Slow oscillatory activity and levodopa-induced dyskinesias in Parkinson’s disease

The pathophysiology of levodopa-induced dyskinesias (LID) in Parkinson’s disease is not well understood. We have recorded local field potentials (LFP) from macroelectrodes implanted in the subthalamic nucleus (STN) of 14 patients with Parkinson’s disease following surgical treatment with deep brain stimulation. Patients were studied in the ‘Off’ medication state and in the ‘On’ motor state after administration of levodopa– carbidopa (po) or apomorphine (sc) that elicited dyskinesias in 11 patients. The logarithm of the power spectrum of the LFP in selected frequency bands (4–10, 11–30 and 60–80 Hz) was compared between the ‘Off’ and ‘On’ medication states. A peak in the 11–30 Hz band was recorded in the ‘Off’ medication state and reduced by 45.2% (P < 0.001) in the ‘On’ state. The ‘On’ was also associated with an increment of 77. 6% (P < 0.001) in the 4–10 Hz band in all patients who showed dyskinesias and of 17.8% (P < 0.001) in the 60–80 Hz band in the majority of patients. When dyskinesias were only present in one limb (n = 2), the 4–10 Hz peak was only recorded in the contralateralSTN. These findings suggest that the 4–10 Hz oscillation is associated with the expression of LID in Parkinson’s disease

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 (5–12 Hz) band power in response to L-DOPA treatment, whilst low beta band power (15–20 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

Trends and Sex Differences in Hospitalizations and Mortality in Parkinson’s Disease in Spain (2010–2019): A Nationwide Population-Based Study

This research was funded by Convenio V-PRICIT de la Comunidad de Madrid y la Universidad Complutense de Madrid (“Programa de Excelencia para el Profesorado Universitario” INV.AY.20.2021.1E126). Universidad Complutense de Madrid. Grupo de Investigación en Epidemiología de las Enfermedades Crónicas de Alta Prevalencia en España (970970).The incidence of hospitalizations of Parkinson´s disease (PD) in Spain suffered a steady rise from 1997 to 2012. However, data on the trends during the following decade (2010–2019) 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 2010–2019. 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 2010–2011 to 94.82 cases in 2018–2019 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 3.96–29.64) and comorbidity (Charlson index ≥ 2, OR 1.77, 95% CI 1.69–1.85). 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 Pública y Materno - InfantilFac. de MedicinaTRUEConvenio V-PRICITUniversidad Complutense de Madrid. Grupo de Investigación en Epidemiología de las Enfermedades Crónicas de Alta Prevalencia en Españapu

Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's 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 Parkinson's 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 (∼0.2%). 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 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 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 ∼15% 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

Focused ultrasound subthalamotomy in patients with asymmetric Parkinson's disease: a pilot study

Ablative neurosurgery has been used to treat Parkinson's disease for many decades. MRI-guided focused ultrasound allows focal lesions to be made in deep brain structures without skull incision. We investigated the safety and preliminary efficacy of unilateral subthalamotomy by focused ultrasound in Parkinson's disease.Fundación de investigación HM Hospitales and Insightec.Peer reviewe

Prospective Long-term Follow-up of Focused Ultrasound Unilateral Subthalamotomy for Parkinson Disease

Unilateral magnetic resonance-guided focused ultrasound subthalamotomy (FUS-STN) has been shown to improve the cardinal motor features of Parkinson disease (PD). Whether this effect is sustained is not known. This study aims to report the long-term outcome of patients with PD treated with unilateral FUS-STN.Peer reviewe

Cognitive safety after unilateral magnetic resonance-guided focused ultrasound thalamotomy for essential tremor

Essential tremor (ET) is the most common movement disorder, affecting 1% of the population worldwide. There is sound evidence that medically refractory tremor improves with thalamotomy and deep brain stimulation (DBS) targeting the thalamic ventralis intermedius nucleus (VIM). In the last few years, the incisionless technique of magnetic resonance- guided focused ultrasound (MRgFUS) has been demonstrated to be an effective procedure for unilateral thalamotomy,1 with a positive profile with regard to side effects. The thalamus is involved in cognitive functions such as attention/executive control, memory and language. Focal ablation of the thalamus, even when targeting a sensorimotor region as the VIM, raises question about potential cognitive side effects. After unilateral VIM-DBS in 40 patients with ET, Fields et al2 showed statistically significant improvements in visuoperceptual function and verbal memory. There was no significant decline in any measure, but four patients with preoperative low verbal fluency showed a further decline. Most studies have shown reduced verbal fluency under active VIM-DBS.2–4 Since focused ultrasound thalamotomy is a less invasive procedure, we hypothesised that the risk of procedure-related cognitive decline is further reduced.Peer reviewe

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 (∼0.2%). 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 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 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 ∼15% 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 Parkinson’s 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 Parkinson’s 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 (∼0.2%). 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 10−34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 7 10−35). Female patients were 22% more likely to have a positive PDGT (P = 3 7 10−4), and for individuals with FH+ this likelihood was 55% higher (P = 1 7 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 ∼15% 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’s disease study

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's 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 Parkinson's 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 (similar to 0.2%). 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 &lt;= 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO &lt;= 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 x 10(-34)). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 x 10(-35)). Female patients were 22% more likely to have a positive PDGT (P = 3 x 10(-4)), and for individuals with FH+ this likelihood was 55% higher (P = 1 x 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 similar to 15% 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