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. 2022 Jan;37(1):52-61.
doi: 10.1002/mds.28785. Epub 2021 Sep 17.

Stratification Tools for Disease-Modifying Trials in Prodromal Synucleinopathy

Dario Arnaldi  1   2 , Pietro Mattioli  1 , Francesco Famà  1   2 , Nicola Girtler  1   2 , Andrea Brugnolo  1   2 , Matteo Pardini  1   2 , Andrea Donniaquio  1 , Federico Massa  1 , Beatrice Orso  1 , Stefano Raffa  3 , Matteo Bauckneht  2   3 , Silvia Morbelli  2   3 , Flavio Nobili  1   2
Affiliations

Stratification Tools for Disease-Modifying Trials in Prodromal Synucleinopathy

Dario Arnaldi et al. Mov Disord. 2022 Jan.

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. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: EEG; REM sleep behavior disorder; SPECT; cognitive; prodromal synucleinopathy.

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Figures

FIG 1
FIG 1
Kaplan–Meier disease‐free survival plot of iRBD patients according to the best predictors of phenoconversion. For each feature, red solid lines indicate patients below cut‐off and green dashed lines indicate patients above cut‐off. [Color figure can be viewed at wileyonlinelibrary.com]
FIG 2
FIG 2
The stratification procedure of iRBD patients using trail‐making part B (TMT‐B) or hyposmia as the first‐line stratification tool and 123I‐FP‐CIT‐SPECT as the second‐line stratification tool. In brackets, the percentage of stratified patients out of the starting sample (47 iRBD patients) is reported. [Color figure can be viewed at wileyonlinelibrary.com]
FIG 3
FIG 3
Scatter plot of centro‐parietal MF versus NPS‐EX data of iRBD patients. The dotted lines indicate the cut‐off used for ROC analysis. Green circles indicate PD converters and red triangles DLB converters. [Color figure can be viewed at wileyonlinelibrary.com]
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