Stratification Tools for Disease-Modifying Trials in Prodromal Synucleinopathy

Dario Arnaldi, Pietro Mattioli, Francesco Famà, Nicola Girtler, Andrea Brugnolo, Matteo Pardini, Andrea Donniaquio, Federico Massa, Beatrice Orso, Stefano Raffa, Matteo Bauckneht, Silvia Morbelli, Flavio Nobili

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Dopamine transporter single photon-emission computed tomography (DAT-SPECT) is the strongest risk factor for phenoconversion in patients with idiopathic rapid eye movement (REM)-sleep behavior disorder (iRBD). However, it might be used as a second-line stratification tool in clinical trials, because it is expensive and mini-invasive. Objective: Aim of the study is to investigate whether other cost-effective and non-invasive biomarkers may be proposed as first-line stratification tools. Methods: Forty-seven consecutive iRBD patients (68.53 ± 7.16 years, 40 males) underwent baseline clinical and neuropsychological assessment, olfaction test, resting electroencephalogram (EEG), and DAT-SPECT. All patients underwent 6 month-based clinical follow-up to investigate the emergence of parkinsonism and/or dementia. Survival analysis and Cox regression were used to estimate conversion risk. Results: Seventeen patients developed an overt synucleinopathy (eight Parkinsonism and nine dementia) 32.8 ± 22 months after diagnosis. The strongest risk factors were putamen specific to non-displaceable binding ratio (SBR) (hazard ratio [HR], 7.3), attention/working memory cognitive function (NPS-AT/WM) (HR, 5.9), EEG occipital mean frequency (HR, 2.7) and clinical motor assessment (HR, 2.3). On multivariate Cox-regression analysis, only putamen SBR and NPS-AT/WM significantly contributed to the model (HR, 6.2, 95% confidence interval [CI], 1.9–19.8). At post-hoc analysis, the trail-making test B (TMT-B) was the single most efficient first-line stratification tool that allowed to reduce the number of eligible subjects to 76.6% (sensitivity 1, specificity 0.37). Combining TMT-B and DAT-SPECT further reduced the sample to 66% (sensitivity 0.88, specificity 0.47). Conclusion: The TMT-B seems to be a cost-effective and efficient first-line screening tool, to be used to select patients that deserve DAT-SPECT as second-line screening tool for disease-modifying clinical trials.

Original languageEnglish
JournalMovement Disorders
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • cognitive
  • EEG
  • prodromal synucleinopathy
  • REM sleep behavior disorder
  • SPECT

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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