Real-time quaking-induced conversion (RT-QuIC), also called protein misfolding cyclic amplification (PMCA), is a diagnostic method that can help in the early detection of Parkinson’s disease by identifying the formation of abnormal clusters of the protein alpha-synuclein. These protein clumps are a hallmark of many neurodegenerative diseases including Parkinson’s, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).
RT-QuIC was initially developed to detect prion diseases such as Creutzfeldt-Jakob Disease (CJD) but has now been refined to aid in the detection of many other neurodegenerative disorders.
RT-QuIC and Parkinson’s disease
Parkinson’s disease is a condition that affects the brain and central nervous system resulting in a progressive loss of control and coordination within the body. Symptoms of Parkinson’s include tremor, bradykinesia, gait and balance problems, cognitive impairment, and depression among others. An accurate diagnosis of Parkinson’s, especially in the early stages, is difficult.
Parkinson’s is also characterized by the formation of misfolded aggregates of alpha-synuclein. Alpha-synuclein plays a major role in the transmission of nerve impulses, and the formation of aggregates of this protein can result in nerve cell dysfunction. It has been observed that alpha-synuclein aggregation occurs long before the onset of disease symptoms. Therefore, detection of these aggregates in body fluids such as the cerebrospinal fluid (CSF) can help in early diagnosis of the disease.
RT-QuIC uses a fluorescent probe to detect misfolded protein aggregates. The intensity of the fluorescence signal indicates the extent of protein aggregation and disease severity.
How RT-QuIC works
RT-QuIC works in two phases. In the first phase, a body fluid sample (usually CSF) from the patient is drawn and mixed with the normal form of alpha-synuclein plus a fluorescent probe to initiate aggregate formation. In the second phase, this combined sample is broken down mechanically into smaller particles. If alpha-synuclein aggregates are present in the CSF sample, each particle starts its own aggregation and growth, amplifying the fluorescence signal many times.
RT-QuIC is a highly sensitive assay, and studies have shown that it has 95 percent sensitivity and 100 percent specificity in differentiating Parkinson’s from other forms of neurodegenerative disorders not involving alpha-synuclein. This minimizes the need to rely on multiple diagnostic tools to confirm Parkinson’s.
Limitations of RT-QuIC
Although RT-QuIC can help in the early diagnosis of Parkinson’s by monitoring the formation of alpha-synuclein aggregates, the technique has certain limitations. For example, RT-QuIC cannot currently be used to distinguish Parkinson’s from other forms of neurodegenerative disorders such as DLB or MSA that also involve alpha-synuclein, and specific modifications to the test might be needed to increase specificity for Parkinson’s.
Another major limitation of RT-QuIC is that it currently uses human CSF as the sample. Withdrawing CSFÂ from a patient is a moderately invasive procedure and might not be always possible. Research is underway to optimize the technique for detecting alpha-synuclein aggregates in the blood for easy diagnosis.
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