Assistant Professor of Clinical Neurology and Assistant Attending Neurologist, New York Presbyterian/Weill Cornell Medical College
SYNOPSIS: This observational study investigated whether the cerebrospinal fluid (CSF) α-synuclein (α-syn) real-time quaking-induced conversion (RT-QuIC) assay, applied to 289 CSF samples, accurately identified patients with mild cognitive impairment (MCI) caused by probable Lewy body (LB) disease. 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, indicating that CSF α-syn RT-QuIC is a robust biomarker for prodromal dementia with Lewy bodies.
SOURCE: Rossi M, Baiardi S, Teunissen CE, et al. Diagnostic value of the CSF α-synuclein real-time quaking-induced conversion assay at the prodromal MCI stage of dementia with Lewy bodies. Neurology 2021;97:e930-e940.
This retrospective, observational study examined two independent cohorts comprising a total of 231 patients with mild cognitive impairment (MCI) and 58 individuals lacking neurologic signs or cognitive impairment, defined as controls. In both cohorts, MCI was diagnosed according to current diagnostic criteria, which included subjective concerns regarding changes in cognition, objective impairment in cognition, preservation of independence of functional abilities, and absence of dementia. Patients with evidence of non-neurodegenerative causes of cognitive decline, including severe white matter lesions on neuroimaging (Fazekas score 3), were excluded. In both cohorts, parkinsonism was assessed systematically during the neurologic examination and was rated present when the examination showed one or more extrapyramidal signs (rest tremor, bradykinesia, and plastic rigidity). Cognitive fluctuations, visual hallucinations, and rapid eye movement (REM) behavior disorder (RBD) were identified as present or absent.
Clinical features, Alzheimer’s disease (AD) core markers, imaging, neurophysiologic data, and evolution at the last follow-up were used to classify the patients into four groups: MCI caused by probable Lewy body (LB) disease (MCI-LB), MCI caused by AD (MCI-AD), MCI caused by other neurodegenerative disorders, and controls. The presence or absence of clinical core features of dementia with Lewy bodies (DLB) was determined according to the definitions and guidelines provided by the DLB Consortium. The application of the “one-year rule” excluded patients with MCI caused by Parkinson disease from the studied cohort. Cerebrospinal fluid was collected at the time of MCI diagnosis in all patient groups and underwent α-synuclein (α-syn) real-time quaking-induced conversion (RT-QuIC) assay, including purification of recombinant wild-type human α-syn. 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 two cohorts (97.3% vs. 93.7%). Thirteen percent of patients with MCI-AD also had a positive test; of note, 44% of them developed one core or supportive clinical feature of DLB at follow-up, suggesting an underlying Lewy body copathology.
There is an urgent need for early and disease-specific biomarkers for neurodegenerative diseases to enable proper patient care and selection in clinical trials. The recent development of ultrasensitive assays that indirectly reveal minute amounts of misfolded amyloid proteins in cerebrospinal fluid, based on a template amplification strategy, has contributed significantly to this goal.
Current evidence indicates that RT-QuIC accurately detects misfolded α-syn in the cerebrospinal fluid of patients with Parkinson disease or DLB with an overall sensitivity of 95% and a specificity of 98%. Preliminary data also indicate that the cerebrospinal fluid of patients with pure autonomic failure and isolated RBD, two prodromal syndromes that often evolve to Parkinson disease or DLB, harbors significant α-syn seeding activity. However, no study has yet specifically explored the diagnostic value of α-syn RT-QuIC in patients with MCI, representing a common prodromal clinical manifestation of DLB. The results of the present study demonstrate that the CSF α-syn RT-QuIC assay accurately detects LB disease in patients with MCI. Application of the assay in two large, distinct groups of patients representing the MCI clinical spectrum identified those diagnosed with probable MCI-LB with a 95.1% overall sensitivity. Furthermore, the test demonstrated 96.6% specificity against cognitively unimpaired controls and close to perfect (98.3%) specificity for LB-related pathology in a cohort of 121 pathologic controls lacking LB at postmortem examination. Therefore, the detection of abnormal α-syn species by RT-QuIC not only is very accurate but also represents an early biomarker for LB disease. Thus, its implementation after repeat validation may help the clinical management and recruitment for clinical trials in memory disorder clinics.