, M. C., & Riedel-Heller, S. G. (2006). Mild cognitive impairment: Long-term course of four clinical subtypes. Neurology, 67(12), 2176–2185.PubMedCrossRef

Cabeza, R., Anderson, N. D., Locantore, J. K., & McIntosh, A. R. (2002). Aging gracefully: compensatory brain activity in high-performing older adults. Neuroimage, 17, 1394–1402.PubMedCrossRef

Caselli, R. J., Reiman, E. M., Osborne, J. G., et al. (2004). Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology, 62, 1990–1995.PubMed

Celsis, P., Agniel, A., Cardebat, D., Demonet, J. F., Ousset, P. J., & Puel, M. (1997). Age related cognitive decline: a clinical entity? A longitudinal study of cerebral blood flow and memory performance. Journal of Neurology, Neurosurgery and Psychiatry, 62, 601–608.CrossRef

Chen, P., Ratcliff, G., Belle, S. H., Cauley, J. A., DeKosky, S. T., & Ganguli, M. (2001). Patterns of cognitive decline in presymptomatic Alzheimer disease: A prospective community study. Archives of general psychiatry, 58, 853–858.PubMedCrossRef

Cherry, B. J., Buckwalter, J. G., & Henderson, V. W. (1996). Memory span procedures in Alzheimer’s disease. Neuropsychology, 10, 286–293.CrossRef

Chui, H. C., Zarow, C., Mack, W. J., et al. (2006). Cognitive impact of subcortical vascular and Alzheimer’s disease pathology. Annals of neurology, 60(6), 677–687.PubMedCrossRef

Collette, F., Salmon, E., Van der Linden, M., Degueldre, C., & Franck, G. (1997). Functional anatomy of verbal and visuospatial span tasks in Alzheimer’s disease. Human brain mapping, 5, 110–118.PubMedCrossRef

Collie, A., & Maruff, P. (2000). The neuropsychology of preclinical Alzheimer’s disease and mild cognitive impairment. Neuroscience and Biobehavioral Reviews, 24, 365–374.PubMedCrossRef

Corder, E. H., Saunders, A. M., Strittmatter, W. J., et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261, 921–923.PubMedCrossRef

Cuetos, R., Arango-Lasprilla, J. C., Uribe, C., Valencia, C., & Lopera, F. (2007). Linguistic changes in verbal expression: A preclinical marker of Alzheimer’s disease. Journal of the International Neuropsychological Society, 13, 433–439.PubMedCrossRef

Cummings, J. L., & Benson, D. F. (1992). Dementia: A clinical approach (2nd ed.). Boston: Butterworth-Heinemann.

DeCarli, C., Miller, B. L., Swan, G. E., Reed, T., Wolf, P. A., & Carmelli, D. (2001). Cerebrovascular and brain morphologic correlates of Mild Cognitive Impairment in the National Heart, Lung, and Blood Institute Twin Study. Archives of neurology, 58(4), 643–647.PubMedCrossRef

DeKosky, S. T., Ikonomovic, M. D., Styren, S. D., Beckett, L., Wisniewski, S., Bennett, D. A., et al. (2002). Up regulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Annals of neurology, 51, 145–155.PubMedCrossRef

Delano-Wood, L., Abeles, N., Sacco, J., et al. (2008). Regional white matter pathology in mild cognitive impairment: Differential influence of lesion type on neuropsychological functioning. Stroke (in press).

de la Torre, J. C. (2002). Alzheimer disease as a vascular disorder: Nosological evidence. Stroke, 33(4), 1152–1162.PubMedCrossRef

Delis, D., & Kaplan, E. (2001). Manual for the Delis-Kaplan Executive Function System. San Antonio: Psychological Corporation.

Delis, D. C., Kiefner, M. G., & Fridlund, A. J. (1988). Visuospatial dysfunction following unilateral brain damage: Dissociations in hierarchical hemispatial analysis. Journal of Clinical & Experimental Neuropsychology, 10, 421–431.CrossRef

Delis, D. C., Massman, P. J., Butters, N., Salmon, D. P., et al. (1992). Spatial cognition in Alzheimer’s disease: Subtypes of global–local impairment. Journal of Clinical & Experimental Neuropsychology, 14, 463–477.CrossRef

de Leon, M., Convit, A., Wolf, O. T., et al. (2001). Prediction of cognitive decline in normal elderly subjects with 2-[(18)F] fluoro-2-deoxy-d-glucose/positron-emission tomography (FDG/PET). Proceedings of the National Academy of Sciences of the United States of America, 98, 10966–10971.PubMedCrossRef

Demadura, T., Delis, D. C., Jacobson, M., & Salmon, D. (2001). Do subgroups of patients with Alzheimer’s disease exhibit asymmetric deficits on memory tests? Journal of Clinical & Experimental Neuropsychology, 23, 164–171.CrossRef

De Santi, S., de Leon, M. J., Rusinek, H., et al. (2001). Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiology of aging, 22, 529–539.PubMedCrossRef

D’Esposito, M., Zarahn, E., Aguirre, G. K., & Rypma, B. (1999). The effect of normal aging on the coupling of neural activity to the BOLD hemodynamic response. NeuroImage, 10, 6–14.PubMedCrossRef

Doody, R. S., Vacca, J. L., Massman, P. J., & Liao, T. Y. (1999). The influence of handedness on the clinical presentation and neuropsychology of Alzheimer disease. Archives of neurology, 56, 1133–1137.PubMedCrossRef

Dori, G. A., & Chelune, G. J. (2004). Education-stratified base-rate information on discrepancy scores within and between the Wechsler Adult Intelligence Scale—Third Edition and the Wechsler Memory Scale—Third Edition. Psychological assessment, 16, 146–154.PubMedCrossRef

Durany, N., Michel, T., Kurt, J., Cruz-Sanchez, F. F., Crevos-Navarro, J., & Riederer, P. (2000). Brain-derived neurotrophic factor and neurotrophin-3 levels in Alzheimer’s disease brains. International Journal of Developmental Neuroscience, 18, 807–813.CrossRef

Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, E. Z., et al. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257–269.PubMedCrossRef

Etiene, D., Kraft, J., Ganju, N., et al. (1998). Cerebrovascular pathology contributes to the heterogeneity of Alzheimer’s disease. Journal of Alzheimer's disease, 1, 119–134.PubMed

Farris, W., Mansourian, S., Chang, Y., et al. (2003). Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proceedings of the National Academy of Sciences, 100(7), 4162–4167.CrossRef

Farris, W., Mansourian, S., Leissring, M. A., et al. (2004). Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impairs degradation of amyloid beta-protein. American journal of pathology, 164(4), 1425–1434.PubMed

Fennema-Notestine, C., Gamst, A. C., Quinn, B. T., et al. (2007). Feasibility of multi-site clinical structural neuroimaging studies of aging using legacy data. Neuroinformatics, 5, 235–245.PubMedCrossRef

Filoteo, J. V., Delis, D. C., Massman, P. J., Demadura, T., et al. (1992). Directed and divided attention in Alzheimer’s disease: Impairment in shifting of attention to global and local stimuli. Journal of Clinical & Experimental Neuropsychology, 14, 871–883.CrossRef

Finton, M. J., Lucas, J. A., Rippeth, J. D., et al. (2003). Cognitive asymmetries associated with apolipoprotein E genotype in patients with Alzheimer’s disease. Journal of the International Neuropsychological Society, 9, 751–759.PubMedCrossRef

Fisk, J. D., & Rockwood, K. (2005). Outcomes of incident mild cognitive impairment in relation to case definition. Journal of Neurology, Neurosurgery and Psychiatry, 76(8), 1175–1177.CrossRef

Franceschi, M., Alberoni, M., Bressi, S., et al. (1995). Correlations between cognitive impairment, middle cerebral artery flow velocity and cortical glucose metabolism in the early phase of Alzheimer’s disease. Dementia, 6, 32–38.PubMed

Fratiglioni, L., & Wang, H. X. (2007). Brain reserve hypothesis in dementia. Journal of Alzheimer's disease, 12, 11–22.PubMed

Geroldi, C., Laakso, M. P., DeCarli, C., et al. (2000). Apolipoprotein E genotype and hippocampal asymmetry in Alzheimer’s disease: A volumetric MRI study. Journal of Neurology, Neurosurgery & Psychiatry, 68, 93–96.CrossRef

Grober, E., & Kawas, C. (1997). Learning and retention in preclinical and early Alzheimer’s disease. Psychology and Aging, 12, 183–188.PubMedCrossRef

Grundman, M., Petersen, R. C., Ferris, S. H., et al. (2004). Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Archives of neurology, 61(1), 59–66.PubMedCrossRef

Guskiewicz, K. M., Marshall, S. W., Bailes, J., McCrea, M., Cantu, R. C., Randolph, C., et al. (2005). Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurg, 57(4), 719–726.CrossRef

Guttman, C. R., Jolesz, F. A., Kikinis, R., Killiany, R. J., Moss, M. B., Sandor, T., et al. (1998). White matter changes with normal aging. Neurology, 50, 972–978.

Han, S. D., Houston, W. S., Jak, A. J., Eyler, L. T., Nagel, B. J., Fleisher, A. S., et al. (2007). Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemisphere compensatory response. Neurobiology of aging, 28, 238–247.PubMedCrossRef

Haxby, J. V., Duara, R., Grady, C. L., & Cutler, N. R. (1985). Rapoport SI. Relations between neuropsychological and cerebral metabolic asymmetries in early Alzheimer’s disease. Journal of cerebral blood flow and metabolism, 5, 193–200.PubMed

Haxby, J. V., Grady, C. L., Koss, E., et al. (1990). Longitudinal study of cerebral metabolic asymmetries and associated neuropsychological patterns in early dementia of the Alzheimer type. Archives of neurology, 47, 753–760.PubMed

Hayden, K. M., Zandi, P. P., Lyketsos, C. G., et al. (2006). Vascular risk factors for incident Alzheimer disease and vascular dementia: The Cache county study. Alz Dis Assoc Disord, 20, 93–100.CrossRef

Heaton, R. K., Grant, I., & Matthews, C. G. (1991). Comprehensive norms for an expanded Halstead-Reitan Battery: Demographic corrections, research findings, and clinical applications. Odessa, FL: Psychological Assessment Resources.

Heaton, R. K., Miller, S. W., Taylor, M. J., & Grant, I. (2004). Revised comprehensive norms for an expanded Halstead-Reitan Battery: Demographically adjusted neuropsychological norms for African American and Caucasian adults Scoring Program. Odessa, FL: Psychological Assessment Resources, Inc.

Helbecque, N., & Amouyel, P. (2004). Commonalities between genetics of cardiovascular disease and neurodegenerative disorders. Current opinion in lipidology, 15, 121–127.PubMedCrossRef

Hensel, A., Angermeyer, M. C., & Riedel-Heller, S. G. (2007). Measuring cognitive change in older adults: Reliable change indices for the Mini-Mental State Examination. Journal of Neurology, Neurosurgery and Psychiatry, 78(12), 1298–1303.CrossRef

Hirao, K., Ohnishi, T., Matsuda, H., et al. (2006). Functional interactions between entorhinal cortex and posterior cingulate cortex at the very early stage of Alzheimer’s disease using brain perfusion single-photon computed tomography. Nuclear Medicine, 27, 151–156.CrossRef

Hirono, N., Kitagaki, H., Kazui, H., et al. (2000). Impact of white matter changes on clinical manifestation of Alzheimer’s disease. Stroke, 31, 2182–2188.PubMed

Hofman, A., Ott, A., & Breteler, M. M. (1997). Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet, 349, 151–154.PubMedCrossRef

Honig, L. S., Tang, M.-X., Albert, S., et al. (2003). Stroke and the risk of Alzheimer disease. Archives of neurology, 60, 1707–1712.PubMedCrossRef

Houston, W. S., Delis, D. C., Lansing, A., et al. (2005). Executive function asymmetry in older adults genetically at-risk for Alzheimer's disease: Verbal versus design fluency. Journal of the International Neuropsychological Society, 11, 863–870.PubMedCrossRef

Iadecola, C., & Gorelick, P. B. (2003). Converging pathogenic mechanisms in vascular and neurodegenerative dementia. Stroke, 34(2), 335–337.PubMedCrossRef

Jack, C. R., Petersen, R. C., Xu, Y. C., Waring, S. C., O’Brien, P. C., et al. (1998). Medial temporal atrophy on MRI in normal aging and very mild Alzheimer’s disease. Neurology, 49, 786–794.

Jacobs, D. M., Sano, M., Dooneief, G., Marder, K., Bell, K. L., & Stern, Y. (1995). Neuropsychological detection and characterization of preclinical Alzheimer’s disease. Neurology, 45, 957–962.PubMed

Jacobson, M. W., Delis, D. C., Bondi, M. W., & Salmon, D. P. (2002). Do neuropsychological tests detect preclinical Alzheimer’s disease: individual-test versus cognitive-discrepancy score analyses. Neuropsychology, 16, 132–139.PubMedCrossRef

Jacobson, M. W., Delis, D. C., Bondi, M. W., & Salmon, D. P. (2005a). Asymmetry in auditory and spatial span attention in normal elderly genetically at risk for Alzheimer’s disease. Journal of Clinical & Experimental Neuropsychology, 27, 240–253.CrossRef

Jacobson, M. W., Delis, D. C., Lansing, A., et al. (2005b). Asymmetries in global-local processing ability in elderly people with the apolipoprotein e-epsilon4 allele. Neuropsychology, 19, 822–829.PubMedCrossRef

Jellinger, K. A. (2004). Head injury and dementia. Current opinion in neurology, 17, 719–723.PubMedCrossRef

Jernigan, T. J., Archibald, S. L., Fennema-Notestine, C., Gamst, A. C., Stout, J. C., Bonner, J., et al. (2001). Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiology of aging, 22, 581–594.PubMedCrossRef

Jick, H., Zornberg, G. L., Jick, S. S., et al. (2000). Statins and the risk of dementia. Lancet, 356(9242), 1627–1631.PubMedCrossRef

Jordan, B. D., Relkin, N. R., Ravdin, L. D., Jacobs, A. R., Bennett, A., & Gandy, S. (1997). Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA, 278, 136–140.PubMedCrossRef

Kawas, C. H., & Katzman, R. (1999). Epidemiology of dementia and Alzheimer disease. In R. D. Terry, R. Katzman, K. L. Bick, & S. S. Sisodia (Eds.), Alzheimer disease, 2nd edition (pp 95–116).

Kivipelto, M., Ngandu, T., Fratiglioni, L., et al. (2005). Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Archives of neurology, 62, 1556–1560.PubMedCrossRef

Knopman, D., Boland, L. L., Mosley, T., Howard, G., Liao, D., Szklo, M., et al. (2001). Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology, 56, 42–8.PubMed

Koenig, P., Smith, E. E., Moore, P., Glosser, G., & Grossman, M. (2007). Categorization of novel animals by patients with Alzheimer’s disease and corticobasal degeneration. Neuropsychology, 21, 193–206.PubMedCrossRef

Kogure, D., Matsuda, H., Ohnishi, T., et al. (2000). Longitudinal evaluation of early Alzheimer’s disease using brain perfusion SPECT. Journal of nuclear medicine, 41, 1155–1162.PubMed

Kramer, A. F., & Erickson, K. I. (2007). Capitalizing on cortical plasticity: Influence of physical activity on cognition and brain function. Trends in cognitive Neurosciences, 11(8), 342–348.CrossRef

Kramer, J. H., Nelson, A., Johnson, J. K., et al. (2006). Multiple cognitive deficits in amnestic mild cognitive impairment. Dementia and Geriatric Cognitive Disorders, 22(4), 306–311.PubMedCrossRef

Kryscio, R. J., Schmitt, F. A., Salazar, J. C., Mendiondo, M. S., & Markesbery, W. R. (2006). Risk factors for transitions from normal to mild cognitive impairment and dementia. Neurology, 66(6), 828–832.PubMedCrossRef

La Rue, A., Matsuyama, S. S., McPherson, S., et al. (1992). Cognitive performance in relatives of patients with probable Alzheimer’s disease: An age at onset effect? Journal of clinical and experimental neuropsychology, 14, 533–538.PubMedCrossRef

Lange, K. L., Bondi, M. W., Galasko, D. G., Delis, D. C., Salmon, D. P., & Thal, L. J. (2002). Decline in verbal memory during preclinical Alzheimer’s disease: Examination of the effect of Apolipoprotein E genotype. Journal of the International Neuropsychological Society, 8, 943–955.PubMedCrossRef

Lange, R. T., Chelune, G. J., & Tulsky, D. S. (2006). Development of WAIS-III General Ability Index Minus WMS-III memory discrepancy scores. Clinical neuropsychology, 20, 382–395.CrossRef

Larrieu, S., Letenneur, L., Orgogozo, J. M., et al. (2002). Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. Neurology, 59(10), 1594–1599.PubMed

Launer, L. J., Ross, G. W., Petrovich, H., et al. (2000). Midlife blood pressure and dementia: The Honolulu-Asia Aging Study. Neurobiology of aging, 21, 49–55.PubMedCrossRef

Levy, J. A., Bergeson, J., Putnam, K., Rosen, V., Cohen, R., Lalonde, F., et al. (2004). Context-specific memory and apolipoprotein E (ApoE) e4: Cognitive evidence from the NIMH prospective study of risk for Alzheimer’s disease. Journal of the International Neuropsychological Society, 10, 362–370.PubMedCrossRef

Lopez, O. L., Becker, J. T., Jagust, W. J., et al. (2006). Neuropsychological characteristics of mild cognitive impairment subgroups. Journal of Neurology, Neurosurgery and Psychiatry, 77(2), 159–165.CrossRef

Luchsinger, J. A., & Mayeux, R. (2004). Cardiovascular risk factors and Alzheimer’s disease. Current atherosclerosis reports, 6(4), 261–266.PubMedCrossRef

Luchsinger, J. A., Reitz, C., Honig, L. S., et al. (2005). Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology, 65(4), 545–551.PubMedCrossRef

Luchsinger, J. A., Reitz, C., Patel, B., et al. (2007). Relation of diabetes to mild cognitive impairment. Archives of neurology, 64(4), 570–575.PubMedCrossRef

Luchsinger, J. A., Tang, M. X., Shea, S., et al. (2004). Hyperinsulinemia and risk of Alzheimer disease. Neurology, 63(7), 1187–1192.PubMed

Manly, J. J., Bell-McGinty, S., Tang, M., Schupf, N., Stern, Y., & Mayeux, R. (2005). Implementing diagnostic criteria and estimating frequency of mild cognitive impairment in an urban community. Archives of neurology, 62(11), 1739–1746.PubMedCrossRef

Margaglione, M., Seripa, D., Gravina, C., et al. (1998). Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke. Stroke, 29, 399–403.PubMed

Martin, A. (1990). Neuropsychology of Alzheimer’s disease: The case for subgroups. In M. F. Schwartz (Ed.) Modular deficits in Alzheimer-type dementia. Issues in the biology of language and cognition (pp. 143–175). Cambridge, MA: The MIT Press.

Masliah, E., Mallory, M., Hansen, L. A., DeTeresa, R., & Terry, R. D. (1993). Quantitative synaptic alterations in the human neocortex during normal aging. Neurology, 43, 192–197.PubMed

Mayeux, R., Ottman, R., Maestre, G., Ngai, C., Tang, M.-X., Ginsberg, H., Chun, M., Tycko, B., et al. (1995). Synergistic effects of traumatic head injury and apolipoprotein e4 in patients with Alzheimer’s disease. Neurology, 45, 555–557.PubMed

Mentis, M. J., Salerno, J., Horwitz, B., et al. (1994). Reduction of functional neuronal connectivity in long-term treated hypertension. Stroke, 25(3), 601–607.PubMed

Mickes, L., Wixted, J. T., Fennema-Notestine, C., Galasko, D., Bondi, M. W., Thal, L. J., et al. (2007). Progressive impairment on neuropsychological tasks in a longitudinal study of preclinical Alzheimer’s disease. Neuropsychology, 21, 696–705.PubMedCrossRef

Miech, R. A., Breitner, J. C., Zandi, P. P., Khachaturian, A. S., Anthony, J. C., & Mayer, L. (2002). Incidence of AD may decline in the early 90s for men, later for women: The Cache County study. Neurology, 58, 209–218.PubMed

Mielke, M. M., Rosenberg, P. B., Tschanz, J., et al. (2007). Vascular factors predict rate of progression in Alzheimer disease. Neurology, 69, 1850–1858.PubMedCrossRef

Mitrushina, M., Uchiyama, C., & Satz, P. (1995). Heterogeneity of cognitive profiles in normal aging: Implications for early manifestations of Alzheimer’s disease. Journal of clinical and experimental neuropsychology, 17, 374–382.PubMedCrossRef

Mortimer, J. A., van Duijn, C. M., Chandra, V., Fratglioni, L., Graves, A. B., Heyman, A., et al. (1991). Head trauma as a risk factor for Alzheimer’s disease: A collaborative re-analysis of case-control studies. International journal of epidemiology, 20(suppl. 2), S28–35.PubMed

Mu, Q., Xie, J., Wen, Z., Weng, Y., & Shuyun, Z. (1999). A quantitative MR study of the hippocampal formation, the amygdala, and the temporal horn of the lateral ventricle in healthy subjects 40 to 90 years of age. AJNR American journal of neuroradiology, 20, 207–211.PubMed

Okamura, N., Shinkawa, M., Arai, H., et al. (2000). Prediction pf progression in patients with mild cognitive impairment using IMP-SPECT. Nippon Ronen Igakkai Zasshi, 37, 974–978.PubMed

Ott, A., Breteler, M. M., de Bruyne, M. C., et al. (1997). Atrial fibrillation and dementia in a population-based study: The Rotterdam Study. Stroke, 28, 316–321.PubMed

Ott, A., Slooter, A. J., Hofman, A., et al. (1998). Smoking and risk of dementia and Alzheimer’s disease in a population-based cohort study: the Rotterdam Study. Lancet, 351, 1840–1843.PubMedCrossRef

Ott, A., Stolk, R. P., Hofman, A., et al. (1999). Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology, 53, 1907–1909.

Parasuraman, R., Greenwood, P. M., Haxby, J. V., & Grady, C. L. (1992). Visuospatial attention in dementia of the Alzheimer type. Brain, 115(Pt 3), 711–733.PubMedCrossRef

Pedraza, O., Bowers, D., & Gilmore, R. (2004). Asymmetry of the hippocampus and amygdala in MRI volumetric measurements of normal adults. Journal of the International Neuropsychological Society, 10, 664–678.PubMedCrossRef

Petersen, R. C. (2004). Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine, 256, 183–194.PubMedCrossRef

Petersen, R. C., Doody, R. S., Kurz, A., et al. (2001). Current concepts in mild cognitive impairment. Archives of neurology, 58(12), 1985–1992.PubMedCrossRef

Petersen, R. C., & Morris, J. C. (2005). Mild cognitive impairment as a clinical entity and treatment target. Archives of Neurology, 62, 1160–1163.PubMedCrossRef

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(3), 303–308.PubMedCrossRef

Petrovich, H., White, L. R., Izmirilian, G., et al. (2000). Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS, Honolulu–Asia Aging Study. Neurobiology of aging, 21, 57–62.

Pfefferbaum, A., Mathalon, D. H., Sullivan, E. V., Rawles, J. M., Zipursky, R. B., & Lim, K. O. (1994). A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Archives of neurology, 51, 874–887.PubMed

Polvikoski, T., Sulkava, R., Myllykangas, L., et al. (2001). Prevalence of Alzheimer’s disease in very elderly people: A prospective neuropathological study. Neurology, 56, 1690–1696.PubMed

Portet, F., Ousset, P. J., Visser, P. J., et al. (2006). Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedure. Report of the MCI Working Group of the European Consortium on Alzheimer’s Disease. Journal of Neurology, Neurosurgery and Psychiatry, 77(6), 714–718.CrossRef

Powell, M. R., Smith, G. E., Knopman, D. S., et al. (2006). Cognitive measures predict pathologic Alzheimer disease. Archives of Neurology, 63, 865–868.PubMedCrossRef

Rasmusson, D. X., & Brandt, J. (1995). Instability of cognitive asymmetry in Alzheimer’s Disease. Journal of Clinical and Experimental Neuropsychology, 17, 449–458.CrossRef

Raz, N., Gunning-Dixon, F., Head, D., Rodrigue, K. M., Williamson, A., & Acker, J. D. (2004). Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume. Neurobiology of aging, 25, 377–396.PubMedCrossRef

Raz, N., & Rodrigue, K. M. (2006). Differential aging of the brain: patterns, cognitive correlates and modifiers. Neuroscience and biobehavioral reviews, 30, 730–748.PubMedCrossRef

Refolo, L. M., Malester, B., LaFrancois, J., et al. (2000). Hypercholestremia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiology of disease, 7(4), 321–331.PubMedCrossRef

Regan, C., Katona, C., Walker, Z., et al. (2006). Relationship of vascular risk to the progression of Alzheimer’s disease. Neurology, 67, 1357–1362.PubMedCrossRef

Rodriguez, G., Vitali, P., Calvini, P., et al. (2000). Hippocampal perfusion in mild cognitive impairment. Psychiatry research, 100, 65–74.PubMedCrossRef

Rosen, V. M., Sunderland, T., Levy, J., Harwell, A., McGee, L., Hammond, C., et al. (2005). Apolipoprotein E and category fluency: evidence for reduced semantic access in healthy normal controls at risk for developing Alzheimer’s disease. Neuropsychologia, 43, 647–658.PubMedCrossRef

Rubin, E. H., Storandt, M., Miller, P., Kinscherf, D. A., Grant, E. A., Morris, J. C., et al. (1998). A prospective study of cognitive function and onset of dementia in cognitively healthy elders. Archives of neurology, 55, 395–401.PubMedCrossRef

Salat, D. H., Kaye, J. A., & Janowsky, J. S. (1999). Prefrontal gray and white matter volumes in healthy aging and Alzheimer disease. Archives of neurology, 56, 338–344.PubMedCrossRef

Salmon, D. P., & Bondi, M. W. (1999). Neuropsychology of Alzheimer’s disease. In R. D. Terry, R. Katzman, K. L. Bick, & S. S. Sisodia (Eds.) Alzheimer Disease (pp. 39–56). Philadelphia: Lippincott Williams & Wilkens.

Salmon, D. P., Thomas, R. G., Pay, M. M., et al. (2002). Alzheimer’s disease can be accurately diagnosed in very mildly impaired individuals. Neurology, 59, 1022–1028.PubMed

Saunders, A. M., Strittmatter, W. J., Schmechel, D., St. George-Hyslop, P. H., Pericak-Vance, M. A., Joo, S. H., et al. (1993). Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer’s disease. Neurology, 43, 1467–1472.PubMed

Schneider, J. A., Wilson, R. S., Bienias, J. L., et al. (2004). Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology, 62(7), 1148–1155.PubMed

Silvestrini, M., Pasqualetti, P., Baruffaldi, R., et al. (2006). Cerebrovascular reactivity and cognitive decline in patients with Alzheimer disease. Stroke, 37(4), 1010–1015.PubMedCrossRef

Small, B. J., Fratiglioni, L., Viitanen, M., Winblad, B., & Bäckman, L. (2000). The course of cognitive impairment in preclinical Alzheimer disease: Three- and 6-year follow-up of a population-based sample. Archives of neurology, 57, 839–844.PubMedCrossRef

Small, G. W., La Rue, A., Komo, S., Kaplan, A., & Mandelkern, M. A. (1995a). Predictors of cognitive change in middle-aged and older adults with memory loss. American Journal of Psychiatry, 152, 1757–64.PubMed

Small, G. W., Mazziotta, J. C., Collins, M. T., Baxter, L. R., Phelps, M. E., Mandelkern, M. A., et al. (1995b). Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA, 273, 942–947.PubMedCrossRef

Small, B. J., Mobly, J. L., Laukka, E. J., Jones, S., & Bäckman, L. (2003). Cognitive deficits in preclinical Alzheimer’s disease. Acta Neurologica Scandinavica, Supplementum, 179, 29–33.CrossRef

Smith, G., Machulda, M., & Kantarci, K. (2006). A perspective from the Mayo Clinic. In H. A. Tuokko, & D. F. Hultsch (Eds.) Mild Cognitive Impairment: International Perspectives (pp. 131–162). New York: Taylor & Francis.

Smith, G. E., Pankratz, V. S., Negash, S., et al. (2007). A plateau in pre-Alzheimer memory decline: Evidence for compensatory mechanisms? Neurology, 69, 133–139.PubMedCrossRef

Snowdon, D. A., Greiner, L. H., Mortimer, J. A., et al. (1997). Brain infraction and the clinical expression of Alzheimer disease. The Nun Study. JAMA, 277, 813–817.PubMedCrossRef

Storandt, M., Grant, E. A., Miller, J. P., & Morris, J. C. (2002). Rates of progression in mild cognitive impairment and early Alzheimer’s disease. Neurology, 59, 1034–1041.PubMed

Storandt, M., Grant, E. A., Miller, J. P., & Morris, J. C. (2006). Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI. Neurology, 67(3), 467–473.PubMedCrossRef

Strite, D., Massman, P. J., Cooke, N., & Doody, R. S. (1997). Neuropsychological asymmetry in Alzheimer’s disease: verbal versus visuoconstructional deficits across stages of dementia. Journal of the International Neuropsychological Society, 3, 420–427.PubMed

Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., et al. (1993). Apolipoprotein-E—High-avidity binding to B-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences [USA], 90, 9649–9653.CrossRef

Swan, G. E., DeCarli, C., Miller, B. L., et al. (2000). Biobehavioral characteristics of nondemented older adults with subclinical brain atrophy. Neurology, 54(11), 2108–2114.PubMed

Tabert, M. H., Manly, J. J., Liu, X., et al. (2006). Neuropsychological prediction of conversion to Alzheimer disease in patients with mild cognitive impairment. Archives of General Psychiatry, 63(8), 916–924.PubMedCrossRef

Terry, R. D., Katzman, R., Bick, K. L., & Sisodia, S. S. (Eds.) (1999). Alzheimer disease (2nd ed.). New York: Lippincott.

Tian, J., Bucks, R. S., Haworth, J., & Wilcock, G. (2003). Neuropsychological prediction of conversion to dementia from questionable dementia: Statistically significant but not yet clinically useful. Journal of Neurology, Neurosurgery and Psychiatry, 74(4), 433–438.CrossRef

Tuokko, H. A., & McDowell, I. (2006). An overview of mild cognitive impairment. In H. A. Tuokko, & D. F. Hultsch (Eds.) Mild Cognitive Impairment: International Perspectives (pp. 3–28). New York: Taylor and Francis.

Twamley, E. W., Ropacki, S., & Bondi, M. W. (2006). Neuropsychological and neuroimaging changes in preclinical Alzheimer’s disease. Journal of the International Neuropsychological Society, 12, 707–735.PubMedCrossRef

Tyas, S. L., Manfreda, J., Strain, L. A., et al. (2001). Risk factors for Alzheimer’s disease: a population-based, longitudinal study in Manitoba, Canada. International journal of epidemiology, 30, 590–597.PubMedCrossRef

van Duijn, C. M., Hofman, A., & Kay, D. W. (1991). Risk factors for Alzheimer's disease: A collaborative re-analysis of case-control studies. International journal of epidemiology, 20(Suppl. 2).

Venneri, A., Pentore, R., Cotticelli, B., & Della Sala, S. (1998). Unilateral spatial neglect in the late stage of Alzheimer’s disease. Cortex, 34, 743–52.PubMedCrossRef

Wetter, S. R., Delis, D. C., Houston, W. S., et al. (2006). Heterogeneity in verbal memory: A marker of preclinical Alzheimer’s disease? Neuropsychology, development, and cognition. Section B, Aging, neuropsychology and cognition, 13, 503–515.PubMed

Wetter, S. R., Delis, D. C., Houston, W. S., Jacobson, M. W., Lansing, A., Cobell, K., et al. (2005). Deficits in inhibition and flexibility are associated with the APOE-E4 allele in nondemented older adults. Journal of clinical and experimental neuropsychology, 27, 943–952.PubMedCrossRef

Whitehouse, P. J., Price, D. L., Struble, R. G., Clark, A. W., Coyle, J. T., & DeLong, M. R. (1982). Alzheimer's disease and senile dementia: Loss of neurons in the basal forebrain. Science, 215, 1237–1239.PubMedCrossRef

Wierenga, C. E., & Bondi, M. W. (2007). The use of functional magnetic resonance imaging in preclinical Alzheimer’s disease. Neuropsychology review, 17, 127–143.PubMedCrossRef

Wilde, N., Strauss, E., Chelune, G., Loring, D., Martin, R., Hermann, B., et al. (2001). WMS-III performance in patients with temporal lobe epilepsy: Group differences and individual classification. Journal of the International Neuropsychological Society, 7, 881–891.PubMed

Wolf, H., Grunwald, M., Kruggel, F., et al. (2001). Hippocampal volume discriminates between normal cognition; questionable and mild dementia in the elderly. Neurobiology of aging, 22, 177–186.PubMedCrossRef

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(4), 312–319.PubMedCrossRef

Zanetti, M., Ballabio, C., Abbate, C., Cutaia, C., Vergani, C., & Bergamaschini, L. (2006). Mild Cognitive impairment subtypes and vascular dementia in community-dwelling elderly people: A 3-year follow-up study. Journal of the American Geriatrics Society, 54(4), 580–586.PubMedCrossRef

Zhang, M., Katzman, R., Salmon, D. P., Jin, H., Cai, G., Wang, Z., et al. (1990). The prevalence of dementia and Alzheimer’s disease (AD) in Shanghai, China: Impact on age, gender and education. Annals of neurology, 27, 428–437.PubMedCrossRef

Titel: Neuropsychological Contributions to the Early Identification of Alzheimer’s Disease
verfasst von: Mark W. Bondi
Amy J. Jak
Lisa Delano-Wood
Mark W. Jacobson
Dean C. Delis
David P. Salmon
Publikationsdatum: 01.03.2008
Verlag: Springer US
Erschienen in: Neuropsychology Review / Ausgabe 1/2008
Print ISSN: 1040-7308
Elektronische ISSN: 1573-6660
DOI: https://doi.org/10.1007/s11065-008-9054-1

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