Elsevier

Neurobiology of Aging

Volume 96, December 2020, Pages 137-147
Neurobiology of Aging

Regular article
Multimodal in vivo and postmortem assessments of tau in Lewy body disorders

https://doi.org/10.1016/j.neurobiolaging.2020.08.003Get rights and content

Highlights

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    LBD has moderate intensity 18F-Flortaucipir retention in temporo-parietal regions.

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    LBD with low CSF Aβ42 has more regions of elevated 18F-Flortaucipir retention.

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    In LBD, 18F-Flortaucipir retention relates to CSF total-tau.

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    In LBD, regional 18F-Flortaucipir retention relates to cognitive dysfunction.

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    In LBD, neuropathologic tau is higher in regions with greater retention.

Abstract

We compared regional retention of 18F-flortaucipir between 20 patients with Lewy body disorders (LBD), 12 Alzheimer’s disease patients with positive amyloid positron emission tomography (PET) scans (AD+Aβ) and 15 healthy controls with negative amyloid PET scans (HC−Aβ). In LBD subjects, we compared the relationship between 18F-flortaucipir retention and cerebrospinal fluid (CSF) tau, cognitive performance, and neuropathological tau at autopsy. The LBD cohort was stratified using an Aβ42 cut-off of 192 pg/mL to enrich for groups likely harboring tau pathology (LBD+Aβ = 11, LBD−Aβ = 9). 18F-flortaucipir retention was higher in LBD+AB than HC−Aβ in five, largely temporal-parietal regions with sparing of medial temporal regions. Higher retention was associated with higher CSF total-tau levels (p = 0.04), poorer domain-specific cognitive performance (p = 0.02–0.04), and greater severity of neuropathological tau in corresponding regions. While 18F-flortaucipir retention in LBD is intermediate between healthy controls and AD, retention relates to cognitive impairment, CSF total-tau, and neuropathological tau. Future work in larger autopsy-validated cohorts is needed to define LBD-specific tau biomarker profiles.

Introduction

Lewy body disorders (LBD)—dementia with Lewy bodies (DLB) and Parkinson’s disease (PD)—are characterized pathologically by alpha-synuclein (SYN) inclusions in postmortem tissue; however, a significant proportion (>50%) of LBD patients have moderate to severe co-occurring Alzheimer’s disease (AD) pathology (Aβ [amyloid beta] plaques and tau neurofibrillary tangles) sufficient for a secondary neuropathological diagnosis of AD (Irwin et al., 2017a). These levels of AD co-pathology are clinically relevant and associated with faster time to dementia, decreased overall survival (Irwin et al., 2017a; Jellinger et al., 2002), and contribute to specific cognitive and motor features in LBD (Coughlin et al., 2019a, Coughlin et al., 2019b; Peavy et al., 2016). Molecular PET (positron emission tomography) imaging provides important in vivo information on the regional distribution of proteinopathies that otherwise has only previously been assessable at autopsy. 18F-flortaucipir is a PET tracer with affinity for paired helical 33R/4R tau (Marquié et al., 2015) that shows increased retention in AD, with binding patterns consistent with pathologic distributions of tau in amnestic and non-amnestic variants (Nasrallah et al., 2018; Pontecorvo et al., 2017), and has recently been approved for use in evaluation for suspected AD based on postmortem studies (Fleisher et al., 2020) based on postmortem work but limited data exist in LBD. In LBD, paired helical 3R/4R tau accumulations are similar to that which is seen in AD (Iseki et al., 2003) and reports of 18F-flortaucipir in LBD find increased retention in temporal, occipital, and parietal lobes, with lower standardized uptake value ratio (SUVR) values than typically seen in AD patients (Gomperts et al., 2016; Kantarci et al., 2017; Lee et al., 2018; Smith et al., 2018). In multimodal PET imaging studies, LBD patients with increased 18F-flortaucipir often show evidence of co-occurring cerebral amyloidosis (Kantarci et al., 2017; Lee et al., 2018) but relationships between 18F-flortaucipir retention and other biomarkers, including cerebrospinal fluid (CSF), are understudied.

We previously found that postmortem tau in LBD has a distinct regional distribution compared to AD, with relatively more tau present in temporal neocortex. Tau pathology was also associated with region-specific cognitive deficits across multiple domains (Coughlin et al., 2019a). Here we use a multimodal approach to examine in vivo tau biomarker profiles in a deeply phenotyped cohort of 20 LBD patients with 18F-flortaucipir PET scanning, CSF sampling, and neuropsychological testing in close temporal proximity with the hypotheses that LBD patients with abnormal CSF Aβ would show regions of increased 18F-flortaucipir compared to healthy controls and that 18F-flortaucipir retention would correlate with CSF tau measures, region-specific neuropsychological performance, and neuropathological tau at autopsy.

Section snippets

Patients

Twenty patients with LBD (DLB: N = 15, PD-MCI [mild cognitive impairment]: N = 4, PDD: N = 1) were enrolled from the University of Pennsylvania’s Movement Disorder Clinic, Frontotemporal Degeneration Center, and/or Alzheimer’s Disease Core Center. All met clinical criteria for probable DLB (McKeith et al., 2017), PD-MCI (Litvan et al., 2011), or PDD (Emre et al., 2007). Five of 20 patients had 123I-Ioflupane single-photon emission computed tomography scans, all of which showed evidence of

Patient characteristics

Patient characteristics are described in Table 1. There were more female participants in the AD+Aβ and HC−Aβ group than in the LBD cohort (χ2 (1) = 11.5, 5.8, p = 0.001, 0.03 respectively), and therefore we covary for sex in all subsequent analyses. LBD+Aβ participants performed worse than LBD−Aβ on MMSE testing (t (18) = 2.4, p = 0.03) and had fewer years of education (t (18) = 3.4, p = 0.004) but otherwise there were no differences in characteristics. There were no significant differences in

Discussion

We examined 18F-flortaucipir retention patterns in LBD patients with cognitive impairment compared to amyloid PET-negative healthy controls and amyloid PET-positive AD patients from the ADNI study matched on age and cognitive impairment. This is a unique multimodal study of 18F-flortaucipir PET imaging, biofluid tau markers, and neuropathological tau in LBD. We find several regions of increased 18F-flortaucipir retention in LBD patients with CSF measurements consistent with cerebral amyloidosis

Disclosure statement

Siderowf was a full time employee of AVID radiopharmaceuticals from July 2012 to June 2017.

CRediT authorship contribution statement

David G. Coughlin: Conceptualization, Formal analysis, Data curation, Investigation, Writing - original draft, Writing - review & editing, Visualization. Jeffrey S. Phillips: Formal analysis, Investigation, Data curation, Visualization, Writing - review & editing. Emily Roll: Data curation, Visualization. Claire Peterson: Data curation, Visualization, Software, Methodology. Rebecca Lobrovich: Data curation, Investigation, Visualization. Katya Rascovsky: Investigation. Molly Ungrady:

Acknowledgments:

Dr. Coughlin is currently affiliated with the University of California San Diego Department of Neurosciences; however, the original work was performed while he was employed at the University of Pennsylvania. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the

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    • Cited by (0)

    Current address of David G. Coughlin: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA

    David J. Irwin and Corey T. McMillan contributed equally to this article.

    Role of the funding source: Avid Radiopharmaceuticals provided 18F-flortaucipir tracer used in this study and were involved in the decision to publish the paper. They were not involved in study design, collection or data, analysis or interpretation of data, or the writing of this report.

    1

    Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

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