Levodopa Equivalent Daily Dose Research Articles

Diffusion along perivascular spaces as marker for impairment of glymphatic system in Parkinson’s disease

The brain glymphatic system is involved in the clearance of misfolding α-synuclein, the impaired glymphatic system may contribute to the progression of Parkinson’s disease (PD). We aimed to analyze the diffusion tensor image along the perivascular space (DTI-ALPS) and perivascular space (PVS) burden to reveal the relationship between the glymphatic system and PD. A cross-sectional study using a 7 T MRI of 76 PD patients and 48 controls was performed to evaluate the brain’s glymphatic system. The DTI-ALPS and PVS burden in basal ganglia were calculated. Correlation analyses were conducted between DTI-ALPS, PVS burden and clinical features. We detected lower DTI-ALPS in the PD subgroup relative to controls, and the differences were more pronounced in patients with Hoehn & Yahr stage greater than two. The decreased DTI-ALPS was only evident in the left hemisphere in patients in the early stage but involved both hemispheres in more advanced PD patients. Decreased DTI-ALPS were also correlated with longer disease duration, higher Unified Parkinson’s Disease Rating Scale motor score (UPDRS III) and UPDRS total scores, as well as higher levodopa equivalent daily dose. Moreover, the decreased DTI-ALPS correlated with increased PVS burden, and both indexes correlated with PD disease severity. This study demonstrated decreased DTI-ALPS in PD, which might initiate from the left hemisphere and progressively involve right hemisphere with the disease progression. Decreased DTI-ALPS index correlated with increased PVS burden, indicating that both metrics could provide supporting evidence of an impaired glymphatic system. MRI evaluation of the PVS burden and diffusion along PVS are potential imaging biomarkers for PD for disease progression.

Oligomeric α-synuclein and tau aggregates in NDEVs differentiate Parkinson's disease from atypical parkinsonisms

The early differential diagnosis of Parkinson's disease (PD) and atypical Parkinsonian syndromes (APS), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), is challenging because of an overlap of clinical features and the lack of reliable biomarkers. Neural-derived extracellular vesicles (NDEVs) isolated from blood provide a window into the brain's biochemistry and may assist in distinguishing between PD and APS. We verified in a case-control study whether oligomeric α-Synuclein and Tau aggregates isolated from NDEVs could allow the differential diagnosis of these conditions.Blood sampling and clinical data, including disease duration, motor severity, global cognition, and levodopa equivalent daily dose (LEDD), were collected from patients with a diagnosis of either PD (n = 70), PSP (n = 21), or CBD (n = 19). NDEVs were isolated from serum by immunocapture using an antibody against the neuronal surface marker L1CAM; oligomeric α-Synuclein and aggregated Tau were measured by ELISA.NDEVs analyses showed that oligomeric α-Synuclein is significantly augmented in PD compared to APS, whereas Tau aggregates are significantly increased in APS compared to PD (p < 0.0001). ROC analyses showed that these two biomarkers have a “good” power of classification (p < 0.0001 for both proteins), with high sensitivity and specificity, with NDEVs concentration of Tau aggregates and oligomeric α-Synuclein being respectively the best biomarker for PD/PSP and PD/CBD diagnostic differentiation.Logistic and multiple regression analysis confirmed that NDEVs-derived oligomeric α-Synuclein and Tau aggregates differentiate PD from CBD and PSP (p < 0.001). Notably, a positive correlation between NDEVs oligomeric α-Synuclein and disease severity (disease duration, p = 0.023; Modified H&Y, p = 0.015; UPDRS motor scores, p = 0.004) was found in PD patients and, in these same patients, NDEVs Tau aggregates concentration inversely correlated with global cognitive scores (p = 0.043).A minimally invasive blood test measuring the concentration of α-synuclein and Tau aggregates in NDEVs can represent a promising tool to distinguish with high sensitivity and specificity PD from CBD or PSP patients. Optimization and validation of these data will be needed to confirm the diagnostic value of these biomarkers in distinguishing synucleinopathies from taupathies.

Comparison of intraoperative imaging guided versus microelectrode recording guided deep brain stimulation for Parkinson's disease: A meta-analysis

BackgroundTraditionally, most centers would use microelectrode recording (MER) to refine targeting in deep brain stimulation (DBS) surgery. In recent years, intraoperative imaging (IMG) guided DBS has become an alternative way to verify lead placement. Currently, there is still controversy surrounding the necessity of MER or IMG for DBS. This meta-analysis aims to explore lead accuracy, clinical efficacy and safety between IMG and MER guided DBS for Parkinson's disease (PD). MethodsPubMed, Embase, Web of Science, Cochrane Library were searched up to Mar, 2021 for studies reporting comparisons between IMG and MER guided DBS for PD. Subgroup analysis was conducted to assess effects of different IMG technology and DBS targeting site. ResultsSix studies, comprising of 478 patients were included in our analysis. The mean difference between the two implantation techniques in stereotactic accuracy, lead passes per trajectory, improvement% of Unified Parkinson's Disease Rating Scale part III and levodopa equivalent daily dose were −0.45 (95% confidence interval, CI=−1.11 to 0.20), −0.18 (95% CI=−0.41 to 0.06), 3.40 (95% CI=−5.36 to 12.16), and 5.00 (95% CI=−1.40 to 11.39), respectively. No significant differences were observed in each adverse event and operation/procedure time between the two implantation techniques. ConclusionsBoth IMG and MER guided DBS offered effective control of motor symptoms for PD. Besides, IMG guided is comparable to MER guided DBS, in terms of safety, accuracy and efficiency. It is recommended for each hospital to select DBS guidance technology based on available resources and equipment.

Sleep benefit in patients with Parkinson’s disease is associated with the dopamine transporter expression in putamen

PurposeSleep benefit (SB) is a well-known phenomenon in patients with Parkinson’s disease (PD); however, the mechanisms underlying this phenomenon remain unclear. This study aimed to evaluate whether the SB phenomenon in PD patients is associated with dopamine transporter (DAT) expression levels in the striatum. MethodsThe data of 125 PD patients were collected and divided into SB (n = 61) and non-SB (nSB) groups (n = 54) depending on whether they had SB or not. DAT expression on both sides of the striatum in PD patients was measured using 2b-carbomethoxy-3b-(4-trimethylstannylphenyl) tropane (11C-CFT) positron emission tomography imaging. The clinical variables, sleep scores, and striatum 11C-CFT uptake index of PD patients between the SB and nSB groups were compared. The associations of clinical variables, sleep scores, and striatum 11C-CFT uptake index with the SB variable were analyzed using logistic regression analysis. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of the striatum 11C-CFT uptake index in distinguishing SB patients from nSB patients. ResultsThe tremor subtype ratio (P = 0.011), levodopa equivalent daily dose (LEDD) (P < 0.001), sleep efficiency score (P = 0.025), habitual sleep efficiency (P = 0.012), and night sleep duration (P = 0.005) in the SB group were significantly different from those in the nSB group. The 11C-CFT uptake index in both the contralateral and ipsilateral striata in the SB group was significantly higher than that in the nSB group (P < 0.05). The binary logistic regression showed that SB variables were significantly and independently associated with tremor subtype (P = 0.048), LEDD (P = 0.021), sleep duration at night (P = 0.035), 11C-CFT uptake index in the contralateral (P = 0.013) and ipsilateral (P = 0.019) putamen in PD patients after correction for important clinical confounders. ROC analysis showed that the 11C-CFT uptake index on the onset side of the putamen had a high capacity (AUC: 0.916) to distinguish SB patients from nSB patients with high sensitivity (83.33 %) and specificity (88.89 %). ConclusionDAT expression in the putamen was associated with the SB phenomenon in PD patients, and the putamen DAT expression level could predict the SB phenomenon in PD patients.

Remote programming for subthalamic deep brain stimulation in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective for the treatment of Parkinson's disease (PD). Moreover, remote programming is widely used in Mainland China. This necessitates evaluating the ability of remote programming to achieve the ideal postoperative effect. Therefore, we aimed to retrospectively evaluate the effects of different programming modes on the effectiveness of STN-DBS 12 months postoperatively in patients with PD. Clinical data were collected retrospectively, before and 12 months after surgery, in 83 patients with PD. Based on the programming modes voluntarily selected by the patients during 12 months postoperatively, they were divided into three groups, namely remote programming alone, hospital programming alone, and hospital + remote programming. We compared the programming data and the effects of different programming methods on STN-DBS-related improvements 12 months postoperatively among these groups. Furthermore, we analyzed STN-DBS-related improvements at 12 months postoperatively in 76 patients. The effectiveness of STN-DBS was not influenced by the three programming modes. The postoperative Movement Disorder Society Unified Parkinson's Disease Rating Scale scores did not reveal statistically significant differences between the remote alone and hospital alone programming groups, except for motor examination. The postoperative decline in the levodopa equivalent daily dose was most apparent in the hospital programming alone group. The programming frequency of the hospital + remote programming group was considerably higher than that of the remaining groups. Seventy-six patients with PD displayed good STN-DBS surgical efficacy. Programming modes do not influence the short-term efficacy of STN-DBS, and remote programming can yield a satisfactory surgical effect.

Short- and Long-Term Efficacy and Safety of Deep-Brain Stimulation in Parkinson's Disease Patients aged 75 Years and Older.

The aim of this study was to investigate the efficacy and safety of deep-brain stimulation (DBS) in the treatment of patients with Parkinson's disease aged 75 years and older. From March 2013 to June 2021, 27 patients with Parkinson's disease (≥75 years old) who underwent DBS surgery at the First Medical Center of the PLA General Hospital were selected. The Unified Parkinson's Disease Rating Scale Part 3 (UPDRS-III), 39-item Parkinson's Disease Questionnaire (PDQ-39), and Barthel Index for Activities of Daily Living (BI) scores were used to evaluate motor function and quality of life before surgery and during on and off periods of DBS at 1 year post operation and at the final follow-up. A series of non-motor scales were used to evaluate sleep, cognition, and mood, and the levodopa equivalent daily dose (LEDD) was also assessed. Adverse events related to surgery were noted. The average follow-up time was 55.08 (21-108) months. Symptoms were significantly improved at 1 year post operation. The median UPDRS-III score decreased from 35 points (baseline) to 19 points (improvement of 45.7%) in the stimulation-on period at 1 year post operation (t = 19.230, p &lt; 0.001) and to 32 points (improvement of 8.6%) at the final follow-up (t = 3.456, p = 0.002). In the stimulation-off period, the median score of UPDRS-III increased from 35 points to 39 points (deterioration of -11.4%) at 1 year post operation (Z = -4.030, p &lt; 0.001) and 45 points (deterioration of -28.6%) at the final follow-up (Z = -4.207, p &lt; 0.001). The PDQ-39 overall scores decreased from 88 points (baseline) to 55 points (improvement of 37.5%) in the stimulation-on period at 1 year post operation (t = 11.390, p &lt; 0.001) and 81 points (improvement of 8.0%) at the final follow-up (t = 2.142, p = 0.044). In the stimulation-off period, the median PDQ-39 score increased from 88 points to 99 points (deterioration of -12.5%) at the final follow-up (Z = -2.801, p = 0.005). The ADL-Barthel Index score increased from 25 points (baseline) to 75 points (improvement of 66.7%) at 1 year post operation (Z = -4.205, p &lt; 0.001) and to 35 points (improvement of 28.6%) at the final follow-up (Z = -4.034, p &lt; 0.001). In the stimulation-off period, BI scores decreased from 25 points to 15 points (deterioration of -40%) at 1 year post operation (Z = -3.225, p = 0.01) and to 15 points (deterioration of -40%) at the final follow-up (Z = -3.959, p = 0.001). Sleep, cognition, and mood were slightly improved at 1 year post operation (p &lt; 0.05), and LEDD was reduced from 650 mg (baseline) to 280 mg and 325 mg at 1 year post operation and the final follow-up, respectively (p &lt; 0.05). One patient had a cortical hemorrhage in the puncture tract on day 2 after surgery, five patients had hallucinations in the acute stage after surgery, and one patient had an exposed left-brain electrode lead at 4 months post operation; there were no infections or death. DBS showed efficacy and safety in treating older patients (≥75 years old) with Parkinson's disease. Motor function, quality of life, activities of daily living, LEDD, and sleep all showed long-term improvements with DBS; short-term improvements in emotional and cognitive function were also noted.

Reversible Pisa syndrome caused by chronic subdural hematoma in a patient with Parkinson’s disease: a case report

BackgroundPisa syndrome (PS), characterized by lateral trunk flexion, is quite common in patients with Parkinson’s disease (PD). Patients with PS are older and have a significantly longer disease duration, more severe motor phenotype, ongoing combined treatment with levodopa and dopamine agonists, and higher levodopa equivalent daily dose. We describe here, to the best of our knowledge, the first case of a woman with PD who developed acute-onset PS caused by chronic subdural hematoma (CSDH).Case presentationA 70-year-old woman developed acute-onset lateral flexion of her trunk to the left side while standing, and she was admitted to our hospital. One month before, she had a mild head trauma with loss of consciousness. At 65 years of age, she noticed difficulty with walking and clumsiness with her hands. She was diagnosed as having PD (Hoehn and Yahr stage 2) and levodopa was initiated. Her symptoms were markedly improved. At 67 years of age, she developed orthostatic hypotension and was treated sequentially with fluids, compression stockings, and midodrine. Urgently performed brain computed tomography (CT) showed a CSDH in the right hemisphere resulting in a marked compression of the hemisphere. After surgical evacuation, her PS disappeared. She has fully recovered to her preoperative level of function.ConclusionThe present case provides a valuable insight, that is, the mesial frontal lobe and its connections from the posterior parietal cortex play crucial roles in maintaining the body schema and in the pathophysiology of PS. This case suggests that CSDH should be considered when clinicians examine acute-onset PS, even in patients with neurodegenerative disorders such as PD. Appropriate patient triage and timely neurosurgical intervention should be considered.

APDM gait and balance measures fail to predict symptom progression rate in Parkinson's disease.

Parkinson's disease (PD) results in progressively worsening gait and balance dysfunction that can be measured using computerized devices. We utilized the longitudinal database of the Parkinson's Disease Biomarker Program to determine if baseline gait and balance measures predict future rates of symptom progression. We included 230, 222, 164, and 177 PD subjects with 6, 12, 18, and 24 months of follow-up, respectively, and we defined progression as worsening of the following clinical parameters: MDS-UPDRS total score, Montreal Cognitive Assessment, PDQ-39 mobility subscale, levodopa equivalent daily dose, Schwab and England score, and global composite outcome. We developed ridge regression models to independently estimate how each gait or balance measure, or combination of measures, predicted progression. The accuracy of each ridge regression model was calculated by cross-validation in which 90% of the data were used to estimate the ridge regression model which was then tested on the 10% of data left out. While the models modestly predicted change in outcomes at the 6-month follow-up visit (accuracy in the range of 66-71%) there was no change in the outcome variables during this short follow-up (median change in MDS-UPDRS total score = 0 and change in LEDD = 0). At follow-up periods of 12, 18, and 24 months, the models failed to predict change (accuracy in the held-out sets ranged from 42 to 60%). We conclude that this set of computerized gait and balance measures performed at baseline is unlikely to help predict future disease progression in PD. Research scientists must continue to search for progression predictors to enhance the performance of disease modifying clinical trials.

Mitochondrial biogenesis, telomere length and cellular senescence in Parkinson’s disease and Lewy body dementia

Progressive age is the single major risk factor for neurodegenerative diseases. Cellular aging markers during Parkinson’s disease (PD) have been implicated in previous studies, however the majority of studies have investigated the association of individual cellular aging hallmarks with PD but not jointly. Here, we have studied the association of PD with three aging hallmarks (telomere attrition, mitochondrial dysfunction, and cellular senescence) in blood and the brain tissue. Our results show that PD patients had 20% lower mitochondrial DNA copies but 26% longer telomeres in blood compared to controls. Moreover, telomere length in blood was positively correlated with medication (Levodopa Equivalent Daily Dose, LEDD) and disease duration. Similar results were found in brain tissue, where patients with Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and Dementia with Lewy Bodies (DLB) showed (46–95%) depleted mtDNA copies, but (7–9%) longer telomeres compared to controls. In addition, patients had lower mitochondrial biogenesis (PGC-1α and PGC-1β) and higher load of a cellular senescence marker in postmortem prefrontal cortex tissue, with DLB showing the highest effect among the patient groups. Our results suggest that mitochondrial dysfunction (copy number and biogenesis) in blood might be a valuable marker to assess the risk of PD. However, further studies with larger sample size are needed to evaluate these findings.

The Role of Microelectrode Recording in Deep Brain Stimulation Surgery for Parkinson's Disease: A Systematic Review and Meta-Analysis.

STN-DBS is a cornerstone in the treatment of advanced Parkinson's disease (PD). The traditional approach is to use an awake operative technique with microelectrode recording (MER). However, more centers start using an asleep MRI-guided technique without MER. We systematically reviewed the literature to compare STN-DBS surgery with and without MER for differences in clinical outcome. We systematically searched PubMed, Embase, MEDLINE, and Web of Science databases for randomized clinical trials and consecutive cohort studies published between 01-01-2000 and 26-08-2021, that included at least 10 PD patients who had received bilateral STN-DBS. 2,129 articles were identified. After abstract screening and full-text review, 26 studies were included in the final analysis, comprising a total of 34 study groups (29 MER and 5 non-MER). The standardized mean difference (SMD) in change in motor symptoms between baseline (OFF medication) and 6-24 months follow-up (OFF medication and ON stimulation) was 1.64 for the MER group and 1.87 for non-MER group (p = 0.59). SMD in change in levodopa equivalent daily dose (LEDD) was 1.14 for the MER group and 0.65 for non-MER group (p < 0.01). Insufficient data were available for comparative analysis of PDQ-39 and complications. The change in motor symptoms from baseline to follow-up did not differ between studies that used MER and those that did not. The postoperative reduction in LEDD from baseline to follow-up was greater in the MER-group. In the absence of high-quality studies comparing both methods, there is a clear need for a well-designed comparative trial.

S1548 GI Dysmotility Symptoms Are Not Associated With Increased L-Dopa Requirements in Parkinson’s Disease Patients

Introduction: Gastrointestinal (GI) motility disorders like gastroparesis or small bowel bacterial overgrowth are thought to impair efficacy of L-dopa, which is absorbed in the proximal small intestine, resulting in motor fluctuations among Parkinson’s Disease (PD) patients that prompt dosage increases. While symptoms of dysmotility are frequently reported in PD, results are mixed concerning their effect, if any, on L-dopa pharmacokinetics. In this study, we compare L-dopa equivalent daily dose (LEDD) and motor function among patient with 5 upper GI symptoms to study the possible relationship between dysmotility symptoms and increased L-dopa requirement. Methods: Two hundred PD patients evaluated by outpatient neurology at Mass General Brigham Healthcare between 2018-2019 were included. History of 5 upper GI symptoms (dysphagia, nausea, vomiting, epigastric pain, and bloating), as well as LEDD were obtained from the medical record. Unified PD Rating Scale (UDPRS) part III motor exam scores off medication were extracted from clinical notes. Differences between LEDD and UDPRS motor scores among patients with and without a history of each of the 5 GI symptoms were calculated via Student t-tests. Results: Dysphagia was significantly associated with increased LEDD (230mg, P=0.0067) as well as increased motor severity (4.6 UDPRS, P=0.036). In contrast, nausea was associated with decreased LEDD (-187 mg, P=0.030) despite similar motor severity (1.1 UDPRS, P=0.63) to those without nausea (Table). There were no differences in LEDD and UDPRS scores among patients with and without vomiting, epigastric pain, and bloating. Conclusion: Except dysphagia, we found that GI dysmotility symptoms were not associated with increased LEDD nor increased motor severity. This suggests that symptomatic GI dysmotility may not be directly related to poor L-dopa absorption, a common clinical question for PD patients referred to GI. While dysphagia was linked with higher LEDD, this may have stemmed from higher UDPRS scores in this population. Interestingly, those with nausea required lower LEDD despite comparable motor severity. Nausea, a frequent symptom of delayed intestinal transit, may extend absorption time leading to better motor outcomes on less L-dopa. However, further studies are needed to discern any underlying mechanism. Our results nonetheless indicate that clinical management of dysmotility may not reduce motor fluctuations and the need for increased L-dopa as previously presumed. Table 1. - Changes in L-dopa Requirements and Motor Severity in the Presence of Dysmotility Symptoms GI Symptom ΔLEDD, mg (SD) P value ΔUDPRS III (SD) P value Nausea -187 (86) 0.03 1 (2) 0.633 Vomiting 11 (95) 0.91 -2 (2) 0.343 Dysphagia 230 (84) 0.007 5 (2) 0.036 Epigastric pain 101 (104) 0.33 0 (3) 0.881 Bloating 62 (99) 0.533 1 (2) 0.764 LEDD—L-dopa equivalent daily dose UDPRS—Unified Parkinson's Disease Rating Scale.

Homocysteine levels, genetic background, and cognitive impairment in Parkinson’s disease

BackgroundHyperhomocysteinemia is considered an independent risk factor for cognitive impairment.ObjectiveTo study the correlation between homocysteine levels and cognitive impairment in patients with PD.MethodsWe conducted a case–control study that included 246 patients with PD, of whom 32 were cognitively impaired. The levels of homocysteine, folate, and vitamin B12 were measured in peripheral blood. Multivariate logistic regression analysis was applied to determine differences in homocysteine levels between PD patients with and without cognitive impairment. A meta-analysis was performed to clarify the role of Hcy levels in PD with cognitive decline. Five polymorphisms in genes involved in Hcy metabolism, including MTHFR rs1801133 and rs1801131, COMT rs4680, MTRR rs1801394, and TCN2 rs1801198, were genotyped.ResultsOur case–control study showed that homocysteine levels were associated with cognitive impairment in PD after adjusting for possible confounding factors such as levodopa equivalent daily dose. The results of our meta-analysis further supported the positive association between homocysteine levels and cognition in PD. We found that the MTHFR rs1801133 TT genotype led to higher homocysteine levels in PD patients, whereas the MTHFR rs1801131 CC genotype resulted in higher folate levels. However, the polymorphisms studied were not associated with cognitive impairment in PD.ConclusionsIncreased homocysteine levels were a risk factor for cognitive decline in PD. However, no association was found between polymorphisms in genes involved in homocysteine metabolism and cognitive impairment in PD. Large-scale studies of ethnically diverse populations are required to definitively assess the relationship between MTHFR and cognitive impairment in PD.

Prevalence of axial postural abnormalities and their subtypes in Parkinson's disease: a systematic review and meta-analysis.

Axial postural abnormalities, mainly involving the spinal deformities, are disabling symptoms of Parkinson's disease (PD). However, the prevalence of axial postural abnormalities in PD and their clinical correlates remain unclear. The present study aimed to conduct a systematic review and meta-analysis of the prevalence of overall and subtypes of axial postural abnormalities in PD. PubMed, Embase, Web of Science and Cochrane databases were searched up to 31st March, 2022. We identified studies that reported the prevalence of axial postural abnormalities in PD. The pooled estimate of prevalence was calculated using a random effect model. Subgroup analysis and meta-regression were performed. There were 19 studies met the inclusion criteria. The overall prevalence of axial postural abnormalities in PD was 22.1% (95% CI 19.7-24.5%). The prevalence of each subtype of axial postural abnormalities was 19.6% for scoliosis (95% CI 10.6-28.7%), 10.2% for camptocormia (95% CI 7.7-12.7%), 8% for Pisa syndrome (95% CI 4.7-11.4%), and 7.9% for antecollis (95% CI 3.9-11.9%). Subgroup analysis showed that the measuring method of axial postural abnormalities exerted significant effects on prevalence estimates. Axial postural abnormalities in PD were associated with older age, longer disease duration, higher H-Y stage, greater levodopa equivalent daily dose, more severe motor symptoms, motor fluctuations, and akinetic-rigid subtype. Axial postural abnormalities, which include scoliosis, camptocormia, Pisa syndrome, and antecollis, are not uncommon in patients with PD. Future research on axial postural abnormalities should be based on uniform diagnostic criteria and measuring methods.

Corneal confocal microscopy differentiates patients with Parkinson’s disease with and without autonomic involvement

Autonomic dysregulation in Parkinson’s disease (PD) can precede motor deficits and is associated with reduced quality of life, disease progression, and increased mortality. Objective markers of autonomic involvement in PD are limited. Corneal confocal microscopy (CCM) is a rapid ophthalmic technique that can quantify small nerve damage in a range of peripheral and autonomic neuropathies. Here we investigated whether CCM can be used to assess autonomic symptoms in PD. Based on the scale for outcomes in Parkinson’s disease for autonomic symptoms (SCOPA-AUT), patients with PD were classified into those without autonomic symptoms (AutD-N), with single (AutD-S), and multiple (AutD-M) domain autonomic dysfunction. Corneal nerve fiber pathology was quantified using CCM, and the relationship with autonomic symptoms was explored. The study enrolled 71 PD patients and 30 control subjects. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and CNBD/CNFD ratio were lower in PD patients with autonomic symptoms compared to those without autonomic symptoms. Autonomic symptoms correlated positively with CNFD (r = −0.350, p = 0.004), and were not related to Levodopa equivalent daily dose (r = 0.042, p = 0.733) after adjusting for age, disease severity, disease duration or cognitive function. CCM parameters had high sensitivity and specificity in distinguishing patients with PD with and without autonomic symptoms. PD patients with autonomic symptoms have corneal nerve loss, and CCM could serve as an objective ophthalmic imaging technique to identify patients with PD and autonomic symptoms.

Targeting Accuracy and Clinical Outcomes of Awake versus Asleep Interventional Magnetic Resonance Imaging-Guided Deep Brain Stimulation for Parkinson's Disease: The University of California, San Francisco Experience.

Interventional MRI (iMRI)-guided implantation of deep brain stimulator (DBS) leads has been developed to treat patients with Parkinson's disease (PD) without the need for awake testing. Direct comparisons of targeting accuracy and clinical outcomes for awake stereotactic with asleep iMRI-DBS for PD are limited. We performed a retrospective review of patients with PD who underwent awake or iMRI-guided DBS surgery targeting the subthalamic nucleus or globus pallidus interna between 2013 and 2019 at our institution. Outcome measures included Unified Parkinson's Disease Rating Scale Part III scores, levodopa equivalent daily dose, radial error between intended and actual lead locations, stimulation parameters, and complications. Of the 218 patients included in the study, the iMRI cohort had smaller radial errors (iMRI: 1.27 ± 0.72 mm, awake: 1.59 ± 0.96 mm, P < .01) and fewer lead passes (iMRI: 1.0 ± 0.16, awake: 1.2 ± 0.41, P < .01). Changes in Unified Parkinson's Disease Rating Scale were similar between modalities, but awake cases had a greater reduction in levodopa equivalent daily dose than iMRI cases ( P < .01), which was attributed to the greater number of awake subthalamic nucleus cases on multivariate analysis. Effective clinical contacts used for stimulation, side effect thresholds, and complication rates were similar between modalities. Although iMRI-DBS may result in more accurate lead placement for intended target compared with awake-DBS, clinical outcomes were similar between surgical approaches. Ultimately, patient preference and surgeon experience with a given DBS technique should be the main factors when determining the "best" method for DBS implantation.

Clinical differences between early-onset and mid-and-late-onset Parkinson's disease: Data analysis of the Hellenic Biobank of Parkinson's disease

BackgroundAge at onset is one of the most critical factors contributing to the clinical heterogeneity of Parkinson's disease (PD), and available evidence is rather conflicting. ObjectiveThe aim of this study is to investigate the clinical differences between early-onset PD (EOPD) and mid-and-late-onset PD (MLOPD) in the Greek population, based on the existing data of the Hellenic Biobank of PD (HBPD). MethodsHBPD contains information of PD cases from two centers in Greece during 2006–2017. Patients with the A53T mutation in the SNCA gene or mutations in the GBA1 gene were excluded. Associations between clinical characteristics (motor and non-motor symptoms, side of onset, first symptom, motor complications) and MLOPD versus EOPD were explored with a single logistic regression model adjusting for gender, family history of PD, disease and dopaminergic therapy duration, disease severity (UPDRS III), levodopa equivalent daily dose, as well as each of the other clinical characteristics. Results675 patients (129 EOPD, 546 MLOPD) were included. EOPD was more frequently associated with dystonia (OR 0.19, 95% CI 0.08–0.50, p < 0.01) and motor complications (0.23, 0.07–0.76, 0.02), compared to MLOPD. Bilateral onset (9.38, 1.05–84.04, 0.045) and autonomic dysfunction (2.31, 1.04–5.11, 0.04) were more frequently associated with MLOPD. ConclusionsEOPD and MLOPD display distinct clinical profiles, regarding motor and non-motor symptoms, side of onset and motor complications in the Greek population. These differences may reflect diverse pathophysiological backgrounds, potentially attributed to genetic or age-related epigenetic influences.

Neuropsychological, neuropsychiatric, and clinical correlates of affective and cognitive theory of mind in Parkinson's disease: A meta-analysis.

Theory of mind (ToM) is the ability to infer others' mental (Cognitive) and emotional (Affective) states, both being impaired in Parkinson's disease (PD). However, the clinical, neuropsychological, and neuropsychiatric features underlying Affective and Cognitive ToM deficits in PD are unclear. Therefore, we performed a meta-analytic study to test whether PD demographical, clinical, neuropsychological, or neuropsychiatric changes related differently to both ToM processes. A systematic literature search was performed up to January 2022, including a total of 31 studies following our search terms. Data from each study were obtained from demographic (age, education), clinical (disease duration, Hoehn & Yahr staging system, Unified Parkinson's Disease Rating Scale-III, levodopa equivalent daily dose), neuropsychological (global cognitive functioning, memory subdomains, executive functions subdomains, processing speed/complex attention/working memory, visuospatial and constructional abilities, and language), and neuropsychiatric (depression, apathy, anxiety) variables. Affective ToM impairment in PD was related to lower educational level and global cognition, deficits of generativity, decision making, attention/working memory, and language. Conversely, Cognitive ToM deficits were associated with advanced age, poorer global cognition, executive dysfunctions, and language impairments. Medication moderated the relationship between attention/working memory and Cognitive ToM, whereas age moderated the association of Affective ToM with language. No significant associations were found between ToM deficits and patients' neuropsychiatric or clinical states. These findings clarify the neuropsychological and clinical features that explain ToM deficits in PD. Possibly, our results suggest the need to explore the complex neural networks involving frontostriatal and temporoparietal circuits behind changes in social cognition in PD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy May Spare Dopaminergic Therapy in Early-Stage Tremor-Dominant Parkinson's Disease: A Pilot Study.

Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is a safe and effective procedure for drug-resistant tremor in Parkinson's disease (PD). The aim of this study was to demonstrate that MRgFUS ventralis intermedius thalamotomy in early-stage tremor-dominant PD may prevent an increase in dopaminergic medication 6 months after treatment compared with matched PD control subjects on standard medical therapy. We prospectively enrolled patients with early-stage PD who underwent MRgFUS ventralis intermedius thalamotomy (PD-FUS) and patients treated with oral dopaminergic therapy (PD-ODT) with a 1:2 ratio. We collected demographic and clinical data at baseline and 6 and 12months after thalamotomy. We included 10 patients in the PD-FUS group and 20 patients in the PD-ODT group. We found a significant increase in total levodopa equivalent daily dose and levodopa plus monoamine oxidase B inhibitors dose in the PD-ODT group 6 months after thalamotomy. In early-stage tremor-dominant PD, MRgFUS thalamotomy may be useful to reduce tremor and avoid the need to increase dopaminergic medications. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuroanatomy and Functional Connectivity in Patients with Parkinson's Disease with or without Restless Legs Syndrome.

Restless legs syndrome (RLS) is a common non-motor symptom in Parkinson's disease (PD), but its pathogenesis remains unclear. This study aimed to explore the potential neural substrates of RLS in a large sample of patients with PD. A total of 42 patients with PD with RLS and 124 patients with PD without RLS were prospectively recruited at our hospital between February 2019 and October 2020 and underwent structural and resting-state functional magnetic resonance imaging. Differences between the two patient groups were assessed using voxel-based morphometry and functional connectivity analysis. PD duration, PartIII of the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) score, and levodopa equivalent daily dose were treated as covariates. Patients with PD with RLS had significantly larger gray matter volume in the bilateral posterior cingulate cortex than patients with PD without RLS (FDR-adjusted P < 0.05). Compared to patients without RLS, those with RLS had significantly lower functional connectivity between the left central opercular cortex and the bilateral precentral gyri and postcentral gyri (FDR-adjusted P < 0.001). Our study provides the first evidence that in patients with PD, RLS is associated with significantly larger gray matter volume in the posterior cingulate cortex and lower resting-state functional connectivity within the sensorimotor network. Our results may help clarify the pathophysiology of RLS in PD and identify possible therapeutic targets.

Non-reference genome transposable elements (TEs) have a significant impact on the progression of the Parkinson's disease.

The pathophysiology of Parkinson's disease (PD) is a complex process of the interaction between genetic and environmental factors. Studies on the genetic component of PD have predominantly focused on single nucleotide polymorphisms (SNPs) using a cross-sectional case-control design in large genome-wide association studies. This approach while giving insight into a significant portion of the genetics of PD does not fully account for all the genetic components resulting in missing heritability. In this study, we approached this problem by focusing on the non-reference genome transposable elements (TEs) and their impact on the progression of PD using a longitudinal study design within the Parkinson's progression markers initiative (PPMI) cohort. We analyzed 2886 Alu repeats, 360 LINE1 and 128 SINE-VNTR-Alus (SVAs) that were called from the whole-genome sequence data which are not within the reference genome. The presence or absence of these non-reference TE variants is known as a retrotransposon insertion polymorphism, and measuring this polymorphism describes the impact of TEs on the traits. The variations for the presence or absence of the non-reference TE elements were modeled to align with the changes in the 114 outcome measures during the five-year follow-up period of the PPMI cohort. Linear mixed-effects models were used, and many TEs were found to have a highly significant effect on the longitudinal changes in the clinically important PD outcomes such as UPDRS subscale II, UPDRS total scores, and modified Schwab and England ADL scale. In addition, the progression of several imaging and functional measures, including the Caudate/Putamen ratio and levodopa equivalent daily dose (LEDD) were also significantly affected by the TEs. In conclusion, this study identified the overwhelming effect of the non-reference TEs on the progression of PD and is a good example of the impact the variations in the "junk DNA" have on complex diseases.