Diagnostic Value of the CSF α-Synuclein Real-Time Quaking-Induced Conversion Assay at the Prodromal MCI Stage of Dementia With Lewy Bodies

Abstract

Objective: To investigate whether the CSF α-synuclein (α-syn) real-time quaking-induced conversion (RT-QuIC) assay accurately identifies patients with mild cognitive impairment (MCI) due to probable Lewy body (LB) disease.

Methods: We applied α-syn RT-QuIC to 289 CSF samples obtained from 2 independent cohorts, including 81 patients with probable MCI-LB (age 70.7 ± 6.6 years, 13.6% female, Mini-Mental State Examination [MMSE] score 26.1 ± 2.4), 120 with probable MCI due to Alzheimer disease (AD) (age 68.6 ± 7.4 years, 45.8% female, MMSE score 25.5 ± 2.8), and 30 with unspecified MCI (age 65.4 ± 9.3 years, 30.0% female, MMSE score 27.0 ± 3.0). Fifty-eight individuals with no cognitive decline or evidence of neurodegenerative disease and 121 individuals lacking brain α-syn deposits at the neuropathologic examination were used as controls.

Results: RT-QuIC identified patients with MCI-LB against cognitively unimpaired controls with 95% sensitivity, 97% specificity, and 96% accuracy and showed 98% specificity in neuropathologic controls. The accuracy of the test for MCI-LB was consistent between the 2 cohorts (97.3% vs 93.7%). Thirteen percent of patients with MCI-AD also had a positive test; of note, 44% of them developed 1 core or supportive clinical feature of dementia with Lewy bodies (DLB) at follow-up, suggesting an underlying LB copathology.

Conclusions: These findings indicate that CSF α-syn RT-QuIC is a robust biomarker for prodromal DLB. Further studies are needed to fully explore the added value of the assay to the current research criteria for MCI-LB.

Classification of evidence: This study provides Class III evidence that CSF α-syn RT-QuIC accurately identifies patients with MCI-LB.

Figure 1. Study Flowchart (Clinical Diagnostic Groups)

AD = Alzheimer disease; ISNB = Institute of Neurological Sciences of Bologna; LB = Lewy body; MCI = mild cognitive impairment; SCD = subjective cognitive decline; VUmc = VU Medical Center.

Figure 2. α-Syn RT-QuIC Kinetic Parameters in the Study Cohort

(A) Mean normalized fluorescence emission of all α-synuclein (α-syn) real-time quaking-induced conversion (RT-QuIC)–positive cases. Black dashed line represents the threshold. Error bars indicate SD. (B) Comparison of the kinetic parameters of α-syn RT-QuIC–positive cases among the most representative groups (mild cognitive impairment [MCI] due to Lewy body (LB) disease and MCI due to Alzheimer disease [AD]). Statistically significant differences between the 2 groups are limited to the maximum intensity of fluorescence (I max) (**p < 0.01). AUC = area under the curve; ns = nonsignificant; RFU = relative fluorescent units.

Figure 3. Analysis of Replicate Kinetic Curves and Distribution in the ISNB and VUmc Cohorts

(A) Distribution analysis of positive replicates in the mild cognitive impairment (MCI) due to Lewy body (LB) disease and MCI due to Alzheimer disease (AD) cohorts. Statistical analyses by the χ² test resulted in **p < 0.01. (B) Kinetic curves across positive cases showing different α-synuclein real-time quaking-induced conversion responses by distinct numbers of positive replicates. Error bars are omitted to increase the readability of the image. Black dashed line represents the threshold. ISNB = Institute of Neurological Sciences of Bologna; RFU = relative fluorescent units; VUmc = VU Medical Center.