Background
Carriers of the G2019S mutation of LRRK2 provide a great opportunity to investigate the premotor stages of Parkinson’s disease (PD). We have studied by serial clinical and dopamine ...transporter single photon emission computed tomography (DaT‐SPECT) evaluations a cohort of asymptomatic carriers of the LRRK2‐G2019S mutation in order to evaluate the usefulness of these tools as biomarkers. Here we report the results of the extended follow‐up of this cohort at 8 years.
Methods
Seventeen participants, of the 25 available from the 4‐year evaluation, completed the 8‐year assessment. UPDRS‐III, UPSIT test and DaT‐SPECT imaging (123I‐ioflupane) were performed. We used repeated‐measures linear mixed effects models to examine the changes in DaT binding over time.
Results
Three carriers had converted to PD at 4 years. One additional carrier converted at 8 years. PD‐converters had lower striatal DaT binding at baseline than non‐converters. There was a significant decline of DaT binding over time, with a mean annual rate of 3.5%, with somewhat inter‐individual and intra‐individual variability and comparable between PD‐converters and non‐converters. No carrier with DAT binding ratio above an undefined threshold between 0.5 and 0.8 developed PD symptoms. The age‐adjusted UPSIT score did not change significantly over time.
Conclusions
The rate of conversion to PD at 8 years in this cohort aged ~58 years at baseline was 16%. The observed decline of DaT binding over time and its association with the phenotype render DaT‐SPECT a potentially useful tool for monitoring the premotor stage of the disease, although at the individual level its ability to predict phenoconversion is limited.
There is 3.5% annual decline in striatal dopamine transporter (DaT) binding (DaT‐SPECT) in asymptomatic carriers of the the LRRK2‐G2019S mutation. This process takes place over a minimum of 8 years in most carriers. Conversion to Parkinson’s disease occurs when a threshold of DaT binding reduction is reached. This event is difficult to anticipate given the intra‐individual variability of the slope over time.
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 4-year evaluation including clinical examination (Unified Parkinsonʼs Disease Rating Scale, part III, olfaction University of Pennsylvania Smell Identification Test UPSIT) and dopamine transporter (DaT) SPECT (I-ioflupane). Visual and semiquantitative analysis of images was performed. The specific striatal binding ratio was calculated (striatal region of interest ROI − occipital ROI/occipital ROI).
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 = 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 = 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.
Abstract Patients with Parkinson's disease (PD) carrying the G2019S mutation of the LRRK2 gene provide an opportunity of studying in a homogeneous setting the molecular pathways involved in the ...pathogenesis of common idiopathic forms of PD. However, whether common mechanisms are involved in both conditions in not known. Here, we compared genome-wide gene expression (RNA sequencing) in peripheral blood between PD patients carrying the G2019S mutation of the LRRK2 gene and idiopathic PD cases, to deepen in the understanding of this topic. In addition, we compared the blood transcriptome between 2 cohorts of carriers of the G2019S mutation (symptomatic and asymptomatic) and 2 cohorts of noncarriers (symptomatic and asymptomatic) for detecting transcriptomic changes attributable to the presence of the G2019S mutation. We searched for gene enrichment in Reactome or Kyoto Encyclopedia of Genes and Genomes pathways. We found that despite some overlap, peripheral blood transcriptome differs widely between idiopathic and LRRK2 G2019S–associated PD, with only 4 deregulated pathways shared by both conditions (complement and coagulation cascades, cell adhesion molecules, hematopoietic cell lineage, and extracellular matrix organization). Changes in the blood transcriptome observed in asymptomatic carriers of the mutation included 6 genes known to be associated with PD in genome-wide association studies and also pathways related with immunity. Our findings emphasize the notion that PD is likely a pathogenically heterogeneous condition and suggest the existence of specific mechanisms involved in LRRK2 -associated PD.
To ascertain in a cross-sectional study whether substantia nigra (SN) echogenicity, olfaction, and dopamine transporter (DaT)-SPECT are reliable premotor biomarkers in a cohort of asymptomatic ...carriers of the LRRK2 G2019S mutation (AsG2019S+).
These biomarkers were evaluated in 49 AsG2019S+ patients, and we also studied olfaction and SN echogenicity in 29 patients with G2019S-associated Parkinson disease (PD-G2019S), 47 relatives who were noncarriers of the LRRK2 G2019S mutation (AsG2019S-), 50 patients with idiopathic Parkinson disease (iPD), and 50 community controls.
Eighty-five percent of unaffected mutation carriers (AsG2019S+) showed pathologic SN hyperechogenicity, with a similar proportion observed among both PD-G2019S and iPD cases, and 41% of AsG2019S- also showing increased SN echogenicity. The proportion of hyposmic individuals was not statistically different in patients with PD-G2019S (50%) and iPD (82%), but hyposmia was significantly less common in both AsG2019S+ (26%) and AsG2019S- (28%). In AsG2019S+ cases, reduced striatal uptake in DaT-SPECT was observed in 43.7%.
Independently of age at examination, the most frequently altered premotor biomarker in LRRK2 G2019S-associated PD was SN hyperechogenicity, whereas abnormal DaT-SPECT predominated in older, unaffected mutation carriers.
In both prodromal and early symptomatic stages of idiopathic PD (iPD) peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer (mGCL) thinning have been identified. Here we ...assessed whether these alterations can also be detected in symptomatic and presymptomatic stages of LRRK2-PD.
218 eyes belonging to 20 iPD, 19 LRRK2-PD (L2PD), 24 LRRK2 non-manifesting carriers (L2NMC), and 46 controls (HCs). pRNFL, mGCL thickness (squares), and Bruch's membrane opening minimum rim width were evaluated by SD-OCT. In L2NMC, 123I-ioflupane SPECT (DaT-SPECT) with semi-quantitative analysis was carried out.
Compared to HCs, iPD patients showed significant thinning of the temporal (BMO-MRW and pRNFL), superior-temporal (BMO-MRW), inferior-temporal (BMO-MRW), superior-nasal (BMO-MRW) and central sectors (BMO-MRW) (p < 0.05), as well as in five mGCL sectors (p < 0.05). No significant differences were found between the L2PD or L2NMC and HCs. BMO-MRW thickness in its temporal-superior, superior-nasal and middle sectors was influenced by disease duration (p < 0.05) and mGCL thickness in sectors TS1, TS2, TS3, NS1 and NS3 was influenced by UPDRSIII and age (p < 0.05).
LRRK2-PD is distinguished from iPD by absent or less retinal nerve involvement, both in clinical and preclinical stages.
•The peripapillary retinal nerve fiber layer of the retina is thinned in idiopathic PD.•In LRRK2-PD there seems to be minor or absent retinal thinning.•OCT might not to be useful to differentiate clinical or asymptomatic LRRK2-PD from healthy controls.
Abstract The commonest known cause of Parkinson's disease (PD) is the G2019S mutation of the LRRK2 gene, but this mutation is not sufficient for causing PD, and many carriers of the mutation never ...develop PD symptoms during life. Differences at the expression level of certain genes, resulting from either genetic variations or environmental interactions, might be one of the mechanisms underlying differential risks for developing both idiopathic and genetic PD. To identify the genes involved in PD pathogenesis, we compared genome-wide gene expression (RNA-seq) in peripheral blood of 20 PD patients carrying the G2019S mutation of the LRRK2 gene, 20 asymptomatic carriers of the mutation, 20 subjects with idiopathic PD, 20 controls and 7 PD patients before and after initiating dopaminergic therapy. We identified 13 common genes ( ADARB2 , CEACAM6 , CNTNAP2 , COL19A1 , DEF4 , DRAXIN , FCER2 , HBG1 , NCAPG2 , PVRL2 , SLC2A14 , SNCA , and TCL1B ) showing significant differential expression between G2019S-associated PD and asymptomatic carriers and also between idiopathic PD and controls but not between untreated and treated patients. Some of these genes are functionally involved in the processes known to be involved in PD pathogenesis, such as Akt signaling, glucose metabolism, or immunity. We consider that these genes merit further attention in future studies as potential candidate genes involved in both idiopathic and LRRK2 -G2019S–associated forms of PD.
There is a need for biomarkers to monitor the earliest phases of Parkinson's disease (PD), especially in premotor stages. Here, we studied whether there are early gait alterations in carriers of the ...G2019S mutation of LRRK2 that can be detected by means of an inertial sensor system.
Twenty-one idiopathic PD patients, 20 LRRK2-G2019S PD, 27 asymptomatic carriers of LRRK2-G2019S mutation (AsG2019S) and 36 controls walked equipped with 16 lightweight inertial sensors in three different experiments: i/normal gait, ii/fast gait and iii/dual-task gait. In the AsG2019S group, DaT-SPECT (123I-ioflupane) with semi-quantitative analysis was carried out. Motor and cognitive performance were evaluated using MDS-UPDRS-III and MoCA scales. We employed neural network techniques to classify individuals based on their walking patterns.
PD patients and controls showed differences in speed, stride length and arm swing amplitude, variability and asymmetry in all three tasks (p < 0.01). In the AsG2019S group, the only differences were detected during fast walking, with greater step time on the non-dominant side (p < 0.05), lower step/stride time variability (p < 0.01) and lower step time asymmetry (p < 0.01). DaT uptake showed a significant correlation with step time during fast walking on the non-dominant side (r = −0.52; p < 0.01). The neural network was able to differentiate between AsG2019S and healthy controls with an accuracy rate of 82.5%.
Our sensor-based analysis did not detect substantial and robust changes in the gait of LRRK2-G2019S asymptomatic mutation carriers. Nonetheless, step or stride time during fast walking, supported by the observed correlation with striatal DaT binding deserves consideration as a potential biomarker in future studies.
•Gait analysis with inertial sensors detects changes in the premotor stages of LRRK2-PD.•Step time during fast gait correlates with striatal DaT binding in asymptomatic carriers of the LRRK2-G2019S mutation.•Artificial intelligence tools trained with gait variables show high potential accuracy as diagnostic biomarkers.
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