Prodromal substantia nigra sonography undermines suggested association between substrate accumulation and the risk for GBA‐related Parkinson's disease


Individuals with GBA (glucocerebrosidase) mutations are at increased risk of Parkinson's disease (PD). It is still debated, however, whether this increased risk results from impaired glucocerebrosidase activity leading to substrate accumulation. Comparing the presence of prodromal PD marker in GBA mutation carriers and in Gaucher patients (in which substrate accumulation is extensive) can assist in clarifying this issue.

In this cross sectional study we compared the hyperechogenic area of the substantia nigra, a prodromal PD marker, in large cohorts of GBA mutation carriers (n=71) and Gaucher patients (n=145). Our control populations were healthy, non‐carriers (n=49) and patients with GBA‐related PD (n=11). Substrate accumulation was assessed from dry blood spot levels of the glucosylsphingosine. Our findings indicate no contribution of substrate accumulation, as the area of hyperechogenicity is similarly enlarged relative to healthy controls in both GBA mutation carriers and Gaucher patients. Moreover, this similarity between GBA carriers and Gaucher patients persists when comparing only carriers of the N370S (c.1226A>G) mutation (n=38) with untreated Gaucher patients who are homozygotes to the same mutation (n=47). In addition, measurements of hyperechogenic area did not correlate with levels of glucosylsphingosine in the untreated Gaucher patients.

The presence of a marker of prodromal PD (substantia nigra hyperechogenicity) is independent from substrate accumulation in a population with mutated GBA. Though further longitudinal studies are needed to determine the precise predictive value of this marker for GBA‐related PD, our findings raise doubts regarding the contribution of substance reduction strategies to PD prevention.