- Email: [email protected]
PET and SPECT imaging of dementia—past, present, and future
International Congress Series 1228 (2002) 55 – 61
PET and SPECT imaging of dementia—past, present, and future Satoshi Minoshima* School of Medicine, University of Washington, Health Sciences Building, NW040J, 1959 N.E. Pacific Street, Box 356004, Seattle, WA 98195-6004, USA
Keywords: Dementia; PET imaging; SPECT imaging
Dementia affects more than 4% of the elderly population over 65 years old [1]. The prevalence of dementia increases with age and it has been reported that more than one quarter of the population over 80 suffers from dementia. Dementia disorders impose significant burdens on the society, healthcare and economy, particularly under the current trend of increasing longevity of the population. Diverse research of dementia is being conducted ranging from molecular mechanisms to socioeconomical analysis. Alzheimer’s disease is reported to be the most common cause of dementia in the elderly population [1,2]. This disease was first reported by Dr. Alzheimer in 1906 [3], and classic pathologic hallmarks including amyloid plaques and neurofibrillary tangles were described. The cerebral blood flow measurement of dementia patients was pioneered by European researchers in the late 1960s to early 1970s before the emergence of crosssectional imaging devices [4 –6]. In the late 1970s and early 1980s, positron emission tomography (PET) permitted the measurements of cerebral blood flow and oxygen as well as glucose metabolism in dementia patients [7 –15]. One of the major findings from initial cross-sectional imaging studies was the regional and selective vulnerability of cerebral cortices (such as temporal and parietal association cortices) in addition to global reduction in blood flow and metabolism [7– 9]. This line of investigation concerning ‘regional vulnerability’ of brain functions in Alzheimer’s disease was followed further in the mid 1990s by means of more advanced brain mapping techniques [16], which revealed a preclinical metabolic reduction in the posterior cingulate and cinguloparietal transitional cortices [17,18]. Although severe degeneration in the posterior cingulate cortex was demonstrated in autopsy brains from end-stage Alzheimer’s disease patients [19], non*
Tel.: +1-206-598-2707; fax: +1-206-598-4192. E-mail address: [email protected] (S. Minoshima).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 5 6 2 - 3
56
S. Minoshima / International Congress Series 1228 (2002) 55–61
invasive and repeatable imaging techniques permit investigations of the earliest functional changes in living human subjects that can be followed longitudinally. Single-photon emission computed tomography (SPECT) and cross-sectional image reconstruction techniques were developed in the late 1960s [20] prior to the development of PET imaging. Owing to the radiopharmaceutical development for cerebral blood flow measurement [21,22], widespread applications of brain SPECT imaging to dementia were started in the mid to late 1980s [23 –25]. Since SPECT imaging devices are now available in most clinical settings, and radiopharmaceuticals are provided commercially, cerebral blood flow imaging with SPECT has been established as a valuable clinical examination for the diagnosis of dementia disorders [26,27]. Since the mid 1980s, considerable research effort has been devoted to the characterization of neurochemical changes in Alzheimer’s disease and other types of dementias. Radiotracers targeting various neurochemical systems including cholinergic, dopaminergic, serotonergic, and GABAergic (benzodiazepine) have been developed for PET and SPECT imaging of dementia disorders. Particular attention was paid to the cholinergic system, stemming from the ‘cholinergic hypothesis’ of Alzheimer’s disease established in the mid 1970s to early 1980s [28 –31]. Nicotinic [32] as well as muscarinic receptors [33 – 37] have been imaged using both PET and SPECT. The results of these imaging studies demonstrated decreased and subtype specific receptor changes in living Alzheimer’s disease patients that were consistent with postmortem neurochemical analyses. A radioiodine labeled vesamicol analogue that binds to the acetylcholine transporter on presynaptic vesicles was applied to Alzheimer’s disease using SPECT and demonstrated decreased presynaptic cholinergic terminals in living human patients [38]. More recently, neurochemical imaging investigations focused on the measurement of acetylcholinesterase activity in living human brains [39 – 42]. It is important to note that acetylcholinesterase has been one of the target molecules for treatment. Extensive effort by the pharmaceutical industry to develop new classes of acetylcholinesterase inhibitors for symptomatic treatment of Alzheimer’s disease has produced several inhibitors that have been approved for clinical use. PET imaging of acetylcholinesterase activity not only permits pathophysiological investigations of dementing disorders, but also allows the noninvasive evaluation of drug effects on the target enzyme within the brains of living patients [43,44]. There are many reports published to date concerning the use of PET and SPECT for the diagnosis of dementia disorders. Most diagnostic applications of SPECT and PET to dementia involve region-specific alterations in cerebral blood flow or metabolism [45,46] and are based on the observation that different types of dementia have different regional selective vulnerability [47]. Alternatively, a specific neurochemical abnormality measured by imaging could be used as a potential diagnostic marker for Alzheimer’s disease [48]. The actual use of PET and SPECT imaging in a typical cognitive disorder clinic, nonetheless, are often limited, particularly in the United States. This is attributed to several reasons. Structural imaging such as computed tomography (CT) and magnetic resonance imaging (MRI) are often required in the diagnosis of Alzheimer’s disease to exclude chronic subdural hematoma, frontal lobe brain tumor, or other types of lesions potentially causing dementia [49]. In contrast, PET and SPECT imaging aims at providing ‘positive’ diagnosis for different types of dementias, but it is unfortunately not included in the current established diagnostic criteria. The current medical diagnosis is still largely
S. Minoshima / International Congress Series 1228 (2002) 55–61
57
based on pathologic classification; however, many SPECT and PET imaging studies published to date that aim to establish diagnostic validity do not include pathologic confirmation (except for a few well-designed investigations [27]). The clinical accessibility for SPECT imaging (and particularly PET imaging) is somewhat limited, although much more widely available than it was when the diagnostic criteria for Alzheimer’s disease were initially developed. Interpretation of SPECT and PET imaging can be highly subjective and inaccurate in part due to a lack of neurological knowledge among general Nuclear Medicine physicians or radiologists. The sensitivity and specificity of SPECT and PET imaging for the diagnosis of Alzheimer’s disease may be as good as or better than clinical examinations alone, but neither is good enough to establish SPECT and PET as a screening or confirmatory diagnostic procedure, respectively. Imaging examinations are generally expensive, although no convincing cost-effective analysis for the use of imaging in the diagnosis of dementia has been published. More importantly, therapeutic options are still limited for dementia disorders, and the potential benefits of an early and accurate diagnosis are yet to be determined from both medical and economical perspectives. These factors should be considered carefully in the diagnostic application of imaging in dementia. Some of these factors can be improved by further development of imaging techniques in the field of Nuclear Medicine. For example, advanced image processing can significantly improve the diagnostic accuracy of PET and SPECT imaging for dementia [50,51]. Development of more specific radiotracers for different types of dementia can potentially permit confirmatory diagnosis. Scanners with higher performance and at a lower cost are becoming available, more widely improving the reliable detection of subtle functional changes. Despite the somewhat limited routine clinical use of PET and SPECT imaging for dementia evaluation, imaging is currently becoming an important tool in the selection of early Alzheimer’s disease patients for experimental therapeutic interventions, which facilitates drug development [52]. Major research progress in dementia and Alzheimer’s disease has been made during the last decade in the field of molecular and genetic research. An increasing number of genetic abnormalities and risk factors have been identified in both familial and sporadic forms of Alzheimer’s disease [53 –55]. Roles of proteins coded by these genes are being extensively investigated, which in turn give great insights into the pathogenesis of the disease. The development of transgenic mice expressing these genes can be used to investigate the sequence of events potentially related to the disease pathogenesis such as the amyloid cascade in Alzheimer’s disease. Pathophysiological investigations have focused on intracellular mechanisms such as oxidative stress, calcium homeostasis, and apoptosis. Recent studies demonstrated that the brain’s immune system may play a role in the progression of Alzheimer’s disease based on the pathological evidence of microglial activation in the brains of Alzheimer’s patients, and in the recent extraordinary findings indicating immunization treatment for amyloid plaques [56]. In fact, some researchers believe that Alzheimer investigations have evolved from neuropathology in the 1960s and 1970s and neurochemistry in the 1980s and 1990s to neuroimmunology in the next decade. There are also exciting developments in the field of peptide and lipid metabolism research in Alzheimer’s disease particularly concerning LDL receptor-related protein (LRP) [57 – 60]. Altered LRP may be the common pathway in the amyloid cascade among various genetic abnormalities seen in Alzheimer’s disease [61,62]. Extensive basic research in Alzheim-
58
S. Minoshima / International Congress Series 1228 (2002) 55–61
er’s disease will unveil continuously fundamental processes of neurodegeneration and eventually develop cures for the disease in the near future. What then is the future of PET and SPECT imaging in dementia? Diagnostic applications of PET and SPECT imaging at a current or modestly improved technical level will continue to aid clinicians to improved management of patients suffering from dementia. This may become particularly important if more effective, but invasive or expensive treatments (such as stem cell transplantation) become more clinically available. PET and SPECT will help select patients for such intensive treatments by providing objective and quantitative evidence of the disease. However, in parallel to a better understanding of pathogenic processes of the disease, simpler and more specific clinical tests would likely emerge in the future and probably replace other diagnostic modalities including imaging studies. Then, will our investment into in vivo imaging in dementia be in vain? The answer is NO. It is often underestimated that the unique ability of in vivo imaging is to provide functional and structural alterations of the brain in living human subjects. For example, pathologists expend effort to speculate on preclinical pathologic changes based on an extrapolation from autopsy brains of cognitively normal elderly subjects or diseased subjects with antemortem dementia; such examinations cannot be performed in living patients or in a longitudinal manner. Transgenic mice overexpressing mutant human APP are important animal models for the investigation of molecular mechanisms of amyloid metabolism and its effects on neurons, but these mice are not suffering from ‘Alzheimer’s disease’. PET and SPECT imaging depicts exactly what is occurring in the actual Alzheimer’s-diseased brain and provides a valuable insight of region-specific disease processes to both basic scientists and clinical investigators. However, to fulfill such important roles, research directions of PET and SPECT imaging investigations need to continuously evolve to tackle the fundamental research questions posed in the field of Alzheimer’s disease and other dementia research. This requires close communication between PET and SPECT imagers and basic scientists as well as clinicians that evaluate authentic patients. If these missions of PET and SPECT imaging are accomplished, in vivo imaging will contribute significantly to the better understanding of dementia diseases that will help develop advanced treatment options and even simpler and more specific diagnostic tests, which in turn will replace PET and SPECT diagnosis in the future. In this regard, we, the PET and SPECT imaging researchers, ought to respect ‘existentialism’ in which we have to define our existence by seamless efforts and confirmation of our scintillating goals.
Acknowledgements The authors thank David E. Kuhl for his kind review of this manuscript and Donna J. Cross, BSE, for her assistance in preparing this manuscript.
References [1] M.F. Folstein, S.S. Bassett, J.C. Anthony, A.J. Romanoski, G.R. Nestadt, Dementia: case ascertainment in a community survey, J. Gerontol. 46 (1991) M132 – M138.
S. Minoshima / International Congress Series 1228 (2002) 55–61
59
[2] L. Fratiglioni, M. Grut, Y. Forsell, et al., Prevalence of Alzheimer’s disease and other dementias in an elderly urban population: relationship with age, sex, and education, Neurology 41 (1991) 1886 – 1892. ¨ ber einen eigenartigen schweren Krankheitsprozess der Hirnrinde, Neurol. Centralbl. 25 [3] A. Alzheimer, U (1906) 1134. [4] A. Brun, The pathology of presenile dementia related to cerebral blood flow, Lakartidningen 71 (1974) 1290 – 1291. [5] D. Ingvar, W. Obrist, E. Chivian, et al., General and regional abnormalities of cerebral blood flow in senile and ‘‘presenile’’ dementia, Scand. J. Clin. Lab. Invest., Suppl. 102 (XII) (1968) B. [6] J. Olesen, D. Simard, O. Paulson, E. Skinhoj, Focal cerebral blood flow, reactivity of cerebral blood vessels and cerebral oxydative metabolism in certain groups of patients with organic dementia, Acta Neurol. Scand. 46 (Suppl. 43) (1970) 76. [7] D.F. Benson, D.E. Kuhl, M.E. Phelps, J.L. Cummings, S.Y. Tsai, Positron emission computed tomography in the diagnosis of dementia, Trans. Am. Neurol. Assoc. 106 (1981) 68 – 71. [8] R.S. Frackowiak, C. Pozzilli, N.J. Legg, et al., Regional cerebral oxygen supply and utilization in dementia. A clinical and physiological study with oxygen-15 and positron tomography, Brain 104 (1981) 753 – 778. [9] D.H. Ingvar, Measurements of regional cerebral blood flow and metabolism in psychopathological states, Eur. Neurol. 20 (1981) 294 – 296. [10] T. Farkas, S.H. Ferris, A.P. Wolf, et al., 18F-2-deoxy-2-fluoro-D-glucose as a tracer in the positron emission tomographic study of senile dementia, Am. J. Psychiatry 139 (1982) 352 – 353. [11] M.J. de Leon, S.H. Ferris, A.E. George, et al., Computed tomography and positron emission transaxial tomography evaluations of normal aging and Alzheimer’s disease, J. Cereb. Blood Flow Metab. 3 (1983) 391 – 394. [12] N.L. Foster, T.N. Chase, P. Fedio, N.J. Patronas, R.A. Brooks, G. Di Chiro, Alzheimer’s disease: focal cortical changes shown by positron emission tomography, Neurology 33 (1983) 961 – 965. [13] D.E. Kuhl, Imaging local brain function with emission computed tomography, Radiology 150 (1984) 625 – 631. [14] N.L. Foster, T.N. Chase, L. Mansi, et al., Cortical abnormalities in Alzheimer’s disease, Ann. Neurol. 16 (1984) 649 – 654. [15] W.J. Jagust, R.P. Friedland, T.F. Budinger, Positron emission tomography with [18F]fluorodeoxyglucose differentiates normal pressure hydrocephalus from Alzheimer-type dementia, J. Neurol., Neurosurg. Psychiatry 48 (1985) 1091 – 1096. [16] S. Minoshima, N.L. Foster, D.E. Kuhl, Posterior cingulate cortex in Alzheimer’s disease, Lancet 344 (1994) 895. [17] E.M. Reiman, R.J. Caselli, L.S. Yun, et al., Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E, N. Engl. J. Med. 334 (1996) 752 – 758. [18] S. Minoshima, B. Giordani, S. Berent, K.A. Frey, N.L. Foster, D.E. Kuhl, Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease, Ann. Neurol. 42 (1997) 85 – 94. [19] A. Brun, L. Gustafson, Distribution of cerebral degeneration in Alzheimer’s disease. A clinico-pathological study, Arch. Psychiatr. Nervenkrankh. 223 (1976) 15 – 33. [20] D.E. Kuhl, R.Q. Edwards, The Mark 3 Scanner: a compact device for multiple-view and section scanning of the brain, Radiology 96 (1970) 563 – 570. [21] D.E. Kuhl, J.R. Barrio, S.C. Huang, et al., Quantifying local cerebral blood flow by N-isopropyl-p-[123I]iodoamphetamine (IMP) tomography, J. Nucl. Med. 23 (1982) 196 – 203. [22] R.D. Neirinckx, Evaluation of regional cerebral blood flow with 99mTc-d, 1 HM-PAO and SPECT, Neurosurg. Rev. 10 (1987) 181 – 184. [23] F.J. Bonte, E.D. Ross, H.H. Chehabi, M.D. Devous, SPECT study of regional cerebral blood flow in Alzheimer disease, J. Comput. Assist. Tomogr. 10 (1986) 579 – 583. [24] C.W. Piez, B.L. Holman, Single photon emission computed tomography, Comput. Radiol. 9 (1985) 201 – 211. [25] C. Derouesne, G. Rancurel, M. Le Poncin Lafitte, J.R. Rapin, M.A. Lassen, Variability of cerebral blood flow defects in Alzheimer’s disease on 123iodo-isopropyl-amphetamine and single photon emission tomography, Lancet 1 (1985) 1282. [26] Assessment of brain SPECT, Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, Neurology 46 (1996) 278 – 285.
60
S. Minoshima / International Congress Series 1228 (2002) 55–61
[27] W. Jagust, R. Thisted, M.D. Devous, et al., SPECT perfusion imaging in the diagnosis of Alzheimer’s disease: a clinical-pathologic study, Neurology 56 (2001) 950 – 956. [28] P. Davies, A.J. Maloney, Selective loss of central cholinergic neurons in Alzheimer’s disease, Lancet 2 (1976) 1403. [29] E.K. Perry, R.H. Perry, G. Blessed, B.E. Tomlinson, Changes in brain cholinesterases in senile dementia of Alzheimer type, Neuropathol. Appl. Neurobiol. 4 (1978) 273 – 277. [30] P.J. Whitehouse, D.L. Price, A.W. Clark, J.T. Coyle, M.R. DeLong, Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis, Ann. Neurol. 10 (1981) 122 – 126. [31] R.T. Bartus, R.L.D. Dean, B. Beer, A.S. Lippa, The cholinergic hypothesis of geriatric memory dysfunction, Science 217 (1982) 408 – 414. [32] A. Nordberg, P. Hartvig, A. Lilja, et al., Nicotine receptors in the brain of patients with Alzheimer’s disease. Studies with 11C-nicotine and positron emission tomography, Acta Radiol., Suppl. 376 (1991) 165 – 166. [33] D.R. Weinberger, U. Mann, R.E. Gibson, et al., Cerebral muscarinic receptors in primary degenerative dementia as evaluated by SPECT with iodine-123-labeled QNB, Adv. Neurol. 51 (1990) 147 – 150. [34] S.F. Boulay, V.K. Sood, M.R. Rayeq, B.R. Zeeberg, W.C. Eckelman, Autoradiographic evidence that (R)-3quinuclidinyl (S )-4-fluoromethylbenzilate ((R,S ) -FMeQNB) displays in vivo selectivity for the muscarinic m2 subtype, Nucl. Med. Biol. 23 (1996) 889 – 896. [35] V.I. Cohen, B.R. Zeeberg, S.F. Boulay, et al., In vivo competition studies of Z-( , )-[125I]IQNP against 3-quinuclidinyl 2-(5-bromothienyl)-2-thienylglycolate (BrQNT) demonstrating in vivo m2 muscarinic subtype selectivity for BrQNT, J. Mol. Neurosci. 11 (1998) 1 – 9. [36] K.A. Bergstrom, C. Halldin, A. Savonen, et al., Iodine-123 labelled Z-(R,R)-IQNP: a potential radioligand for visualization of M(1) and M(2) muscarinic acetylcholine receptors in Alzheimer’s disease, Eur. J. Nucl. Med. 26 (1999) 1482 – 1485. [37] B.L. Holman, R.E. Gibson, T.C. Hill, W.C. Eckelman, M. Albert, R.C. Reba, Muscarinic acetylcholine receptors in Alzheimer’s disease. In vivo imaging with iodine 123-labeled 3-quinuclidinyl-4-iodobenzilate and emission tomography, Jama 254 (1985) 3063 – 3066. [38] D.E. Kuhl, R.A. Koeppe, J.A. Fessler, et al., In vivo mapping of cholinergic neurons in the human brain using SPECT and IBVM, J. Nucl. Med. 35 (1994) 405 – 410. [39] H. Namba, T. Irie, K. Fukushi, M. Iyo, In vivo measurement of acetylcholinesterase activity in the brain with a radioactive acetylcholine analog, Brain Res. 667 (1994) 278 – 282. [40] T. Irie, K. Fukushi, H. Namba, et al., Brain acetylcholinesterase activity: validation of a PET tracer in a rat model of Alzheimer’s disease, J. Nucl. Med. 37 (1996) 649 – 655. [41] D.E. Kuhl, R.A. Koeppe, S. Minoshima, et al., In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer’s disease, Neurology 52 (1999) 691 – 699. [42] M.R. Kilbourn, S.E. Snyder, P.S. Sherman, D.E. Kuhl, In vivo studies of acetylcholinesterase activity using a labeled substrate, N-[11C]methylpiperdin-4-yl propionate ([11C]PMP), Synapse 22 (1996) 123 – 131. [43] H. Shinotoh, A. Aotsuka, K. Fukushi, et al., Effect of donepezil on brain acetylcholinesterase activity in patients with AD measured by PET, Neurology 56 (2001) 408 – 410. [44] D.E. Kuhl, S. Minoshima, K.A. Frey, N.L. Foster, M.R. Kilbourn, R.A. Koeppe, Limited donepezil inhibition of acetylcholinesterase measured with positron emission tomography in living Alzheimer cerebral cortex, Ann. Neurol. 48 (2000) 391 – 395. [45] S. Minoshima, K.A. Frey, R.A. Koeppe, N.L. Foster, D.E. Kuhl, A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET, J. Nucl. Med. 36 (1995) 1238 – 1248. [46] K. Herholz, R. Adams, J. Kessler, B. Szelies, M. Grond, W.-D. Heiss, Criteria for the diagnosis of Alzheimer’s disease with positron emission tomography, Dementia 1 (1990) 156 – 164. [47] D.E. Kuhl, Dementia: clinical application of positron emission tomography, Am. J. Physiol. Imaging 3 (1988) 59 – 60. [48] N. Tanaka, K. Fukushi, H. Shinotoh, et al., Positron emission tomographic measurement of brain acetylcholinesterase activity using N-[(11)C]methylpiperidin-4-yl acetate without arterial blood sampling: methodology of shape analysis and its diagnostic power for Alzheimer’s disease, J. Cereb. Blood Flow Metab. 21 (2001) 295 – 306. [49] G. McKhann, D. Drachman, M. Folstein, R. Katzman, D. Price, E.M. Stadlan, Clinical diagnosis of
S. Minoshima / International Congress Series 1228 (2002) 55–61
[50] [51]
[52] [53] [54] [55] [56] [57]
[58]
[59] [60] [61] [62]
61
Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease, Neurology 34 (1984) 939 – 944. P. Bartenstein, S. Minoshima, C. Hirsch, et al., Quantitative assessment of cerebral blood flow in patients with Alzheimer’s disease by SPECT, J. Nucl. Med. 38 (1997) 1095 – 1101. J.H. Burdette, S. Minoshima, T. Vander Borght, D.D. Tran, D.E. Kuhl, Alzheimer disease: improved visual interpretation of PET images by using three-dimensional stereotaxic surface projections, Radiology 198 (1996) 837 – 843. N.R. Cutler, J.J. Sramek, Review of the next generation of Alzheimer’s disease therapeutics: challenges for drug development, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 25 (2001) 27 – 57. D.J. Selkoe, Alzheimer’s disease: genotypes, phenotypes, and treatments, Science 275 (1997) 630 – 631. M.A. Pericak-Vance, M.P. Bass, L.H. Yamaoka, et al., Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12, Jama 278 (1997) 1237 – 1241. L. Bertram, D. Blacker, K. Mullin, et al., Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q, Science 290 (2000) 2302 – 2303. D. Schenk, R. Barbour, W. Dunn, et al., Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse, Nature 400 (1999) 173 – 177. M.Z. Kounnas, R.D. Moir, G.W. Rebeck, et al., LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation, Cell 82 (1995) 331 – 340. C.L. Lendon, C.J. Talbot, N.J. Craddock, et al., Genetic association studies between dementia of the Alzheimer’s type and three receptors for apolipoprotein E in a Caucasian population, Neurosci. Lett. 222 (1997) 187 – 190. J.C. Lambert, F. Wavrant-De Vrieze, P. Amouyel, M.C. Chartier-Harlin, Association at LRP gene locus with sporadic late-onset Alzheimer’s disease, Lancet 351 (1998) 1787 – 1788. D.E. Kang, C.U. Pietrzik, L. Baum, et al., Modulation of amyloid beta-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor-related protein pathway, J. Clin. Invest. 106 (2000) 1159 – 1166. E. Van Uden, D.E. Kang, E.H. Koo, E. Masliah, LDL receptor-related protein (LRP) in Alzheimer’s disease: towards a unified theory of pathogenesis, Microsc. Res. Tech. 50 (2000) 268 – 272. B.T. Hyman, D. Strickland, G.W. Rebeck, Role of the low-density lipoprotein receptor-related protein in beta-amyloid metabolism and Alzheimer disease, Arch. Neurol. 57 (2000) 646 – 650.
PET and SPECT imaging of dementia—past, present, and future Satoshi Minoshima* School of Medicine, University of Washington, Health Sciences Building, NW040J, 1959 N.E. Pacific Street, Box 356004, Seattle, WA 98195-6004, USA
Keywords: Dementia; PET imaging; SPECT imaging
Dementia affects more than 4% of the elderly population over 65 years old [1]. The prevalence of dementia increases with age and it has been reported that more than one quarter of the population over 80 suffers from dementia. Dementia disorders impose significant burdens on the society, healthcare and economy, particularly under the current trend of increasing longevity of the population. Diverse research of dementia is being conducted ranging from molecular mechanisms to socioeconomical analysis. Alzheimer’s disease is reported to be the most common cause of dementia in the elderly population [1,2]. This disease was first reported by Dr. Alzheimer in 1906 [3], and classic pathologic hallmarks including amyloid plaques and neurofibrillary tangles were described. The cerebral blood flow measurement of dementia patients was pioneered by European researchers in the late 1960s to early 1970s before the emergence of crosssectional imaging devices [4 –6]. In the late 1970s and early 1980s, positron emission tomography (PET) permitted the measurements of cerebral blood flow and oxygen as well as glucose metabolism in dementia patients [7 –15]. One of the major findings from initial cross-sectional imaging studies was the regional and selective vulnerability of cerebral cortices (such as temporal and parietal association cortices) in addition to global reduction in blood flow and metabolism [7– 9]. This line of investigation concerning ‘regional vulnerability’ of brain functions in Alzheimer’s disease was followed further in the mid 1990s by means of more advanced brain mapping techniques [16], which revealed a preclinical metabolic reduction in the posterior cingulate and cinguloparietal transitional cortices [17,18]. Although severe degeneration in the posterior cingulate cortex was demonstrated in autopsy brains from end-stage Alzheimer’s disease patients [19], non*
Tel.: +1-206-598-2707; fax: +1-206-598-4192. E-mail address: [email protected] (S. Minoshima).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 5 6 2 - 3
56
S. Minoshima / International Congress Series 1228 (2002) 55–61
invasive and repeatable imaging techniques permit investigations of the earliest functional changes in living human subjects that can be followed longitudinally. Single-photon emission computed tomography (SPECT) and cross-sectional image reconstruction techniques were developed in the late 1960s [20] prior to the development of PET imaging. Owing to the radiopharmaceutical development for cerebral blood flow measurement [21,22], widespread applications of brain SPECT imaging to dementia were started in the mid to late 1980s [23 –25]. Since SPECT imaging devices are now available in most clinical settings, and radiopharmaceuticals are provided commercially, cerebral blood flow imaging with SPECT has been established as a valuable clinical examination for the diagnosis of dementia disorders [26,27]. Since the mid 1980s, considerable research effort has been devoted to the characterization of neurochemical changes in Alzheimer’s disease and other types of dementias. Radiotracers targeting various neurochemical systems including cholinergic, dopaminergic, serotonergic, and GABAergic (benzodiazepine) have been developed for PET and SPECT imaging of dementia disorders. Particular attention was paid to the cholinergic system, stemming from the ‘cholinergic hypothesis’ of Alzheimer’s disease established in the mid 1970s to early 1980s [28 –31]. Nicotinic [32] as well as muscarinic receptors [33 – 37] have been imaged using both PET and SPECT. The results of these imaging studies demonstrated decreased and subtype specific receptor changes in living Alzheimer’s disease patients that were consistent with postmortem neurochemical analyses. A radioiodine labeled vesamicol analogue that binds to the acetylcholine transporter on presynaptic vesicles was applied to Alzheimer’s disease using SPECT and demonstrated decreased presynaptic cholinergic terminals in living human patients [38]. More recently, neurochemical imaging investigations focused on the measurement of acetylcholinesterase activity in living human brains [39 – 42]. It is important to note that acetylcholinesterase has been one of the target molecules for treatment. Extensive effort by the pharmaceutical industry to develop new classes of acetylcholinesterase inhibitors for symptomatic treatment of Alzheimer’s disease has produced several inhibitors that have been approved for clinical use. PET imaging of acetylcholinesterase activity not only permits pathophysiological investigations of dementing disorders, but also allows the noninvasive evaluation of drug effects on the target enzyme within the brains of living patients [43,44]. There are many reports published to date concerning the use of PET and SPECT for the diagnosis of dementia disorders. Most diagnostic applications of SPECT and PET to dementia involve region-specific alterations in cerebral blood flow or metabolism [45,46] and are based on the observation that different types of dementia have different regional selective vulnerability [47]. Alternatively, a specific neurochemical abnormality measured by imaging could be used as a potential diagnostic marker for Alzheimer’s disease [48]. The actual use of PET and SPECT imaging in a typical cognitive disorder clinic, nonetheless, are often limited, particularly in the United States. This is attributed to several reasons. Structural imaging such as computed tomography (CT) and magnetic resonance imaging (MRI) are often required in the diagnosis of Alzheimer’s disease to exclude chronic subdural hematoma, frontal lobe brain tumor, or other types of lesions potentially causing dementia [49]. In contrast, PET and SPECT imaging aims at providing ‘positive’ diagnosis for different types of dementias, but it is unfortunately not included in the current established diagnostic criteria. The current medical diagnosis is still largely
S. Minoshima / International Congress Series 1228 (2002) 55–61
57
based on pathologic classification; however, many SPECT and PET imaging studies published to date that aim to establish diagnostic validity do not include pathologic confirmation (except for a few well-designed investigations [27]). The clinical accessibility for SPECT imaging (and particularly PET imaging) is somewhat limited, although much more widely available than it was when the diagnostic criteria for Alzheimer’s disease were initially developed. Interpretation of SPECT and PET imaging can be highly subjective and inaccurate in part due to a lack of neurological knowledge among general Nuclear Medicine physicians or radiologists. The sensitivity and specificity of SPECT and PET imaging for the diagnosis of Alzheimer’s disease may be as good as or better than clinical examinations alone, but neither is good enough to establish SPECT and PET as a screening or confirmatory diagnostic procedure, respectively. Imaging examinations are generally expensive, although no convincing cost-effective analysis for the use of imaging in the diagnosis of dementia has been published. More importantly, therapeutic options are still limited for dementia disorders, and the potential benefits of an early and accurate diagnosis are yet to be determined from both medical and economical perspectives. These factors should be considered carefully in the diagnostic application of imaging in dementia. Some of these factors can be improved by further development of imaging techniques in the field of Nuclear Medicine. For example, advanced image processing can significantly improve the diagnostic accuracy of PET and SPECT imaging for dementia [50,51]. Development of more specific radiotracers for different types of dementia can potentially permit confirmatory diagnosis. Scanners with higher performance and at a lower cost are becoming available, more widely improving the reliable detection of subtle functional changes. Despite the somewhat limited routine clinical use of PET and SPECT imaging for dementia evaluation, imaging is currently becoming an important tool in the selection of early Alzheimer’s disease patients for experimental therapeutic interventions, which facilitates drug development [52]. Major research progress in dementia and Alzheimer’s disease has been made during the last decade in the field of molecular and genetic research. An increasing number of genetic abnormalities and risk factors have been identified in both familial and sporadic forms of Alzheimer’s disease [53 –55]. Roles of proteins coded by these genes are being extensively investigated, which in turn give great insights into the pathogenesis of the disease. The development of transgenic mice expressing these genes can be used to investigate the sequence of events potentially related to the disease pathogenesis such as the amyloid cascade in Alzheimer’s disease. Pathophysiological investigations have focused on intracellular mechanisms such as oxidative stress, calcium homeostasis, and apoptosis. Recent studies demonstrated that the brain’s immune system may play a role in the progression of Alzheimer’s disease based on the pathological evidence of microglial activation in the brains of Alzheimer’s patients, and in the recent extraordinary findings indicating immunization treatment for amyloid plaques [56]. In fact, some researchers believe that Alzheimer investigations have evolved from neuropathology in the 1960s and 1970s and neurochemistry in the 1980s and 1990s to neuroimmunology in the next decade. There are also exciting developments in the field of peptide and lipid metabolism research in Alzheimer’s disease particularly concerning LDL receptor-related protein (LRP) [57 – 60]. Altered LRP may be the common pathway in the amyloid cascade among various genetic abnormalities seen in Alzheimer’s disease [61,62]. Extensive basic research in Alzheim-
58
S. Minoshima / International Congress Series 1228 (2002) 55–61
er’s disease will unveil continuously fundamental processes of neurodegeneration and eventually develop cures for the disease in the near future. What then is the future of PET and SPECT imaging in dementia? Diagnostic applications of PET and SPECT imaging at a current or modestly improved technical level will continue to aid clinicians to improved management of patients suffering from dementia. This may become particularly important if more effective, but invasive or expensive treatments (such as stem cell transplantation) become more clinically available. PET and SPECT will help select patients for such intensive treatments by providing objective and quantitative evidence of the disease. However, in parallel to a better understanding of pathogenic processes of the disease, simpler and more specific clinical tests would likely emerge in the future and probably replace other diagnostic modalities including imaging studies. Then, will our investment into in vivo imaging in dementia be in vain? The answer is NO. It is often underestimated that the unique ability of in vivo imaging is to provide functional and structural alterations of the brain in living human subjects. For example, pathologists expend effort to speculate on preclinical pathologic changes based on an extrapolation from autopsy brains of cognitively normal elderly subjects or diseased subjects with antemortem dementia; such examinations cannot be performed in living patients or in a longitudinal manner. Transgenic mice overexpressing mutant human APP are important animal models for the investigation of molecular mechanisms of amyloid metabolism and its effects on neurons, but these mice are not suffering from ‘Alzheimer’s disease’. PET and SPECT imaging depicts exactly what is occurring in the actual Alzheimer’s-diseased brain and provides a valuable insight of region-specific disease processes to both basic scientists and clinical investigators. However, to fulfill such important roles, research directions of PET and SPECT imaging investigations need to continuously evolve to tackle the fundamental research questions posed in the field of Alzheimer’s disease and other dementia research. This requires close communication between PET and SPECT imagers and basic scientists as well as clinicians that evaluate authentic patients. If these missions of PET and SPECT imaging are accomplished, in vivo imaging will contribute significantly to the better understanding of dementia diseases that will help develop advanced treatment options and even simpler and more specific diagnostic tests, which in turn will replace PET and SPECT diagnosis in the future. In this regard, we, the PET and SPECT imaging researchers, ought to respect ‘existentialism’ in which we have to define our existence by seamless efforts and confirmation of our scintillating goals.
Acknowledgements The authors thank David E. Kuhl for his kind review of this manuscript and Donna J. Cross, BSE, for her assistance in preparing this manuscript.
References [1] M.F. Folstein, S.S. Bassett, J.C. Anthony, A.J. Romanoski, G.R. Nestadt, Dementia: case ascertainment in a community survey, J. Gerontol. 46 (1991) M132 – M138.
S. Minoshima / International Congress Series 1228 (2002) 55–61
59
[2] L. Fratiglioni, M. Grut, Y. Forsell, et al., Prevalence of Alzheimer’s disease and other dementias in an elderly urban population: relationship with age, sex, and education, Neurology 41 (1991) 1886 – 1892. ¨ ber einen eigenartigen schweren Krankheitsprozess der Hirnrinde, Neurol. Centralbl. 25 [3] A. Alzheimer, U (1906) 1134. [4] A. Brun, The pathology of presenile dementia related to cerebral blood flow, Lakartidningen 71 (1974) 1290 – 1291. [5] D. Ingvar, W. Obrist, E. Chivian, et al., General and regional abnormalities of cerebral blood flow in senile and ‘‘presenile’’ dementia, Scand. J. Clin. Lab. Invest., Suppl. 102 (XII) (1968) B. [6] J. Olesen, D. Simard, O. Paulson, E. Skinhoj, Focal cerebral blood flow, reactivity of cerebral blood vessels and cerebral oxydative metabolism in certain groups of patients with organic dementia, Acta Neurol. Scand. 46 (Suppl. 43) (1970) 76. [7] D.F. Benson, D.E. Kuhl, M.E. Phelps, J.L. Cummings, S.Y. Tsai, Positron emission computed tomography in the diagnosis of dementia, Trans. Am. Neurol. Assoc. 106 (1981) 68 – 71. [8] R.S. Frackowiak, C. Pozzilli, N.J. Legg, et al., Regional cerebral oxygen supply and utilization in dementia. A clinical and physiological study with oxygen-15 and positron tomography, Brain 104 (1981) 753 – 778. [9] D.H. Ingvar, Measurements of regional cerebral blood flow and metabolism in psychopathological states, Eur. Neurol. 20 (1981) 294 – 296. [10] T. Farkas, S.H. Ferris, A.P. Wolf, et al., 18F-2-deoxy-2-fluoro-D-glucose as a tracer in the positron emission tomographic study of senile dementia, Am. J. Psychiatry 139 (1982) 352 – 353. [11] M.J. de Leon, S.H. Ferris, A.E. George, et al., Computed tomography and positron emission transaxial tomography evaluations of normal aging and Alzheimer’s disease, J. Cereb. Blood Flow Metab. 3 (1983) 391 – 394. [12] N.L. Foster, T.N. Chase, P. Fedio, N.J. Patronas, R.A. Brooks, G. Di Chiro, Alzheimer’s disease: focal cortical changes shown by positron emission tomography, Neurology 33 (1983) 961 – 965. [13] D.E. Kuhl, Imaging local brain function with emission computed tomography, Radiology 150 (1984) 625 – 631. [14] N.L. Foster, T.N. Chase, L. Mansi, et al., Cortical abnormalities in Alzheimer’s disease, Ann. Neurol. 16 (1984) 649 – 654. [15] W.J. Jagust, R.P. Friedland, T.F. Budinger, Positron emission tomography with [18F]fluorodeoxyglucose differentiates normal pressure hydrocephalus from Alzheimer-type dementia, J. Neurol., Neurosurg. Psychiatry 48 (1985) 1091 – 1096. [16] S. Minoshima, N.L. Foster, D.E. Kuhl, Posterior cingulate cortex in Alzheimer’s disease, Lancet 344 (1994) 895. [17] E.M. Reiman, R.J. Caselli, L.S. Yun, et al., Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E, N. Engl. J. Med. 334 (1996) 752 – 758. [18] S. Minoshima, B. Giordani, S. Berent, K.A. Frey, N.L. Foster, D.E. Kuhl, Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease, Ann. Neurol. 42 (1997) 85 – 94. [19] A. Brun, L. Gustafson, Distribution of cerebral degeneration in Alzheimer’s disease. A clinico-pathological study, Arch. Psychiatr. Nervenkrankh. 223 (1976) 15 – 33. [20] D.E. Kuhl, R.Q. Edwards, The Mark 3 Scanner: a compact device for multiple-view and section scanning of the brain, Radiology 96 (1970) 563 – 570. [21] D.E. Kuhl, J.R. Barrio, S.C. Huang, et al., Quantifying local cerebral blood flow by N-isopropyl-p-[123I]iodoamphetamine (IMP) tomography, J. Nucl. Med. 23 (1982) 196 – 203. [22] R.D. Neirinckx, Evaluation of regional cerebral blood flow with 99mTc-d, 1 HM-PAO and SPECT, Neurosurg. Rev. 10 (1987) 181 – 184. [23] F.J. Bonte, E.D. Ross, H.H. Chehabi, M.D. Devous, SPECT study of regional cerebral blood flow in Alzheimer disease, J. Comput. Assist. Tomogr. 10 (1986) 579 – 583. [24] C.W. Piez, B.L. Holman, Single photon emission computed tomography, Comput. Radiol. 9 (1985) 201 – 211. [25] C. Derouesne, G. Rancurel, M. Le Poncin Lafitte, J.R. Rapin, M.A. Lassen, Variability of cerebral blood flow defects in Alzheimer’s disease on 123iodo-isopropyl-amphetamine and single photon emission tomography, Lancet 1 (1985) 1282. [26] Assessment of brain SPECT, Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, Neurology 46 (1996) 278 – 285.
60
S. Minoshima / International Congress Series 1228 (2002) 55–61
[27] W. Jagust, R. Thisted, M.D. Devous, et al., SPECT perfusion imaging in the diagnosis of Alzheimer’s disease: a clinical-pathologic study, Neurology 56 (2001) 950 – 956. [28] P. Davies, A.J. Maloney, Selective loss of central cholinergic neurons in Alzheimer’s disease, Lancet 2 (1976) 1403. [29] E.K. Perry, R.H. Perry, G. Blessed, B.E. Tomlinson, Changes in brain cholinesterases in senile dementia of Alzheimer type, Neuropathol. Appl. Neurobiol. 4 (1978) 273 – 277. [30] P.J. Whitehouse, D.L. Price, A.W. Clark, J.T. Coyle, M.R. DeLong, Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis, Ann. Neurol. 10 (1981) 122 – 126. [31] R.T. Bartus, R.L.D. Dean, B. Beer, A.S. Lippa, The cholinergic hypothesis of geriatric memory dysfunction, Science 217 (1982) 408 – 414. [32] A. Nordberg, P. Hartvig, A. Lilja, et al., Nicotine receptors in the brain of patients with Alzheimer’s disease. Studies with 11C-nicotine and positron emission tomography, Acta Radiol., Suppl. 376 (1991) 165 – 166. [33] D.R. Weinberger, U. Mann, R.E. Gibson, et al., Cerebral muscarinic receptors in primary degenerative dementia as evaluated by SPECT with iodine-123-labeled QNB, Adv. Neurol. 51 (1990) 147 – 150. [34] S.F. Boulay, V.K. Sood, M.R. Rayeq, B.R. Zeeberg, W.C. Eckelman, Autoradiographic evidence that (R)-3quinuclidinyl (S )-4-fluoromethylbenzilate ((R,S ) -FMeQNB) displays in vivo selectivity for the muscarinic m2 subtype, Nucl. Med. Biol. 23 (1996) 889 – 896. [35] V.I. Cohen, B.R. Zeeberg, S.F. Boulay, et al., In vivo competition studies of Z-( , )-[125I]IQNP against 3-quinuclidinyl 2-(5-bromothienyl)-2-thienylglycolate (BrQNT) demonstrating in vivo m2 muscarinic subtype selectivity for BrQNT, J. Mol. Neurosci. 11 (1998) 1 – 9. [36] K.A. Bergstrom, C. Halldin, A. Savonen, et al., Iodine-123 labelled Z-(R,R)-IQNP: a potential radioligand for visualization of M(1) and M(2) muscarinic acetylcholine receptors in Alzheimer’s disease, Eur. J. Nucl. Med. 26 (1999) 1482 – 1485. [37] B.L. Holman, R.E. Gibson, T.C. Hill, W.C. Eckelman, M. Albert, R.C. Reba, Muscarinic acetylcholine receptors in Alzheimer’s disease. In vivo imaging with iodine 123-labeled 3-quinuclidinyl-4-iodobenzilate and emission tomography, Jama 254 (1985) 3063 – 3066. [38] D.E. Kuhl, R.A. Koeppe, J.A. Fessler, et al., In vivo mapping of cholinergic neurons in the human brain using SPECT and IBVM, J. Nucl. Med. 35 (1994) 405 – 410. [39] H. Namba, T. Irie, K. Fukushi, M. Iyo, In vivo measurement of acetylcholinesterase activity in the brain with a radioactive acetylcholine analog, Brain Res. 667 (1994) 278 – 282. [40] T. Irie, K. Fukushi, H. Namba, et al., Brain acetylcholinesterase activity: validation of a PET tracer in a rat model of Alzheimer’s disease, J. Nucl. Med. 37 (1996) 649 – 655. [41] D.E. Kuhl, R.A. Koeppe, S. Minoshima, et al., In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer’s disease, Neurology 52 (1999) 691 – 699. [42] M.R. Kilbourn, S.E. Snyder, P.S. Sherman, D.E. Kuhl, In vivo studies of acetylcholinesterase activity using a labeled substrate, N-[11C]methylpiperdin-4-yl propionate ([11C]PMP), Synapse 22 (1996) 123 – 131. [43] H. Shinotoh, A. Aotsuka, K. Fukushi, et al., Effect of donepezil on brain acetylcholinesterase activity in patients with AD measured by PET, Neurology 56 (2001) 408 – 410. [44] D.E. Kuhl, S. Minoshima, K.A. Frey, N.L. Foster, M.R. Kilbourn, R.A. Koeppe, Limited donepezil inhibition of acetylcholinesterase measured with positron emission tomography in living Alzheimer cerebral cortex, Ann. Neurol. 48 (2000) 391 – 395. [45] S. Minoshima, K.A. Frey, R.A. Koeppe, N.L. Foster, D.E. Kuhl, A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET, J. Nucl. Med. 36 (1995) 1238 – 1248. [46] K. Herholz, R. Adams, J. Kessler, B. Szelies, M. Grond, W.-D. Heiss, Criteria for the diagnosis of Alzheimer’s disease with positron emission tomography, Dementia 1 (1990) 156 – 164. [47] D.E. Kuhl, Dementia: clinical application of positron emission tomography, Am. J. Physiol. Imaging 3 (1988) 59 – 60. [48] N. Tanaka, K. Fukushi, H. Shinotoh, et al., Positron emission tomographic measurement of brain acetylcholinesterase activity using N-[(11)C]methylpiperidin-4-yl acetate without arterial blood sampling: methodology of shape analysis and its diagnostic power for Alzheimer’s disease, J. Cereb. Blood Flow Metab. 21 (2001) 295 – 306. [49] G. McKhann, D. Drachman, M. Folstein, R. Katzman, D. Price, E.M. Stadlan, Clinical diagnosis of
S. Minoshima / International Congress Series 1228 (2002) 55–61
[50] [51]
[52] [53] [54] [55] [56] [57]
[58]
[59] [60] [61] [62]
61
Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease, Neurology 34 (1984) 939 – 944. P. Bartenstein, S. Minoshima, C. Hirsch, et al., Quantitative assessment of cerebral blood flow in patients with Alzheimer’s disease by SPECT, J. Nucl. Med. 38 (1997) 1095 – 1101. J.H. Burdette, S. Minoshima, T. Vander Borght, D.D. Tran, D.E. Kuhl, Alzheimer disease: improved visual interpretation of PET images by using three-dimensional stereotaxic surface projections, Radiology 198 (1996) 837 – 843. N.R. Cutler, J.J. Sramek, Review of the next generation of Alzheimer’s disease therapeutics: challenges for drug development, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 25 (2001) 27 – 57. D.J. Selkoe, Alzheimer’s disease: genotypes, phenotypes, and treatments, Science 275 (1997) 630 – 631. M.A. Pericak-Vance, M.P. Bass, L.H. Yamaoka, et al., Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12, Jama 278 (1997) 1237 – 1241. L. Bertram, D. Blacker, K. Mullin, et al., Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q, Science 290 (2000) 2302 – 2303. D. Schenk, R. Barbour, W. Dunn, et al., Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse, Nature 400 (1999) 173 – 177. M.Z. Kounnas, R.D. Moir, G.W. Rebeck, et al., LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation, Cell 82 (1995) 331 – 340. C.L. Lendon, C.J. Talbot, N.J. Craddock, et al., Genetic association studies between dementia of the Alzheimer’s type and three receptors for apolipoprotein E in a Caucasian population, Neurosci. Lett. 222 (1997) 187 – 190. J.C. Lambert, F. Wavrant-De Vrieze, P. Amouyel, M.C. Chartier-Harlin, Association at LRP gene locus with sporadic late-onset Alzheimer’s disease, Lancet 351 (1998) 1787 – 1788. D.E. Kang, C.U. Pietrzik, L. Baum, et al., Modulation of amyloid beta-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor-related protein pathway, J. Clin. Invest. 106 (2000) 1159 – 1166. E. Van Uden, D.E. Kang, E.H. Koo, E. Masliah, LDL receptor-related protein (LRP) in Alzheimer’s disease: towards a unified theory of pathogenesis, Microsc. Res. Tech. 50 (2000) 268 – 272. B.T. Hyman, D. Strickland, G.W. Rebeck, Role of the low-density lipoprotein receptor-related protein in beta-amyloid metabolism and Alzheimer disease, Arch. Neurol. 57 (2000) 646 – 650.