Alpha‐Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure

Abstract

Objective To explore the role of alpha‐synuclein (αSyn) oligomers and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) of patients with pure autonomic failure (PAF) as markers of future phenoconversion to multiple system atrophy (MSA). Methods Well‐characterized patients with PAF (n = 32) were enrolled between June 2016 and February 2019 at Mayo Clinic Rochester and followed prospectively with annual visits to determine future phenoconversion to MSA, Parkinson's disease (PD), or dementia with Lewy bodies (DLB). ELISA was utilized to measure NfL and protein misfolding cyclic amplification (PMCA) to detect αSyn oligomers in CSF collected at baseline. Results Patients were followed for a median of 3.9 years. Five patients converted to MSA, 2 to PD, and 2 to DLB. NfL at baseline was elevated only in patients who later developed MSA, perfectly separating those from future PD and DLB converters as well as non‐converters. ASyn‐PMCA was positive in all but two cases (94%). The PMCA reaction was markedly different in five samples with maximum fluorescence and reaction kinetics previously described in MSA patients; all of these patients later developed MSA. Interpretation αSyn‐PMCA is almost invariably positive in the CSF of patients with PAF establishing this condition as α‐synucleinopathy. Both NfL and the magnitude and reaction kinetics of αSyn PMCA faithfully predict which PAF patients will eventually phenoconvert to MSA. This finding has important implications not only for prognostication, but also for future trials of disease modifying therapies, allowing for differentiation of MSA from Lewy body synucleinopathies before motor symptoms develop. ANN NEUROL 2021;89:1212–1220

High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease

“…Likewise, out of 12 HC subjects in the tested cohort with SCOPA-AUT score ≥ 7, 2 (17%) showed positive αSyn-SAA (#3112 in Amprion Y3, and #3264 by all groups). Several studies have now noted much higher positivity rates of αSyn-SAA in prodromal cases [ 24 , 37 , 38 ]. Up to 59% of patients with RBD confirmed by polysomnography can have DAT deficit at baseline [ 39 ], vs. none in the PPMI control subjects with RBD symptoms.…”

“…These SWEDD subjects did have early motor signs of parkinsonism, indicating manifest nigrostriatal dysfunction, but the relative preservation of dopaminergic terminals by imaging suggests that diagnosis by αSyn-SAA may be possible before significant neuron loss. αSyn-SAA has already been tested in several cohorts of prodromal synucleinopathies, including RBD or pure autonomic failure, detecting seeding-competent αSyn forms before definite motor or cognitive phenotypes emerge [ 24 , 37 , 38 , 44 ]. Decreased binding of radioligand can indicate disruption of the nigrostriatal pathway, but this is not specific to PD or to αSyn-dependent degenerative processes, as this can be seen in other forms of parkinsonism, such as PSP or CBD.…”

The Concept of α-Synuclein Strains and How Different Conformations May Explain Distinct Neurodegenerative Disorders

“…Recent studies have also tried to decipher whether α-syn strains from PAF or iRBD patients differ from the ones of PD, DLB and MSA. In this regard, Singer and colleagues demonstrated the presence of α-syn in the CSF of most PAF cases included in the study, showing a similar amplification kinetic to PD and DLB cases, and significantly different from those with MSA ( 101 ). In addition, they observed that all PAF patients that later progressed toward MSA were the only ones showing amplification kinetics previously described in MSA patients ( 101 ).…”

“…In this regard, Singer and colleagues demonstrated the presence of α-syn in the CSF of most PAF cases included in the study, showing a similar amplification kinetic to PD and DLB cases, and significantly different from those with MSA ( 101 ). In addition, they observed that all PAF patients that later progressed toward MSA were the only ones showing amplification kinetics previously described in MSA patients ( 101 ). Thus, the use of amplification assays might constitute a potential diagnostic tool for MSA even at early-stages.…”

The role of cardiovascular autonomic failure in the differential diagnosis of α-synucleinopathies

“…A very recent study prospectively followed a well-characterized cohort of PAF individuals to determine the role of α-synuclein oligomers and neurofilament light chain (Nfl) in cerebrospinal fluid as markers of phenoconversion [ 33 ]. As previously shown for the distinction of MSA from Lewy body disorders [ 36 ], higher Nfl measurements and lower maximum-thioflavin-fluorescence in the protein misfolding cyclic amplification (PMCA) assay of baseline cerebrospinal fluid accurately distinguished future phenoconversion to MSA versus Lewy body disorders or stable PAF [ 33 ].…”