Neuroimaging biomarkers for clinical trials in atypical parkinsonian disorders: Proposal for a Neuroimaging Biomarker Utility System

Abstract

Introduction Therapeutic strategies targeting protein aggregations are ready for clinical trials in atypical parkinsonian disorders. Therefore, there is an urgent need for neuroimaging biomarkers to help with the early detection of neurodegenerative processes, the early differentiation of the underlying pathology, and the objective assessment of disease progression. However, there currently is not yet a consensus in the field on how to describe utility of biomarkers for clinical trials in atypical parkinsonian disorders. Methods To promote standardized use of neuroimaging biomarkers for clinical trials, we aimed to develop a conceptual framework to characterize in more detail the kind of neuroimaging biomarkers needed in atypical parkinsonian disorders, identify the current challenges in ascribing utility of these biomarkers, and propose criteria for a system that may guide future studies. Results As a consensus outcome, we describe the main challenges in ascribing utility of neuroimaging biomarkers in atypical parkinsonian disorders, and we propose a conceptual framework that includes a graded system for the description of utility of a specific neuroimaging measure. We included separate categories for the ability to accurately identify an intention-to-treat patient population early in the disease (Early), to accurately detect a specific underlying pathology (Specific), and the ability to monitor disease progression (Progression). Discussion We suggest that the advancement of standardized neuroimaging in the field of atypical parkinsonian disorders will be furthered by a well-defined reference frame for the utility of biomarkers. The proposed utility system allows a detailed and graded description of the respective strengths of neuroimaging biomarkers in the currently most relevant areas of application in clinical trials.

Novel decision algorithm to discriminate parkinsonism with combined blood and imaging biomarkers

“…Taken together, these limitations call for prospective studies of patient cohorts at an early disease stage to further validate the proposed decision algorithm in those disease stages where current clinical criteria have their greatest limitations. Such studies should also further characterize the added value of the current algorithm over others solely relying on neuroimaging [2].…”

“…Therefore, early and correct diagnosis is required [1]. Recently, an utility system has been proposed for clinical trials in atypical parkinsonian disorders, that allows a detailed and graded description of the respective strengths of neuroimaging biomarkers [2]. Based on clinical grounds solely, early diagnostic discrimination between PD, PSP and MSA remains challenging despite stringent consensus criteria [1,3,4].…”

“…A useful diagnostic biomarker, however, has to be more accurate than a simultaneously applied clinical marker. Ideally, this marker would also help differential diagnosis of clinical entities at an earlier time point [2].…”

Empfehlung zum differenzierten Einsatz nuklearmedizinischer Diagnostik bei Parkinson-Syndromen

“…Die Unterscheidung von PSP und CBD gelingt weniger gut, wobei häufig die PSP als CBD fehlinterpretiert wird [38], was mit dem breiten Überlappungsbereich der zugrundeliegenden Tauopathien erklärt wird [39] und auch begründet, warum man klinisch besser von einem kortikobasalen Syndrom (CBS) als von einer kortikobasalen Degeneration (CBD), die eine eigene pathologische Signatur hat, sprechen sollte [40]. Verfügbare Daten legen jedoch nahe, dass die FDG-PET eher die Topologie der Neuropathologie als das klinische Syndrom widerspiegelt und so zur Differenzialdiagnose zwischen den neuropathologisch definierten Krankheitsentitäten beitragen kann [41,42]. Ferner ergeben sich aus longitudinalen Studien Hinweise, dass die FDG-PET hilfreich ist für die Prädiktion einer Demenz beim IPS [43] und der Abschätzbarkeit des Überlebens bei APS [44].…”

Central autonomic dysfunction in multiple system atrophy: can we measure it with MRI?

“…However, inclusion of MSA patients in clinical trials early in the disease course is problematic since accurate diagnosis can be difficult at this stage. Due to the timely demand for a more systematic description of utility in the field of neuroimaging biomarkers in atypical parkinsonian disorders, including MSA, a recent proposal has been made to address these pending issues [10]. In sum, neuroimaging is a powerful tool with great utility for both: the unveiling of neuropathological mechanisms of disease, and the identification of markers which increase the likelihood of a condition (i.e., diagnostic biomarkers).…”