Claustre Pont-Sunyer

The Onset of Nonmotor Symptoms in Parkinson's disease (The ONSET PD Study)

Nonmotor symptoms (NMS) in Parkinsons 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.

Factors Associated With a High Risk of Recurrence in Patients With Transient Ischemic Attack or Minor Stroke

Background and Purpose— The aim of our study was to identify factors associated with stroke recurrence after an initial minor stroke or transient ischemic attack (TIA) in a prospective hospital-series. Methods— Included in the series were 689 patients with NIHSS lower than 4 at hospital admission. The end point was a new neurological event (worsening ≥4 points in the initial NIHSS was considered as recurrence) at 90 days (and additionally at 7 days). Factors based on two previous reported scores (ABCD and SPI-II) were analyzed in relation with stroke recurrence: age, duration of symptoms >1 hour, weakness, speech impairment, initial hypertension, hypertension, diabetes, coronary disease, minor stroke versus TIA, prior stroke, and heart failure. We also analyzed: gender, hyperlipidemia, severe alcohol intake (>60gr/d), current smoking habits, peripheral arterial disease, atrial fibrillation, acute lesion in initial head computed tomography, severe symptomatic extra or intracranial arterial disease (SSAD; arterial stenosis ≥70%), previous TIA, and vertebrobasilar event. Patients were also analyzed separately according to diagnosis of TIA or minor stroke. Results— 90-day recurrence occurred in 111 patients (16.1%), whereas 62 patients had 7-day recurrence (9%). The independent variables associated with 90-day recurrence were: SSAD (OR=4.97), weakness (OR=3.25), speech impairment (OR=1.96), severe alcohol intake (OR=4.18), heart failure (OR=2.41), previous TIA (OR=4.62), and vertebrobasilar events (OR=2.87). SSAD was independently associated with 7-day recurrence (OR=7.73) and also for TIA (OR=3.45) and minor stroke (OR=5.15) patients. Conclusions— An arterial study to discard SSAD would be necessary, in combination with clinical factors, to improve the identification of patients with a higher risk of 90-day recurrence after an initial minor stroke or TIA.

Psychogenic movement disorders in children: A report of 15 cases and a review of the literature

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.

Combined dementia-risk biomarkers in Parkinson's disease: A prospective longitudinal study

Neuropsychological (mostly posterior-cortical) deficits, quantitative magnetic resonance imaging (MRI) atrophy patterns, and low cerebrospinal fluid (CSF) levels of amyloid-β have been separately related to worsening cognition in Parkinsons disease (PD). However, these biomarkers have not been longitudinally assessed in combination as PD-dementia predictors. In this prospective longitudinal study, 27 non-demented PD patients underwent CSF, neuropsychological and 3-T brain-MRI studies at baseline and were re-assessed 18 months later in terms of progression to dementia (primary outcome) and longitudinal neuropsychological and cortical thickness changes (secondary outcomes). At follow-up 11 patients (41%) had progressed to dementia. Lower CSF amyloid-β, worse verbal learning, semantic fluency and visuoperceptual scores, and thinner superior-frontal/anterior cingulate and precentral regions were significant baseline dementia predictors in binary logistic regressions as quantitative and/or dichotomised traits. All participants without baseline biomarker abnormalities remained non-demented whereas all with abnormalities in each biomarker type progressed to dementia, with intermediate risk for those showing abnormalities in a single to two biomarker types (p = 0.006). Both the dementia-outcome and low baseline CSF amyloid-β were prospectively associated with limbic and posterior-cortical neuropsychological decline and frontal, limbic and posterior-cortical thinning from baseline to follow-up. These findings suggest that the combination of CSF amyloid-β, neuropsychological and cortical thickness biomarkers might provide a basis for dementia-risk stratification and progression monitoring in PD.

Identification of blood serum micro-RNAs associated with idiopathic and LRRK2 Parkinson's disease.

Blood‐cell‐free circulating micro‐RNAs (miRNAs) have been proposed as potential accessible biomarkers for neurodegenerative diseases such as Parkinsons disease (PD). Here we analyzed the serum levels of 377 miRNAs in a discovery set of 10 idiopathic Parkinsons 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.

Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder

Objective: To investigate the expression of α-synuclein in colonic biopsies of patients with idiopathic REM sleep behavior disorder (iRBD) and address if α-synuclein immunostaining of tissue obtained via colonic biopsies holds promise as a diagnostic biomarker for prodromal Parkinson disease (PD). Methods: Patients with iRBD, patients with PD, and healthy controls were prospectively recruited to undergo colonic biopsies for comparison of α-synuclein immunoreactivity patterns between the groups by using 2 different antibodies. Results: There was no difference in colonic mucosal and submucosal immunostaining between groups using the 15G7 α-synuclein antibody, which was found in almost all participants enrolled in this study. By contrast, immunostaining for serine 129-phosphorylated α-synuclein (pSyn) in submucosal nerve fibers or ganglia was found in none of 14 controls but was observed in 4 of 17 participants with iRBD and 1 out of 19 patients with PD. Conclusions: The present findings of pSyn immunostaining of colonic biopsies in a substantial proportion of iRBD participants raise the possibility that this tissue marker may be a suitable candidate to study further as a prodromal PD marker in at-risk cohorts.

Impulse control disorders in Parkinson's disease

Impulse control disorders (ICDs), a group of complex behavioral disorders, occur more commonly in Parkinsons disease (PD) patients than in the general population, with a reported prevalence up to 13.6% in some studies. The most common ICDs reported are pathological gambling (PG), hypersexuality (HS), compulsive shopping and compulsive eating. More than a quarter of the patients with ICDs have 2 or more behavioral addictions. These abnormal behaviors impair activities of daily living and have a negative impact on quality of life of patients and their families. As with many other non motor symptoms in PD, ICDs are frequently under-reported by patients and caregivers and may be under-recognized by the treating physicians. Treatment with dopamine agonists (DA) is the main risk factor for developing ICDs, and stimulation of mesolimbic D3 receptors by DA is thought to underlie their development. The DA effect seems to be a class effect and not specific for any DA. Levodopa can also induce ICDs but much less so than the DAs. The management of ICDs in PD is complex. Modifications in dopaminergic drug treatment are frequently necessary. In some cases alternative therapies such as atypical antipsychotics, antidepressants or deep brain stimulation if motor symptoms become incapacitating after adjustment of dopamine replacement therapy should be considered.

Progress in defining the premotor phase of Parkinson's disease

Several studies have suggested that a variety of non-motor symptoms (NMS) frequently antedate the development of the classical motor symptoms in Parkinsons disease (PD). Some of these premotor symptoms are well known, like REM sleep behaviour disorder, smell loss and constipation and can precede the motor symptoms by years or even decades. The appearance of these symptoms seems to correlate with the neuropathological changes occurring during Braaks stages I to III. Also studies of the nigrostriatal dopaminergic pathways with neuroimaging show that substantia nigra degeneration occurs before motor symptoms onset. Studies on the premotor phase of PD are important for our understanding of when and where does PD start and how it evolves in these initial stages. Several ongoing studies combine clinical, genetic and neuroimaging investigations to study the premotor phase in subjects at high risk for developing such as hyposmic individuals (PARS study) or nonmanifesting carriers of LRRK2 mutations (ASAP Study). The diagnosis of premotor PD remains still elusive but the information becoming available on premotor PD should guide the search for predictive biomarkers and the identification of risk or protective factors for PD.

Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers

Objective In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). Methods A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD. Results Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC. Conclusions Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.

Motor and nonmotor heterogeneity of LRRK2‐related and idiopathic Parkinson's disease

Parkinsons 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.