Technique Identifying Protein Build-Up Linked To Parkinson's Can Aid In Early Detection, Improve Treatment: Study In Lancet

The technique can accurately detect people with Parkinson's disease and identify individuals who are at risk of developing the neurodegenerative disease, and also those with early symptoms.

A technique capable of identifying abnormal protein build-up linked to Parkinson's disease could allow early detection of the brain disorder and help in improved diagnosis and treatment, according to a study published April 13 (6:30 pm ET on April 12) in The Lancet Neurology journal. 

The technique is known as α-synuclein seed and amplification assay (αSyn-SAA). A protein called α-synuclein is linked neuropathologically and genetically to Parkinson's disease.

How is αSyn-SAA a useful technique?

According to the study, the technique can accurately detect people with Parkinson's disease and identify individuals who are at risk of developing the neurodegenerative disease, and also those with early, non-motor symptoms prior to diagnosis. 

The pathological hallmark of Parkinson's disease is the presence of misfolded α-synuclein protein aggregates in the brain. 

In a statement released by The Lancet, Professor Andrew Siderowf of the University of Pennsylvania Perelman School of Medicine, co-lead author on the paper, said recognising heterogeneity in underlying pathology among patients with Parkinson's disease has been a major challenge. This means that it is difficult to recognise diverseness in underlying pathology among patients with the disease. 

Why it is important to identify an effective biomarker for Parkinson’s disease

It is important to identify an effective biomarker for Parkinson's disease pathology because this could have profound implications for the way the condition is treated. If an effective biomarker is identified on time, the disease can be diagnosed earlier. This would allow physicians to identify the best treatments for different subsets of patients. Also, clinical trials can be performed at a relatively quicker pace. 

Luis Concha, co-lead author on the paper, said the findings suggest that the αSyn-SAA technique is highly accurate at detecting the α-synuclein biomarker for Parkinson's disease, regardless of the clinical features. This makes it possible to accurately diagnose Parkinson's disease in patients at early stages. 

According to Concha, the results indicate that misfolded α-synuclein is detectable before damage to dopamine-producing neurons in the brain is about to be observed by imaging. This suggests that a ubiquitous spread of misfolded proteins takes place before substantial neuronal damage has occurred. 

How the study was conducted

The new study is unique because it is the largest analysis of the diagnostic performance of αSyn-SAA for Parkinson's disease. The research is the first large-scale study that analyses αSyn-SAA in such a broad range of carefully described participants with Parkinson's disease. 

Therefore, αSyn-SAA is useful for identifying underlying heterogeneity in people with Parkinson's disease, and can detect early signs of the neurodegenerative disease. In order to assess the usefulness of αSyn-SAA, the researchers used data from the Parkinson's Progression Markers Initiative (PPMI) cohort. 

The analysis involved 1,123 participants. Among these participants, there were individuals with a diagnosis of Parkinson's disease, and at-risk people with two gene variants — GBA and LRRK2 — linked to the condition. Prodromal individuals, who are patients with early signs and symptoms of a disease that appear before the major signs and symptoms start, were also included. 

What symptoms did the prodromal participants show?

The prodromal participants had non-motor symptoms such as sleep disturbance or loss of smell. These can be early signs of Parkinson's disease. The prodromal participants had not been diagnosed with Parkinson's disease, and had none of the typical motor symptoms, such as tremors or muscle stiffness, which come later in the development of Parkinson's disease. 

The reason the researchers included prodromal patients was to determine whether αSyn-SAA can predict the onset of Parkinson's disease and help diagnose people with established symptoms. 

The αSyn-SAA technique can amplify very small amounts of misfolded aggregates of α-synuclein

The researchers analysed samples of cerebrospinal fluid that surrounds the brain and spinal cord, from each participant, using αSyn-SAA.

Using this breakthrough technique, very small amounts of misfolded aggregates of α-synuclein in samples from Parkinson's disease patients can be amplified to the point that they can be detected using standard laboratory techniques. 

Findings of the study

After the analysis was complete, the results confirmed that αSyn-SAA identified people with Parkinson's disease with high accuracy. It showed positive results in 88 per cent of all participants with a diagnosis. 

About 93 per cent of the sporadic cases, or patients with no known genetic cause, had a positive αSyn-SAA result. For the patients with genetic forms of Parkinson's disease, αSyn-SAA identified 96 per cent of patients with the GBA variant and 68 per cent of the patients with LRRK2. 

Positive αSyn-SAA results in most prodromal patients, or those not diagnosed with Parkinson's disease but showing early symptoms, indicated the fact that they had α-synuclein aggregates, despite not yet being diagnosed with the neurodegenerative disease. 

Of participants recruited based on their loss of smell, 88 per cent had positive αSyn-SAA results. Also, 85 per cent of participants with REM sleep behaviour disorder, a disturbance known to be a precursor to Parkinson's disease, showed positive αSyn-SAA results. 

There were some participants who carried GBA or LRRK2 variants, but had no Parkinson's disease diagnosis or prodromal symptoms. Such patients are known as non-manifesting carriers (NMCs). Of the NMCs with LRRK2, nine per cent had positive αSyn-SAA results. Also, seven per cent of the NMCs with GBA had positive αSyn-SAA results. 

Brain scans of the prodromal participants and NMCs were conducted. The authors found that most of these patients' brain scans did not show a decline in the expected number of dopamine-producing neurons. A decline in the expected number of dopamine-producing neurons is a biomarker signature that is present even before diagnosis. Since no decline in these neurons was observed, it implies that a build up of α-synuclein aggregates may be a very early indicator of disease onset. 

Loss of smell was the clinical feature that most strongly predicted a positive αSyn-SAA result. This is one of the most common symptoms in prodromal participants and those with a Parkinson's disease diagnosis. 

Among the patients with Parkinson's disease who had a loss of smell, 97 per cent showed a positive αSyn-SAA result. Meanwhile, among Parkinson's disease patients whose sense of smell was unchanged, 63 per cent showed a positive αSyn-SAA result. 

According to the study, 55 per cent of female Parkinson's disease patients with an LRRK2 variant had a positive αSyn-SAA result, while 79 per cent of male Parkinson's disease patients with an LRRK2 variant had a positive αSyn-SAA result. 

The researchers conducted an autopsy of 15 participants who had had a Parkinson's disease diagnosis in life, and found that 14 showed typical pathology and were  αSyn-SAA positive. The one patient with a negative αSyn-SAA result was an individual whose sense of smell was unchanged in life, and also carried the LRRK2 variant. 

Limitations to the study

The authors noted some limitations to their study, including the fact longer-term studies are needed to further investigate differences in αSyn-SAA results between people with different genetic forms of Parkinson's disease.