The ability to diagnose chronic neurodegenerative disease before it has become clinically evident has long been something of a Holy Grail for neurology. However, disease-modifying therapy (DMT) that only slowed the rate of progression could still, by its earlier introduction, be expected to provide greater benefit to both patients and society.
Prior to such an approach, the ability to identify patients who could participate in preventative clinical studies of potential DMTs would help avoid the expensive and, to date, fruitless pattern of trialling seen over the last 20+ years in Alzheimer’s disease and (to a lesser extent) Parkinson’s disease (PD). This has seen candidate DMTs being tested firstly in those with advanced disease, then in those with early disease, then in those with prodromal disease and finally in those with increased risk of disease – based on genetic or other markers of risk. Such a pattern appears rational (starting where the clinical need and pathological impact are greatest, and working backwards from there) but it also sets the hardest test conditions first – trying to prevent or delay a process that has been ‘at work’ for years and has already irreversibly destroyed much neuronal function.
One of the key pathological features of PD – the presence of α-synuclein (αSYN) aggregates in affected neuronal structures (as Lewy bodies or Lewy neurites) – occurs not only in the central nervous system, but also in peripheral neuronal tissues, particularly those that possess significant autonomic innervation. The possibility of sampling such tissues as surrogates for central nervous system tissue has led to easily accessible examples (like the gastrointestinal [GI] tract, skin and olfactory apparatus) being extensively researched as possible sources of a prodromal diagnosis for PD over the last 30+ years but until recently without much success. The GI tract looks to be the most promising peripheral tissue for biopsy sampling due to its extensive neural system that is easily accessible by endoscopic examination (Schneider, 2016). Other approaches such as biomarkers in cerebrospinal fluid (CSF) or blood have also not provided much success.
Many earlier studies were confounded by differences in approach to sampling (choice of biopsy sites), testing, analysis, and in particular the precise marker being targeted, resulting in wide variations in sensitivity and specificity and failure to identify a single, usable methodology (Schneider, 2016). More recently, it has been suggested that the pathological process is strongly reflected in the presence of post-translational phosphorylated αSYN (phosαSYN), which is far more difficult to detect in a quantitative manner, although a recent publication has reported a highly sensitive assay that detects phosαSYN in plasma even though it is not detectable in CSF (Cariulo, 2019). Others have proposed that diverse ‘strains’ of αSYN have leading roles in different synucleinopathies (Peng, 2018). Another approach is the detection of misfolded αSYN aggregates in GI biopsies using a protein misfolding cyclic amplification method which correlates well with phosαSYN immunochemistry findings (Fenyi, 2019).
Although no single, simple method yet exists for identifying preclinical PD (or other synucleinopathies), practical methods targeting a range of biomarkers are emerging that could, in combination, become a usable panel for this purpose. Then, perhaps, we will finally be in a position to conduct trials of potential DMTs, in high risk patients through to those with advanced disease, that offer a better chance of delivering the outcomes that are so desperately needed.
- Cariulo C, Martufi P, Verani M, et al. Phospho-S129 alpha-synuclein is present in human plasma but not in cerebrospinal fluid as determined by an ultrasensitive immunoassay. Front Neurosci 2019; 13: 889
- Fenyi A, Leclair-Visonneau L, Clairembault T, et al. Detection of alpha-synuclein aggregates in gastrointestinal biopsies by protein misfolding cyclic amplification. Neurobiol Dis 2019; 129: 38-43
- Peng C, Gathagan RJ, Lee VM-Y. Distinct α-Synuclein strains and implications for heterogeneity among α-synucleinopathies. Neurobiol Dis 2018; 109(Pt B): 209–218
- Schneider SA, Boettner M, Alexoudi A, et al. Can we use peripheral tissue biopsies to diagnose Parkinson’s disease? A review of the literature. Eur J Neurol