Search

Estimates of the spectrum and frequency of pathogenic variants in Parkinsons disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinsons disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Background: Video-oculography constitutes a highly-sensitive method of characterizing ocular movements, which could detect subtle premotor changes and contribute to the early diagnosis of Parkinson's disease (PD). Objective: To investigate potential oculomotor differences between idiopathic PD (iPD) and PD associated with the G2019S variant of LRRK2 (L2PD), as well as to evaluate oculomotor function in asymptomatic carriers of the G2019S variant of LRRK2. Methods: The study enrolled 129 subjects: 30 PD (16 iPD, 14 L2PD), 23 asymptomatic carriers, 13 non-carrier relatives of L2PD patients, and 63 unrelated HCs. The video-oculographic evaluation included fixation, prosaccade, antisaccade, and memory saccade tests. Results: We did not find significant differences between iPD and L2PD. Compared to controls, PD patients displayed widespread oculomotor deficits including larger microsaccades, hypometric vertical prosaccades, increased latencies in all tests, and lower percentages of successful antisaccades and memory saccades. Non-carrier relatives showed oculomotor changes with parkinsonian features, such as fixation instability and hypometric vertical saccades. Asymptomatic carriers shared multiple similarities with PD, including signs of unstable fixation and hypometric vertical prosaccades; however, they were able to reach percentages of successful antisaccade and memory saccades similar to controls, although at the expense of longer latencies. Classification accuracy of significant oculomotor parameters to differentiate asymptomatic carriers from HCs ranged from 0.68 to 0.74, with BCEA, a marker of global fixation instability, being the parameter with the greatest classification accuracy. Conclusions: iPD and LRRK2-G2019S PD patients do not seem to display a differential oculomotor profile. Several oculomotor changes in asymptomatic carriers of LRRK2 mutations could be considered premotor biomarkers. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is often detected only in later stages, when about 50% of nigrostriatal dopaminergic projections have already been lost. Thus, there is a need for biomarkers to monitor the earliest phases, especially for those that are at higher risk. In this work, we explore the use of machine learning methods to diagnose PD by analyzing gait alterations via an inertial sensors system that participants in the study wear while walking down a 15 m long corridor in three different scenarios. To achieve this goal, we have trained six well-known machine learning models: support vector machines, logistic regression, neural networks, k nearest neighbors, decision trees and random forest. We thoroughly explored several ways to mitigate the problems derived from the small amount of available data. We found that, while achieving accuracy rates of over 70% is quite common, the accuracy of the best model trained is only slightly above the 80% mark. This model has high precision and specificity (over 90%), but lower sensitivity (only 71%). We believe that these results are promising, especially given the size of the population sample (41 PD patients and 36 healthy controls), and that this research venue should be further explored. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggest a link between CAG repeat number in the HTT gene and non-Huntington neurodegenerative diseases.Objective: The aim is to analyze whether expanded HTT CAG alleles and/or their size are associated with the risk for developing α-synucleinopathies or their behavior as modulators of the phenotype.Methods: We genotyped the HTT gene CAG repeat number and APOE-Ɛ isoforms in a case-control series including patients with either clinical or neuropathological diagnosis of α-synucleinopathy.Results: We identified three Parkinson's disease (PD) patients (0.30%) and two healthy controls (0.19%) carrying low-penetrance HTT repeat expansions whereas none of the dementia with Lewy bodies (DLB) or multisystem atrophy (MSA) patients carried pathogenic HTT expansions. In addition, a clear increase in the number of HTT CAG repeats was found among DLB and PD groups influenced by the male gender and also by the APOE4 allele among DLB patients. HTT intermediate alleles' (IAs) distribution frequency increased in the MSA group compared with controls (8.8% vs. 3.9%, respectively). These differences were indeed statistically significant in the MSA group with neuropathological confirmation. Two MSA HTT CAG IAs carriers with 32 HTT CAG repeats showed isolated polyQ inclusions in pons and basal nuclei, which are two critical structures in the neurodegeneration of MSA.Conclusions: Our results point to a link between HTT CAG number, HTT IAs, and expanded HTT CAG repeats with other non-HD brain pathology and support the hypothesis that they can share common neurodegenerative pathways. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Freezing of gait is a disabling phenomenon that appears in a substantial number of Parkinson's disease (PD) patients as the disease evolves. It is considered to be one of the most relevant contributing factors to worsening of quality of life. Current pharmacological or surgical treatment options have limited efficacy. Thus, alternative nonpharmacological/nonsurgical approaches have emerged in recent years in an attempt to improve quality of life in PD. This systematic review summarizes studies of such therapies over the past 5 years. Thirty-five studies were evaluated by use of a qualitative evaluation, while the methodological quality was assessed using validated tools. According to our results, there appear to be two broad categories of nonpharmacological therapies: those that seek a long-lasting benefit and those that aim to achieve a transient effect to overcome the freezing of gait episode. Among the former, it is possible to differentiate between "passive" therapies, which include transcranial magnetic stimulation or transcranial direct current stimulation, and "active" therapies, which are based on different cognitive or physical training programs. Finally, "transient effect" therapies use different types of cues, such as visual, auditory, or proprioceptive stimuli, to attempt to shift the patient's habitual motor control to a goal-directed one. In conclusion, a broad spectrum of nonpharmacological/nonsurgical approaches for freezing of gait has emerged in recent years with promising results. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objectives: A recent study showed that Arab-Berbers GG homozygous at rs2421947(C/G) in the dynamin 3 gene (DNM3) had 12.5 years earlier age at onset of leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD) (L2PD). We explored whether this variant modulates the L2PD age at onset in Spain.Methods: We genotyped rs2421947 in 329 participants (210 L2PD patients, 119 L2PD nonmanifesting p.G2019S carriers), and marker rs356219 (A/G) in the α-synuclein gene (SNCA).Results: By Kaplan Meier and Cox regression analyses, we did not find an association of the DNM3 polymorphism with L2PD age at onset. However, we found an association of the SNCA marker with up to an 11 years difference in the L2PD median age at onset (58 years for GG carriers vs 69 years for AA).Conclusion: Our results indicate that SNCA rs356219 but not dynamin 3 DNM3 rs2421947 modifies the penetrance of the mutation G2019S in the Spanish population by influencing the L2PD age at onset. These findings suggest that different genetic modifiers may influence the L2PD age at onset in different populations. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder causing motor and non-motor symptoms that can affect independence, social adjustment and the quality of life (QoL) of both patients and caregivers. Studies designed to find diagnostic and/or progression biomarkers of PD are needed. We describe here the study protocol of COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015), an integral PD project based on four aspects/concepts: 1) PD as a global disease (motor and non-motor symptoms); 2) QoL and caregiver issues; 3) Biomarkers; 4) Disease progression.Methods/design: Observational, descriptive, non-interventional, 5-year follow-up, national (Spain), multicenter (45 centers from 15 autonomous communities), evaluation study. Specific goals: (1) detailed study (clinical evaluations, serum biomarkers, genetic studies and neuroimaging) of a population of PD patients from different areas of Spain, (2) comparison with a control group and (3) follow-up for 5 years. COPPADIS-2015 has been specifically designed to assess 17 proposed objectives.Study Population: approximately 800 non-dementia PD patients, 600 principal caregivers and 400 control subjects. Study evaluations: (1) baseline includes motor assessment (e.g., Unified Parkinson's Disease Rating Scale part III), non-motor symptoms (e.g., Non-Motor Symptoms Scale), cognition (e.g., Parkinson's Disease Cognitive Rating Scale), mood and neuropsychiatric symptoms (e.g., Neuropsychiatric Inventory), disability, QoL (e.g., 39-item Parkinson's disease Quality of Life Questionnaire Summary-Index) and caregiver status (e.g., Zarit Caregiver Burden Inventory); (2) follow-up includes annual (patients) or biannual (caregivers and controls) evaluations. Serum biomarkers (S-100b protein, TNF-α, IL-1, IL-2, IL-6, vitamin B12, methylmalonic acid, homocysteine, uric acid, C-reactive protein, ferritin, iron) and brain MRI (volumetry, tractography and MTAi [Medial Temporal Atrophy Index]), at baseline and at the end of follow-up, and genetic studies (DNA and RNA) at baseline will be performed in a subgroup of subjects (300 PD patients and 100 control subjects). Study periods: (1) recruitment period, from November, 2015 to February, 2017 (basal assessment); (2) follow-up period, 5 years; (3) closing date of clinical follow-up, May, 2022.Funding: Public/Private.Discussion: COPPADIS-2015 is a challenging initiative. This project will provide important information on the natural history of PD and the value of various biomarkers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

ABSTRACT Nonmotor symptoms (NMS) in Parkinson's disease (PD) can precede onset of motor symptoms. Relationship between premotor symptoms onset and motor features is limited. Our aim is to describe the presence and perceived onset of NMS in PD as well as their possible association with motor phenotype. Presence and onset of NMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls from 11 Spanish and Austrian centers. Seventeen of thirty-one NMS were more common in patients than controls ( P < 0.05). They were usually mild and frequently reported to occur at different time-spans before motor symptoms. Anhedonia, apathy, memory complaints, and inattention occurred more frequently during the 2-year premotor period. Those reported more frequently in the 2- to 10-year premotor period were smell loss, mood disturbances, taste loss, excessive sweating, fatigue, and pain. Constipation, dream-enacting behavior, excessive daytime sleepiness, and postprandial fullness were frequently perceived more than 10 years before motor symptoms. No correlation between NMS burden and motor severity, age, or gender was observed. NMS associated in four clusters: rapid eye movement sleep behavior disorder symptoms-constipation, cognition-related, mood-related, and sensory clusters. No cluster was associated with a specific motor phenotype or severity. NMS are common in early unmedicated PD and frequently reported to occur in the premotor period. They are generally mild, but a patient subgroup showed high NMS burden mainly resulting from cognition-related symptoms. Certain NMS when present at the time of assessment or in the premotor stage, either alone or in combination, allowed discriminating PD from controls. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Idiopathic Parkinson’s disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. Objective: To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. Methods: The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. Results: University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. Conclusion: Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Low serum uric acid (UA) levels have been associated with increased Parkinson's disease (PD) risk and accelerated disease progression. We analyzed the effect of polymorphisms in 9 genes influencing serum UA concentration on the risk of PD. Methods We genotyped SLC2A9 rs734553, ABCG2 rs2231142, SLC17A1 rs1183201, SLC22A11 rs17300741, SLC22A12 rs505802, GCKR rs780094, PDZK1 rs12129861, LRRC16A+SCGN rs742132, and SLC16A9 rs12356193 in 1061 PD patients and 754 controls. For each subject we calculated a cumulative genetic risk score (GRS), defined as the total number of PD-risk alleles (range, 2-15) associated to lower serum UA levels. Serum UA levels were measured in a subgroup of 365 PD cases and 132 controls. Results Serum UA levels were significantly lower in men with PD than in controls. Subjects (both men and women) carrying more than 9 risk alleles (third GRS tertile) had a 1.5 higher risk of developing PD than subjects with less than 8 risk alleles (first GRS tertile). An inverse correlation was observed between higher GRS and lower serum UA concentration in both men and women. Conclusions Genetic variability influencing serum UA levels might modify susceptibility to PD. © 2013 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Common variants in the LRRK2 gene influence the risk of Parkinson's disease (PD) in Asians, but whether the same is true in European-derived populations is less clear. Methods: We genotyped 66 LRRK2 tagging single-nucleotide polymorphisms (SNPs) in 575 PD patients and 689 controls from the northwestern United States (tier 1). PD-associated SNPs ( P < .05) were then genotyped in an independent sample of 3617 cases and 2512 controls from the United States and Spain (tier 2). Logistic regression was used to model additive SNP genotype effects adjusted for age and sex among white individuals. Results: Two regions showed independent association with PD in tier 1, and SNPs in both regions were successfully replicated in tier 2 (rs10878226, combined odds ratio [OR], 1.20; 95% confidence interval [CI], 1.08-1.33; P = 6.3 × 10−4; rs11176013, OR, 0.89; CI, 0.83-0.95; P = 4.6 × 10−4). Conclusions: Our data suggest that common variation within LRRK2 conveys susceptibility for PD in individuals of European ancestry. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Abstract: Poly (ADP-ribose) polymerase-1 (PARP-1) is involved in crucial pathogenic events in Parkinson''s disease (PD). We studied the effect of promoter variations of PARP-1 gene on the risk for PD in a case-control association study comprising 146 PD patients and 161 controls from Northern Spain. Three polymorphisms from the promoter region of PARP-1 gene were analyzed: −410C/T, −1672G/A, and a (CA)n microsatellite. A protective effect against PD was found for heterozygosity at (−410) (OR 0.44) and (CA)n microsatellite (OR 0.53) polymorphisms, and heterozygosity at (−1672) polymorphism delayed by 4 years on the onset age of PD. Variations in the regulatory region of PARP-1 gene might modify the risk for PD. [Copyright &y& Elsevier]

Abstract: Mutations in the leucine-rich repat kinase 2 (LRRK2) gene have been shown to cause both autosomal dominant and sporadic Parkinson''s disease (PD). The common G2019S mutation shows wide geographical distribution while R1441G has been only reported in Northern Spain. The overall frequency of these mutations remains to be established. To determine the prevalence of G2019S and R1441G mutations in our population of Cantabria (Northern Spain), we recruited 105 consecutive PD patients and 310 controls and conducted genetic analysis of these mutations. G2019S was detected in eight late-onset patients (7.6%). Five of them had no relevant family history. R1441G was not detected in any of our study subjects. The prevalence of G2019S mutation in unselected late-onset PD patients might be higher than previously reported: 3/16 (18.7%) of familial PD and 5/82 (6.1%) of sporadic PD. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Introduction: 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.Methods: 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.Results: 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%.Conclusion: 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. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Abstract: Objective: Low serum uric acid (UA) levels have been associated with a worse cognitive function later in life and also with a higher risk and faster progression of Parkinson's disease (PD). Here we studied whether serum UA levels and the genetic variants related to its variability are associated with the presence of dementia in a cohort of patients with PD. Methods: The study included 343 PD patients, which were examined for the presence of dementia according to the MDS Task Force criteria (level 1). The predominant PD phenotype and UPDRS-III and Hoehn-Yahr scales were recorded. Serum UA levels were determined in each participant. Genotyping of SLC2A9 rs734553, ABCG2 rs2231142, SLC17A1 rs1183201, SLC22A11 rs17300741, SLC22A12 rs505802, GCKR rs780094, PDZK1 rs12129861, LRRC16A + SCGN rs742132, and SLC16A9 rs12356193 was carried out by Taqman analysis. For each subject we calculated a cumulative genetic risk score (GRS), defined as the total number of risk alleles (range 2–15) associated to lower serum UA levels. Results: 72 out of 343 PD patients (21%) presented dementia. Serum UA levels were not different between PD patients with or without dementia. No significant association was detected between any single SNP and the risk of PD-dementia. When we analyzed the combined effect of the eight SNPs using the cumulative GRS no significant association between the number of risk alleles and the risk of PD was observed. Conclusions: Our data suggest that serum UA levels have not a significant impact on the risk of dementia in PD. [Copyright &y& Elsevier]

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3 , and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk. • Analysis of DNM3 in previously unpublished data does not show an interaction between DNM3 and LRRK2 G2019S for AAO. • There was no evidence for linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699. • Analysis of sporadic PD patients stratified by the PD risk variant rs10878226 indicates a possible interaction between LRRK2 and VAMP4. [ABSTRACT FROM AUTHOR]