128 research outputs found
Slow oscillatory activity and levodopa-induced dyskinesias in Parkinsonâs disease
The pathophysiology of levodopa-induced dyskinesias (LID) in Parkinsonâs disease is not well understood.
We have recorded local field potentials (LFP) from macroelectrodes implanted in the subthalamic nucleus
(STN) of 14 patients with Parkinsonâs disease following surgical treatment with deep brain stimulation. Patients
were studied in the âOffâ medication state and in the âOnâ motor state after administration of levodopaâ
carbidopa (po) or apomorphine (sc) that elicited dyskinesias in 11 patients. The logarithm of the power
spectrum of the LFP in selected frequency bands (4â10, 11â30 and 60â80 Hz) was compared between the
âOffâ and âOnâ medication states. A peak in the 11â30 Hz band was recorded in the âOffâ medication state
and reduced by 45.2% (P < 0.001) in the âOnâ state. The âOnâ was also associated with an increment of 77. 6%
(P < 0.001) in the 4â10 Hz band in all patients who showed dyskinesias and of 17.8% (P < 0.001) in the 60â80 Hz
band in the majority of patients. When dyskinesias were only present in one limb (n = 2), the 4â10 Hz peak was
only recorded in the contralateralSTN. These findings suggest that the 4â10 Hz oscillation is associated with the
expression of LID in Parkinsonâs disease
Trends and Sex Differences in Hospitalizations and Mortality in Parkinsonâs Disease in Spain (2010â2019): A Nationwide Population-Based Study
This research was funded by Convenio V-PRICIT de la Comunidad de Madrid y la Universidad Complutense de Madrid (âPrograma de Excelencia para el Profesorado Universitarioâ INV.AY.20.2021.1E126). Universidad Complutense de Madrid. Grupo de InvestigaciĂłn en EpidemiologĂa de las Enfermedades CrĂłnicas de Alta Prevalencia en España (970970).The incidence of hospitalizations of ParkinsonÂŽs disease (PD) in Spain suffered a steady rise from 1997 to 2012. However, data on the trends during the following decade (2010â2019) are lacking. Hospital admissions with a primary and secondary diagnosis of PD were selected using the Spanish National Hospital Discharge Database (SNHDD) for the period 2010â2019. The primary endpoint was the incidence of hospitalizations and in-hospital mortality, stratified in biannual periods. The incidence of PD hospitalizations increased progressively over time from 81.25 cases in 2010â2011 to 94.82 cases in 2018â2019 per 100,000 inhabitants. Male sex, age and comorbidity also increased progressively in PD inpatients. PD as a comorbid condition presented a higher increment (annual percentage of change, APC +1.71%, p 80 years, OR = 12.76, 95% CI 3.96â29.64) and comorbidity (Charlson index â„ 2, OR 1.77, 95% CI 1.69â1.85). Adjusted mortality by age, sex, comorbidity and diagnostic position remained stable. In conclusion, PD hospitalizations in Spain have increased, with a parallel increment in mean age, male sex and higher comorbidities. However, adjusted mortality remains unchanged. The burden of this disease may increase the complexity and costs of hospital care in the future.Depto. de Salud PĂșblica y Materno - InfantilFac. de MedicinaTRUEConvenio V-PRICITUniversidad Complutense de Madrid. Grupo de InvestigaciĂłn en EpidemiologĂa de las Enfermedades CrĂłnicas de Alta Prevalencia en Españapu
Involvement of the subthalamic nucleus in engagement with behaviourally relevant stimuli
In this study we investigate how the basal ganglia (BG) may process the behavioural relevance of environmental cues by recording local field potentials (LFPs) in the subthalamic nucleus of patients with Parkinsonâs disease who had undergone implantation of electrodes for deep brain stimulation. Fourteen patients were recorded as they performed a paradigm dissociating warning cue presentation from programming related to execution of specific tasks. Target and non-target warning cues of differing behavioural relevance were contrasted, and we evaluated if warning cue-evoked activities varied according to whether the eventual task to be performed was motor or cognitive and whether patients were receiving or withdrawn from dopaminergic therapy. Warning cues evoked a complex temporal sequence of activities with three epochs over the 760 ms following the onset of the warning cue. In contrast to the initial evoked LFP, evoked activities over two later periods were significantly influenced by behavioural relevance and by treatment state. The early activity was likely related to the initial orientating of attention induced by a novel target, while the delayed responses in our paradigm may reflect processing related to the non-motor resource implications of cues. The results suggest that the BG are intimately involved in the evaluation of changes in the environment and of their behavioural significance. The latter process is partly modulated by dopamine. Weakness in this function might contribute to the behavioural impairment that can follow BG lesions and surgery
The Parkinsonian subthalamic network: measures of power, linear, and non-linear synchronization and their relationship to L-DOPA treatment and OFF state motor severity
In this paper we investigated the dopaminergic modulation of neuronal interactions occurring in the subthalamic nucleus (STN) during Parkinson's disease (PD). We utilized linear measures of local and long range synchrony such as power and coherence, as well as Detrended Fluctuation Analysis for Phase Synchrony (DFA-PS)- a recently developed non-linear method that computes the extent of long tailed autocorrelations present in the phase interactions between two coupled signals. Through analysis of local field potentials (LFPs) taken from the STN we seek to determine changes in the neurodynamics that may underpin the pathophysiology of PD in a group of 12 patients who had undergone surgery for deep brain stimulation. We demonstrate up modulation of alpha-theta (5â12 Hz) band power in response to L-DOPA treatment, whilst low beta band power (15â20 Hz) band-power is suppressed. We also find evidence for significant local connectivity within the region surrounding STN although there was evidence for its modulation via administration of L-DOPA. Further to this we present evidence for a positive correlation between the phase ordering of bilateral STN interactions and the severity of bradykinetic and rigidity symptoms in PD. Although, the ability of non-linear measures to predict clinical state did not exceed standard measures such as beta power, these measures may help identify the connections which play a role in pathological dynamics
A torque-based method demonstrates increased rigidity in Parkinsonâs disease during low-frequency stimulation
Low-frequency oscillations in the basal ganglia are prominent in patients with Parkinsonâs disease off medication. Correlative and more recent interventional studies potentially implicate these rhythms in the pathophysiology of Parkinsonâs disease. However, effect sizes have generally been small and limited to bradykinesia. In this study, we investigate whether these effects extend to rigidity and are maintained in the on-medication state. We studied 24 sides in 12 patients on levodopa during bilateral stimulation of the STN at 5, 10, 20, 50, 130 Hz and in the off-stimulation state. Passive rigidity at the wrist was assessed clinically and with a torque-based mechanical device. Low-frequency stimulation at â€20 Hz increased rigidity by 24 % overall (p = 0.035), whereas high-frequency stimulation (130 Hz) reduced rigidity by 18 % (p = 0.033). The effects of low-frequency stimulation (5, 10 and 20 Hz) were well correlated with each other for both flexion and extension (r = 0.725 ± SEM 0.016 and 0.568 ± 0.009, respectively). Clinical assessments were unable to show an effect of low-frequency stimulation but did show a significant effect at 130 Hz (p = 0.002). This study provides evidence consistent with a mechanistic link between oscillatory activity at low frequency and Parkinsonian rigidity and, in addition, validates a new method for rigidity quantification at the wrist
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Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinsons disease study.
Estimates of the spectrum and frequency of pathogenic variants in Parkinsons disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinsons disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (âŒ0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO †50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO †50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 Ă 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 Ă 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 Ă 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 Ă 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that âŒ15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD
Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson\u27s disease study
\ua9 The Author(s) 2024. Estimates of the spectrum and frequency of pathogenic variants in Parkinsonâs disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinsonâs disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (âŒ0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO †50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO †50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9
7 10â34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1
7 10â35). Female patients were 22% more likely to have a positive PDGT (P = 3
7 10â4), and for individuals with FH+ this likelihood was 55% higher (P = 1
7 10â14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that âŒ15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD
The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients
The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the âREGISTRYâ cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis
Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study
Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008â11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003â13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 Ă 10â10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 Ă 10â8 DHFR p=8·37 Ă 10â7 MTRNR2L2 p=2·15 Ă 10â9) and to a lesser extent in REGISTRY (MSH3 p=9·36 Ă 10â4 DHFR p=8·45 Ă 10â4 MTRNR2L2 p=1·20 Ă 10â3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 Ă 10â8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16â0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06â0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation
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