No evidence for amyloid pathology as a key mediator of neurodegeneration post-stroke - a seven-year follow-up study

Guri Hagberg, Hege Ihle-Hansen, Brynjar Fure, Bente Thommessen, Håkon Ihle-Hansen, Anne Rita Øksengård, Mona K Beyer, Torgeir B Wyller, Ebba Gløersen Müller, Sarah T Pendlebury, Per Selnes, Guri Hagberg, Hege Ihle-Hansen, Brynjar Fure, Bente Thommessen, Håkon Ihle-Hansen, Anne Rita Øksengård, Mona K Beyer, Torgeir B Wyller, Ebba Gløersen Müller, Sarah T Pendlebury, Per Selnes

Abstract

Background: Cognitive impairment (CI) with mixed vascular and neurodegenerative pathologies after stroke is common. The role of amyloid pathology in post-stroke CI is unclear. We hypothesize that amyloid deposition, measured with Flutemetamol (18F-Flut) positron emission tomography (PET), is common in seven-year stroke survivors diagnosed with CI and, further, that quantitatively assessed 18F-Flut-PET uptake after 7 years correlates with amyloid-β peptide (Aβ42) levels in cerebrospinal fluid (CSF) at 1 year, and with measures of neurodegeneration and cognition at 7 years post-stroke.

Methods: 208 patients with first-ever stroke or transient Ischemic Attack (TIA) without pre-existing CI were included during 2007 and 2008. At one- and seven-years post-stroke, cognitive status was assessed, and categorized into dementia, mild cognitive impairment or normal. Etiologic sub-classification was based on magnetic resonance imaging (MRI) findings, CSF biomarkers and clinical cognitive profile. At 7 years, patients were offered 18F-Flut-PET, and amyloid-positivity was assessed visually and semi-quantitatively. The associations between 18F-Flut-PET standardized uptake value ratios (SUVr) and measures of neurodegeneration (medial temporal lobe atrophy (MTLA), global cortical atrophy (GCA)) and cognition (Mini-Mental State Exam (MMSE), Trail-making test A (TMT-A)) and CSF Aβ42 levels were assessed using linear regression.

Results: In total, 111 patients completed 7-year follow-up, and 26 patients agreed to PET imaging, of whom 13 had CSF biomarkers from 1 year. Thirteen out of 26 patients were diagnosed with CI 7 years post-stroke, but only one had visually assessed amyloid positivity. CSF Aβ42 levels at 1 year, MTA grade, GCA scale, MMSE score or TMT-A at 7 years did not correlate with 18F-Flut-PET SUVr in this cohort.

Conclusions: Amyloid binding was not common in 7-year stroke survivors diagnosed with CI. Quantitatively assessed, cortical amyloid deposition did not correlate with other measures related to neurodegeneration or cognition. Therefore, amyloid pathology may not be a key mediator of neurodegeneration 7 years post-stroke.

Trial registration: Clinicaltrials.gov (NCT00506818). July 23, 2007. Inclusion from February 2007, randomization and intervention from May 2007 and trial registration in July 2007.

Keywords: Cerebrospinal fluid; Cognitive impairment; Positron emission tomography; Prognosis; Stroke.

Conflict of interest statement

Hege Ihle-Hansen is a member of the editorial board in BMC neurology.

Figures

Fig. 1
Fig. 1
Flow chart
Fig. 2
Fig. 2
Associations between composite 18F-Flut-PET SUVr and CSF Aβ42 levels at 1 year

References

    1. Brainin M, Tuomilehto J, Heiss WD, Bornstein NM, Bath PM, Teuschl Y, et al. Post-stroke cognitive decline: an update and perspectives for clinical research. Eur J Neurol. 2015;22(2):229–238. doi: 10.1111/ene.12626.
    1. Organization WH. The ICD-10 classification of mental and Behavioural disorders: diagnostic criteria for research. Geneva. 1993.
    1. Ballard C, Rowan E, Stephens S, Kalaria R, Kenny RA. Prospective follow-up study between 3 and 15 months after stroke: improvements and decline in cognitive function among dementia-free stroke survivors >75 years of age. Stroke. 2003;34(10):2440–2444. doi: 10.1161/01.STR.0000089923.29724.CE.
    1. Rasquin SM, Lodder J, Verhey FR. Predictors of reversible mild cognitive impairment after stroke: a 2-year follow-up study. Journal of the neurological sciences. 2005;229–230:21–5.
    1. Tang EY, Amiesimaka O, Harrison SL, Green E, Price C, Robinson L, et al. Longitudinal Effect of Stroke on Cognition: A Systematic Review. Journal of the American Heart Association. 2018;7(2).
    1. Rothwell PM, Coull AJ, Giles MF, Howard SC, Silver LE, Bull LM, et al. Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford vascular study) Lancet. 2004;363(9425):1925–1933. doi: 10.1016/S0140-6736(04)16405-2.
    1. Kandiah N, Chander RJ, Lin X, Ng A, Poh YY, Cheong CY, et al. Cognitive impairment after mild stroke: development and validation of the SIGNAL2 risk score. Journal of Alzheimer's disease : JAD. 2016;49(4):1169–1177. doi: 10.3233/JAD-150736.
    1. Chander RJ, Lam BYK, Lin X, Ng AYT, Wong APL, Mok VCT, et al. Development and validation of a risk score (CHANGE) for cognitive impairment after ischemic stroke. Sci Rep. 2017;7(1):12441. doi: 10.1038/s41598-017-12755-z.
    1. Yang J, Wong A, Wang Z, Liu W, Au L, Xiong Y, et al. Risk factors for incident dementia after stroke and transient ischemic attack. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2015;11(1):16–23. doi: 10.1016/j.jalz.2014.01.003.
    1. Liu W, Wong A, Au L, Yang J, Wang Z, Leung EY, et al. Influence of amyloid-beta on cognitive decline after stroke/transient ischemic attack: three-year longitudinal study. Stroke. 2015;46(11):3074–3080. doi: 10.1161/STROKEAHA.115.010449.
    1. Lopez OL, Klunk WE, Mathis C, Coleman RL, Price J, Becker JT, et al. Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old. Neurology. 2014;83(20):1804–1811. doi: 10.1212/WNL.0000000000000977.
    1. Roberts RO, Aakre JA, Kremers WK, Vassilaki M, Knopman DS, Mielke MM, et al. Prevalence and outcomes of amyloid positivity among persons without dementia in a longitudinal. Population-Based Setting JAMA Neurol. 2018;75(8):970–979. doi: 10.1001/jamaneurol.2018.0629.
    1. van Maurik IS, van der Kall LM, de Wilde A, Bouwman FH, Scheltens P, van Berckel BNM, et al. Added value of amyloid PET in individualized risk predictions for MCI patients. Alzheimer's & dementia (Amsterdam, Netherlands). 2019;11:529–37.
    1. Leuzy A, Savitcheva I, Chiotis K, Lilja J, Andersen P, Bogdanovic N, et al. Clinical impact of [(18)F] flutemetamol PET among memory clinic patients with an unclear diagnosis. Eur J Nucl Med Mol Imaging. 2019;46(6):1276–1286. doi: 10.1007/s00259-019-04297-5.
    1. Muller EG, Edwin TH, Stokke C, Navelsaker SS, Babovic A, Bogdanovic N, et al. Amyloid-beta PET-correlation with cerebrospinal fluid biomarkers and prediction of Alzheimer s disease diagnosis in a memory clinic. PLoS One. 2019;14(8):e0221365. doi: 10.1371/journal.pone.0221365.
    1. Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010;6(3):131–144. doi: 10.1038/nrneurol.2010.4.
    1. Perani D, Schillaci O, Padovani A, Nobili FM, Iaccarino L, Della Rosa PA, et al. A survey of FDG- and amyloid-PET imaging in dementia and GRADE analysis. Biomed Res Int. 2014;2014:785039. doi: 10.1155/2014/246586.
    1. Ikonomovic MD, Fantoni ER, Farrar G, Salloway S. Infrequent false positive [(18)F] flutemetamol PET signal is resolved by combined histological assessment of neuritic and diffuse plaques. Alzheimers Res Ther. 2018;10(1):60. doi: 10.1186/s13195-018-0387-6.
    1. Zhang S, Smailagic N, Hyde C, Noel-Storr AH, Takwoingi Y, McShane R, et al. (11) C-PIB-PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). The Cochrane database of systematic reviews. 2014;7:Cd010386.
    1. Palmqvist S, Zetterberg H, Blennow K, Vestberg S, Andreasson U, Brooks DJ, et al. Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid beta-amyloid 42: a cross-validation study against amyloid positron emission tomography. JAMA Neurol. 2014;71(10):1282–1289. doi: 10.1001/jamaneurol.2014.1358.
    1. Adamczuk K, Schaeverbeke J, Vanderstichele HM, Lilja J, Nelissen N, Van Laere K, et al. Diagnostic value of cerebrospinal fluid Abeta ratios in preclinical Alzheimer's disease. Alzheimers Res Ther. 2015;7(1):75. doi: 10.1186/s13195-015-0159-5.
    1. Hansson O, Seibyl J, Stomrud E, Zetterberg H, Trojanowski JQ, Bittner T, et al. CSF biomarkers of Alzheimer's disease concord with amyloid-beta PET and predict clinical progression: a study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2018;14(11):1470–1481. doi: 10.1016/j.jalz.2018.01.010.
    1. Whitehead S, Cheng G, Hachinski V, Cechetto DF. Interaction between a rat model of cerebral ischemia and beta-amyloid toxicity: II. Effects of triflusal. Stroke. 2005;36(8):1782–1789. doi: 10.1161/01.STR.0000173405.02425.d6.
    1. Whitehead SN, Hachinski VC, Cechetto DF. Interaction between a rat model of cerebral ischemia and beta-amyloid toxicity: inflammatory responses. Stroke. 2005;36(1):107–112. doi: 10.1161/01.STR.0000149627.30763.f9.
    1. Amtul Z, Nikolova S, Gao L, Keeley RJ, Bechberger JF, Fisher AL, et al. Comorbid Abeta toxicity and stroke: hippocampal atrophy, pathology, and cognitive deficit. Neurobiol Aging. 2014;35(7):1605–1614. doi: 10.1016/j.neurobiolaging.2014.01.005.
    1. Thiel A, Cechetto DF, Heiss WD, Hachinski V, Whitehead SN. Amyloid burden, neuroinflammation, and links to cognitive decline after ischemic stroke. Stroke. 2014;45(9):2825–2829. doi: 10.1161/STROKEAHA.114.004285.
    1. Leys D, Henon H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. The Lancet Neurology. 2005;4(11):752–759. doi: 10.1016/S1474-4422(05)70221-0.
    1. Fein G, Di Sclafani V, Tanabe J, Cardenas V, Weiner MW, Jagust WJ, et al. Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease. Neurology. 2000;55(11):1626–1635. doi: 10.1212/WNL.55.11.1626.
    1. Lee JH, Kim SH, Kim GH, Seo SW, Park HK, Oh SJ, et al. Identification of pure subcortical vascular dementia using 11C-Pittsburgh compound B. Neurology. 2011;77(1):18–25. doi: 10.1212/WNL.0b013e318221acee.
    1. Selnes P, Grambaite R, Rincon M, Bjornerud A, Gjerstad L, Hessen E, et al. Hippocampal complex atrophy in poststroke and mild cognitive impairment. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2015;35(11):1729–1737. doi: 10.1038/jcbfm.2015.110.
    1. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke. 2011;42(9):2672–2713. doi: 10.1161/STR.0b013e3182299496.
    1. Sahathevan R, Linden T, Villemagne VL, Churilov L, Ly JV, Rowe C, et al. Positron emission tomographic imaging in stroke: cross-sectional and follow-up assessment of amyloid in ischemic stroke. Stroke. 2016;47(1):113–119. doi: 10.1161/STROKEAHA.115.010528.
    1. Yasuno F, Kajimoto K, Ihara M, Taguchi A, Yamamoto A, Fukuda T, et al. Amyloid beta deposition in subcortical stroke patients and effects of educational achievement: a pilot study. International journal of geriatric psychiatry. 2019.
    1. Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer's disease. Neuron. 2009;63(3):287–303. doi: 10.1016/j.neuron.2009.06.026.
    1. al Pe. in press. 2020.
    1. Gottesman RF, Schneider AL, Zhou Y, Coresh J, Green E, Gupta N, et al. Association between midlife vascular risk factors and estimated brain amyloid deposition. Jama. 2017;317(14):1443–1450. doi: 10.1001/jama.2017.3090.
    1. Wollenweber FA, Darr S, Muller C, Duering M, Buerger K, Zietemann V, et al. Prevalence of amyloid positron emission tomographic positivity in Poststroke mild cognitive impairment. Stroke. 2016;47(10):2645–2648. doi: 10.1161/STROKEAHA.116.013778.
    1. Mok V, Leung EY, Chu W, Chen S, Wong A, Xiong Y, et al. Pittsburgh compound B binding in poststroke dementia. J Neurol Sci. 2010;290(1–2):135–137. doi: 10.1016/j.jns.2009.12.014.
    1. Mok V, Xiong Y, Wong KK, Wong A, Schmidt R, Chu WW, et al. Predictors for cognitive decline in patients with confluent white matter hyperintensities. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2012;8(5 Suppl):S96–s103. doi: 10.1016/j.jalz.2011.10.004.
    1. Hagberg G, Fure B, Thommessen B, Ihle-Hansen H, Oksengard AR, Nygard S, et al. Predictors for favorable cognitive outcome post-stroke: A-seven-year follow-up study. Dement Geriatr Cogn Disord. 2019:1–11.
    1. Ihle-Hansen H, Thommessen B, Wyller TB, Engedal K, Oksengard AR, Stenset V, et al. Incidence and subtypes of MCI and dementia 1 year after first-ever stroke in patients without pre-existing cognitive impairment. Dement Geriatr Cogn Disord. 2011;32(6):401–407. doi: 10.1159/000335361.
    1. Jack CR, Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. The Lancet Neurology. 2013;12(2):207–216. doi: 10.1016/S1474-4422(12)70291-0.
    1. Jorm AF, Scott R, Cullen JS, MacKinnon AJ. Performance of the informant questionnaire on cognitive decline in the elderly (IQCODE) as a screening test for dementia. Psychol Med. 1991;21(3):785–790. doi: 10.1017/S0033291700022418.
    1. Hagberg G, Fure B, Sandset EC, Thommessen B, Ihle-Hansen H, Oksengard AR, et al. Long-term effects on survival after a 1-year multifactorial vascular risk factor intervention after stroke or TIA: secondary analysis of a randomized controlled trial, a 7-year follow-up study. Vasc Health Risk Manag. 2019;15:11–18. doi: 10.2147/VHRM.S191873.
    1. Adams HP, Jr, Biller J. Classification of subtypes of ischemic stroke: history of the trial of org 10172 in acute stroke treatment classification. Stroke. 2015;46(5):e114–e117. doi: 10.1161/STROKEAHA.114.007773.
    1. Goldstein LB, Bertels C, Davis JN. Interrater reliability of the NIH stroke scale. Arch Neurol. 1989;46(6):660–662. doi: 10.1001/archneur.1989.00520420080026.
    1. Folstein MF, Folstein SE, McHugh PR. "mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–198. doi: 10.1016/0022-3956(75)90026-6.
    1. Eddy JR, Sriram S. Clock-drawing and telling time as diagnostic aids. Neurology. 1977;27(6):595. doi: 10.1212/WNL.27.6.595.
    1. RM R. Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills 1958;8:271–276.
    1. Randolph C, Tierney MC, Mohr E, Chase TN. The repeatable battery for the assessment of neuropsychological status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 1998;20(3):310–319. doi: 10.1076/jcen.20.3.310.823.
    1. Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–699. doi: 10.1111/j.1532-5415.2005.53221.x.
    1. Barry D, Bates ME, Labouvie E. FAS and CFL forms of verbal fluency differ in difficulty: a meta-analytic study. Appl Neuropsychol. 2008;15(2):97–106. doi: 10.1080/09084280802083863.
    1. Sulter G, Steen C, De Keyser J. Use of the Barthel index and modified Rankin scale in acute stroke trials. Stroke. 1999;30(8):1538–1541. doi: 10.1161/01.STR.30.8.1538.
    1. Sjogren M, Vanderstichele H, Agren H, Zachrisson O, Edsbagge M, Wikkelso C, et al. Tau and Abeta42 in cerebrospinal fluid from healthy adults 21-93 years of age: establishment of reference values. Clin Chem. 2001;47(10):1776–1781. doi: 10.1093/clinchem/47.10.1776.
    1. Scheltens P, Weinstein HC, Leys D. Neuro-imaging in the diagnosis of Alzheimer's disease. I. Computer tomography and magnetic resonance imaging. Clin Neurol Neurosurg. 1992;94(4):277–289. doi: 10.1016/0303-8467(92)90175-3.
    1. Pantoni L, Basile AM, Pracucci G, Asplund K, Bogousslavsky J, Chabriat H, et al. Impact of age-related cerebral white matter changes on the transition to disability -- the LADIS study: rationale, design and methodology. Neuroepidemiology. 2005;24(1–2):51–62. doi: 10.1159/000081050.
    1. Pasquier F, Leys D, Weerts JG, Mounier-Vehier F, Barkhof F, Scheltens P. Inter- and intraobserver reproducibility of cerebral atrophy assessment on MRI scans with hemispheric infarcts. Eur Neurol. 1996;36(5):268–272. doi: 10.1159/000117270.
    1. Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002;33(3):341–355. doi: 10.1016/S0896-6273(02)00569-X.
    1. Chincarini A, Peira E, Morbelli S, Pardini M, Bauckneht M, Arbizu J, et al. Semi-quantification and grading of amyloid PET: a project of the European Alzheimer's disease consortium (EADC) NeuroImage Clinical. 2019;23:101846. doi: 10.1016/j.nicl.2019.101846.
    1. Buckley CJ, Sherwin PF, Smith AP, Wolber J, Weick SM, Brooks DJ. Validation of an electronic image reader training programme for interpretation of [18F] flutemetamol beta-amyloid PET brain images. Nucl Med Commun. 2017;38(3):234–241. doi: 10.1097/MNM.0000000000000633.
    1. Thal DR, Rub U, Orantes M, Braak H. Phases of a beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58(12):1791–1800. doi: 10.1212/WNL.58.12.1791.
    1. Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage. 2006;31(3):968–980. doi: 10.1016/j.neuroimage.2006.01.021.
    1. Thal DR, Attems J, Ewers M. Spreading of amyloid, tau, and microvascular pathology in Alzheimer's disease: findings from neuropathological and neuroimaging studies. Journal of Alzheimer's disease : JAD. 2014;42(Suppl 4):S421–S429. doi: 10.3233/JAD-141461.
    1. Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, et al. Mild cognitive impairment--beyond controversies, towards a consensus: report of the international working group on mild cognitive impairment. J Intern Med. 2004;256(3):240–246. doi: 10.1111/j.1365-2796.2004.01380.x.
    1. Thurfjell L, Lilja J, Lundqvist R, Buckley C, Smith A, Vandenberghe R, et al. Automated quantification of 18F-flutemetamol PET activity for categorizing scans as negative or positive for brain amyloid: concordance with visual image reads. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2014;55(10):1623–1628. doi: 10.2967/jnumed.114.142109.
    1. Petersen RC, Wiste HJ, Weigand SD, Rocca WA, Roberts RO, Mielke MM, et al. Association of Elevated Amyloid Levels with Cognition and Biomarkers in cognitively Normal people from the community. JAMA Neurol. 2016;73(1):85–92. doi: 10.1001/jamaneurol.2015.3098.
    1. Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. Jama. 2015;313(19):1924–1938. doi: 10.1001/jama.2015.4668.
    1. Logallo N, Novotny V, Assmus J, Kvistad CE, Alteheld L, Ronning OM, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. The Lancet Neurology. 2017;16(10):781–788. doi: 10.1016/S1474-4422(17)30253-3.
    1. Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019;25(2):270–276. doi: 10.1038/s41591-018-0297-y.
    1. Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and dysfunction of the blood-brain barrier. Cell. 2015;163(5):1064–1078. doi: 10.1016/j.cell.2015.10.067.
    1. Hesse C, Rosengren L, Vanmechelen E, Vanderstichele H, Jensen C, Davidsson P, et al. Cerebrospinal fluid markers for Alzheimer's disease evaluated after acute ischemic stroke. Journal of Alzheimer's disease : JAD. 2000;2(3–4):199–206. doi: 10.3233/JAD-2000-23-402.
    1. Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, et al. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol. 2015;11(8):457–470. doi: 10.1038/nrneurol.2015.119.
    1. Garcia-Alloza M, Gregory J, Kuchibhotla KV, Fine S, Wei Y, Ayata C, et al. Cerebrovascular lesions induce transient beta-amyloid deposition. Brain : a journal of neurology. 2011;134(Pt 12):3697–3707. doi: 10.1093/brain/awr300.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel