Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort

Abstract

We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 11% had hyposmia (defined as ≤15th percentile for age and sex). Only 5 of 176 LRRK2 NMCs developed PD during follow-up. Although NMCs scored significantly worse on numerous clinical scales at baseline than HCs, there was no longitudinal change in any clinical measures over 2 years or in DAT binding. There were no longitudinal differences in CSF and serum biomarkers between NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but did not change longitudinally. Neither baseline biofluid biomarkers nor the presence of DAT deficit correlated with 2-year change in clinical outcomes. We observed no significant 2-year longitudinal change in clinical or biomarker measures in LRRK2 G2019S NMCs in this large, well-characterized cohort even in the participants with baseline DAT deficit. These findings highlight the essential need for further enrichment biomarker discovery in addition to DAT deficit and longer follow-up to enable the selection of NMCs at the highest risk for conversion to enable future prevention clinical trials.

Characteristics of fatigue in Parkinson’s disease: A longitudinal cohort study

“…Other studies have also confirmed the longitudinal progression of both motor and non-motor symptoms, including autonomic dysfunction, EDS, and cognitive impairment (Amara et al, 2017;Simuni et al, 2018;Stanković et al, 2019;Myers et al, 2022). It should be noted that a subset of symptoms have shown stability, relief, and improvement in longitudinal studies (Cilia et al, 2020;Simuni et al, 2022). However, despite these inconsistencies, most studies have reported an overall deterioration of motor and non-motor symptoms, consistent with our data.…”

Defining the Riddle in Order to Solve It: There Is More Than One “Parkinson's Disease”

“…Second, mutations in LRRK2 are the most common cause of a monogenic form of clinically typical PD although the proportion of asymptomatic carriers developing symptoms may be lower than initially predicted. 93 Yet, strikingly, LBs are not detectable in a substantial fraction of patients with LRRK2 mutations analyzed postmortem, and this pattern has been confirmed in patients with several disease-causing mutations in this gene (Table 1). 15,94 In some of these LRRK2 patients, tau-positive pathology is found.…”

Age- and Sex-Dependent Behavioral and Neurochemical Alterations in hLRRK2-G2019S BAC Mice

“…This mutation might increase the susceptibility of DA neurons to degeneration. Interestingly, in a recent longitudinal clinical study with carriers of the G2019S mutation, which do not manifest symptoms, 13% of the patients had a significant reduction in the dopamine transporter (DAT) in the caudate putamen [8], which indicates neurochemical alterations before the disease develops. In order to investigate the roles of LRRK2, and mutated LRRK2, in the development of Parkinsonism, several rodent models bearing the G2019S mutation have been generated using, for example, bacterial artificial chromosome (BAC) and knock-in (KI) to express human or murine LRRK2 or LRRK2-G2019S [9][10][11][12][13][14][15].…”