In a clinical proceedings white paper published by the Clinical Neurological Society of America (CNSA) last month, skin biopsy testing for alpha-synuclein (α-syn) was among the three biomarker tests identified as clinically useful in diagnosing synucleinopathies.
The white paper focuses on the many burdens of Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy (MSA). Specifically, the white paper highlights the significant financial, emotional, and social burdens these conditions place on patients and caregivers. One of the key challenges posed by synucleinopathies is that these conditions can take several years to diagnose, mostly because of their overlapping symptoms and heterogeneous clinical presentations, making a differential clinical diagnosis complicated. Furthermore, there is a shortage of clinically trained neurologists, delaying patient visits while disease progresses.
Research presented at the 2020 American Academy of Neurology Annual Meeting found that only 5% of neurologists practice in nonmetropolitan areas, and less than half a percent practice in the rural areas. This research highlights a key concern of the CNSA: neurologists are not adequately distributed to meet the needs of an aging population nationwide, which can lead to further delays in diagnosis. This concern is underscored by James E. Galvin, MD, MPH, a contributing author to the CNSA white paper: “If you have dementia with Lewy bodies, where you only have 4 to 6 years to live with the disease, and you have to wait 6 to 8 months to see a neurologist, you end up not being diagnosed for the first quarter of the disease course.”
An earlier, more timely diagnosis offers several benefits to patients and their caregivers, such as the prompt selection of appropriate treatment, minimizing unnecessary patient discomfort, and allowing families more time to plan for their future living with a synucleinopathy. An accurate diagnosis also allows researchers to select the right patient population in which to study potential new treatments for synucleinopathies.
Biomarker tests, primarily those aimed at detecting phosphorylated (abnormal) alpha-synuclein (P-SYN), are a promising avenue to achieving early and accurate diagnoses, helping patients maintain quality of life and helping researchers find appropriate patients for clinical trials. Three such tests, the α-syn skin biopsy, the α-syn seed amplification assay, and the DaTscan™ test, have what the authors of the white paper consider the key features of “ideal” biomarker tests for synucleinopathies.
These tests offer high sensitivity and selectivity, the biological samples needed are easy for clinicians to access, and the samples allow for quick evaluation in a lab or clinical setting. Tests like these provide patients and caregivers more opportunity to identify and manage synucleinopathies more effectively, early.
The α-syn skin biopsy detects the presence of P-SYN in nerve cells in the skin. This test has demonstrated high sensitivity and selectivity* in clinical studies while using a minimally invasive punch biopsy procedure performed by any licensed clinician. Along with accurately identifying synucleinopathies, preliminary research suggests that P-SYN deposition patterns may help distinguish between synucleinopathies, highlighting potentially expanded value of a skin biopsy test for P-SYN.
Additional research is underway to determine skin-biopsy sensitivity as an early marker of disease, particularly in REM sleep behavior disorder, a condition that some research suggests indicates risk of developing synucleinopathies. “More work is necessary to validate these findings and determine their clinical value; however, such results indicate that this biomarker may prove to have even more diagnostic benefits than those that are currently recognized,” state the authors of the white paper.
A study published last year showed that α-syn skin biopsy testing had a significant impact on patients’ clinical care. Of the 97 patients studied, nearly 80% had a change in their clinical care as a result of the test. Among the most impactful results from this study, almost two-thirds of patients tested had their original diagnosis changed, and more than half had their treatment changed after receiving the results.
Another common biomarker test is the α-syn seed amplification assay (SAA), which uses cerebrospinal fluid (CSF) to test for the presence and aggregation of P-SYN. The SAA has demonstrated high sensitivity and specificity in diagnosing Parkinson’s and dementia with Lewy bodies; results in MSA are variable. This may be at least partially explained by the fact that α-syn variants found in CSF differ in patients with this condition.
DaTscan is used to help confirm suspected Parkinsonian syndromes (PS) or suspected dementia with Lewy bodies (DLB). The tests use an injected dye that labels dopaminergic neurons for analysis with single photon emission computed tomography (SPECT) brain imaging. The test has demonstrated up to 90% sensitivity and 92% specificity in differentiating Parkinson’s from other conditions that cause similar motor symptoms. Another meta-analysis also found that DaTscan was able to distinguish between patients with and without dementia with Lewy bodies with 86.5% sensitivity and 93.6% specificity.
“Biomarkers found in skin and CSF may be more accurate than the DaTscan. They’re similar in specificity, but they tend to be higher in sensitivity. Combinations of such high sensitivity and specificity together changes their predictive value in the real world,” said white paper contributing author David Houghton, MD, MPH.
This white paper highlights the promise of biomarker testing, which is contributing to early and accurate diagnoses in patients who suffer from these progressive and debilitating disorders. Prompt and accurate diagnoses can improve quality of life for patients and their caregivers and help further research of potential treatments.
The white paper was supported in part with grants from CND Life Sciences, Parkinson & Movement Disorder Alliance, and Movement Disorders Foundation of Arizona.
Read the paper
Learn more about the Syn-One Test
Follow CND Life Sciences on LinkedIn
*Prospective, blinded study (N=428) demonstrated 95.5% sensitivity and 96.3% specificity rates across synucleinopathies.
References:
Curtis K, Elrahi S, Bilello J, Rai P. Geographical distribution of neurologists in the United States. Neurology. 2020;94(suppl 15):727. doi: 10.1212/wnl.94
Gibbons CH, Levine T, Adler C, et al. Skin biopsy detection of phosphorylated α-synuclein in patients with synucleinopathies. JAMA. 2024;331(15):1298–1306. doi:10.1001/jama.2024.0792
Isaacson JR, Freeman R, Gibbons CH. Clinical utility of synuclein skin biopsy in the diagnosis and evaluation of synucleinopathies. Front Neurol. 2024;15:1510796. doi:10.3389/fneur.2024.1510796
