Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B
William E. Klunk MD, PhD
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorHenry Engler MD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorAgneta Nordberg MD, PhD
Neurotec Department, Karolinska Institute, Huddinge University Hospital, Stockholm
Department of Geriatric Medicine, Huddinge University Hospital, Stockholm, Sweden
Search for more papers by this authorYanming Wang PhD
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorGunnar Blomqvist PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorDaniel P. Holt BS
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorMats Bergström PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorIrina Savitcheva MD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorGuo-Feng Huang PhD
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorSergio Estrada PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorBirgitta Ausén MSCI
Department of Geriatric Medicine, Huddinge University Hospital, Stockholm, Sweden
Search for more papers by this authorManik L. Debnath MS
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorJulien Barletta BS
Department of Organic Chemistry, Uppsala University, Uppsala, Sweden
Search for more papers by this authorJulie C. Price PhD
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorJohan Sandell PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorBrian J. Lopresti BS
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorAnders Wall PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorPernilla Koivisto PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorGunnar Antoni PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorCorresponding Author
Chester A. Mathis PhD
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
PET Facility, B-938 UPMC Presbyterian, 200 Lothrop Street, Pittsburgh, PA 15213-2582Search for more papers by this authorBengt Långström PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Department of Organic Chemistry, Uppsala University, Uppsala, Sweden
Search for more papers by this authorWilliam E. Klunk MD, PhD
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorHenry Engler MD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorAgneta Nordberg MD, PhD
Neurotec Department, Karolinska Institute, Huddinge University Hospital, Stockholm
Department of Geriatric Medicine, Huddinge University Hospital, Stockholm, Sweden
Search for more papers by this authorYanming Wang PhD
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorGunnar Blomqvist PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorDaniel P. Holt BS
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorMats Bergström PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorIrina Savitcheva MD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorGuo-Feng Huang PhD
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorSergio Estrada PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorBirgitta Ausén MSCI
Department of Geriatric Medicine, Huddinge University Hospital, Stockholm, Sweden
Search for more papers by this authorManik L. Debnath MS
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorJulien Barletta BS
Department of Organic Chemistry, Uppsala University, Uppsala, Sweden
Search for more papers by this authorJulie C. Price PhD
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorJohan Sandell PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorBrian J. Lopresti BS
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
Search for more papers by this authorAnders Wall PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorPernilla Koivisto PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorGunnar Antoni PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Search for more papers by this authorCorresponding Author
Chester A. Mathis PhD
Department of Radiology, PET Facility, University of Pittsburgh, Pittsburgh, PA
PET Facility, B-938 UPMC Presbyterian, 200 Lothrop Street, Pittsburgh, PA 15213-2582Search for more papers by this authorBengt Långström PhD
Uppsala University, PET Centre/Uppsala Imanet AB, Uppsala
Department of Organic Chemistry, Uppsala University, Uppsala, Sweden
Search for more papers by this authorAbstract
This report describes the first human study of a novel amyloid-imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were observed in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 years) and six older healthy controls (69.5 ± 11 years) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metabolism determined with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = −0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.
References
- 1 Klunk WE, Debnath ML, Pettegrew JW. Development of small molecule probes for the beta-amyloid protein of Alzheimer's disease. Neurobiol Aging 1994; 15: 691–698.
- 2 Zhen W, Han H, Anguiano M, et al. Synthesis and amyloid binding properties of rhenium complexes: preliminary progress toward a reagent for SPECT imaging of Alzheimer's disease brain. J Med Chem 1999; 42: 2805–2815.
- 3 Dezutter NA, Dom RJ, de Groot TJ, et al. 99mTc-MAMA-chrysamine G, a probe for beta-amyloid protein of Alzheimer's disease. Eur J Nucl Med 1999; 26: 1392–1399.
- 4 Wengenack TM, Curran GL, Poduslo JF. Targeting Alzheimer amyloid plaques in vivo. Nat Biotechnol 2000; 18: 868–872.
- 5 Klunk WE, Wang Y, Huang G-F, et al. Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. Life Sci 2001; 69: 1471–1484.
- 6 Agdeppa ED, Kepe V, Liu J, et al. Binding characteristics of radiofluorinated 6-dialkylamino-2- naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer's disease. J Neurosci 2001; 21: RC189.
- 7 Zhuang ZP, Kung MP, Hou C, et al. Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates. J Med Chem 2001; 44: 1905–1914.
- 8 Mathis CA, Bacskai BJ, Kajdasz ST, et al. A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorganic Med Chem Lett 2002; 12: 295–298.
- 9 Wang Y, Mathis CA, Huang G-F, et al. Synthesis and evaluation of 2-(3′-iodo-4′-amino)-6-hydroxy-benzothiazole for in vivo quantitation of amyloid deposits in Alzheimer's disease. J Mol Neurosci 2002; 19: 11–16.
- 10 Mathis CA, Wang Y, Holt DP, et al. Synthesis and evaluation of 11C-labeled 6-substituted 2-aryl benzothiazoles as amyloid imaging agents. J Med Chem 2003; 46: 2740–2754.
- 11 Klunk WE, Wang Y, Huang G-F, et al. The binding of 2-(4′-methylaminophenyl)benzothiazole to post-mortem brain homogenates is dominated by the amyloid component. J Neurosci 2003; 23: 2086–2092.
- 12 Bacskai BJ, Hickey GA, Skoch J, et al. Four-dimensional imaging of brain entry, amyloid-binding and clearance of an amyloid-β ligand in transgenic mice using multiphoton microscopy. Proc Natl Acad Sci USA 2003; 100: 12462–12467.
- 13 Bergström M, Grahnén A, Långström B. PET-microdosing, a new concept with application in early clinical drug development. Eur J Clin Pharmacol 2003; 59: 357–366.
- 14 McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 1984; 34: 939–944.
- 15 Watson CC, Newport D, Casey ME, et al. Evaluation of simulation-based scatter correction for 3D PET cardiac imaging. IEEE Trans Nucl Sci 1997; 44: 90–97.
- 16 Andersson JL, Thurfjell L. Implementation and validation of a fully automatic system for intra- and interindividual registration of PET brain scans. J Comput Assist Tomogr 1997; 21: 136–144.
- 17 Engler H, Lundberg PO, Ekbom K, et al. Multitracer study with positron emission tomography in Creutzfeldt-Jakob disease. Eur J Nucl Med Mol Imaging 2003; 30: 85–95.
- 18 Joachim CL, Morris JH, Selkoe DJ. Diffuse senile plaques occur commonly in the cerebellum in Alzheimer's disease. Am J Pathol 1989; 135: 309–319.
- 19 Yamaguchi H, Hirai S, Morimatsu M, et al. Diffuse type of senile plaques in the cerebellum of Alzheimer- type dementia demonstrated by beta protein immunostain. Acta Neuropathol 1989; 77: 314–319.
- 20 Logan J, Fowler JS, Volkow ND, et al. Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(−)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 1990; 10: 740–747.
- 21 Logan J, Fowler AH, Volkow ND, et al. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996; 16: 834–840.
- 22 Gjedde A. High- and low-affinity transport of D-glucose from blood to brain. J Neurochem 1981; 36: 1463–1471.
- 23 Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 1983; 3: 1–7.
- 24 Patlak CS, Blasberg RG. Graphical evaluation of blood-to-brain transfer constants from multiple- time uptake data. Generalizations. J Cereb Blood Flow Metab 1985; 5: 584–590.
- 25 Thal DR, Rub U, Orantes M, et al. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 2002; 58: 1791–1800.
- 26 Arnold SE, Hyman BT, Flory J, et al. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb Cortex 1991; 1: 103–116.
- 27 Wolf DS, Gearing M, Snowdon DA, et al. Progression of regional neuropathology in Alzheimer disease and normal elderly: findings from the Nun study. Alzheimer Dis Assoc Disord 1999; 13: 226–231.
- 28 Brilliant MJ, Elble RJ, Ghobrial M, et al. The distribution of amyloid beta protein deposition in the corpus striatum of patients with Alzheimer's disease. Neuropathol Appl Neurobiol 1997; 23: 322–325.
- 29 Suenaga T, Hirano A, Llena JF, et al. Modified Bielschowsky stain and immunohistochemical studies on striatal plaques in Alzheimer's disease. Acta Neuropathol 1990; 80: 280–286.
- 30 Braak H, Braak E. Alzheimer's disease: striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol 1990; 49: 215–224.
- 31 Friedland RP, Budinger TF, Ganz E, et al. Regional cerebral metabolic alterations in dementia of the Alzheimer type: positron emission tomography with [18F]fluorodeoxyglucose. J Comput Assist Tomogr 1983; 7: 590–598.
- 32 Jelic V, Nordberg A. Early diagnosis of Alzheimer disease with positron emission tomography. Alzheimer Dis Assoc Disord 2000; 14(suppl 1): S109–S113.
- 33 Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 2001; 286: 2120–2127.
- 34 Alexander GE, Chen K, Pietrini P, et al. Longitudinal PET evaluation of cerebral metabolic decline in dementia: a potential outcome measure in Alzheimer's disease treatment studies. Am J Psychiatry 2002; 159: 738–745.
- 35 Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239–259.
- 36 Lewis DA, Campbell MJ, Terry RD, et al. Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices. J Neurosci 1987; 7: 1799–1808.
- 37 Matsuda H. Cerebral blood flow and metabolic abnormalities in Alzheimer's disease. Ann Nucl Med 2001; 15: 85–92.
- 38 Styren SD, Hamilton RL, Styren GC, et al. X-34, a fluorescent derivative of Congo red: a novel histochemical stain for Alzheimer's disease pathology. J Histochem Cytochem 2000; 48: 1223–1232.
- 39
Morris JC,
Storandt M,
McKeel DW Jr, et al.
Cerebral amyloid deposition and diffuse plaques in “normal” aging: evidence for presymptomatic and very mild Alzheimer's disease.
Neurology
1996;
96:
707–719.
10.1212/WNL.46.3.707 Google Scholar
- 40 Goldman WP, Price JL, Storandt M, et al. Absence of cognitive impairment or decline in preclinical Alzheimer's disease. Neurology 2001; 56: 361–367.
- 41 Morris JC, Price AL. Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer's disease. J Mol Neurosci 2001; 17: 101–118.
- 42 Schmitt FA, Davis DG, Wekstein DR, et al. “Preclinical” AD revisited: neuropathology of cognitively normal older adults. Neurology 2000; 55: 370–376.
- 43 Small GW, Mazziotta JC, Collins MT, et al. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 1995; 273: 942–947.
- 44 Reiman EM, Caselli RJ, Yun LS, et al. Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 1996; 96: 752–758.
- 45 Kennedy AM, Frackowiak RS, Newman SK, et al. Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer's disease. Neurosci Lett 1995; 186: 17–20.
- 46 Wahlund LO, Basun H, Almkvist O, et al. A follow-up study of the family with the Swedish APP 670/671 Alzheimer's disease mutation. Dement Geriatr Cogn Disord 1999; 10: 526–533.
- 47 Ohm TG, Kirca M, Bohl J, et al. Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation. Neuroscience 1995; 66: 583–587.
- 48 Pirttila T, Soininen H, Mehta PD, et al. Apolipoprotein E genotype and amyloid load in Alzheimer disease and control brains. Neurobiol Aging 1997; 18: 121–127.
- 49 Berg L, McKeel DWJ, Miller JP, et al. Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 1998; 55: 326–335.
- 50 Friedland RP, Kalaria R, Berridge M, et al. Neuroimaging of vessel amyloid in Alzheimer's disease. Ann NY Acad Sci 1997; 826: 242–247.
- 51 Shoghi-Jadid K, Small GW, Agdeppa ED, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 2002; 10: 24–35.
- 52 Glenner GG. Alzheimer's disease. The commonest form of amyloidosis. Arch Pathol Lab Med 1983; 107: 281–282.