Performance of αSynuclein RT-QuIC in relation to neuropathological staging of Lewy body disease

Abstract

Currently, there is a need for diagnostic markers in Lewy body disorders (LBD). α-synuclein (αSyn) RT-QuIC has emerged as a promising assay to detect misfolded αSyn in clinically or neuropathologically established patients with various synucleinopathies. In this study, αSyn RT-QuIC was used to analyze lumbar CSF in a clinical cohort from the Swedish BioFINDER study and postmortem ventricular CSF in a neuropathological cohort from the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (AZSAND/BBDP). The BioFINDER cohort included 64 PD/PDD, 15 MSA, 15 PSP, 47 controls and two controls who later converted to PD/DLB. The neuropathological cohort included 101 cases with different brain disorders, including LBD and controls. In the BioFINDER cohort αSyn RT-QuIC identified LBD (i.e. PD, PDD and converters) vs. controls with a sensitivity of 95% and a specificity of 83%. The two controls that converted to LBD were αSyn RT-QuIC positive. Within the AZSAND/BBDP cohort, αSyn RT-QuIC identified neuropathologically verified "standard LBD" (i.e. PD, PD with AD and DLB; n = 25) vs. no LB pathology (n = 53) with high sensitivity (100%) and specificity (94%). Only 57% were αSyn RT-QuIC positive in the subgroup with "non-standard" LBD (i.e., AD with Lewy Bodies not meeting criteria for DLB or PD, and incidental LBD, n = 23). Furthermore, αSyn RT-QuIC reliably identified cases with LB pathology in the cortex (97% sensitivity) vs. cases with no LBs or LBs present only in the olfactory bulb (93% specificity). However, the sensitivity was low, only 50%, for cases with LB pathology restricted to the brainstem or amygdala, not affecting the allocortex or neocortex. In conclusion, αSyn RT-QuIC of CSF samples is highly sensitive and specific for identifying cases with clinicopathologically-defined Lewy body disorders and shows a lower sensitivity for non-standard LBD or asymptomatic LBD or in cases with modest LB pathology not affecting the cortex.

Keywords: Autopsy; Biomarkers; Cerebrospinal fluid; Dementia with Lewy bodies; Diagnosis; Lewy body dementia; Parkinson disease.

Fig. 1

Stacked bar chart depicting αSyn RT-QuIC status by LB stage in the neuropathology-based AZSAND/BBDP cohort. 97% of the cases with LB stage III-IV were αSyn RT-QuIC positive and 93% of the cases in LB stage 0–1 were αSyn RT-QuIC negative. However, only 56% of cases with LB pathology in stage IIa-IIb were αSyn RT-QuIC positive

Fig. 2

Stacked bar chart depicting αSyn RT-QuIC status by LB distribution in the neuropathology-based AZSAND/BBDP cohort. 97% of cases with LB pathology in the cortex (allocortex and/or neocortex) were αSyn RT-QuIC positive whereas 93% of cases with no LBs or LB restricted to the olfactory bulb only were αSyn RT-QuIC negative. Of the cases with LB pathology in the brainstem and/or amygdala, but with no cortical involvement, 50% were αSyn RT-QuIC positive

Fig. 3

Stacked bar chart depicting αSyn RT-QuIC status by LB density in the neuropathology-based AZSAND/BBDP cohort. 97% of cases with total LB density score > 10 score (established by summing the regional density scores from the ten predefined regions yielding a maximum score of 40) were αSyn RT-QuIC positive. 93% of cases with total LB density score of 0–4 were αSyn RT-QuIC negative. Only 64% of cases with an intermediate LB density score of 5–10 were αSyn RT-QuIC positive