Prospective clinical and DaT-SPECT imaging in premotor LRRK2 G2019S-associated Parkinson disease

Abstract

Objective: To assess the value of baseline clinical and imaging biomarkers in a cohort of asymptomatic LRRK2 G2019S carriers for predicting conversion to Parkinson disease (PD) at 4 years.Methods: Thirty-two asymptomatic carriers of LRRK2 G2019S mutation underwent baseline and Results: Three carriers, asymptomatic at baseline, had converted to PD at 4-year evaluation.Twenty-three participants were fully evaluated. PD converters had lower striatal DaT binding at baseline than nonconverters (p 5 0.002). A baseline scan with a ratio of bilateral striatal uptake below 1 predicted conversion to PD within the 4-year period with high sensitivity and specificity (area under the curve 1; p 5 0.006). The slope of DaT binding decline between the 2 scans was similar in PD converters and nonconverters. Age-adjusted UPSIT score at baseline and at 4 years was similar in both groups.Conclusions: Semiquantitative DaT-SPECT could be used to predict early conversion to PD in asymptomatic carriers of the LRRK2 G2019S mutation. Rate of conversion to PD at 4 years in this cohort aged ;64 years was 12%. The slope of DaT binding decline on DaT-SPECT imaging seems to be similar across different stages of the premotor period. The G2019S mutation of the LRRK2 gene is the commonest known cause of Parkinson disease (PD). 1 Clinically and pathologically, this form of the disease is indistinguishable from idiopathic PD, and therefore it constitutes an ideal scenario in which to deepen our knowledge about the disease. The identification and follow-up of carriers of the LRRK2 G2019S mutation who still have not developed motor symptoms of PD represents a unique opportunity for studying the prodromal stage of PD. We lack information on the timing between the beginning of the neurodegenerative process and the appearance of the motor symptoms of PD and the pace of cell loss at the substantia nigra (SN) at the premotor stage. Shedding light into the prodromal stages of the disease is going to be crucial for planning drug trials aiming to modify the disease process early, before most of the damage is already done. The penetrance of the LRRK2 G2019S mutation is age-dependent and only a proportion of LRRK2 G2019S mutation carriers will develop motor symptoms of PD. 2 Besides age, no other clinical marker has been proven to be useful to predict conversion to manifest PD in asymptomatic carriers. In a previous study by our group, we characterized a cohort of 32 asymptomatic carriers of the LRRK2 G2019S mutation with brain imaging ( 123 I-ioflupane SPECT and transcranial sonography) and olfaction tests. 3

α‐synuclein RT‐QuIC in cerebrospinal fluid of LRRK2‐linked Parkinson's disease

“…Variable neuropathological substrates, even in the same kindreds as has been well documented to occur in cases with other pathogenic LRRK2 mutations, could explain this finding. A decline in DaT‐SPECT ( 123 I‐ioflupane) binding has been previously suggested to be a useful tool to predict phenoconversion in LRRK2‐NMC . In our study two of three (66.7%) LRRK2‐NMC with a positive RTQuIC had an abnormal DaT‐SPECT result, whereas this occurred only in two of 13 (15.3%) of the negative ones.…”

Prodromal Parkinson's Disease: The Decade Past, the Decade to Come

“…Dopaminergic imaging abnormalities were also found in some (but not all) studies of at‐risk PD gene carriers, providing additional indirect evidence of predictive value . A small prospective study documented predictive value of DAT scanning in asymptomatic LRRK2 carriers . So far, based on estimates from the PARS study, dopaminergic PET/SPECT is the strongest neuroimaging marker (relative risk = 17), making it second only to RBD in predictive value for prodromal PD …”

“…Predictive value was confirmed in other population‐based studies, although RR were lower (RR = 8.1 and 7.9). Studies in LRRK2 cohorts also found high prevalence of SNpc abnormalities, providing indirect evidence of predictive value (albeit with no clear predictive value in a small prospective follow‐up). Intriguingly, patients with melanoma (a risk factor for PD) had higher rates of hyperechogenicity, an effect that was partially explained by skin pigmentation .…”

“…85 A small prospective study documented predictive value of DAT scanning in asymptomatic LRRK2 carriers. 86 So far, based on estimates from the PARS study, dopaminergic PET/SPECT is the strongest neuroimaging marker (relative risk = 17), making it second only to RBD in predictive value for prodromal PD. 12,87 Nondopaminergic PET markers also were found to have predictive value.…”

The prodromes of Parkinson's disease

“…Once manifest, the motor features of LRRK2 ‐PD are largely indistinguishable from idiopathic PD, and examination of carriers of LRRK2 mutations therefore provide a useful model for prodromal PD. In the last few years, several longitudinal cohort studies of LRRK2 carriers have been published (Mestre et al., ; Mirelman et al., , ; Pont‐Sunyer et al., ; Sierra et al., , ). However, unlike in “idiopathic” PD, anosmia has been reported to be infrequent in LRRK2 PD cases (Marras et al., ) and also in LRRK2 carriers (Mestre et al., ; Mirelman et al., ; Pont‐Sunyer et al., ).…”