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Performance of [18F]RO948 PET, MRI and CSF neurofilament light in the differential diagnosis of progressive supranuclear palsy

Open AccessPublished:November 17, 2022DOI:https://doi.org/10.1016/j.parkreldis.2022.11.018

      Highlights

      • First evaluation of [18F]RO948 PET signal in the basal ganglia as a biomarker for PSP.
      • [18F]RO948 PET, MRI and CSF NfL contribute individually to separate PSP patients from controls and from LBD patients.
      • A model with all studied biomarkers combined was the most effective in separating PSP from LBD.

      Abstract

      Introduction

      The diagnosis of progressive supranuclear palsy (PSP) is often challenging since PSP may clinically resemble other neurodegenerative disorders. Recently, the tau PET tracer [18F]RO948, a potential new biomarker for PSP, was developed. The aim of this study was to determine the ability of three different biomarkers, including [18F]RO948 PET, to distinguish PSP patients from healthy controls and from patients with α-synucleinopathies.

      Methods

      Patients with PSP (n = 23), α-synucleinopathies (n = 47) and healthy controls (n = 61) were included from the BioFINDER-2 study. [18F]RO948 standardized uptake value ratios (SUVR), magnetic resonance imaging midbrain/pons ratio, and cerebrospinal fluid neurofilament light (NfL) levels were compared between diagnostic groups individually and in combination.

      Results

      [18F]RO948 PET SUVR in the globus pallidus, NfL, and midbrain/pons area ratios were all able to differentiate PSP patients from controls and from patients with α-synucleinopathies ([18F]RO948 [mean ± SD]: controls 1.24 ± 0.22; PSP 1.47 ± 0.4; PD 1.18 ± 0.2; DLB 1.25 ± 0.24, p < 0.05), (NfL pg/mL [mean ± SD]: controls 1055 ± 569; PSP 2197 ± 1010; PD 1038 ± 416; DLB 1548 ± 687, p < 0.001) and (midbrain/pons ratio [mean ± SD]: controls 0.46 ± 0.07; PSP 0.34 ± 0.09; PD 0.43 ± 0.06; DLB 0.40 ± 0.07, p < 0.01). Receiver operating characteristic (ROC) analyses indicated that combining the three biomarkers resulted in the highest area under the ROC values (0.94 [0.88–1.00]) for separating controls from PSP and (0.92 [0.85–0.99]) for separating PSP from α-synucleinopathies.

      Conclusions

      All studied biomarkers could individually separate PSP from controls and α-synucleinopathies patients at a group level. The optimal prediction models included NfL and midbrain/pons ratio for separating controls from PSP and all three biomarkers for separating PSP from α-synucleinopathies.

      1. Introduction

      Progressive supranuclear palsy (PSP) is a neurodegenerative disease that was first described in 1964 [
      • Steele J.C.
      • Richardson J.C.
      • Olszewski J.
      Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia.
      ]. The classic presentation is characterized by supranuclear gaze palsy, axial rigidity, postural instability with falls and cognitive decline. Though the symptomatology of PSP can resemble that of Parkinson's disease (PD) it is caused by the accumulation of 4-repeat tau instead of α-synuclein [
      • Rösler T.W.
      • Tayaranian Marvian A.
      • Brendel M.
      • Nykänen N.P.
      • Höllerhage M.
      • Schwarz S.C.
      • Hopfner F.
      • Koeglsperger T.
      • Respondek G.
      • Schweyer K.
      • Levin J.
      • Villemagne V.L.
      • Barthel H.
      • Sabri O.
      • Müller U.
      • Meissner W.G.
      • Kovacs G.G.
      • Höglinger G.U.
      Four-repeat tauopathies.
      ], and can be diagnosed post-mortem by the presence of tau protein in tufted tau positive astrocytes, and atrophy of the globus pallidus, the midbrain, and the subthalamic nucleus [
      • Rösler T.W.
      • Tayaranian Marvian A.
      • Brendel M.
      • Nykänen N.P.
      • Höllerhage M.
      • Schwarz S.C.
      • Hopfner F.
      • Koeglsperger T.
      • Respondek G.
      • Schweyer K.
      • Levin J.
      • Villemagne V.L.
      • Barthel H.
      • Sabri O.
      • Müller U.
      • Meissner W.G.
      • Kovacs G.G.
      • Höglinger G.U.
      Four-repeat tauopathies.
      ,
      • Williams D.R.
      • Lees A.J.
      Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges.
      ]. PSP is classified as a parkinsonian disorder together with multiple system atrophy (MSA), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) [
      • Levin J.
      • Kurz A.
      • Arzberger T.
      • Giese A.
      • Höglinger G.U.
      The differential diagnosis and treatment of atypical parkinsonism.
      ]. Though modern clinical criteria for PSP have shown improved sensitivity compared to earlier criteria for PSP and perform favourably in comparison to clinical criteria for other neurodegenerative disorders [
      • Ali F.
      • Martin P.R.
      • Botha H.
      • Ahlskog J.E.
      • Bower J.H.
      • Masumoto J.Y.
      • Maraganore D.
      • Hassan A.
      • Eggers S.
      • Boeve B.F.
      • Knopman D.S.
      • Drubach D.
      • Petersen R.C.
      • Dunkley E.D.
      • van Gerpen J.
      • Uitti R.
      • Whitwell J.L.
      • Dickson D.W.
      • Josephs K.A.
      Sensitivity and specificity of diagnostic criteria for progressive supranuclear palsy.
      ], false positives remain a challenge due to the overlap in symptoms between PSP and other parkinsonian disorders. As a result, biomarkers are increasingly used to help in the diagnosis of PSP, including the calculation of a midbrain to pons (midbrain/pons) atrophy ratio using magnetic resonance imaging (MRI) [
      • Massey L.A.
      • Jäger H.R.
      • Paviour D.C.
      • O'Sullivan S.S.
      • Ling H.
      • Williams D.R.
      • Kallis C.
      • Holton J.
      • Revesz T.
      • Burn D.J.
      • Yousry T.
      • Lees A.J.
      • Fox N.C.
      • Micallef C.
      The midbrain to pons ratio: a simple and specific MRI sign of progressive supranuclear palsy.
      ]. This atrophy is often present early on in the disease course, enabling a relatively early diagnosis [
      • Ahn J.H.
      • Kim M.
      • Kim J.S.
      • Youn J.
      • Jang W.
      • Oh E.
      • Lee P.H.
      • Koh S.B.
      • Ahn T.B.
      • Cho J.W.
      Midbrain atrophy in patients with presymptomatic progressive supranuclear palsy-Richardson's syndrome.
      ]. Another biomarker that has been studied in neurodegenerative diseases is neurofilament light (NfL), a protein that is a part of the intermediate filament structure of neurons and abundantly present in large, myelinated axons. Higher concentrations of cerebrospinal fluid (CSF) NfL have been shown in PSP and other atypical parkinsonian disorders (MSA and CBD), as compared to PD [
      • Hall S.
      • Öhrfelt A.
      • Constantinescu R.
      • Andreasson U.
      • Surova Y.
      • Bostrom F.
      • Nilsson C.
      • Håkan W.
      • Decraemer H.
      • Någga K.
      • Minthon L.
      • Londos E.
      • Vanmechelen E.
      • Holmberg B.
      • Zetterberg H.
      • Blennow K.
      • Hansson O.
      Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders.
      ,
      • Constantinescu R.
      • Rosengren L.
      • Johnels B.
      • Zetterberg H.
      • Holmberg B.
      Consecutive analyses of cerebrospinal fluid axonal and glial markers in Parkinson's disease and atypical Parkinsonian disorders.
      ].
      An extensive amount of research has been performed over the past few years with the aim of finding tau-specific ligands that enable the visualisation and quantification of tau deposits using positron emission tomography (PET) [
      • Mattsson-Carlgren N.
      • Janelidze S.
      • Bateman R.J.
      • Smith R.
      • Stomrud E.
      • Serrano G.E.
      • Reiman E.M.
      • Palmqvist S.
      • Dage J.L.
      • Beach T.G.
      • Hansson O.
      Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau.
      ]. While tau PET has been shown to reliably detect the mixed 3 and 4 repeat tau found in Alzheimer's disease (AD) [
      • Ossenkoppele R.
      • Rabinovici G.D.
      • Smith R.
      • Cho H.
      • Schöll M.
      • Strandberg O.
      • Palmqvist S.
      • Mattsson N.
      • Janelidze S.
      • Santillo A.
      • Ohlsson T.
      • Jögi J.
      • Tsai R.
      • La Joie R.
      • Kramer J.
      • Boxer A.L.
      • Gorno-Tempini M.L.
      • Miller B.L.
      • Choi J.Y.
      • Ryu Y.H.
      • Lyoo C.H.
      • Hansson O.
      Discriminative accuracy of [18F]flortaucipir positron emission tomography for alzheimer disease vs other neurodegenerative disorders.
      ,
      • Leuzy A.
      • Smith R.
      • Ossenkoppele R.
      • Santillo A.
      • Borroni E.
      • Klein G.
      • Ohlsson T.
      • Jögi J.
      • Palmqvist S.
      • Mattsson-Carlgren N.
      • Strandberg O.
      • Stomrud E.
      • Hansson O.
      Diagnostic performance of RO948 F 18 tau positron emission tomography in the differentiation of alzheimer disease from other neurodegenerative disorders.
      ], capturing tau pathology in non-AD disorders has proved more challenging. Though the uptake of [18F]flortaucipir - to date, the most studied tau PET tracer - has been found to be increased in the basal ganglia in PSP compared to controls at a group level [
      • Smith R.
      • Schain M.
      • Nilsson C.
      • Strandberg O.
      • Olsson T.
      • Hägerström D.
      • Jögi J.
      • Borroni E.
      • Schöll M.
      • Honer M.
      • Hansson O.
      Increased basal ganglia binding of (18) F-AV-1451 in patients with progressive supranuclear palsy.
      ,
      • Cho H.
      • Choi J.Y.
      • Lee S.H.
      • Ryu Y.H.
      • Lee M.S.
      • Lyoo C.H.
      (18) F-AV-1451 binds to putamen in multiple system atrophy.
      ,
      • Whitwell J.L.
      • Lowe V.J.
      • Tosakulwong N.
      • Weigand S.D.
      • Senjem M.L.
      • Schwarz C.G.
      • Spychalla A.J.
      • Petersen R.C.
      • Jack Jr., C.R.
      • Josephs K.A.
      [(18) F]AV-1451 tau positron emission tomography in progressive supranuclear palsy.
      ], its tendency to show off-target binding in the basal ganglia reduces the ability to reliably separate PSP patients from controls at an individual level. More promise, however, has been tied to novel tau tracers with reduced basal ganglia retention, such as [18F]PI-2620 and [18F]RO948. Using [18F]PI-2620, PSP patients could be separated from controls with a sensitivity of 85% and a specificity of 77% [
      • Brendel M.
      • Barthel H.
      • van Eimeren T.
      • Marek K.
      • Beyer L.
      • Song M.
      • Palleis C.
      • Gehmeyr M.
      • Fietzek U.
      • Respondek G.
      • Sauerbeck J.
      • Nitschmann A.
      • Zach C.
      • Hammes J.
      • Barbe M.T.
      • Onur O.
      • Jessen F.
      • Saur D.
      • Schroeter M.L.
      • Rumpf J.J.
      • Rullmann M.
      • Schildan A.
      • Patt M.
      • Neumaier B.
      • Barret O.
      • Madonia J.
      • Russell D.S.
      • Stephens A.
      • Roeber S.
      • Herms J.
      • Bötzel K.
      • Classen J.
      • Bartenstein P.
      • Villemagne V.
      • Levin J.
      • Höglinger G.U.
      • Drzezga A.
      • Seibyl J.
      • Sabri O.
      Assessment of 18F-PI-2620 as a biomarker in progressive supranuclear palsy.
      ], with the most significant difference in tracer retention between groups seen in the globus pallidus. A head-to-head comparison between [18F]Flortaucipir and [18F]RO948 indicated that [18F]RO948 has little or no off-target binding in the basal ganglia [
      • Smith R.
      • Schöll M.
      • Leuzy A.
      • Jögi J.
      • Ohlsson T.
      • Strandberg O.
      • Hansson O.
      Head-to-head comparison of tau positron emission tomography tracers [(18)F]flortaucipir and [(18)F]RO948.
      ]. Previous studies using [18F]RO948 have primarily focused on [18F]RO948 binding in AD. The tracer can detect concomitant tau pathology in DLB [
      • Hall S.
      • Janelidze S.
      • Londos E.
      • Leuzy A.
      • Stomrud E.
      • Dage J.L.
      • Hansson O.
      Plasma phospho-tau identifies alzheimer's Co-pathology in patients with Lewy body disease.
      ], but cortical retention of [18F]RO948 in other neurodegenerative disorders, including PSP, PD and MSA is limited [
      • Leuzy A.
      • Smith R.
      • Ossenkoppele R.
      • Santillo A.
      • Borroni E.
      • Klein G.
      • Ohlsson T.
      • Jögi J.
      • Palmqvist S.
      • Mattsson-Carlgren N.
      • Strandberg O.
      • Stomrud E.
      • Hansson O.
      Diagnostic performance of RO948 F 18 tau positron emission tomography in the differentiation of alzheimer disease from other neurodegenerative disorders.
      ]. To date, no studies have been performed analyzing the diagnostic value of [18F]RO948 PET signal in the basal ganglia in PSP patients. The aims of this study were therefore to assess the performance of [18F]RO948 PET in the basal ganglia as a biomarker for separating PSP patients from controls and patients with α-synucleinopathies in comparison to established PSP biomarkers such as the midbrain/pons volume ratio and CSF NfL, and to find the most parsimonious biomarker model for separating these disorders.

      2. Material and methods

      2.1 Participants

      Participants were recruited from the Neurology and Memory clinics at Skåne University Hospital, Sweden as part of the ongoing Swedish BioFINDER-2 study (www.biofinder.se; NCT03174938). We included 23 participants with PSP [
      • Höglinger G.U.
      • Respondek G.
      • Stamelou M.
      • Kurz C.
      • Josephs K.A.
      • Lang A.E.
      • Mollenhauer B.
      • Müller U.
      • Nilsson C.
      • Whitwell J.L.
      • Arzberger T.
      • Englund E.
      • Gelpi E.
      • Giese A.
      • Irwin D.J.
      • Meissner W.G.
      • Pantelyat A.
      • Rajput A.
      • van Swieten J.C.
      • Troakes C.
      • Antonini A.
      • Bhatia K.P.
      • Bordelon Y.
      • Compta Y.
      • Corvol J.C.
      • Colosimo C.
      • Dickson D.W.
      • Dodel R.
      • Ferguson L.
      • Grossman M.
      • Kassubek J.
      • Krismer F.
      • Levin J.
      • Lorenzl S.
      • Morris H.R.
      • Nestor P.
      • Oertel W.H.
      • Poewe W.
      • Rabinovici G.
      • Rowe J.B.
      • Schellenberg G.D.
      • Seppi K.
      • van Eimeren T.
      • Wenning G.K.
      • Boxer A.L.
      • Golbe L.I.
      • Litvan I.
      Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria.
      ], 22 participants with PD [
      • Gelb D.J.
      • Oliver E.
      • Gilman S.
      Diagnostic criteria for Parkinson disease.
      ] and 25 participants with DLB [
      • McKeith I.G.
      • Boeve B.F.
      • Dickson D.W.
      • Halliday G.
      • Taylor J.P.
      • Weintraub D.
      • Aarsland D.
      • Galvin J.
      • Attems J.
      • Ballard C.G.
      • Bayston A.
      • Beach T.G.
      • Blanc F.
      • Bohnen N.
      • Bonanni L.
      • Bras J.
      • Brundin P.
      • Burn D.
      • Chen-Plotkin A.
      • Duda J.E.
      • El-Agnaf O.
      • Feldman H.
      • Ferman T.J.
      • Ffytche D.
      • Fujishiro H.
      • Galasko D.
      • Goldman J.G.
      • Gomperts S.N.
      • Graff-Radford N.R.
      • Honig L.S.
      • Iranzo A.
      • Kantarci K.
      • Kaufer D.
      • Kukull W.
      • Lee V.M.Y.
      • Leverenz J.B.
      • Lewis S.
      • Lippa C.
      • Lunde A.
      • Masellis M.
      • Masliah E.
      • McLean P.
      • Mollenhauer B.
      • Montine T.J.
      • Moreno E.
      • Mori E.
      • Murray M.
      • O'Brien J.T.
      • Orimo S.
      • Postuma R.B.
      • Ramaswamy S.
      • Ross O.A.
      • Salmon D.P.
      • Singleton A.
      • Taylor A.
      • Thomas A.
      • Tiraboschi P.
      • Toledo J.B.
      • Trojanowski J.Q.
      • Tsuang D.
      • Walker Z.
      • Yamada M.
      • Kosaka K.
      Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium.
      ]. PD was then sub-classified as Tremor-Dominant (TD) or Postural Instability/Gait difficulties (PIGD) [
      • Stebbins G.T.
      • Goetz C.G.
      • Burn D.J.
      • Jankovic J.
      • Khoo T.K.
      • Tilley B.C.
      How to identify tremor dominant and postural instability/gait difficulty groups with the movement disorder society unified Parkinson's disease rating scale: comparison with the unified Parkinson's disease rating scale.
      ] (Table 1). The different PSP clinical subtypes were defined according to Höglinger et al. [
      • Höglinger G.U.
      • Respondek G.
      • Stamelou M.
      • Kurz C.
      • Josephs K.A.
      • Lang A.E.
      • Mollenhauer B.
      • Müller U.
      • Nilsson C.
      • Whitwell J.L.
      • Arzberger T.
      • Englund E.
      • Gelpi E.
      • Giese A.
      • Irwin D.J.
      • Meissner W.G.
      • Pantelyat A.
      • Rajput A.
      • van Swieten J.C.
      • Troakes C.
      • Antonini A.
      • Bhatia K.P.
      • Bordelon Y.
      • Compta Y.
      • Corvol J.C.
      • Colosimo C.
      • Dickson D.W.
      • Dodel R.
      • Ferguson L.
      • Grossman M.
      • Kassubek J.
      • Krismer F.
      • Levin J.
      • Lorenzl S.
      • Morris H.R.
      • Nestor P.
      • Oertel W.H.
      • Poewe W.
      • Rabinovici G.
      • Rowe J.B.
      • Schellenberg G.D.
      • Seppi K.
      • van Eimeren T.
      • Wenning G.K.
      • Boxer A.L.
      • Golbe L.I.
      • Litvan I.
      Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria.
      ] and are provided in Table 1. All patients with PSP with Richardson's syndrome (PSP-RS) subtype were classified as “probable” but 1 patient that was classified as “definite” and 1 that was classified as “possible” according to the diagnostic criteria. 2 patients in the PSP-group and 2 patients in the PD-group were CSF Aβ-positive. 61 age-matched cognitively unimpaired, Aβ-negative, healthy controls were enrolled from the prospective Malmö Diet and Cancer study cohort [
      • Manjer J.
      • Carlsson S.
      • Elmståhl S.
      • Gullberg B.
      • Janzon L.
      • Lindström M.
      • Mattisson I.
      • Berglund G.
      The Malmö Diet and Cancer Study: representativity, cancer incidence and mortality in participants and non-participants.
      ]. At the baseline visit participants underwent cognitive screening (MMSE and Animal fluency tests). Written informed consent was obtained from all patients before inclusion in the study. All procedures were approved by the Regional Ethics Committee at Lund University, the Radiation Protection Committee at Skåne University Hospital, and the Swedish Medical Products Agency.
      Table 1Demographics.
      Healthy ControlsPSPPDDLBp-values
      N61232225
      Clinical subtypes, N (%)PSP-RS, 10 (43.5)

      PSP-P, 6 (26)

      PSP-F, 4 (17.4)

      PSP-PGF, 2 (8.7)

      PSP-SL, 1 (4.3)
      TD, 5 (22.7)

      PIGD, 11 (50)

      Indeterminate, 6 (27.3)
      Age, mean ± SD, years71.9 ± 8.869.1 ± 8.470.9 ± 10.273.9 ± 6.3n.s.
      Sex, (Male/Female)28/3310/1313/920/5HC vs DLB ***

      PSP vs DLB *
      MMSE, mean ± SD28.9 ± 1.225.5 ± 3.427.7 ± 3.422.6 ± 5.3HC vs PSP ***

      HC vs DLB ***

      PSP vs DLB **

      PD vs DLB ***
      Disease duration, mean ± SD, years3.55 ± 2.03.2 ± 3.34.32 ± 2.9n.s. (PSPvsDLBvsPD)
      Animal fluency, mean ± SD24 ± 611 ± 718 ± 714 ± 7HC vs PSP ***

      HC vs PD ***

      HC vs DLB ***

      PSP vs PD ***

      PD vs DLB *
      β-amyloid positivity (%)08.79.152
      Tau PET SUVR putamen, mean ± SD1.15 ± 0.181.18 ± 0.221.11 ± 0.171.15 ± 0.17n.s.
      Tau PET SUVR globus pallidus, mean ± SD1.24 ± 0.221.47 ± 0.381.18 ± 0.21.25 ± 0.24HC vs PSP *

      PSP vs PD ***

      PSP vs DLB *
      Tau PET SUVR substantia nigra, mean ± SD2.03 ± 0.331.83 ± 0.351.66 ± 0.241.71 ± 0.33HC vs PSP *

      HC vs PD ***

      HC vs DLB ***
      CSF NfL pg/mL, mean ± SD1055 ± 5692197 ± 10101038 ± 4161548 ± 687HC vs PSP ***

      HC vs DLB ***

      PSP vs PD ***

      PSP vs DLB **

      PD vs DLB *
      CSF total tau pg/mL, mean ± SD318.4 ± 127.4242.9 ± 106287.7 ± 113.7335.4 ± 172.33n.s.
      Midbrain/Pons ratio, mean ± SD0.46 ± 0.070.34 ± 0.090.43 ± 0.060.4 ± 0.07HC vs PSP ***

      HC vs DLB ***

      PSP vs PD ***

      DLB vs PSP *
      Baseline demographic characteristics. CSF – cerebrospinal fluid; DLB – Dementia with Lewy Bodies; PD – Parkinson's Disease; PIGD – Parkinson's disease with postural instability/gait difficulty; PSP – Progressive Supranuclear Palsy; PSP-F - PSP with predominant frontotemporal dysfunction; PSP-P - PSP with predominant parkinsonism; PSP-PGF - PSP with progressive gait freezing; PSP-RS - PSP with Richardson's syndrome; PSP-SL- PSP with speech/language disorders; SD – standard deviation; SUVR – standardized uptake value ratio; TD – tremor dominant Parkinson's disease. *p < 0.05, **p < 0.01, ***p < 0.001. n.s. – non significant.

      2.2 MRI imaging, PET scanning, and CSF analysis

      T1-weighted magnetization-prepared rapid acquisition with gradient echo (MP-RAGE) images were obtained using a 3T Siemens Magnetom Prisma MRI scanner (resolution 1 mm3) and were used to determine midbrain/pons area ratios. Ratios were calculated by a rater blinded to the clinical diagnosis of each participant following manual segmentation of midsagittal images using ITK SNAP (version 3.6.0) as previously described [
      • Massey L.A.
      • Jäger H.R.
      • Paviour D.C.
      • O'Sullivan S.S.
      • Ling H.
      • Williams D.R.
      • Kallis C.
      • Holton J.
      • Revesz T.
      • Burn D.J.
      • Yousry T.
      • Lees A.J.
      • Fox N.C.
      • Micallef C.
      The midbrain to pons ratio: a simple and specific MRI sign of progressive supranuclear palsy.
      ,
      • Ahn J.H.
      • Kim M.
      • Kim J.S.
      • Youn J.
      • Jang W.
      • Oh E.
      • Lee P.H.
      • Koh S.B.
      • Ahn T.B.
      • Cho J.W.
      Midbrain atrophy in patients with presymptomatic progressive supranuclear palsy-Richardson's syndrome.
      ].
      The participants underwent [18F]RO948 PET scans on digital PET/CT scanners (Discovery MI; GE Healthcare). Images were acquired as 4 × 5 minute time frames 70–90 min after an intravenous bolus injection of ∼370 MBq of [18F]RO948. PET images were calculated as standardized uptake value ratio (SUVRs) images with the inferior cerebellar cortex region as reference region. For image coregistration, grey/white matter segmentation, template normalization, and parcellation of grey matter into regions-of-interest (ROIs) the T1-weighted MP-RAGE MRI image was used. Parcellation into cortical and subcortical ROIs was performed using Free Surfer 6.0. To evaluate the performance of [18F]RO948 PET in differentiating PSP patients from controls and other diseases, the mean (left and right, volume weighted) SUVRs in the globus pallidus, putamen and substantia nigra were utilized.
      The analysis and collection procedure of CSF followed the Alzheimer's Association Flow Chart for CSF biomarkers [
      • Blennow K.
      • Hampel H.
      • Weiner M.
      • Zetterberg H.
      Cerebrospinal fluid and plasma biomarkers in Alzheimer disease.
      ]. CSF NfL levels were determined in clinical routine analysis at Sahlgrenska University Hospital, Gothenburg, Sweden [
      • Gaetani L.
      • Höglund K.
      • Parnetti L.
      • Pujol-Calderon F.
      • Becker B.
      • Eusebi P.
      • Sarchielli P.
      • Calabresi P.
      • Di Filippo M.
      • Zetterberg H.
      • Blennow K.
      A new enzyme-linked immunosorbent assay for neurofilament light in cerebrospinal fluid: analytical validation and clinical evaluation.
      ]. CSF Aβ-42/40 ratio levels were determined using a Mesoscale Discovery assay (MSD; Rockville, MD, USA) and <0.752 used as cut off [
      • Palmqvist S.
      • Janelidze S.
      • Quiroz Y.T.
      • Zetterberg H.
      • Lopera F.
      • Stomrud E.
      • Su Y.
      • Chen Y.
      • Serrano G.E.
      • Leuzy A.
      • Mattsson-Carlgren N.
      • Strandberg O.
      • Smith R.
      • Villegas A.
      • Sepulveda-Falla D.
      • Chai X.
      • Proctor N.K.
      • Beach T.G.
      • Blennow K.
      • Dage J.L.
      • Reiman E.M.
      • Hansson O.
      Discriminative accuracy of plasma phospho-tau217 for alzheimer disease vs other neurodegenerative disorders.
      ].

      2.3 Statistical analysis

      All statistical analyses were performed using R version (4.0.3). The mean SUVRs in the globus pallidus, the midbrain/pons volume ratio and mean CSF NfL levels were compared between groups using Kruskal-Wallis tests. When significant, Mann-Whitney U-tests were performed between groups. Comparisons of differences in sex distribution were performed using Chi Square tests. Correlations between biomarkers and clinical tests were calculated using Pearson's correlations. Receiver operating characteristic (ROC) analyses were performed and an area under the ROC curve (AUC) was calculated for each diagnostic method comparing two patient groups at a time. ROC analyses were adjusted for age and gender. AUC were presented with a 95% confidence interval (CI) and differences were assessed using Roc.test (pROC) with 2000 bootstraps for two correlated ROC curves.
      To assess the individual contribution of the biomarkers in the diagnosis of PSP compared to healthy controls or to α-synucleinopathies (PD and DLB combined) we performed logistic regressions with diagnosis as the outcome variable, age and sex as covariates and the three biomarkers as predictors. The models were assessed sequentially, with t-values (and p-values) calculated for each biomarker and the Akaike information criterion (AIC) calculated for each model. Stepwise removal of the variable with the highest p-value was performed to end up with the most parsimonious model (i.e., the model with the fewest predictors with an AIC <2 larger than the model with lowest AIC [optimal model]). P < 0.05 was regarded as statistically significant.

      3. Data availability statement

      The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

      4. Results

      4.1 Participants

      A total of 131 participants were included in this analysis, including 61 neurologically healthy participants (age [mean ± SD] 71.9 ± 8.8), 25 patients with DLB (73.9 ± 6.3), 22 patients with PD (70.9 ± 10.2), and 23 patients with PSP (69.1 ± 8.4). There were more males in the DLB group compared to healthy controls and PSP participants. DLB participants performed worse on a general cognitive assessment (MMSE) than all other groups, and PSP participants had lower MMSE scores compared to controls. In a test of executive function (animal fluency) all disease groups performed worse than controls and PSP and DLB groups worse than PD participants. The proportion of β-amyloid positive participants was 52% in the DLB group compared to 8.7% in the PSP group, 9.1% in PD and 0% in healthy controls. Participants were considered β-amyloid positive when CSF Aβ42/40 ratio was <0.752. The demographic characteristics are summarized in Table 1.

      4.2 Individual biomarker performance

      PET imaging with [18F]RO948 showed significantly higher SUVR values in the globus pallidus of PSP ([mean ± SD] 1.47 ± 0.38) patients compared to controls (1.24 ± 0.22, p = 0.013), DLB (1.18 ± 0.20, p = 0.026) and PD patients (1.25 ± 0.24, p = 0.005) (Table 1; Fig. 1A). Compared to controls (2.03 ± 0.33), a lower SUVR was seen in the substantia nigra of PSP (1.83 ± 0.35, p = 0.03), PD (1.66 ± 0.24, p < 0.001) and DLB patients (1.71 ± 0.33, p < 0.001) (Table 1; Supplementary data Fig. 2.) No significant differences in SUVR values were seen between groups in the putamen (Table 1).
      Fig. 1
      Fig. 1Biomarkers for diagnosis of progressive supranuclear palsy. A) [18F]RO948 SUVR in the globus pallidus. B) Midsagittal midbrain to pons area ratios. C) Cerebrospinal fluid levels of neurofilament light. D-F) Receiver Operating Characteristic Curves for separating D) healthy controls from PSP participants; E) PSP versus α-synucleinopathies (PD and DLB combined); and, F) healthy controls from participants with PD and DLB. AUC with 95% confidence intervals for the individual and combined biomarkers are indicated. All – all biomarkers combined; AUC – Area under the curve; CSF – Cerebrospinal Fluid; DLB - Dementia with Lewy bodies; M:P – midbrain/pons area ratio; NfL – Neurofilament Light; PD - Parkinson's disease; PSP - Progressive Supranuclear Palsy; SUVR - Standardized uptake value ratio; Tau PET - [18F]RO948 SUVR in the globus pallidus. * = p < 0.05, ** = p < 0.01, *** = p < 0.001.
      Midbrain/pons area ratio (M:P) differed significantly between controls (0.46 ± 0.07) and PSP patients (0.34 ± 0.09, p < 0.001). A significantly lower M:P was also seen in PSP compared to the α-synucleinopathies (DLB 0.40 ± 0.07, p < 0.05 and PD: 0.43 ± 0.06, p < 0.001). However, the M:P ratio was also reduced in DLB compared to healthy controls (p < 0.001) (Table 1; Fig. 1B). Patients with a clinical diagnosis of PSP had significantly higher mean levels CSF NfL (pg/mL [mean ± SD] 2197 ± 1010) compared to healthy controls (1055 ± 569, p < 0.001), participants with DLB (1548 ± 687, p = 0.015) and PD patients (1038 ± 416, p < 0.001) (Table 1; Fig. 1C). CSF NfL was not changed in PD patients compared to healthy controls, but in the group with DLB, a statistically significant increase in the mean NfL was seen compared to healthy controls (p < 0.001) (Table 1). No significant differences in CSF total-tau values were seen between groups (Table 1). A sensitivity analysis excluding β-amyloid positive individuals from PD and PSP groups did not alter the main results presented above.
      Correlations between CSF NfL values and MMSE and animal fluency tests are presented in the supplementary material (Supplementary Fig. 1). No correlations were found between the other biomarkers and the cognitive measures above.

      4.3 Biomarkers combined

      We next generated ROC curves comparing the ability of each biomarker to predict the correct diagnosis for PSP versus healthy controls, PSP vs α-synucleinopathies, and healthy controls vs α-synucleinopathies. ROC curves are presented in Fig. 1D–F. AUCs [95% confidence intervals] for distinguishing PSP against healthy controls were 0.77[0.65–0.89] for PET SUVR in the globus pallidus, 0.88[0.79–0.97] for M:P, and 0.89[0.82–0.97] for NfL. All biomarkers combined resulted in an AUC of 0.94 [0.88–1.00]. The AUC for all biomarkers combined was significantly better than that for Tau-PET alone (p = 0.004) and the M:P ratio alone (p = 0.024), but did not perform significantly better than NfL alone.
      In distinguishing PSP patients from patients with α-synucleinopathies the M:P ratio (AUC 0.81[0.69–0.93]) performed worse than all the biomarkers combined (AUC 0.92[0.85–0.98], p = 0.019). [18F]RO948 PET (AUC 0.85 [0.75–0.95]) and CSF NfL (AUC 0.87 [0.77–0.96]) alone performed comparably to all the biomarkers combined (Fig. 1E). The biomarker AUCs for separating α-synucleinopathies from healthy controls were generally lower (range 0.65–0.75) and RO948 PET alone performed significantly worse than the biomarkers combined (Fig. 1F).
      Using stepwise removal of biomarkers to find the most parsimonious biomarker model to support a PSP diagnosis we found that to separate healthy controls from PSP, a model containing M:P ratio and CSF NfL performed the best (ΔAIC -1.1 compared to the full model including RO948 PET in the globus pallidus). For separating PSP from the α-synucleinopathies the full model including all three biomarkers resulted in the lowest AIC (Table 2). RO948 PET in the substantia nigra, added value to the model separating PSP from controls but did not contribute to the model distinguishing PSP from α-synucleinopathies (Supplementary Fig. 1 and Supplementary Table 1).
      Table 2Model selection based on Akaike Information Criterion.
      PSP vs ControlAgeSexRO948 PETCSF-NfLMidbrain/PonsAIC
      Basic Model−1.28 (0.21)0.20 (0.84)109
      Full model0.87 (0.39)4.38 (<0.001)−5.28 (<0.001)44.6
      Full model −14.96 (<0.001)−5.66 (<0.001)43.5
      Full model −2−7.72 (<0.001)64.3
      PSP vs PD/DLBAgeSexMidbrain/PonsRO948 PETCSF-NfLAIC
      Basic Model−1.76 (0.08)2.33 (0.02)92.9
      Full model−2.04 (0.045)2.56 (0.012)3.08 (0.003)59.8
      Full model −12.71 (0.009)3.94 (<0.001)62.3
      Full model −25.59 (<0.001)67.7
      Logistic regression models were created for differentiating controls and synucleinopathies (PD and DLB) from PSP-patients: diagnosis ∼ RO948 PET + CSF-NfL + Midbrain/Pons. Age and sex were included as covariates. The biomarker with the highest p-value was sequentially removed from the model, one biomarker at a time. The model with the lowest Akaike Information Criterion (AIC) value was selected as the best model. RO948 PET indicates [18F]RO948 uptake in bilateral globus pallidus. Midbrain/Pons – the midsagittal area ratio of midbrain to pons. CSF – cerebrospinal fluid; DLB – Dementia with Lewy Bodies; PD – Parkinson's Disease; PSP – Progressive Supranuclear Palsy.

      5. Discussion

      This study presents the first investigation of the individual and combined contributions of [18F]RO948 PET signal in the basal ganglia, midbrain/pons ratio, and CSF NfL as biomarkers in PSP. Previous studies on [18F]RO948 PET as a biomarker for AD, also included PSP patients and patients with other parkinsonian disorders, but only analyzed 18F]RO948 PET signal in cortical regions [
      • Leuzy A.
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      • Strandberg O.
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      Diagnostic performance of RO948 F 18 tau positron emission tomography in the differentiation of alzheimer disease from other neurodegenerative disorders.
      ,
      • Leuzy A.
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      • Hansson O.
      A multicenter comparison of [(18)F]flortaucipir, [(18)F]RO948, and [(18)F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis.
      ]. We found higher [18F]RO948 SUVRs in the globus pallidus of PSP patients compared to controls and patients with α-synucleinopathies. The globus pallidus is a region that previously has been shown to be one of the most affected by tau pathology in PSP neuropathological studies [
      • Williams D.R.
      • Lees A.J.
      Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges.
      ]. Previous tau-PET studies using [18F]flortaucipir and [18F]PI-2620 have also reported the highest SUVRs in the globus pallidus [
      • Cho H.
      • Choi J.Y.
      • Lee S.H.
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      (18) F-AV-1451 binds to putamen in multiple system atrophy.
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      • Whitwell J.L.
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      [(18) F]AV-1451 tau positron emission tomography in progressive supranuclear palsy.
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      ]. Interestingly, we did not find an increase in [18F]RO948 retention in the putamen, a region that is also known to harbor tau pathology in PSP, albeit at a lower level compared to the pallidum. We found higher [18F]RO948 SUVRs in the substantia nigra of controls compared to the diseased groups (PD, PSP and DLB), with the lowest mean values in the PD group. This finding is likely related to [18F]RO948 binding to neuromelanin in the substantia nigra, a previously known off-target binding site for tau tracers [
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      ].
      Previous results have indicated that the midbrain/pons area ratio can be used in the diagnosis of PSP [
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      ], with the most pronounced changes seen with the classical Richardson syndrome presentation. A relatively large previous study has indicated that there is no mesencephalic atrophy in PD [
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      ]. The results in this study are in line with previous studies showing that there is a significant difference in the midbrain/pons ratio in PSP compared to healthy controls and other α-synucleinopathies. We found no midsagittal midbrain atrophy in PD, but a slight mesencephalic atrophy in DLB compared to healthy controls. A midsagittal ratio will not include the substantia nigra and may therefore not detect PD-related nigral atrophy. This likely makes a midsagittal midbrain/pons area ratio a preferable measure when differentiating PD from PSP.
      CSF NfL has previously been shown to distinguish PSP patients from healthy controls and other neurological diseases [
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      ]. Similar to previous reports, we found an increased level of CSF NfL levels in PSP patients compared to healthy controls and α-synucleinopathies (Fig. 1c).
      In previous studies, CSF total-tau has been shown to be slightly decreased at a group level in PSP patients compared to controls [
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      ], but differences between the groups were small and there was a substantial overlap. We did not find statistically significant differences in CSF total-tau between the groups in this study.
      A small proportion of PSP and PD patients included were β-amyloid positive (Table 1). None of the patients had clinical symptoms of AD. According to the clinical diagnostic criteria used, the presence of a pathological CSF Aβ42/40 ratio level does not exclude a PSP or PD diagnosis [
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      ]. In a sensitivity analysis, excluding the β-amyloid positive individuals, we did not find any changes to the main results. The included clinical subtypes in the PSP group (PSP-RS vs PSP-nonRS) and in the PD-group did not differ significantly in midbrain/pons ratio, CSF NfL or [18F]RO948 PET.
      In ROC curve analyses of controls versus PSP we find that CSF NfL and a model combining all three biomarkers performed significantly better in separating PSP patients from controls, than [18F]RO948 PET and M:P ratio alone. When assessing the contribution of individual biomarkers, the best model fit did not include [18F]RO948 PET, but the ΔAIC compared to the full model was rather low (1.4; Table 2). For separating PSP from α-synucleinopathies the best model included all three biomarkers, but in this case the M:P ratio provided the least information.
      As in previous studies using [18F]flortaucipir PET in PSP and controls, a large overlap in globus pallidus retention [
      • Smith R.
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      ,
      • Cho H.
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      (18) F-AV-1451 binds to putamen in multiple system atrophy.
      ,
      • Whitwell J.L.
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      • Senjem M.L.
      • Schwarz C.G.
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      [(18) F]AV-1451 tau positron emission tomography in progressive supranuclear palsy.
      ], was seen between controls and patients using [18F]RO948 PET despite group level differences. In a similar fashion there are also overlaps between groups in the CSF NfL and M:P ratio values. Nonetheless, the combined diagnostic accuracy was high for the combined model including all biomarkers (Fig. 1D–E), reaching AUCs of 0.92 in the separation of PSP from α-synucleinopathies and 0.94 in separating PSP from healthy controls.
      In autoradiography studies for [18F]flortaucipir there is very little binding in 4R tauopathies [
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      ], and the correlation of [18F]flortaucipir in vivo using PET [
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      (18) F-AV-1451 binds to putamen in multiple system atrophy.
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      • Rabinovici G.D.
      (18) F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: a multicenter study.
      ] to 4R tau in the cerebral cortex as assessed neuropathologically post mortem [
      • Smith R.
      • Schöll M.
      • Honer M.
      • Nilsson C.F.
      • Englund E.
      • Hansson O.
      Tau neuropathology correlates with FDG-PET, but not AV-1451-PET, in progressive supranuclear palsy.
      ,
      • Smith R.
      • Pawlik D.
      • Nilsson C.F.
      • Englund E.
      • Hansson O.
      [18F]Flortaucipir distinguishes Alzheimer's disease from progressive supranuclear palsy pathology in a mixed-pathology case.
      ], is low. The primary regions with PET-ligand retention in vivo using tau tracers in PSP are the basal ganglia and the substantia nigra, however these are regions known to be affected by off-target binding using several of the tau PET tracers. [18F]RO948 shows lower off-target binding compared to [18F]flortaucipir, and may therefore be a more suitable tracer in PSP [
      • Smith R.
      • Schöll M.
      • Leuzy A.
      • Jögi J.
      • Ohlsson T.
      • Strandberg O.
      • Hansson O.
      Head-to-head comparison of tau positron emission tomography tracers [(18)F]flortaucipir and [(18)F]RO948.
      ]. Similarly, the structurally related tau-PET tracer [18F]PI-2620 shows a lower degree of off-target binding in the basal ganglia. Brendel and coworkers present data suggesting a binding of [18F]PI-2620 to 4R tau using autoradiography and promising results for the [18F]PI-2620 ligand in vivo in separating PSP patients from controls and participants with α-synucleinopathies [
      • Brendel M.
      • Barthel H.
      • van Eimeren T.
      • Marek K.
      • Beyer L.
      • Song M.
      • Palleis C.
      • Gehmeyr M.
      • Fietzek U.
      • Respondek G.
      • Sauerbeck J.
      • Nitschmann A.
      • Zach C.
      • Hammes J.
      • Barbe M.T.
      • Onur O.
      • Jessen F.
      • Saur D.
      • Schroeter M.L.
      • Rumpf J.J.
      • Rullmann M.
      • Schildan A.
      • Patt M.
      • Neumaier B.
      • Barret O.
      • Madonia J.
      • Russell D.S.
      • Stephens A.
      • Roeber S.
      • Herms J.
      • Bötzel K.
      • Classen J.
      • Bartenstein P.
      • Villemagne V.
      • Levin J.
      • Höglinger G.U.
      • Drzezga A.
      • Seibyl J.
      • Sabri O.
      Assessment of 18F-PI-2620 as a biomarker in progressive supranuclear palsy.
      ]. A recent study however, did not show any correlation of [18F]PI-2620 retention to post mortem 4R tau pathology in a case with corticobasal degeneration [
      • Tezuka T.
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      • Funaki K.
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      • Ueda R.
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      • Kubota M.
      • Okita H.
      • Takao M.
      • Jinzaki M.
      • Nakahara J.
      • Mimura M.
      • Ito D.
      Evaluation of [(18)F]PI-2620, a second-generation selective tau tracer, for assessing four-repeat tauopathies.
      ]. It is possible that the higher uptake seen in vivo in the globus pallidus with tau PET tracers is in part due to higher detected levels of 4R tau in these regions, but it is equally possible that this signal may represent off-target binding to a more general neurodegenerative processes, such as coexisting gliosis or neurodegeneration in combination with the relatively high blood flow of the basal ganglia.
      The findings reported here are one step further in the understanding of how [18F]RO948 can be used to assist clinical diagnosis of PSP. Our data suggests that an increased [18F]RO948 PET uptake in the basal ganglia adds to the separation of PSP from α-synuclein related disorders, and performs similar to CSF-NfL. Potentially even better separation could be achieved by using dynamic scans, as suggested by Brendel et al. using the related tau tracer [18F]PI-2620 [
      • Brendel M.
      • Barthel H.
      • van Eimeren T.
      • Marek K.
      • Beyer L.
      • Song M.
      • Palleis C.
      • Gehmeyr M.
      • Fietzek U.
      • Respondek G.
      • Sauerbeck J.
      • Nitschmann A.
      • Zach C.
      • Hammes J.
      • Barbe M.T.
      • Onur O.
      • Jessen F.
      • Saur D.
      • Schroeter M.L.
      • Rumpf J.J.
      • Rullmann M.
      • Schildan A.
      • Patt M.
      • Neumaier B.
      • Barret O.
      • Madonia J.
      • Russell D.S.
      • Stephens A.
      • Roeber S.
      • Herms J.
      • Bötzel K.
      • Classen J.
      • Bartenstein P.
      • Villemagne V.
      • Levin J.
      • Höglinger G.U.
      • Drzezga A.
      • Seibyl J.
      • Sabri O.
      Assessment of 18F-PI-2620 as a biomarker in progressive supranuclear palsy.
      ].
      This study has several limitations. First, the study sample size was relatively limited across each of the three patient groups. Second, the CSF-NfL analysis was performed in a clinical routine setting with samples being analyzed following collection instead of in batch analysis that might have reduced the variability of the NfL results. On the other hand, this approach is closer to the real-world use of this biomarker and may therefore better reflect its use in clinical settings. Third, clinical diagnoses were used as gold standard with neuropathological confirmation only obtained in a minority of cases. To increase diagnostic accuracy the participants were followed longitudinally, and diagnoses revised at regular intervals. The results will need to be interpreted with this in mind.

      6. Conclusion

      We found that [18F]RO948 PET SUVR in the globus pallidus, CSF NfL and M:P ratio are all able to distinguish PSP patients from controls and from patients with α-synucleinopathies at a group level. CSF-NfL alone performed significantly better than [18F]RO948 PET in separating PSP from controls, but for separating PSP both from controls and α-synucleinopathies a combination of all three biomarkers showed the best performance.

      Author contributions

      Kevin Oliveira Hauer Design, execution, analysis, writing and editing of final version of the manuscript. Daria Pawlik Design, analysis and editing of final version of the manuscript. Antoine Leuzy Data analysis, editing of final version of the manuscript. Shorena Janelidze Data acquisition, editing of final version of the manuscript. Sara Hall Data acquisition, editing of final version of the manuscript. Oskar Hansson Funding, overall design of the BioFINDER2 study. Editing of final version of the manuscript. Ruben Smith Design, analysis, writing and editing of final version of the manuscript.

      Relevant conflicts of interest/financial disclosure

      In the past 2 years, Oskar Hansson he has received consultancy/speaker fees from Amylyx, Alzpath, BioArctic, Biogen , Cerveau, Fujirebio , Genentech , Novartis , Roche , and Siemens .
      Kevin Oliveira Hauer, Daria Pawlik, Antoine Leuzy, Shorena Janelidze, PhD, Sara Hall, and Ruben Smith report no relevant conflicts of interest related to the present study.

      Funding

      Work at the authors' research center was supported by the Swedish Research Council ( 2016-00906 ), the Knut and Alice Wallenberg foundation ( 2017-0383 ), the Marianne and Marcus Wallenberg foundation ( 2015.0125 ), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University , the Swedish Alzheimer Foundation ( AF-939932 ; AF-939981 ), the Swedish Brain Foundation ( FO2021-0293 ), The Parkinson foundation of Sweden (1280/20), the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse , the Skåne University Hospital Foundation ( 2020-O000028 ), Regionalt Forskningsstöd ( 2020-0314; 2020-0241 ) and the Swedish federal government under the ALF agreement (2018-Projekt0279). The precursor of 18F-RO948 was provided by Roche. The funding sources had no role in the design and conduct of the study; in the collection, analysis, interpretation of the data; or in the preparation, review, or approval of the manuscript.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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