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The Onset of Nonmotor Symptoms in Parkinson's disease (The ONSET PD Study)
Pont-Sunyer, Claustre; Hotter, Anna; Gaig, Carles ...
Movement disorders,
February 2015, Volume:
30, Issue:
2
Journal Article
Peer reviewed
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
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Arm swing as a potential new prodromal marker of Parkinson's disease
Mirelman, Anat; Bernad-Elazari, Hagar; Thaler, Avner ...
Movement disorders,
10/2016, Volume:
31, Issue:
10
Journal Article
Peer reviewed
Open access
ABSTRACT
Background
Reduced arm swing is a well‐known clinical feature of Parkinson's disease (PD), often observed early in the course of the disease. We hypothesized that subtle changes in arm swing ...
and axial rotation may also be detectable in the prodromal phase.
Objective
The purpose of this study was to evaluate the relationship between the LRRK2‐G2019S mutation, arm swing, and axial rotation in healthy nonmanifesting carriers and noncarriers of the G2019S mutation and in patients with PD.
Methods
A total of 380 participants (186 healthy nonmanifesting controls and 194 PD patients) from 6 clinical sites underwent gait analysis while wearing synchronized 3‐axis body‐fixed sensors on the lower back and bilateral wrists. Participants walked for 1 minute under the following 2 conditions: (1) usual walking and (2) dual‐task walking. Arm swing amplitudes, asymmetry, variability, and smoothness were calculated for both arms along with measures of axial rotation.
Results
A total of 122 nonmanifesting participants and 67 PD patients were carriers of the G2019S mutation. Nonmanifesting mutation carriers walked with greater arm swing asymmetry and variability and lower axial rotation smoothness under the dual task condition when compared with noncarriers (P < .04). In the nonmanifesting mutation carriers, arm swing asymmetry was associated with gait variability under dual task (P = .003). PD carriers showed greater asymmetry and variability of movement than PD noncarriers, even after controlling for disease severity (P < .009).
Conclusions
The G2019S mutation is associated with increased asymmetry and variability among nonmanifesting participants and patients with PD. Prospective studies should determine if arm swing asymmetry and axial rotation smoothness may be used as motor markers of prodromal PD. © 2016 International Parkinson and Movement Disorder Society
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Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls
Agalliu, Ilir; Ortega, Roberto A.; Luciano, Marta San ...
Movement disorders,
September 2019, Volume:
34, Issue:
9
Journal Article
Peer reviewed
Open access
ABSTRACT
Background
Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2‐PD) in comparison with ...
idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls.
Methods
Cancer outcomes were compared among 257 LRRK2‐PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed‐effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2‐PD and 1946 IPD patients.
Results
Although cancer prevalence was similar among LRRK2‐PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2‐PD had increased risks of leukemia (odds ratio OR = 4.55; 95% confidence interval CI, 1.46–10.61) and skin cancer (OR = 1.61; 95% CI, 1.09–2.37). In the pooled analysis, LRRK2‐PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15–44.94) and colon cancer (OR = 2.34; 95% CI, 1.15–4.74) when compared with IPD patients.
Conclusions
The increased risks of leukemia as well as skin and colon cancers among LRRK2‐PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society
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Motor and nonmotor heterogeneity of LRRK2-related and idiopathic Parkinson's disease
Marras, Connie; Alcalay, Roy N.; Caspell-Garcia, Chelsea ...
Movement disorders,
08/2016, Volume:
31, Issue:
8
Journal Article
Peer reviewed
ABSTRACT
Background
Parkinson's disease (PD) associated with LRRK2 mutations has been described as similar to idiopathic PD with minor clinical differences. No study has compared the clinical ...
features of LRRK2‐associated PD due to different mutations. The objective of this study was to compare LRRK2‐associated PD due to G2019S and G2385R mutations and to compare each to idiopathic PD.
Methods
Sites within the international LRRK2 Cohort Consortium undertook family‐based, community‐based, or clinic‐based studies to gather clinical data on manifesting carriers and patients with idiopathic PD.
Results
Five hundred sixteen PD patients with the G2019S mutation, 199 with the G2385R mutation, and 790 patients with idiopathic PD were included in the data set. Adjusted for age, sex, disease duration, and levodopa‐equivalent daily dose, mean MDS‐UPDRS part II or III scores and the frequency of motor fluctuations were higher in the G2385R mutation carriers than in either the G2019S mutation carriers or idiopathic PD patients. G2019S mutation carriers had significantly lower UPDRS part III scores than idiopathic PD patients. Both G2019S and G2385R mutation carriers had a higher proportion of the postural instability gait disorder phenotype compared with idiopathic PD patients. LRRK2 G2019S PD patients had better UPSIT scores and lower Geriatric Depression Scale scores than idiopathic PD patients in adjusted analyses.
Conclusions
G2385R and G2019S PD appear to have motor differences that may be explained by contrasting local treatment or measurement practices or differences in the biology of the disease. Longitudinal studies should evaluate whether progression is faster in G2385R mutation carriers compared with G2019S PD or idiopathic PD. © 2016 International Parkinson and Movement Disorder Society
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Identification of blood serum micro-RNAs associated with idiopathic and LRRK2 Parkinson's disease
Botta-Orfila, Teresa; Morató, Xavier; Compta, Yaroslau ...
Journal of neuroscience research,
August 2014, Volume:
92, Issue:
8
Journal Article
Peer reviewed
Blood‐cell‐free circulating micro‐RNAs (miRNAs) have been proposed as potential accessible biomarkers for neurodegenerative diseases such as Parkinson's disease (PD). Here we analyzed the serum ...
levels of 377 miRNAs in a discovery set of 10 idiopathic Parkinson's disease (IPD) patients, 10 PD patients carriers of the LRRK2 G2019S mutation (LRRK2 PD), and 10 controls by using real‐time quantitative PCR‐based TaqMan MicroRNA arrays. We detected candidate differentially expressed miRNAs, which were further tested in a first validation set consisting of 20 IPD, 20 LRRK2 PD, and 20 control samples. We found four statistically significant miRNAs that were downregulated in either LRRK2 or IPD (miR‐29a, miR‐29c, miR‐19a, and miR‐19b). Subsequently, we validated these findings in a third set of samples consisting of 65 IPD and 65 controls and confirmed the association of downregulated levels of miR‐29c, miR‐29a, and miR‐19b in IPD. Differentially expressed miRNAs are predicted to target genes belonging to pathways related to ECM–receptor interaction, focal adhesion, MAPK, Wnt, mTOR, adipocytokine, and neuron projection. Results from our exploratory study indicate that downregulated levels of specific circulating serum miRNAs are associated with PD and suggest their potential use as noninvasive biomarkers for PD. Future studies should further confirm the association of these miRNAs with PD. © 2014 Wiley Periodicals, Inc.
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The prodromal phase of leucine‐rich repeat kinase 2–associated Parkinson disease: Clinical and imaging Studies
Pont‐Sunyer, Claustre; Tolosa, Eduardo; Caspell‐Garcia, Chelsea ...
Movement disorders,
20/May , Volume:
32, Issue:
5
Journal Article
Peer reviewed
ABSTRACT
Background: Asymptomatic, nonmanifesting carriers of leucine‐rich repeat kinase 2 mutations are at increased risk of developing PD. Clinical and neuroimaging features may be associated with ...
gene carriage and/or may demarcate individuals at greater risk for phenoconversion to PD.
Objectives: To investigate clinical and dopamine transporter single‐photon emission computed tomography imaging characteristics of leucine‐rich repeat kinase 2 asymptomatic carriers.
Methods: A total of 342 carriers' and 259 noncarriers' relatives of G2019S leucine‐rich repeat kinase 2/PD patients and 39 carriers' and 31 noncarriers' relatives of R1441G leucine‐rich repeat kinase 2/PD patients were evaluated. Motor and nonmotor symptoms were assessed using specific scales and questionnaires. Neuroimaging quantitative data were obtained in 81 carriers and compared with 41 noncarriers.
Results: G2019S carriers scored higher in motor scores and had lower radioligand uptake compared to noncarriers, but no differences in nonmotor symptoms scores were observed. R1441G carriers scored higher in motor scores, had lower radioligand uptake, and had higher scores in depression, dysautonomia, and Rapid Eye Movements Sleep Behavior Disorder Screening Questionnaire scores, but had better cognition scores than noncarriers. Among G2019S carriers, a group with “mild motor signs” was identified, and was significantly older, with worse olfaction and lower radioligand uptake.
Conclusions: G2019S and R1441G carriers differ from their noncarriers' relatives in higher motor scores and slightly lower radioligand uptake. Nonmotor symptoms were mild, and different nonmotor profiles were observed in G2019S carriers compared to R1441G carriers. A group of G2019S carriers with known prodromal features was identified. Longitudinal studies are required to determine whether such individuals are at short‐term risk of developing overt parkinsonism. © 2017 International Parkinson and Movement Disorder Society
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Nigral and striatal connectivity alterations in asymptomatic LRRK2 mutation carriers: A magnetic resonance imaging study
Vilas, Dolores; Segura, Bàrbara; Baggio, Hugo C. ...
Movement disorders,
12/2016, Volume:
31, Issue:
12
Journal Article
Peer reviewed
ABSTRACT
Background
The study of functional connectivity by means of magnetic resonance imaging (MRI) in asymptomatic LRRK2 mutation carriers could contribute to the characterization of the ...
prediagnostic phase of LRRK2‐associated Parkinson's disease (PD). The objective of this study was to characterize MRI functional patterns during the resting state in asymptomatic LRRK2 mutation carriers.
Methods
We acquired structural and functional MRI data of 18 asymptomatic LRRK2 mutation carriers and 18 asymptomatic LRRK2 mutation noncarriers, all first‐degree relatives of LRRK2‐PD patients. Starting from resting‐state data, we analyzed the functional connectivity of the striatocortical and the nigrocortical circuitry. Structural brain data were analyzed by voxel‐based morphometry, cortical thickness, and volumetric measures.
Results
Asymptomatic LRRK2 mutation carriers had functional connectivity reductions between the caudal motor part of the left striatum and the ipsilateral precuneus and superior parietal lobe. Connectivity in these regions correlated with subcortical gray‐matter volumes in mutation carriers. Asymptomatic carriers also showed increased connectivity between the right substantia nigra and bilateral occipital cortical regions (occipital pole and cuneus bilaterally and right lateral occipital cortex). No intergroup differences in structural MRI measures were found. In LRRK2 mutation carriers, age and functional connectivity correlated negatively with striatal volumes. Additional analyses including only subjects with the G2019S mutation revealed similar findings.
Conclusions
Asymptomatic LRRK2 mutation carriers showed functional connectivity changes in striatocortical and nigrocortical circuits compared with noncarriers. These findings support the concept that altered brain connectivity precedes the onset of classical motor features in a genetic form of PD. © 2016 International Parkinson and Movement Disorder Society
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Psychogenic movement disorders in children: A report of 15 cases and a review of the literature
Schwingenschuh, Petra; Pont-Sunyer, Claustre; Surtees, Robert ...
Movement disorders,
15 October 2008, Volume:
23, Issue:
13
Journal Article
Peer reviewed
Data on psychogenic movement disorders (PMD) in children are scarce, with most existing literature relating to adults only. We report 15 cases with the aim of highlighting the clinical ...
characteristics, risk factors, comorbidity, treatment, outcome, and prognosis of PMD in children. Only 13% of cases had onset before age 10, with the mean age at onset being 12.3 years. Females were predominantly affected (F:M = 4:1). The most common types of movement disorders seen were dystonia (47%), tremor (40%), and gait disorders (13%). Multiple hyperkinetic phenomenologies were observed in many cases. Abrupt onset and precipitation by minor injuries, and stressful life events were commonly reported. Clinical clues on examination suggesting a psychogenic origin were similar to those identified in adults. A distinct feature of PMD in children was the predominant involvement of the dominant limb. The underlying psychiatric diagnosis was conversion disorder in the majority of cases. Time from symptom onset until diagnosis of a PMD varied broadly (between 2 weeks and 5 years). Treatment with cognitive and behavioral therapy and rehabilitation by a multidisciplinary team led to improvement in most cases. However, treatment was much more effective in children with a short time from symptom onset to diagnosis and treatment. © 2008 Movement Disorder Society
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MicroRNA Deregulation in Blood Serum Identifies Multiple System Atrophy Altered Pathways
Pérez‐Soriano, Alexandra; Bravo, Paloma; Soto, Marta ...
Movement disorders,
October 2020, 2020-10-00, 20201001, Volume:
35, Issue:
10
Journal Article
Peer reviewed
Open access
Background and Objectives
MicroRNA (miRNA) changes are observed in PD but remain poorly explored in other α‐synucleinopathies such as MSA.
Methods
By genome‐wide analysis we profiled microRNA ...
expression in serum from 20 MSA cases compared to 40 controls. By qPCR we validated top differentially expressed microRNAs in another sample of 20 MSA and 20 controls. We also assessed the expression of MSA differentially expressed microRNAs in two consecutive sets of 19 and 18 PD patients.
Results
In the discovery set we identified 25 differentially expressed microRNAs associated with MSA, which are related to prion disease, fatty acid metabolism, and Notch signaling. Among these, we selected nine differentially expressed microRNAs and by qPCR confirmed array findings in a second MSA sample. MicroRNA‐7641 and microRNA‐191 consistently differentiated between MSA and PD.
Conclusions
Serum microRNA changes occur in MSA and may reflect disease‐associated mechanisms. We identified two microRNAs which may differentiate MSA from PD. © 2020 International Parkinson and Movement Disorder Society
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Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non‐Ashkenazi Jewish ancestry
Lee, Annie J.; Wang, Yuanjia; Alcalay, Roy N. ...
Movement disorders,
October 2017, Volume:
32, Issue:
10
Journal Article
Peer reviewed
Open access
ABSTRACT
Background
Penetrance estimates of the leucine‐rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%‐100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ...
ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non‐Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non‐Ashkenazi Jews to age 80.
Methods
The kin‐cohort method was used to estimate penetrance in 474 first‐degree relatives of 69 non‐Ashkenazi Jewish LRRK2 p.G2019S carrier probands at 8 sites from the Michael J. Fox LRRK2 Cohort Consortium. An identical validated family history interview was administered to assess age at onset of PD, current age, or age at death for relatives in different ethnic groups at each site. Neurological examination and LRRK2 genotype of relatives were included when available.
Results
Risk of PD in non‐Ashkenazi Jewish relatives who carry a LRRK2 p.G2019S mutation was 42.5% (95% confidence interval CI: 26.3%‐65.8%) to age 80, which is not significantly higher than the previously estimated 25% (95% CI: 16.7%‐34.2%) in Ashkenazi Jewish carrier relatives. The penetrance of PD to age 80 in LRRK2 p.G2019S mutation carrier relatives was significantly higher than the noncarrier relatives, as seen in Ashkenazi Jewish relatives.
Conclusions
The similar penetrance of LRRK2 p.G2019S estimated in Ashkenazi Jewish carriers and non‐Ashkenazi Jewish carriers confirms that p.G2019S penetrance is 25% to 42.5% at age 80 in all populations analyzed. © 2017 International Parkinson and Movement Disorder Society
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