Neurofilament light chain and α-synuclein RT-QuIC as differential diagnostic biomarkers in parkinsonisms and related syndromes

Abstract

Neurofilament light chain (NfL) and α-synuclein oligomeric seeds (α-syn-s) are promising biomarkers for patients with parkinsonism. We assessed their performance in discriminating Parkinson disease (PD) from atypical parkinsonisms (APDs) and evaluated the association between NfL levels and clinical measures of disease severity. We measured NfL in cerebrospinal fluid (CSF) and/or plasma by immunoassays and α-syn-s in CSF by real-time quaking-induced conversion (RT-QuIC) in patients with PD (n = 153), multiple system atrophy (MSA) (n = 80), progressive supranuclear palsy/cortico-basal syndrome (PSP/CBS) (n = 58), dementia with Lewy bodies (n = 64), isolated REM-sleep behaviour disorder (n = 19), and isolated autonomic failure (n = 30). Measures of disease severity included disease duration, UPDRS-III score, Hoehn and Yahr stage, orthostatic hypotension, MMSE score, and CSF amyloid-beta profile. Both CSF NfL (cNfL) and plasma NfL (pNfL) levels were markedly elevated in APDs, and allowed differentiation with PD (vs. APDs, cNfL AUC 0.96; pNfL AUC 0.95; vs. MSA cNfL AUC 0.99; pNfL AUC 0.97; vs. PSP/CBS cNfL AUC 0.94; pNfL AUC 0.94). RT-QuIC detected α-syn-s in 91.4% of PD, but only 2.5% of APDs (all MSA). In PD/PDD, motor scales significantly correlated with cNfL levels. Although pNfL and both cNfL and α-syn-s accurately distinguished PD from APDs, the combined assessment of CSF markers provided a higher diagnostic value (PD vs. APDs AUC 0.97; vs. MSA AUC 0.97; vs. PSP/CBS AUC 0.99) than RT-QuIC alone (p = 0.047 vs. APDs; p = 0.002 vs MSA; p = 0.007 vs PSP/CBS), or cNfL alone (p = 0.011 vs. APDs; p = 0.751 vs MSA; p = 0.0001 vs. PSP/CBS). The results support the use of these assays in specialised clinics.

α-Synuclein Seed Amplification Assays for Diagnosing Synucleinopathies

“…Similarly, the association of α-syn SAA positivity with increased CSF levels of neurofilament light chain (NfL), a well-established marker of axonal degeneration, may indicate a synucleinopathy in which neurodegeneration is relevant, which is more suggestive of MSA, rather than PD. 24,44 Indeed, in a recent investigation, Quadalti et al 44 demonstrated that the measurement of CSF NfL significantly increased the ability of α-syn SAA in differentiating PD from MSA and PD from PSP/CBS.…”

Retinal Nerve Fiber Layer Thickness and Associations With Cognitive Impairment in Parkinson’s Disease

“…Parkinson’s disease (PD) is a highly prevalent neurodegenerative disorder worldwide with characteristic motor dysfunctions including bradykinesia, stiffness and resting tremor ( Tolosa et al, 2021 ). Ours and other studies have indicated that some indicators such as neuroinflammatory, neuroimaging mediators and serum neurofilament light chain are usually applied as markers in diagnosing and evaluating the progression and severity of PD and PD Syndromes ( Wang et al, 2020 , 2021 ; Yang et al, 2020 ; Zhu et al, 2020 , 2021a ; Bestwick et al, 2021 ; Liu et al, 2021 ; Quadalti et al, 2021 ). Identifying potential biomarkers for early diagnosis and assessment is one of the research hotspots in the field of PD ( Avenali et al, 2020 ; Papuć and Rejdak, 2020 ; Ma et al, 2021 ).…”

The Future of Seed Amplification Assays and Clinical Trials

“…Combinations of seed amplification assays that identify the underlying proteinopathy together with other biomarkers, for example, neurofilament light chain as a measure of neuroaxonal breakdown, have the potential to further improve diagnostic accuracy. For example, in one recent study typical α-synuclein seeding activity on RT-QuIC distinguished PD from MSA, CBD, and PSP with a sensitivity of 91.4% and specificity 97.5%, whereas a combination of α-synuclein RT-QuIC positivity and NfL below a certain threshold achieved a sensitivity of 98.3% and specificity of 95.8% and a greater area under the receiver operating characteristic curve (Quadalti et al, 2021 ). With recent advances in ultrasensitive, high-throughput protein detection and commercial availability of plasma proteomics panels incorporating thousands of proteins, we anticipate progress in combinatorial approaches in which proteopathic seed identification could be combined with signatures of plasma protein alterations to improve diagnostic and prognostic classification, with potential for enrichment of clinical trials with patient subgroups most likely to benefit from specific treatments (Assarsson et al, 2014 ; Olink, 2021 ).…”

“…One report of good diagnostic accuracy in slow IPD with RT-QuIC using recombinant human PrP substrate (Sano et al, 2013 Rossi et al (2020). In a different study aiming to distinguish PD and atypical Parkinsonian disorders, RT-QuIC was negative in all PAF patients (Quadalti et al, 2021).…”