Neuronal induction and bioenergetics characterization of human forearm adipose stem cells from Parkinson's disease patients and healthy controls.

Neurodegenerative diseases, such as Parkinson's disease, are heterogeneous disorders with a multifactorial nature involving impaired bioenergetics. Stem-regenerative medicine and bioenergetics have been proposed as promising therapeutic targets in the neurologic field. The rationale of the present study was to assess the potential of human-derived adipose stem cells (hASCs) to transdifferentiate into neuronal-like cells (NhASCs and neurospheres) and explore the hASC bioenergetic profile. hASC neuronal transdifferentiation was performed through neurobasal media and differentiation factor exposure. High resolution respirometry was assessed. Increased MAP-2 neuronal marker protein expression upon neuronal induction (p<0.05 undifferentiated hASCs vs. 28-36 days of differentiation) and increased bIII-tubulin neuronal marker protein expression upon neuronal induction (p<0.05 undifferentiated hASCs vs. 6-28-36 days of differentiation) were found. The bioenergetic profile was detectable through high-resolution respirometry approaches in hASCs but did not lead to differential oxidative capacity rates in healthy or clinically diagnosed PD-hASCs. We confirmed the capability of transdifferentiation to the neuronal-like profile of hASCs derived from the forearms of human subjects and characterized the bioenergetic profile. Suboptimal maximal respiratory capacity trends in PD were found. Neuronal induction leading to positive neuronal protein expression markers is a relevant issue that encourages the suitability of NhASC models in neurodegeneration.

Olfaction in LRRK2 Linked Parkinson's Disease: Is It Different from Idiopathic Parkinson's Disease?

BACKGROUND: Studies on olfaction in LRRK2-associated Parkinson's disease (LRRK2-PD) have yielded variable results. The impact of smell dysfunction upon daily life activities have been rarely assessed in PD. OBJECTIVE: To characterize the olfactory deficit in LRRK2-PD and its impact on daily life activities. METHODS: Twenty-four LRRK2-PD, 40 idiopathic PD (IPD), and 49 age-sex-matched controls were interviewed about olfactory characteristics and the impact of smell on daily life activities. The Barcelona Smell Identification test (BAST-24) and the Spanish-version of the 40-item University of Pennsylvania smell test (UPSIT) were applied. RESULTS: Nineteen (79.2%) LRRK2-PD patients reported subjective smell impairment with a low impact upon daily living activities. UPSIT score was higher in LRRK2-PD than in IPD (22.54±7.98 vs 18.84±6.03; p = 0.042). All IPD and 95.8% LRRK2-PD patients had hyposmia/anosmia, assessed by means of the UPSIT. No differences were found between LRRK2-PD and IPD regarding smell detection, memory or forced-choice identification. CONCLUSION: Most LRRK2-PD patients reported subjective smell impairment and presented hyposmia, according to validated smell tests, with a low impact of the smell dysfunction on daily life activities.

Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls.

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.

Clinical Outcome of Ischemic Stroke in Old Patients Versus Oldest-Old.

BACKGROUND: It is unclear whether very old patients benefit from stroke unit. The aim of our work was to compare the clinical outcome of patients with ischemic stroke aged either 70 or 80 (G 1) versus oldest-old greater than or equal to 81 years (G 2). METHODS: Of 1187 patients admitted with stroke during 5 years in our stroke unit, we included 252 patients with independent functional status (modified Rankin scale, [mRS] ≤ 2) before the stroke. All patients underwent clinical examination, blood test, electrocardiography, brain imaging, and cerebrovascular ultrasound. Clinical outcome was assessed with the mRS and National Institutes of Health Stroke Scale (NIHSS) at discharge. We considered favorable outcome mRS 0-2 at discharge. RESULTS: Of 252 patients included, 55% were male, 150 (59.5%) patients belonged to G1 and 102 (40.5%) G2. We detected a significant increase of atrial fibrillation, bronchoaspiration, mortality, higher NIHSS at admission, and worse functional status at discharge in G2. No significant differences in other demographic, vascular risk factors, hospital stay, NIHSS at discharge or subtype of stroke were found. NIHSS at discharge was the only independent predictor of good functional status (odds ratio 0.4; 95% confidence interval, 0.3-0.6; P < .001). CONCLUSIONS: Oldest-old patients showed similar NIHSS at discharge than younger patients despite having higher neurological severity at admission. Our results support the hypothesis that oldest-old patients have good recovery potential, and should not be excluded from the stroke unit. The worse functional status detected at discharge in these patients could be attributed to others factors and not to neurological severity.

Clustering of motor and nonmotor traits in leucine-rich repeat kinase 2 G2019S Parkinson's disease nonparkinsonian relatives: A multicenter family study.

OBJECTIVES: The objective of this study was to determine phenotypic features that differentiate nonparkinsonian first-degree relatives of PD leucine-rich repeat kinase 2 (LRRK2) G2019S multiplex families, regardless of carrier status, from healthy controls because nonparkinsonian individuals in multiplex families seem to share a propensity to present neurological features. METHODS: We included nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases and unrelated healthy controls participating in established multiplex family LRRK2 cohorts. Study participants underwent neurologic assessment including cognitive screening, olfaction testing, and questionnaires for daytime sleepiness, depression, and anxiety. We used a multiple logistic regression model with backward variable selection, validated with bootstrap resampling, to establish the best combination of motor and nonmotor features that differentiates nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases from unrelated healthy controls. RESULTS: We included 142 nonparkinsonian family members and 172 unrelated healthy controls. The combination of past or current symptoms of anxiety (adjusted odds ratio, 4.16; 95% confidence interval, 2.01-8.63), less daytime sleepiness (adjusted odds ratio [1 unit], 0.90; 95% confidence interval, 0.83-0.97], and worse motor UPDRS score (adjusted odds ratio [1 unit], 1.4; 95% confidence interval, 1.20-1.67) distinguished nonparkinsonian family members, regardless of LRRK2 G2019S mutation status, from unrelated healthy controls. The model accuracy was good (area under the curve = 79.3%). CONCLUSIONS: A set of motor and nonmotor features distinguishes first-degree relatives of LRRK2 G2019S probands, regardless of mutation status, from unrelated healthy controls. Environmental or non-LRRK2 genetic factors in LRRK2-associated PD may influence penetrance of the LRRK2 G2019S mutation. The relationship of these features to actual PD risk requires longitudinal observation of LRRK2 familial PD cohorts. © 2018 International Parkinson and Movement Disorder Society.

Transcriptional alterations in skin fibroblasts from Parkinson's disease patients with parkin mutations.

Mutations in the parkin gene (PRKN) are the most common cause of autosomal-recessive juvenile Parkinson's disease (PD). PRKN encodes an E3 ubiquitin ligase that is involved in multiple regulatory functions including proteasomal-mediated protein turnover, mitochondrial function, mitophagy, and cell survival. However, the precise molecular events mediated by PRKN mutations in PRKN-associated PD (PRKN-PD) remain unknown. To elucidate the cellular impact of parkin mutations, we performed an RNA sequencing study in skin fibroblasts from PRKN-PD patients carrying different PRKN mutations (n = 4) and genetically unrelated healthy subjects (n = 4). We identified 343 differentially expressed genes in PRKN-PD fibroblasts. Gene ontology and canonical pathway analysis revealed enrichment of differentially expressed genes in processes such as cell adhesion, cell growth, and amino acid and folate metabolism among others. Our findings indicate that PRKN mutations are associated with large global gene expression changes as observed in fibroblasts from PRKN-PD patients and support the view of PD as a systemic disease affecting also non-neural peripheral tissues such as the skin.

Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry.

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.

The prodromal phase of leucine-rich repeat kinase 2-associated Parkinson disease: Clinical and imaging Studies.

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.

Nigral and striatal connectivity alterations in asymptomatic LRRK2 mutation carriers: A magnetic resonance imaging study.

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.

Arm swing as a potential new prodromal marker of Parkinson's disease.

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.

Inflammatory profile in LRRK2-associated prodromal and clinical PD.

BACKGROUND: There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson's disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients. METHODS: We assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium. RESULTS: A large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles. CONCLUSIONS: Concomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.

Cerebrospinal fluid biomarkers and clinical features in leucine-rich repeat kinase 2 (LRRK2) mutation carriers.

BACKGROUND: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of inherited Parkinson's disease (PD). Nonmanifesting carriers of LRRK2 mutations are at high risk for developing PD. Information available on cerebrospinal fluid (CSF) biomarkers in LRRK2 carriers remains preliminary. OBJECTIVES: To measure CSF levels of α-synuclein, ß amyloid1-42 , total-tau, and phospho-tau181 , in LRRK2-associated PD, idiopathic PD, nonmanifesting carriers, and first-degree relatives of LRRK2-associated PD patients without the mutation (nonmanifesting noncarriers). To correlate the clinical features and the integrity of the nigrostriatal pathway assessed by neuroimaging with the CSF biomarkers. METHODS: 138 CSF samples provided by the Michael J. Fox Foundation LRRK2 Cohort Consortium were analyzed: 28 LRRK2-associated PD, 35 idiopathic PD, 41 nonmanifesting carriers, and 34 nonmanifesting noncarriers. All of the participants in the study were clinically assessed. Most of the participants underwent a dopamine transporter scan to assess the integrity of the nigrostriatal pathway. RESULTS: CSF levels of α-synuclein were similar in LRRK2-associated PD, nonmanifesting carriers, and nonmanifesting noncarriers but significantly higher than in idiopathic PD (P = .041). No differences were found in the concentrations of ß amyloid1-42 , total-tau, or phospho-tau181 among study groups. CSF alpha-synuclein levels strongly correlated with total-tau and phospo-tau181 levels in all groups. No significant correlation was found between the CSF biomarkers and the striatal binding ratios for (123)I-FP-CIT in nonmanifesting carriers. CONCLUSION: The CSF protein profile differs in LRRK2-associated PD and idiopathic PD, suggesting that pathophysiological mechanisms different from IPD underlie LRRK2-associated PD. Cerebrospinal fluid biomarkers did not prove helpful in differentiating asymptomatic LRRK2 mutation carriers from noncarriers. © 2016 International Parkinson and Movement Disorder Society.

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

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.

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.

Clinical and imaging markers in premotor LRRK2 G2019S mutation carriers.

BACKGROUND: Substantia nigra hyperechogenicity (SN+) has been proposed as a risk marker of Parkinson's disease (PD). Asymptomatic LRRK2 mutation carriers (aLRRK2+), at high risk for developing PD, provide an opportunity for the study of preclinical biomarkers. OBJECTIVE: To assess SN echogenicity and other echographic features in LRRK2 G2019S carriers and their clinical and imaging correlates. METHODS: Transcranial sonography was performed in 26 LRRK2 G2019S PD patients, 50 first-degree relatives, 31 idiopathic PD (IPD) patients and 26 controls. SN echogenicity and other echographic features were assessed in all study subjects. Dopamine transporter imaging (DAT-SPECT) was performed in 29 first-degree relatives. RESULTS: 75% of the LRRK2-PD and 87.5% of the IPD showed SN+ (p = 0.087). aLRRK2+ had a higher frequency of SN+ than non carriers (58.3% vs. 25%, p = 0.039) and controls (58.3% vs. 12.5%; p = 0.002) and had a larger area of SN echogenicity than non carriers (p = 0.030) and controls (p < 0.001). The width of the third ventricle was significantly lower in LRRK2-PD than in IPD (1.9 mm [1.38; 2.75] vs. 3.0 mm [2.3; 5.3]; p = 0.003). Four out of 5 (80%) of the aLRRK2+ with an abnormal DAT-SPECT and four of the 5 (80%) of those with REM sleep behaviour disorder (RBD) had SN+. CONCLUSIONS: SN+ is very frequent in LRRK2-PD and aLRRK2+. Most aLRRK2 with possible surrogate markers of PD such as abnormal DAT-SPECT or RBD, also had SN+, which supports that this echofeature might be a marker of PD in these asymptomatic population.

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.

Brainstem raphe and substantia nigra echogenicity in idiopathic REM sleep behavior disorder with comorbid depression.

In Parkinson disease (PD), REM sleep behavior disorder (RBD) and depression may occur before the onset of parkinsonism. Transcranial sonography (TCS) shows that hyperechogenicity of the substantia nigra (SN+) and hypoechogenicity of the brainstem raphe (BR+) are frequent in PD, particularly when depression is associated. Combined SN+ and BR+ identify PD subjects in whom depression antedates parkinsonism onset. It can be speculated that SN+ and BR+ may also identify idiopathic RBD (IRBD) subjects with comorbid depression, supporting the clinical diagnosis of this mood disorder. We aimed to study the brainstem raphe and substantia nigra echogenicity and their ability to predict comorbid depression in IRBD. Seventy-two IRBD patients and 71 age and sex-matched controls underwent TCS. Depression was diagnosed by means of DSM-IV criteria. Depression was more frequent in IRBD patients than in controls (44.4 vs. 18.3 %; p = 0.001). BR+ was more frequent in depressed than in nondepressed IRBD patients (32.0 vs. 11.4 %; p = 0.050). Sensitivity of BR+ to predict depression in IRBD was 32.0 %, specificity was 88.6 %, and relative risk was 1.88. Sensitivity of SN+ to predict depression in IRBD was 72.0 %, specificity was 44.1 %, and relative risk was 1.53. Sensitivity of combined BR+ and SN+ to predict depression in IRBD was 23.1 %, specificity 97.1 %, and relative risk was 2.31. Hypoechogenicity of the brainstem raphe, particularly when combined with hyperechogenicity of the substantia nigra, detects comorbid depression in IRBD. This finding suggests that dysfunction of the serotonergic dorsal raphe may be involved in the pathophysiology of depression in IRBD.

Disclosure of research results in genetic studies of Parkinson's disease caused by LRRK2 mutations.

With the advent of large genetic studies examining both symptomatic and asymptomatic individuals, whether and how to disclose genetic research results have become pressing questions. The need is particularly acute in the case of LRRK2 research: Movement centers worldwide are recruiting cohorts of individuals with Parkinson's disease (PD) and their family members, including asymptomatic carriers. Clinical features and treatment are complex and evolving, and disclosure policies vary at different sites and have been modified during the course of some studies. We present the major ethical principles of autonomy, beneficence, nonmaleficence, and honesty that should guide disclosure policies in studies of families with LRRK2 mutations. We make recommendations regarding genetic counseling, policies of either active or passive disclosure, responsibilities of funders to budget for genetic counseling, clinical genetic testing where locally required for disclosure, and aspects of study design to avoid mandatory disclosure whenever feasible. © 2015 International Parkinson and Movement Disorder Society.

The onset of nonmotor symptoms in Parkinson's disease (the ONSET PD study).

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.