Molecular imaging using [123I]-metaiodobenzylguanidine cardiac scintigraphy (cardiac mIBG) can demonstrate the integrity of myocardial post-ganglionic sympathetic nerve terminals. Uptake of the mIBG tracer in the myocardium has been shown to be reduced in patients with Lewy body diseases, including dementia with Lewy bodies (DLB)Reference McKeith1,Reference Komatsu2 and mild cognitive impairment with Lewy bodies (MCI-LB),Reference McKeith3 and is a diagnostic biomarker in consensus criteria for both disease stages.
We previously reported that 22 of 37 participants with probable MCI-LB in the Newcastle SUPErB study had reduced cardiac mIBG uptake.Reference Roberts, Durcan, Donaghy, Lawley, Ciafone and Hamilton4 The remaining 15 participants meeting criteria for probable MCI-LB had baseline cardiac mIBG uptake within two standard deviations of that of healthy controls. Nine of these participants had baseline dopaminergic brain imaging within normal limits; six had abnormal results.
In this study, we rescanned participants with probable MCI-LB from the Newcastle SUPErB study who had normal cardiac mIBG uptake at baseline, after an interval of at least 2 years. We aimed to determine whether there was a significant change in cardiac mIBG uptake at follow-up and to identify the proportion of scans that changed from normal at baseline to abnormal at follow-up.
Method
Participants
The methods used for recruitment and assessment of participants have been detailed previously.Reference Roberts, Durcan, Donaghy, Lawley, Ciafone and Hamilton4 Participants with a diagnosis of probable MCI-LB who had normal baseline cardiac mIBG and who still met criteria for probable MCI-LB at follow-up were approached and asked to consent to a repeat scan. One participant was on a different serotonin–norepinephrine reuptake inhibitor at repeat scan compared with baseline; all other participants had no changes in medications known to interfere with mIBG uptake.Reference Jacobson and Travin5
Ethics statement
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All participants gave written informed consent to participate. The study received ethical approval from the National Research Ethics Service Committee North East Newcastle & North Tyneside 2 (ID 15/NE/0420).
The lead author, G.G., affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
Diagnosis
Consensus diagnoses of probable MCI-LB, possible MCI-LB or MCI due to Alzheimer's disease (MCI-AD) were made blinded to cardiac mIBG results, as described in our previous publications.Reference Roberts, Durcan, Donaghy, Lawley, Ciafone and Hamilton4,Reference Roberts, Lloyd, Kane, Durcan, Lawley and Howe6 Briefly, probable MCI-LB was diagnosed in participants with either two or more core features of Lewy body disease or at least one core feature with abnormal dopaminergic imaging. Participants were grouped as possible MCI-LB if they presented with only one core feature or abnormal dopaminergic imaging. Participants were grouped as MCI-AD if they had no core features, normal dopaminergic imaging and a decline characteristic of Alzheimer's disease.
Imaging
Cardiac mIBG scans were acquired using the same procedure and scanner as at baseline.Reference Roberts, Durcan, Donaghy, Lawley, Ciafone and Hamilton4,Reference Roberts, Lloyd, Kane, Durcan, Lawley and Howe6 Briefly, this consisted of a 111 MBq [123I]-mIBG injection and planar imaging at 3–4 h following injection using medium energy collimators. The heart to mediastinum ratio (HMR) at baseline and follow-up was calculated using the processing method developed in previous work.Reference Roberts, Kane, Lloyd, Petrides, Howe and O'Brien7 The baseline and follow-up images were processed at the same time, by the same operator (G.G.).
Analysis
HMR values were compared between baseline and repeat using a paired t-test, and the mean difference was recorded, with P-value and 95% confidence interval. The proportion of participants with repeat HMRs below the normal threshold of 1.85 was also recorded. The mean annual change in uptake was calculated using linear interpolation.
Results
Of the 15 participants with probable MCI-LB and normal scans, four could not be approached for a repeat scan as they had progressed to DLB (an endpoint within the main study criteria). One participant had died, one had withdrawn from the study and one participant was unwilling to attend owing to concerns about contracting COVID-19. The remaining eight participants were scanned between November 2020 and June 2021 (Table 1).
Table 1 Participant diagnostic features and imaging biomarker results
FP-CIT, [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([123I]Ioflupane); HMR, heart to mediastinum ratio; MCI-LB, mild cognitive impairment with Lewy bodies; mIBG, [123I]-metaiodobenzylguanidine; RBD, rapid eye movement sleep behaviour disorder; Pt, participant.
The mean change in HMR between baseline and repeat was −5.2% (range: −23.8% to +7.0%; Table 1). The interpolated mean change over a 12-month period was −1.6%. No significant change was found between baseline and repeat HMR (P = 0.22), and none of the participants had abnormal follow-up mIBG scans. Three of the eight participants had an HMR change greater than 10% (all lower at follow-up).
Discussion
In our previous publication, we reported that 41% of probable MCI-LB participants had normal cardiac mIBG scans at baseline; that is, they had an HMR within two standard deviations of the mean of local normal controls.Reference McKeith3 Eight of these participants consented to be rescanned between 2 and 4 years later, and all eight scans remained within normal limits. The participant with the greatest change in uptake (−24%) had had a pacemaker fitted between baseline and follow-up. However, this is not expected to reduce sympathetic innervation or attenuate tracer signal.
The annual mean change in uptake in our participants was −1.6%, a lower rate of change than that seen in patients with Parkinson's disease. Watanabe et alReference Watanabe, Takeda, Nakamagoe and Tamaoka8 conducted baseline and repeat cardiac mIBG imaging in 44 patients with Parkinson's disease, with a mean interval of 9 months. The mean change in cardiac uptake was −2.9%. However, as expected for a Parkinson's disease cohort, most scans showed low or absent uptake at baseline. Lamotte et alReference Lamotte, Holmes, Wu and Goldstein9 repeated [18F]-dopamine positron emission tomography in 31 participants with Parkinson's disease with a median follow-up of 3.5 years. They reported a mean annual change in cardiac uptake of −3% in patients with Parkinson's disease with orthostatic hypotension and −4% in Parkinson's disease patients without. We found no previous studies assessing change in cardiac sympathetic imaging in patients with either MCI-LB or DLB, so this study provides pilot data to inform the direction of future repeatability studies.
To estimate the longitudinal variability, we assumed that any increases in cardiac uptake in our study were random and reflected the repeatability. Two participants had increases in HMR, both of 7%. One participant, whose HMR dropped by 13%, has recently been assessed as not having a neurodegenerative disease after all. Excluding the two participants with large decreases in uptake of 19 and 24%, the mean change was 6%. This suggests that, in practice, there could be more variation in follow-up cardiac mIBG scanning than the 4% found by Bateman et alReference Bateman, Ananthasubramaniam, Berman, Gerson, Gropler and Henzlova10 with repeat scanning after 1–2 weeks. In our recent publication on serial dopaminergic imaging,Reference Durcan, Roberts, Hamilton, Donaghy, Howe and Colloby11 we also demonstrated higher test–retest repeatability than previously reported. This may have been because in our study repeat scans were done years after baseline and were designed to mimic typical clinical scans rather than following an unrealistic tightly controlled research protocol.
For five participants, there was no evidence of any decrease in cardiac mIBG uptake. These individuals may have no involvement of the cardiac sympathetic nervous system, or perhaps mild denervation that cannot yet be detected. The sensitivity of cardiac mIBG is known to be higher at the dementia stage.Reference Komatsu2 Raffel et al postulated that the molecular structure of the tracer makes cardiac mIBG imaging insensitive to mild to moderate changes in innervation.Reference Raffel, Jung, Gildersleeve, Sherman, Moskwa and Tluczek12,Reference Raffel, Koeppe, Jung, Gu, Jang and Sherman13 This suggests that planar [123I]-mIBG imaging may not be suitable for detecting subtle early changes in cardiac sympathetic function.
The key limitation of this extension to our main study was that we had no definitive reference standard for Lewy body disease, as no participants have yet donated brain tissue. Three participants had core clinical features of MCI-LB but normal scans at both baseline and follow-up. Their continued follow-up is of particular interest. Further limitations include the small all-male sample and that participants who had progressed to dementia could not be included. One participant was on a different antidepressant medication at repeat imaging compared with baseline; however, these were both the same serotonin–noradrenaline reuptake inhibitor class.
In conclusion, a decline in cardiac mIBG uptake compared with normal baseline imaging is seen in some individuals with MCI-LB, but the rate of change appears to be small. In our study, all follow-up scans remained within normal limits.
Data availability
The data and materials that support the findings of this study are available from the corresponding author, G.G., upon reasonable request.
Acknowledgements
We thank the people living with mild cognitive impairment who participated in this study and their family members for giving up so much of their time. We thank Helen Kain, research support secretary, for her ongoing support with patient liaison and data entry for the study; the Nuclear Medicine department at the Newcastle upon Tyne Hospitals NHS Foundation Trust for scanning the participants and reporting scans; and the staff of the National Institute for Health Research (NIHR) Clinical Research Network North East and Cumbria for their invaluable support with participant recruitment for this study.
Author contributions
G.G.: conception, organisation and execution of the research project; design and execution of the statistical analysis; and writing of the first draft of the manuscript. C.A.H.: organisation and execution of the research project; and review and critique of the manuscript. P.C.D.: execution of the research project; review and critique of the statistical analysis; and review and critique of the manuscript. M.F.: conception of the research project; design, review and critique of the statistical analysis, and review and critique of the manuscript. N.A.B.: organisation and execution of the research project; and review and critique of the manuscript. L.A.: conception and execution of the research project; design and review and critique of the statistical analysis; and review and critique of the manuscript. G.S.P.: conception and execution of the research project; and review and critique of the manuscript. J.-P.T.: conception and execution of the research project; design and review and critique of the statistical analysis; and review and critique of the manuscript. J.T.O.: conception and execution of the research project; design and review and critique of the statistical analysis; and review and critique of the manuscript. A.J.T.: conception and execution of the research project; design and review and critique of the statistical analysis; and writing of the first draft and review and critique of the manuscript.
Funding
The SUPErB study was funded by a major project research grant from Alzheimer's Research UK (ARUK-PG2015-13, principal investigator: A.J.T.) and the amendment for repeat scans by an ARUK local network grant (principal investigator: G.G.). Infrastructure support was provided to authors based at Newcastle University by the NIHR Newcastle Biomedical Research Centre, a partnership between Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. J.T.O. is supported by the NIHR Cambridge Biomedical Research Centre and the Cambridge Centre for Parkinson's Plus. P.C.D. is supported by the Medical Research Council (grant number MR/W000229/1).
Declaration of interest
G.G. has received honoraria from GE Healthcare for educational presentations; G.S.P. has received honoraria from GE Healthcare for educational presentations and fees for reporting dopaminergic imaging; and J.-P.T. has received honoraria from GE Healthcare for delivering educational presentations on Lewy body disease and has consulted for Sosei-Heptares and Kyowa-Kirin. J.T.O. has no conflicts related to this work. Outside this work, he has acted as a consultant for TauRx, Novo Nordisk, Biogen, Roche, Lilly and GE Healthcare and has received grant or academic support from Avid/Lilly, Merck and Alliance Medical. A.J.T. has received support for investigator-led studies and honoraria from GE Healthcare.
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