Alpha synuclein by RT-QuIC in dementia with Lewy Bodies: a systematic review and meta-analysis

Abstract

Dementia with Lewy Bodies (DLB) is the second most common cause of neurodegenerative dementia but the field is still lacking a specific biomarker for its core pathology: alpha-synuclein. Real-time quaking induced conversion (RT-QuIC) has recently emerged as a strong candidate of alpha-synuclein biomarker. However, the variability in the technique parameters and the heterogeneity of DLB patients makes complex the reproducibility of the results. We provide an overview of the state-of-the-art research with regard to RT-QuIC in DLB focused on: (1) the capacity of RT-QuIC to discriminate DLB from controls, Parkinson’s disease (PD) and Alzheimer’s disease (AD); (2) the capacity of RT-QuIC to identify prodromal stages of DLB; (3) and the influence of co-pathologies on the RT-QuIC’s performance. We also assessed the influence of different factors on the RT-QuIC’s performance, such as technical conditions (e.g. temperature, pH, shaking-rest cycles), sample type, and clinical diagnosis versus autopsy confirmation. Our meta-analysis shows that RT-QuIC reaches very high diagnostic performance in discriminating DLB from both controls (pooled sensitivity and specificity of 0.94 and 0.96, respectively) and AD (pooled sensitivity and specificity of 0.95 and 0.88), and is promising for prodromal phases of DLB). However, the RT-QuIC’s performance to discriminate DLB from PD is currently low due to low specificity (pooled sensitivity and specificity of 0.94 and 0.11). Further, our analyses showed that the RT-QuIC’s performance is not substantialy influenced by sample type or clinical diagnosis versus autopsy confirmation. Co-pathologies did not seem to influence the RT-QuIC’s performance, but the number of studies is currently limited. We observed technical variability across studies but, for the published articles, we could not find that this variability has a clear effect on the reported results. We conclude that there is currently enough evidence to test alpha-synuclein by RT-QuIC for clinical use. We anticipate that harmonization of protocols across centres and advances in standardization will facilitate the clinical establishment and generalization of alpha-synuclein by RT-QuIC.

α-Synuclein: A Promising Biomarker for Parkinson’s Disease and Related Disorders

“…63 In a meta-analysis for DLB, the diagnostic sensitivity and specificity of CSF were reported to be 0.95 and 0.96, respectively. 65 However, it has been noted that the α-syn SAA can be positively applied in biologically confirmed Alzheimer's disease patients, especially in older patients, necessitating consideration of diagnostic bias. 66 The diagnostic sensitivity and specificity of the α-syn SAA for some patients with idiopathic RBD have been reported to be high, at 0.80 (95% CI, 0.58-0.92) and 1.00 (95% CI, 0.82-1.00), respectively.…”

What's in a Name? The Time Has Come to Unify Parkinson's Disease and Dementia with Lewy Bodies

“…Although we currently have parallel tracks for PD and DLB, the strongest case is for a single track. It is true, and not surprising, that some some pathophysiological differences between PD and DLB have been noted (eg, postulated phenotypic diversity on the basis of differential vulnerability of neuroanatomical regions and cellular populations to α-synuclein aggregation, 37 α-synuclein conformations, [38][39][40] the α-synuclein gene, 41 and neuroimaging patterns [42][43][44] ), but these differences appear to be quantitative, and not clearly qualitative, in nature. The most prominent differences are the timing of onset and location of Lewy body pathology (ie, more extensive and cortical early in DLB compared with PD) and the presence of comorbid AD (amyloid) copathology (ie, more in DLB compared with PD), 45,46 perhaps partly explained by an average 10-year increased age at disease onset and increased frequency of the APOE ε4 allele in DLB compared with PD.…”

Plasma biomarkers of amyloid, tau, axonal and neuroinflammation pathologies in dementia with Lewy bodies

“…Measure of alpha-synuclein levels in plasma have only yielded inconsistent results (7)(8)(9). RT-Quick assays are showing very promising results to identify alpha-synucleinopathies but still require further validation, especially in plasma (10)(11)(12)(13). Interestingly, number of amyloid and tau plasma biomarkers, as well as axonal and neuroin ammatory markers have been studied in DLB and appear modi ed.…”