ABSTRACT
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder resulting from a CAG expansion in the huntingtin (HTT) gene, which leads to the production and accumulation of mutant huntingtin (mHTT). While primarily considered a disorder of the central nervous system, multiple changes have been described to occur throughout the body, including activation of the immune system. In other neurodegenerative disorders, activation of the immune system has been shown to include the production of antibodies against disease-associated pathological proteins. However, the existence of mHTT-targeted antibodies has never been reported. In this study, we assessed the presence and titer of antibodies recognizing HTT/mHTT in patients with HD (n = 66) and age- and gender-matched healthy controls (n = 66) using a combination of Western blotting and ELISA. Together, these analyses revealed that antibodies capable of recognizing HTT/mHTT were detectable in the plasma samples of all participants, including healthy controls. When antibody levels were monitored at different disease stages, it was observed that antibodies against full-length mHTT were highest in patients with severe disease while antibodies against HTTExon1 were elevated in patients with mild disease. Combined, these results suggest that antibodies detecting different forms of mHTT peak at different disease stages.
Subject(s)
Huntington Disease , Neurodegenerative Diseases , Humans , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Huntington Disease/metabolism , AntibodiesABSTRACT
BACKGROUND: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. OBJECTIVE: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. METHODS: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. RESULTS: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10-8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10-6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10-8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). CONCLUSION: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.
Subject(s)
Genome-Wide Association Study , Torticollis , Death Domain Receptor Signaling Adaptor Proteins/genetics , Gene Frequency , Genetic Predisposition to Disease/genetics , Guanine Nucleotide Exchange Factors/genetics , Humans , Polymorphism, Single Nucleotide/genetics , Reproducibility of Results , Torticollis/geneticsABSTRACT
The production of extracellular vesicles (EV) is a ubiquitous feature of eukaryotic cells but pathological events can affect their formation and constituents. We sought to characterize the nature, profile and protein signature of EV in the plasma of Parkinson's disease (PD) patients and how they correlate to clinical measures of the disease. EV were initially collected from cohorts of PD (nâ¯=â¯60; Controls, nâ¯=â¯37) and Huntington's disease (HD) patients (Pre-manifest, nâ¯=â¯11; manifest, nâ¯=â¯52; Controls, nâ¯=â¯55) - for comparative purposes in individuals with another chronic neurodegenerative condition - and exhaustively analyzed using flow cytometry, electron microscopy and proteomics. We then collected 42 samples from an additional independent cohort of PD patients to confirm our initial results. Through a series of iterative steps, we optimized an approach for defining the EV signature in PD. We found that the number of EV derived specifically from erythrocytes segregated with UPDRS scores corresponding to different disease stages. Proteomic analysis further revealed that there is a specific signature of proteins that could reliably differentiate control subjects from mild and moderate PD patients. Taken together, we have developed/identified an EV blood-based assay that has the potential to be used as a biomarker for PD.
Subject(s)
Erythrocytes/metabolism , Extracellular Vesicles/metabolism , Parkinson Disease/blood , Aged , Biomarkers/blood , Blood Cell Count , Erythrocytes/ultrastructure , Extracellular Vesicles/ultrastructure , Female , Humans , Huntington Disease/blood , Huntington Disease/diagnosis , Huntington Disease/pathology , Male , Middle Aged , Parkinson Disease/diagnosis , Parkinson Disease/pathology , ProteomicsABSTRACT
Huntington's disease (HD) is a hereditary disorder that typically manifests in adulthood with a combination of motor, cognitive and psychiatric problems. The pathology is caused by a mutation in the huntingtin gene which results in the production of an abnormal protein, mutant huntingtin (mHtt). This protein is ubiquitously expressed and known to confer toxicity to multiple cell types. We have recently reported that HD brains are also characterised by vascular abnormalities, which include changes in blood vessel density/diameter as well as increased blood-brain barrier (BBB) leakage. OBJECTIVES: Seeking to elucidate the origin of these vascular and BBB abnormalities, we studied platelets that are known to play a role in maintaining the integrity of the vasculature and thrombotic pathways linked to this, given they surprisingly contain the highest concentration of mHtt of all blood cells. METHODS: We assessed the functional status of platelets by performing ELISA, western blot and RNA sequencing in a cohort of 71 patients and 68 age- and sex-matched healthy control subjects. We further performed haemostasis and platelet depletion tests in the R6/2 HD mouse model. RESULTS: Our findings indicate that the platelets in HD are dysfunctional with respect to the release of angiogenic factors and functions including thrombosis, angiogenesis and vascular haemostasis. CONCLUSION: Taken together, our results provide a better understanding for the impact of mHtt on platelet function.
Subject(s)
Blood-Brain Barrier/physiopathology , Huntingtin Protein/blood , Huntington Disease/blood , Platelet Activation/physiology , Adult , Aged , Angiogenic Proteins/blood , Animals , Blood Coagulation Factors/metabolism , Case-Control Studies , Cohort Studies , Disease Models, Animal , Female , Fibroblast Growth Factor 2/blood , Humans , Huntington Disease/complications , Male , Mice , Middle Aged , Platelet CountABSTRACT
BACKGROUND: In Parkinson's disease cognitive impairment is an early nonmotor feature, but it is still unclear why some patients are able to maintain their cognitive performance at normal levels, as quantified by neuropsychological tests, whereas others cannot. The objectives of this study were to perform a cross-sectional study and analyze the white matter changes in the cognitive and motor bundles in patients with Parkinson's disease. METHODS: Sixteen Parkinson's disease patients with normal cognitive performance, 19 with mild cognitive impairment (based on their performance of 1.5 standard deviations below the healthy population mean), and 16 healthy controls were compared with respect to their tractography patterns between the cortical cognitive / motor regions and subcortical structures, using high angular resolution diffusion imaging and constrained spherical deconvolution computation. RESULTS: Motor bundles showed decreased apparent fiber density in both PD groups, associated with a significant increase in diffusivity metrics, number of reconstructed streamlines, and track volumes, compared with healthy controls. By contrast, in the cognitive bundles, decreased fiber density in both Parkinson's groups was compounded by the absence of changes in diffusivity in patients with normal cognition, whereas patients with cognitive impairment had increased diffusivity metrics, lower numbers of reconstructed streamlines, and lower track volumes. CONCLUSIONS: Both PD groups showed similar patterns of white matter neurodegeneration in the motor bundles, whereas cognitive bundles showed a distinct pattern: Parkinson's patients with normal cognition had white matter diffusivity metrics similar to healthy controls, whereas in patients with cognitive impairment white matter showed a neurodegeneration pattern. © 2018 International Parkinson and Movement Disorder Society.
Subject(s)
Cognition Disorders/etiology , Leukoencephalopathies/complications , Parkinson Disease/complications , Parkinson Disease/diagnostic imaging , Aged , Brain Mapping , Cross-Sectional Studies , Diffusion Magnetic Resonance Imaging , Female , Humans , Image Processing, Computer-Assisted , Leukoencephalopathies/diagnostic imaging , Male , Middle Aged , Neural Pathways/diagnostic imaging , Neural Pathways/pathology , Neuropsychological TestsABSTRACT
INTRODUCTION: Mutations in teneurin transmembrane protein 4 were reported to be a risk factor for essential tremor, but the relevance of this across different population remains to be examined. The aim of this study was to determine the frequency and spectrum of variations in teneurin transmembrane protein 4 in a cohort of Canadian essential tremor cases. METHODS: The coding portion of teneurin transmembrane protein 4 was sequenced in 269 unrelated essential tremor cases and 288 matched control individuals using a targeted and high-throughput sequencing approach. RESULTS: A total of 157 single nucleotide variations were identified, and from these 99 were a missense or nonsense mutation. A total of 68 cases were carriers of ≥1 rare missense or nonsense mutations, and 39 control individuals were carriers of the same types of variations. Gene-based association tests were used to jointly analyze the single nucleotide variations. CONCLUSIONS: Our results do not support a positive association between teneurin transmembrane protein 4 and the Canadian population. © 2017 International Parkinson and Movement Disorder Society.
Subject(s)
Essential Tremor/genetics , Membrane Glycoproteins/genetics , Aged , Canada/epidemiology , Essential Tremor/epidemiology , Female , Humans , Male , Middle AgedABSTRACT
In Parkinson's disease, electroencephalographic abnormalities during wakefulness and non-rapid eye movement sleep (spindles) were found to be predictive biomarkers of dementia. Because rapid eye movement sleep is regulated by the cholinergic system, which shows early degeneration in Parkinson's disease with cognitive impairment, anomalies during this sleep stage might mirror dementia development. In this prospective study, we examined baseline electroencephalographic absolute spectral power across three states of consciousness (non-rapid eye movement sleep, rapid eye movement sleep, and wakefulness) in 68 non-demented patients with Parkinson's disease and 44 healthy controls. All participants underwent baseline polysomnographic recordings and a comprehensive neuropsychological assessment. Power spectral analyses were performed on standard frequency bands. Dominant occipital frequency during wakefulness and ratios of slow-to-fast frequencies during rapid eye movement sleep and wakefulness were also computed. At follow-up (an average 4.5 years after baseline), 18 patients with Parkinson's disease had developed dementia and 50 patients remained dementia-free. In rapid eye movement sleep, patients with Parkinson's disease who later developed dementia showed, at baseline, higher absolute power in delta and theta bands and a higher slowing ratio, especially in temporal, parietal, and occipital regions, compared to patients who remained dementia-free and controls. In non-rapid eye movement sleep, lower baseline sigma power in parietal cortical regions also predicted development of dementia. During wakefulness, patients with Parkinson's disease who later developed dementia showed lower dominant occipital frequency as well as higher delta and slowing ratio compared to patients who remained dementia-free and controls. At baseline, higher slowing ratios in temporo-occipital regions during rapid eye movement sleep were associated with poor performance on visuospatial tests in patients with Parkinson's disease. Using receiver operating characteristic curves, we found that best predictors of dementia in Parkinson's disease were rapid eye movement sleep slowing ratios in posterior regions, wakefulness slowing ratios in temporal areas, and lower dominant occipital frequency. These results suggest that electroencephalographic slowing during sleep is a new promising predictive biomarker for Parkinson's disease dementia, perhaps as a marker of cholinergic denervation.
Subject(s)
Consciousness/physiology , Dementia/diagnosis , Dementia/physiopathology , Parkinson Disease/diagnosis , Parkinson Disease/physiopathology , Prodromal Symptoms , Aged , Dementia/epidemiology , Electroencephalography/trends , Female , Follow-Up Studies , Humans , Male , Middle Aged , Parkinson Disease/epidemiology , Polysomnography/trends , Prospective Studies , Wakefulness/physiologyABSTRACT
We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
Subject(s)
Essential Tremor/genetics , Genome-Wide Association Study , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Protein Serine-Threonine Kinases/genetics , alpha Catenin/genetics , Humans , Polymorphism, Single NucleotideABSTRACT
INTRODUCTION: Depressive symptoms are very common in patients with Parkinson's disease (PD) and have a significant impact on the quality of life. METHODS: The present study analyzed the correlations between over-time changes in depressive symptoms and gray matter parameters of cortical thickness and subcortical volumes in non-demented PD patients. RESULTS: A significant correlation was observed, between increased scores for depression over time and lower cortical thickness over time in the right temporo-parietal junction, right occipital medial region, right dorsolateral prefrontal cortex, right posterior cingulate region, left middle temporal as well as left supplementary motor area. Furthermore, the presence of depressive symptoms at baseline predicted increased cortical thinning over time in the left middle temporal, left anterior cingulate, right posterior cingulate and right parahippocampal cortices. Finally, a statistically significant negative correlation has been revealed between the thalamus' volume changes over time and the change in depressive symptoms scores. All other analyzed subcortical structures didn't reveal any significant correlations. CONCLUSION: These results suggest that depressive symptoms in PD patients are associated with gray matter cortical thinning and thalamus volume shrinkage over time and higher scores of depressive symptoms at baseline correlate with a higher rate of cortical thinning longitudinally. The present study highlights the importance of addressing depressive symptoms in PD patients early in the disease.
Subject(s)
Cerebral Cortex/pathology , Depression/psychology , Disease Progression , Parkinson Disease/pathology , Parkinson Disease/psychology , Thalamus/pathology , Aged , Atrophy/pathology , Depressive Disorder , Female , Humans , Longitudinal Studies , Magnetic Resonance Imaging , Male , Middle AgedABSTRACT
BACKGROUND: Individuals with Parkinson's disease (PD) often present with visual symptoms (e.g., difficulty in reading, double vision) that can also be found in convergence insufficiency (CI). Our objective was to estimate the prevalence of CI-type visual symptomatology in individuals with PD, in comparison with controls. METHODS: Participants ≥50 years with (n=300) and without (n=300) PD were recruited. They were administered the Convergence Insufficiency Symptom Survey (CISS-15) over the phone. A score of ≥21 on the CISS-15, considered positive for CI-type symptomatology, served as the cutoff. Data from individuals (n=87 with, n=94 without PD) who were approached but who reported having a known oculovisual condition were analysed separately. Student's t test and chi-square at the 0.05 level were employed for statistical significance. RESULTS: A total of 29.3% of participants with versus 7.3% without PD presented with a score of ≥21 on the CISS-15 (p=0.001). Of the participants having a known oculovisual condition, 39.1% with versus 19.1% without PD presented with a score of ≥21 on the CISS-15 (p=0.01). CONCLUSIONS: The prevalence of CI-type visual symptoms is higher in individuals with versus without PD whether or not they have a coexisting oculovisual condition. These results suggest that PD per se places individuals with the disease at greater risk of visual symptomatology. These results further underline the importance of providing regular eye exams for individuals with PD.
Subject(s)
Ocular Motility Disorders/epidemiology , Parkinson Disease/epidemiology , Aged , Female , Humans , Male , Middle Aged , Ocular Motility Disorders/diagnosis , Ocular Motility Disorders/etiology , Parkinson Disease/complications , Prevalence , Risk , Surveys and Questionnaires , Vision Disorders/epidemiology , Vision Disorders/etiologyABSTRACT
BACKGROUND: Continuous administration of levodopa-carbidopa intestinal gel (carbidopa-levodopa enteral suspension) through a percutaneous endoscopic gastrojejunostomy is a treatment option for advanced Parkinson disease (PD) patients with motor fluctuations resistant to standard oral medications. Safety data from 4 prospective studies were integrated to assess the safety of this therapy. METHODS: Safety data from 4 studies were summarized using 2 overlapping data sets, permitting the separation of procedure/device-associated (n = 395) from non-procedure/device adverse events (n = 412). RESULTS: At the data cutoff, median exposure to levodopa-carbidopa intestinal gel was 911 days (range, 1-1980 days) with 963 total patient-years of exposure. Procedure/device adverse events occurred in 300 patients (76%), and serious adverse events occurred in 68 (17%); most frequently reported procedure/device adverse events and serious adverse events were complications of device insertion (41% and 8%, respectively) and abdominal pain (36% and 4%, respectively). Non-procedure/device adverse events occurred in 92% (379), with most frequently reported being insomnia (23%) and falls (23%); 42% (171) had non-procedure/device serious adverse events, with most frequently reported being pneumonia (5%) and PD symptoms (2%). Adverse events led to discontinuation in 17% (72), most frequently because of complication of device insertion (2.4%). There were 34 treatment-emergent deaths (8.3%) in the overlapping data sets, 2 of which (0.5%) were considered "possibly related" to the treatment system. CONCLUSION: In the largest collection of levodopa-carbidopa intestinal gel safety data from prospective clinical studies, procedure/device events were frequently reported and occasionally life threatening. Most non-procedure/device events were typical for levodopa treatment and an elderly population. These factors combined with high treatment efficacy led to a relatively low discontinuation rate in advanced PD patients.
Subject(s)
Antiparkinson Agents/adverse effects , Carbidopa/adverse effects , Clinical Trials, Phase III as Topic/statistics & numerical data , Gastric Bypass/adverse effects , Infusions, Parenteral/adverse effects , Levodopa/adverse effects , Outcome Assessment, Health Care/statistics & numerical data , Parkinson Disease/drug therapy , Aged , Antiparkinson Agents/administration & dosage , Carbidopa/administration & dosage , Drug Combinations , Female , Gels , Humans , Levodopa/administration & dosage , Male , Middle Aged , Multicenter Studies as Topic/statistics & numerical data , Prospective StudiesABSTRACT
BACKGROUND: The prevalence of sleep disturbances among patients with Parkinson's disease (PD) is estimated to occur in 37% to 98% of patients. Sleep disturbances have been associated with a reduced quality of life for patients with PD. The objective of this study was to assess the impact of rasagiline treatment on the severity of sleep disturbances among patients with idiopathic PD. METHODS: In this open-label, multicentre study, 110 adult patients with idiopathic PD were treated with rasagiline either as monotherapy or as adjunct therapy. The primary endpoint was the change in severity of sleep disturbances, assessed with the PD Sleep Scale from baseline to month 2. Exploratory endpoints included change in daytime sleepiness, assessed with the Epworth Sleep Scale, treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication, patient's overall improvement or deterioration over time measured with the Clinical Global Impression of Improvement, tolerability, and safety. FINDINGS: Patients treated with rasagiline as mono- or adjunct therapy showed a statistically significant improvement in sleep quality after 2 months. There was no change in daytime sleepiness. Overall, patients were satisfied with rasagiline treatment with a mean Treatment Satisfaction Questionnaire for Medication [standard deviation] total score at month 2 of 68% [16.1]. At the end of study, 64 patients (65.9%) were judged, by the investigator, as being at least minimally improved from baseline on the Clinical Global Impression of Improvement. Rasagiline was safe and well-tolerated. INTERPRETATION: Rasagiline as mono- or adjunct-therapy may improve sleep experience in patients with PD in the short term.
Subject(s)
Indans/therapeutic use , Neuroprotective Agents/therapeutic use , Parkinson Disease/complications , Sleep Wake Disorders/drug therapy , Sleep Wake Disorders/etiology , Aged , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Retrospective Studies , Severity of Illness Index , Treatment OutcomeABSTRACT
The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
Subject(s)
Obsessive-Compulsive Disorder/genetics , Quantitative Trait, Heritable , Tourette Syndrome/genetics , Gene Frequency , Genome-Wide Association Study , Humans , Obsessive-Compulsive Disorder/pathology , Phenotype , Polymorphism, Single Nucleotide , Tourette Syndrome/pathologyABSTRACT
Essential tremor (ET) is a common neurodegenerative disorder that is characterized by a postural or motion tremor. Despite a strong genetic basis, a gene with rare pathogenic mutations that cause ET has not yet been reported. We used exome sequencing to implement a simple approach to control for misdiagnosis of ET, as well as phenocopies involving sporadic and senile ET cases. We studied a large ET-affected family and identified a FUS p.Gln290(∗) mutation as the cause of ET in this family. Further screening of 270 ET cases identified two additional rare missense FUS variants. Functional considerations suggest that the pathogenic effects of ET-specific FUS mutations are different from the effects observed when FUS is mutated in amyotrophic lateral sclerosis cases; we have shown that the ET FUS nonsense mutation is degraded by the nonsense-mediated-decay pathway, whereas amyotrophic lateral sclerosis FUS mutant transcripts are not.
Subject(s)
Essential Tremor/genetics , Exome/genetics , Genetic Predisposition to Disease/genetics , RNA-Binding Protein FUS/genetics , Base Sequence , Humans , Molecular Sequence Data , Point Mutation/genetics , Quebec , Sequence Analysis, DNAABSTRACT
Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. L-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces L-dopa-plasma-level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day "off" time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, "on" time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks.
Subject(s)
Antiparkinson Agents/therapeutic use , Carbidopa/therapeutic use , Gels , Intestines/physiology , Levodopa/therapeutic use , Parkinson Disease/drug therapy , Adult , Aged , Drug Combinations , Female , Gels/therapeutic use , Humans , Intestines/drug effects , Male , Middle Aged , Prospective Studies , Severity of Illness Index , Treatment OutcomeABSTRACT
Parkinson's disease is a neurodegenerative condition that affects motor function along with a wide range of cognitive domains, including executive function. The hallmark of the pathology is its significant loss of nigrostriatal dopamine, which is necessary for the cortico-striatal interactions that underlie executive control. Striatal dopamine reuptake is mediated by the SLC6A3 gene (formerly named DAT1) and its polymorphisms, which have been largely overlooked in Parkinson's disease. Thirty patients (ages 53-68 years; 19 males, 11 females) at early stages of Parkinson's disease, were genotyped according to a 9-repeat (9R) or 10-repeat (10R) allele on the SLC6A3/DAT1 gene. They underwent neuropsychological assessment and functional magnetic resonance imaging while performing a set-shifting task (a computerized Wisconsin Card Sorting Task) that relies on fronto-striatal interactions. Patients homozygous on the 10R allele performed significantly better on working memory tasks than 9R-carrier patients. Most importantly, patients carrying a 9R allele exhibited less activation than their 10R homozygous counterparts in the prefrontal cortex, premotor cortex and caudate nucleus, when planning and executing a set-shift. This pattern was exacerbated for conditions that usually recruit the striatum compared to those that do not. This is the first study indicating that the SLC6A3/DAT1 genotype has a significant effect on fronto-striatal activation and performance in Parkinson's disease. This effect is stronger for conditions that engage the striatum. Longitudinal studies are warranted to assess this polymorphism's effect on the clinical evolution of patients with Parkinson's disease, especially with cognitive decline.
Subject(s)
Dopamine Plasma Membrane Transport Proteins/physiology , Executive Function/physiology , Frontal Lobe/physiopathology , Neostriatum/physiopathology , Parkinson Disease/physiopathology , Aged , Dopamine Plasma Membrane Transport Proteins/genetics , Female , Functional Neuroimaging , Heterozygote , Homozygote , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Parkinson Disease/genetics , Polymorphism, GeneticABSTRACT
Previous studies have shown greater atrophy in grey and white matter of various brain regions in patients with Parkinson's disease with mild cognitive impairment than in those without. These anatomical differences likely account for the distinct clinical profiles observed between those groups, but do not account for the evolution of regional brain degradation observed as the disease evolves. Although we have shown recently that cortical thinning correlates significantly more with disease duration in Parkinson's patients with mild cognitive impairment than in those without, to the best of our knowledge no study to date has explored this longitudinally. The present study investigated the longitudinal changes of the cortical and subcortical grey matter in patients with Parkinson's disease with and without mild cognitive impairment. Additionally, these two groups were compared with healthy controls. We found a higher rate of cortical thinning in the temporal, occipital, parietal and supplementary motor area, in patients with Parkinson's disease with mild cognitive impairment compared with both cognitively stable patients and healthy controls. On the other hand cognitively stable patients had only one lateral occipital and one fusiform cluster with increased rate of thinning compared with healthy individuals. Correlating the rate of change of cortical thickness with the results of Montreal Cognitive Assessment scores revealed significant thinning associated with cognitive decline in the group of all patients, in similar regions including temporal and medial occipital lobe. Finally, a significant decrease in the volume of the amygdala and nucleus accumbens was observed specifically in patients with Parkinson's disease with mild cognitive impairment. These results indicate that the early presence of mild cognitive impairment in patients with Parkinson's disease is associated with a faster rate of grey matter thinning in various cortical regions as well as a significant diminishment of limbic subcortical structures. This specific pattern of brain degradation associated with the early presence of mild cognitive impairment might serve as a marker of development toward dementia.
Subject(s)
Cerebral Cortex/pathology , Cognitive Dysfunction/etiology , Cognitive Dysfunction/pathology , Parkinson Disease/complications , Parkinson Disease/pathology , Aged , Atrophy/pathology , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Middle Aged , Neuropsychological Tests , Parkinson Disease/psychologyABSTRACT
PURPOSE: The purpose of this qualitative study was to develop, test and evaluate a dyadic intervention for elderly couples living with moderate-stage Parkinson disease. METHODS: Based on Meleis's theory of transitions and following systemic and participatory approaches, the study comprised four steps informed by the intervention mapping process: 1) assessing couples' intervention needs, preferences and objectives; 2) developing and validating a dyadic intervention proposal; 3) formalizing the dyadic intervention; and 4) testing and evaluating the dyadic intervention. RESULTS: The dyadic intervention consisted of seven 90-minutes sessions held every other week. Intervention content and strategies used were based on couples' needs, preferences and objectives, as well as specific theories, models and empirical findings. CONCLUSION: This study can assist nurses involved in different domains of practice and interested in developing and evaluating theoretically based dyadic interventions.
Subject(s)
Parkinson Disease/drug therapy , Aged , Humans , Qualitative Research , Treatment OutcomeABSTRACT
Mild cognitive impairment (MCI) can occur early in the course of Parkinson's disease (PD), and its presence increases the risk of developing dementia. Determining the cortical changes associated with MCI in PD, thus, may be useful in predicting the future development of dementia. To address this objective, 37 patients with PD, divided into 2 groups according to the presence or absence MCI (18 with and 19 without) and 16 matched controls, underwent anatomic magnetic resonance imaging. Corticometry analyses were performed to measure the changes in cortical thickness and surface area as well as their correlation with disease duration. Compared with healthy controls, the PD-MCI group exhibited increased atrophy and changes of local surface area in the bilateral occipital, left temporal, and frontal cortices; whereas the PD non-MCI group exhibited only unilateral thinning and decreased surface area in the occipital lobe and in the frontal cortex. In addition, a comparison between the PD-MCI and PD non-MCI groups revealed increased local surface area in the occipital lobe, temporal lobe, and postcentral gyrus for the cognitively impaired patients. It is noteworthy that, in the PD-MCI group, cortical thickness had a significant negative correlation with disease duration in the precentral, supramarginal, occipital, and superior temporal cortices; whereas, in the PD non-MCI group, such a correlation was absent. The findings from this study reveal that, at the same stage of PD evolution, the presence of MCI is associated with a higher level of cortical changes, suggesting that cortical degeneration is increased in patients with PD because of the presence of MCI.
Subject(s)
Cerebral Cortex/pathology , Cognitive Dysfunction/etiology , Cognitive Dysfunction/pathology , Nerve Degeneration/pathology , Parkinson Disease/complications , Parkinson Disease/pathology , Aged , Cognitive Dysfunction/psychology , Disease Progression , Female , Frontal Lobe/pathology , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Middle Aged , Nerve Degeneration/psychology , Neuropsychological Tests , Parkinson Disease/psychology , Temporal Lobe/pathologyABSTRACT
Numerous studies have explored the potential relationship between rapid eye movement sleep behavior disorder (RBD) and manifestations of PD. Our aim was to perform an expanded extensive assessment of motor and nonmotor manifestations in PD to identify whether RBD was associated with differences in the nature and severity of these manifestations. PD patients underwent polysomnography (PSG) to diagnose the presence of RBD. Participants then underwent an extensive evaluation by a movement disorders specialist blinded to PSG results. Measures of disease severity, quantitative motor indices, motor subtypes, therapy complications, and autonomic, psychiatric, visual, and olfactory dysfunction were assessed and compared using regression analysis, adjusting for disease duration, age, and sex. Of 98 included patients, 54 had RBD and 44 did not. PD patients with RBD were older (P = 0.034) and were more likely to be male (P < 0.001). On regression analysis, the most consistent links between RBD and PD were a higher systolic blood pressure (BP) change while standing (-23.9 ± 13.9 versus -3.5 ± 10.9; P < 0.001), a higher orthostatic symptom score (0.89 ± 0.82 versus 0.44 ± 0.66; P = 0.003), and a higher frequency of freezing (43% versus 14%; P = 0.011). A systolic BP drop >10 could identify PD patients with RBD with 81% sensitivity and 86% specificity. In addition, there was a probable relationship between RBD and nontremor predominant subtype of PD (P = 0.04), increased frequency of falls (P = 0.009), and depression (P = 0.009). Our results support previous findings that RBD is a multifaceted phenomenon in PD. Patients with PD who have RBD tend to have specific motor and nonmotor manifestations, especially orthostatic hypotension.