Levodopa Equivalent Daily Dosage: Geographical Variations and Real-Life Modules in Parkinson's Disease.

BACKGROUND: The Levodopa Equivalent Daily Dosage (LEDD) calculation algorithms help in capturing and harmonization of Parkinson's Disease (PD) therapies. Analyzing these updates is essential for validating their effectiveness. OBJECTIVE: To assess updated LEDD conversion factors in capturing the newer therapies in PD and therapy modules in different geographical cohorts. METHODS: Data were sourced from 10 Centers from 6 countries representing 2 different continents. The study compared the LEDD conversion factors proposed by Tomlinson et al and Jost et al, alongside investigating demographic disparities. RESULTS: The analysis involved 2943 subjects; 87% (n = 2577) met the UK Brain Bank criteria for PD. The LEDD differed significantly across methodologies (Tomlinson vs. Jost, 598 mg vs 610 mg, P < 0.0001). Geographical disparities highlighted variations in PD onset age (P < 0.0001). Jost and Tomlinson's calculations demonstrated consistency within but significant differences across countries (P < 0.0001).Age at onset revealed statistically significant differences in LEDD requirements (P < 0.0001), which were particularly higher in 21-50 years (718 mg vs 566 mg). This subgroup also demonstrated increased usage of non-Levodopa therapies (P < 0.0001). Men exhibited higher total LEDD (P = 0.001). 34% reported dyskinesia, associated with higher LEDD (756 mg, P < 0.0001). Surgically treated patients also had higher LEDD (P < 0.0001) and a significant difference between Jost and Tomlinson dosages (761 mg vs716mg) reflecting the incorporation of newer therapeutic molecules. CONCLUSION: This analysis delineates the importance of updated LEDD algorithms and intricacies in the landscape of PD treatment, underscored by geographical, age-related, and gender-specific variations, in real-life management scenarios.

Long-Term Medication Profiles in Parkinson's Disease under Subthalamic Deep Brain Stimulation: A Controlled Study.

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) reduces antiparkinsonian medications in Parkinson's disease (PD) compared with the preoperative state. Longitudinal and comparative studies on this effect are lacking. OBJECTIVE: To compare longitudinal trajectories of antiparkinsonian medication in STN-DBS treated patients to non-surgically treated control patients. METHODS: We collected retrospective information on antiparkinsonian medication from PD patients that underwent subthalamic DBS between 1999 and 2010 and control PD patients similar in age at onset and baseline, sex-distribution, and comorbidities. RESULTS: In 74 DBS patients levodopa-equivalent daily dose (LEDD) were reduced by 33.9-56.0% in relation to the preoperative baseline over the 14-year observational period. In 61 control patients LEDDs increased over approximately 10 years, causing a significant divergence between groups. The largest difference amongst single drug-classes was observed for dopamine agonists. CONCLUSION: In PD patients, chronic STN-DBS was associated with a lower LEDD compared with control patients over 14 years.

Blood D-serine levels correlate with aging and dopaminergic treatment in Parkinson's disease.

We recently described increased D- and L-serine concentrations in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, the post-mortem caudate-putamen of human Parkinson's disease (PD) brains and the cerebrospinal fluid (CSF) of de novo living PD patients. However, data regarding blood D- and L-serine levels in PD are scarce. Here, we investigated whether the serum profile of D- and L-serine, as well as the other glutamate N-methyl-D-aspartate ionotropic receptor (NMDAR)-related amino acids, (i) differs between PD patients and healthy controls (HC) and (ii) correlates with clinical-demographic features and levodopa equivalent daily dose (LEDD) in PD. Eighty-three consecutive PD patients and forty-one HC were enrolled. PD cohort underwent an extensive clinical characterization. Serum levels of D- and L-serine, L-glutamate, L-glutamine, L-aspartate, L-asparagine and glycine were determined using High Performance Liquid Chromatography. In age- and sex-adjusted analyses, no differences emerged in the serum levels of D-serine, L-serine and other NMDAR-related amino acids between PD and HC. However, we found that D-serine and D-/Total serine ratio positively correlated with age in PD but not in HC, and also with PD age at onset. Moreover, we found that higher LEDD correlated with lower levels of D-serine and the other excitatory amino acids. Following these results, the addition of LEDD as covariate in the analyses disclosed a selective significant increase of D-serine in PD compared to HC (Δ ≈ 38%). Overall, these findings suggest that serum D-serine and D-/Total serine may represent a valuable biochemical signature of PD.

Course of Impulse Control Disorder Symptoms in Parkinson's Disease: Deep Brain Stimulation Versus Medications.

Background: The effect of surgery on impulse control disorders (ICDs) remains unclear in Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS). Objective: To examine changes in ICD symptoms in PD patients undergoing DBS compared to a medication-only control group. Methods: The study was a 2-center, 12-month, prospective, observational investigation of PD patients undergoing DBS and a control group matched on age, sex, dopamine agonist use, and baseline presence of ICDs. Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) and total levodopa equivalent daily dose (LEDD) were collected at baseline, 3, 6, and 12 months. Linear mixed-effects models assessed changes in mean QUIP-RS score (sum of buying, eating, gambling, and hypersexuality items). Results: The cohort included 54 participants (DBS = 26, controls = 28), mean (SD) age 64.3 (8.1) and PD duration 8.0 (5.2) years. Mean baseline QUIP-RS was higher in the DBS group at baseline (8.6 (10.7) vs. 5.3 (6.9), P = 0.18). However, scores at 12 months follow-up were nearly identical (6.6 (7.3) vs. 6.0 (6.9) P = 0.79). Predictors of change in QUIP-RS score were baseline QUIP-RS score (ß = 0.483, P < 0.001) and time-varying LEDD (ß = 0.003, P = 0.02). Eight patients (four in each group) developed de novo ICD symptoms during follow-up, although none met diagnostic criteria for an impulse control disorder. Conclusions: ICD symptoms (including de novo symptoms) at 12 months follow-up were similar between PD patients undergoing DBS and patients treated with pharmacological therapy only. Monitoring for emergence of ICD symptoms is important in both surgically- and medication-only-treated PD patients.

Shaping the course of early-onset Parkinson's disease: insights from a longitudinal cohort.

INTRODUCTION: Early -onset Parkinson's disease (EOPD) labels those cases with onset earlier than fifty. Although peculiarities emerged either in clinical or pathological features, EOPD is managed alike typical, late-onset PD. A customized approach would be, instead, better appropriate. Accordingly, a deeper characterization of the clinical course, with an estimation of the disease progression rate, the therapy flow, and the main motor and non-motor complications occurrence, is needed. METHODS: A longitudinal cohort of 193 EOPD patients (selected on a single-centre population of 2000 PD cases) was retrospectively analysed, providing descriptive statics on a series of clinical parameters (genetics, phenotype, comorbidities, therapies, motor and non-motor complications, marital and gender issues) and modelling the trajectories from diagnosis to 10 years later of both Hoehn and Yahr (H&Y) stage and levodopa equivalent daily dose (LEDD). RESULTS: EOPD had a prevalence of 9.7%, including few monogenic cases. It mostly appeared as a motor syndrome, with asymmetric, rigid-akinetic presentation. H&Y linearly progressed with an increment of 0.92 points/10 years; LEDD flow had a non-linear trend, increasing of 526.90 mg/day in 0-5 years, and 166.83 mg/day in 5-10 years. Motor fluctuations started 6.5 ± 3.2 years from onset, affecting up to 80% of the cohort. Neuropsychiatric troubles interested the 50%, sexual complaints the 12%. Gender-specific motor disturbances emerged. CONCLUSION: We shaped EOPD course, modelling a "brain-first" PD subtype, slowly progressive, with non-linear dopaminergic requirement. Major burden mostly resulted from motor fluctuations, neuropsychiatric complications, sexual and marital complaints, with a considerable gender-effect.

Levodopa Dose Equivalency in Parkinson's Disease: Updated Systematic Review and Proposals.

BACKGROUND: To compare drug regimens across clinical trials in Parkinson's disease (PD) conversion formulae between antiparkinsonian drugs have been developed. These are reported in relation to levodopa as the benchmark drug in PD pharmacotherapy as 'levodopa equivalent dose' (LED). Currently, the LED conversion formulae proposed in 2010 by Tomlinson et al. based on a systematic review are predominantly used. However, new drugs with established and novel mechanisms of action and novel formulations of longstanding drugs have been developed since 2010. Therefore, consensus proposals for updated LED conversion formulae are needed. OBJECTIVES: To update LED conversion formulae based on a systematic review. METHODS: The MEDLINE, CENTRAL, and Embase databases were searched from January 2010 to July 2021. Additionally, in a standardized process according to the GRADE grid method, consensus proposals were issued for drugs with scarce data on levodopa dose equivalency. RESULTS: The systematic database search yielded 3076 articles of which 682 were eligible for inclusion in the systematic review. Based on these data and the standardized consensus process, we present proposals for LED conversion formulae for a wide range of drugs that are currently available for the pharmacotherapy of PD or are expected to be introduced soon. CONCLUSIONS: The LED conversion formulae issued in this Position Paper will serve as a research tool to compare the equivalence of antiparkinsonian medication across PD study cohorts and facilitate research on the clinical efficacy of pharmacological and surgical treatments as well as other non-pharmacological interventions in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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

Objective: 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. Methods: 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. Results: 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 < 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 < 0.001) and 45 points (deterioration of −28.6%) at the final follow-up (Z = −4.207, p < 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 < 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 < 0.001) and to 35 points (improvement of 28.6%) at the final follow-up (Z = −4.034, p < 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 < 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 < 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. Conclusion: 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.

Comparison of Motor Scores between OFF and ON States in Tremor-Dominant Parkinson's Disease after MRgFUS Treatment.

Objective: To compare the motor function improvements in ON and OFF states in tremor-dominant Parkinson's disease (TDPD) patients within one year of follow-up after ablation of the unilateral ventral intermediate nucleus of the thalamus (Vim) by magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS). Methods: A total of nine consecutive patients confirmed with TDPD who underwent unilateral Vim ablation by MRgFUS between April 2019 and September 2019 were included. The Movement Disorder Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRSIII) and Clinical Rating Scale for Tremor (CRST) were performed in the ON and OFF stages to distinguish the surgical effects from drug therapy effects. The adverse events and adjustment of drug doses were also recorded. Results: The preoperative MDS-UPDRSIII score in OFF and ON states was 55.0 (48.0, 65.5) and 26.0 (17.0, 27.0), while the CRST score was 46.0 (39.5, 53.5) and 20.0 (13.0, 23.5), respectively; the Levodopa equivalent dose was 600 (456, 600) mg/d. At 1 year after operation, the total MDS-UPDRSIII score and CRST score were 40.0 (30.0, 60.5) and 16.0 (10.0, 29.5) in the OFF state, and 21.0 (17.5, 27.0) and 2.0 (1.5, 7.0) in the ON state, respectively. Compared with the preoperative levels, follow-up at the two-time points (three months and one year after operation) showed the total MDS-UPDRSIII score, as well as MDS-UPDRSIII tremor, bradykinesia, and rigidity scores of contralateral limbs all significantly improved in OFF state. However, in the ON state, only the total MDS-UPDRSIII score and tremor score of contralateral limbs significantly improved. The total CRST score and the CRST (A + B) score of contralateral limbs significantly improved at three months and one year after the operation compared with before the operation in both ON and OFF states. The Levodopa equivalent dose at one and three months were not significantly different from the preoperative dose (p > 0.05). No serious adverse responses were observed. Conclusion: Treating TDPD with unilateral Vim ablation by MRgFUS could improve the symptoms of limb tremor and the other core symptoms, such as bradykinesia and rigidity, as well as some non-motor symptoms and the symptoms of ipsilateral limbs.

Neural synchronization analysis of electroencephalography coherence in patients with Parkinson's disease-related mild cognitive impairment.

Introduction: The underlying pathophysiology of slight cognitive dysfunction in Parkinson's disease-related mild cognitive impairment (PD-MCI) is yet to be elucidated. Our study aimed to evaluate the association between cognitive function and brain functional connectivity (FC) in patients with PD-MCI. Methods: Twenty patients with sporadic PD-MCI were evaluated for FC in the brain network. Further, electroencephalography (EEG) coherence analysis in the whole-brain and quantified regional coherence using phase coupling were performed for each frequency, and motor and cognitive function were assessed in the whole-brain. Results: The degree of cognitive impairment was related to a decrease in the coherence in the alpha ranges. The regional coherence in the left frontal-left parietal region rather than the right frontal-right parietal region showed a higher correlation with the cognitive function scores. Conclusion: The differences in EEG coherence across different types of cognitive dysfunction reflect a compensatory response to the heterogeneous and complex clinical presentation of PD-MCI. Our findings indicate decreased brain efficiency and impaired neural synchronization in PD-MCI; these results may be crucial in elucidating the pathological exacerbation of PD-MCI.

Long-term clinical outcomes of bilateral GPi deep brain stimulation in advanced Parkinson's disease: 5 years and beyond.

OBJECTIVE: Few studies have reported long-term outcomes of globus pallidus internus (GPi) deep brain stimulation (DBS) in Parkinson's disease (PD). The authors aimed to investigate long-term outcomes of bilateral GPi DBS for 5 years and beyond for PD patients. METHODS: The authors retrospectively analyzed the clinical outcomes in 65 PD patients treated with bilateral GPi DBS at a single center. The outcome measures of motor symptoms and health-related quality of life (HRQoL) included the Unified Parkinson's Disease Rating Scale (UPDRS) and the Parkinson's Disease Questionnaire (PDQ-39). Scores at baseline were compared with those at 1, 3, 5, and 6-8 years after implantation using Wilcoxon signed-rank tests with α correction. RESULTS: GPi DBS significantly improved the off-medication UPDRS III total scores, UPDRS IV, and dyskinesia score at 1 year when compared with baseline (all p < 0.001). The off- and on-medication tremor scores, UPDRS IV, and dyskinesia scores showed moderate and sustained improvement (the ranges of the mean percentage improvement at each time point were 61%-75%, 30%-80%, 29%-40%, and 40%-65%, respectively) despite lacking statistical significance at long-term follow-up with diminishing sample sizes. The off-medication UPDRS III total scores did not show significant improvement at 5 years or later, primarily because of worsening in rigidity, akinesia, speech, gait, and postural stability scores. The on-medication UPDRS III total scores also worsened over time, with a significant worsening at 6-8 years when compared with baseline (p = 0.008). The HRQoL analyses based on the PDQ-39 revealed significant improvement in the activities of daily living and discomfort domains at 1 year (p = 0.003 and 0.006, respectively); however, all the domains showed gradual worsening at the later time points without reaching statistical significance. At 3 years, the communication domain showed significant worsening compared with baseline scores (p = 0.002). CONCLUSIONS: GPi DBS in PD patients in this single-center cohort was associated with sustained long-term benefits in the off- and on-medication tremor score and motor complications. HRQoL and the cardinal motor symptoms other than tremor may worsen gradually in the long term. When counseling patients, it is important to recognize that benefits in tremor and dyskinesia are expected to be most persistent following bilateral GPi DBS implantation.

Sex-specific effects of subthalamic nucleus stimulation on pain in Parkinson's disease.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is known to reduce motor symptoms of Parkinson's disease (PD). The effects of DBS on various nonmotor symptoms often differ from patient to patient. The factors that determine whether or not a patient will respond to treatment have not been elucidated. Here, the authors evaluated sex differences in pain relief after DBS for PD. METHODS: The authors prospectively evaluated 20 patients preoperatively and postoperatively after bilateral STN DBS with the validated numeric rating scale (NRS), Revised Oswestry Disability Index for low-back pain (RODI), and King's Parkinson's Disease Pain Scale (KPDPS) and assessed the impact of sex as a biological variable. RESULTS: The cohort consisted of 6 female and 14 male patients with a mean duration of 11.8 ± 2.0 months since DBS surgery. Females were significantly older (p = 0.02). Covariate analysis, however, showed no effect of age, stimulation settings, or other confounding variables. KPDPS total scores statistically significantly improved only among males (p < 0.001). Males improved more than females in musculoskeletal and chronic subsets of the KPDPS (p = 0.03 and p = 0.01, respectively). RODI scores significantly improved in males but not in females (p = 0.03 and p = 0.30, respectively). Regarding the NRS score, the improvements seen in both sexes in NRS were not significant. CONCLUSIONS: Although it is well recognized that pain complaints in PD are different between men and women, this study is unique in that it examines the sex-specific DBS effects on this symptom. Considering sex as a biological variable may have important implications for DBS pain outcome studies moving forward.

Prediction of the Clinical Severity of Progressive Supranuclear Palsy by Diffusion Tensor Imaging.

Progressive supranuclear palsy (PSP) is characterized by a rapid and progressive clinical course. A timely and objective image-based evaluation of disease severity before standard clinical assessments might increase the diagnostic confidence of the neurologist. We sought to investigate whether features from diffusion tensor imaging of the entire brain with a machine learning algorithm, rather than a few pathogenically involved regions, may predict the clinical severity of PSP. Fifty-three patients who met the diagnostic criteria for probable PSP were subjected to diffusion tensor imaging. Of them, 15 underwent follow-up imaging. Clinical severity was assessed by the neurological examinations. Mean diffusivity and fractional anisotropy maps were spatially co-registered, normalized, and parcellated into 246 brain regions from the human Brainnetome atlas. The predictors of clinical severity from a stepwise linear regression model were determined after feature reduction by the least absolute shrinkage and selection operator. Performance estimates were obtained using bootstrapping, cross-validation, and through application of the model in the patients who underwent repeated imaging. The algorithm confidently predicts the clinical severity of PSP at the individual level (adjusted R2: 0.739 and 0.892, p < 0.001). The machine learning algorithm for selection of diffusion tensor imaging-based features is accurate in predicting motor subscale of unified Parkinson's disease rating scale and postural instability and gait disturbance of PSP.

Complete resolution of postherpetic neuralgia following pallidotomy: case report.

The authors report on a female patient with left-dominant Parkinson's disease with motor fluctuations and levodopa-induced dyskinesias and comorbid postherpetic neuralgia (PHN), who underwent a right-sided pallidotomy. Besides a substantial improvement in her Parkinson's symptoms, she reported an immediate and complete disappearance of PHN. This neuralgia had been long-standing, pharmacologically refractory, and severe (preoperative Brief Pain Inventory [BPI] pain severity score of 8.0, BPI pain interference score of 7.3, short-form McGill Pain Questionnaire sensory pain rating index of 7 and affective pain rating index of 10, Present Pain Intensity rank value of 4, and visual analog scale score of 81 mm; all postoperative scores were 0). She continued to be pain free at 16 months postoperatively.This peculiar finding adds substantially to the largely unrecognized evidence for the role of the pallidum in pain processing, based on previous electrophysiological, metabolic, anatomical, pharmacological, and clinical observations. Therefore, the potential of the pallidum as a neurosurgical target for neuropathic pain warrants further investigation.

Effect of unilateral subthalamic deep brain stimulation in highly asymmetrical Parkinson's disease: 7-year follow-up.

OBJECTIVEFor patients with highly asymmetrical Parkinson's disease (PD), unilateral subthalamic nucleus (STN) deep brain stimulation (DBS) has been suggested as a reasonable treatment. However, the results of a previous 2-year follow-up study involving patients with prominently asymmetrical PD who had unilateral STN DBS suggested that simultaneous bilateral surgery should be performed. In the present study, the authors analyze 7-year follow-up data from the same patient group to examine changes in motor benefit from unilateral STN DBS over time and the interval between initial unilateral surgery and a second (contralateral) STN DBS surgery.METHODSEight patients with highly asymmetrical parkinsonism who underwent unilateral STN DBS were evaluated. The factors measured were scores on the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS III), Hoehn and Yahr (HY) stage, and levodopa equivalent daily dose (LEDD). Evaluations occurred at 3, 6, and 12 months after the initial surgery and annually thereafter.RESULTSThe mean follow-up period was 91.5 months (range 36-105 months). Three years after the initial unilateral surgery, motor benefits on the contralateral side continued; however, an aggravation of the ipsilateral parkinsonism attenuated the improvement in total UPDRS III scores, which reverted to baseline. Axial motor score, LEDD, and HY stage did not differ from the baseline. Seven of 8 patients (87.5%) were considered candidates for a second surgery to offer additional motor benefits. Of the 7 candidates, 4 patients (50% of total patients) underwent the second surgery at 58.5 ± 11.6 (mean ± SD) months after the initial surgery. Three patients were not able to have the second surgery: one patient died of gastric cancer, one patient was severely immobilized by an accident, and one patient could not afford the second surgery. One patient remained content with the initial unilateral surgery throughout the follow-up period.CONCLUSIONSSeven of 8 patients with unilateral STN DBS became candidates for second surgery before battery replacement surgery of the first implanted device. Baseline asymmetry alone may not predict appropriate candidates for unilateral STN DBS. This study provides further evidence that, from a long-term perspective, initial simultaneous bilateral STN DBS should be considered for PD patients with prominently asymmetrical motor symptoms.

Comparison of elderly and young patient populations treated with deep brain stimulation for Parkinson's disease: long-term outcomes with up to 7 years of follow-up.

OBJECTIVE: Deep brain stimulation (DBS) is the procedure of choice for Parkinson's disease (PD). It has been used in PD patients younger than 70 years because of better perceived intra- and postoperative outcomes than in patients 70 years or older. However, previous studies with limited follow-up have demonstrated benefits associated with the treatment of elderly patients. This study aims to evaluate the long-term outcomes in elderly PD patients treated with DBS in comparison with a younger population. METHODS: PD patients treated with DBS at the authors' institution from 2008 to 2014 were divided into 2 groups: 1) elderly patients, defined as having an age at surgery ≥ 70 years, and 2) young patients, defined as those < 70 years at surgery. Functional and medical treatment outcomes were evaluated using the Unified Parkinson's Disease Rating Scale part III (UPDRS III), levodopa-equivalent daily dose (LEDD), number of daily doses, and number of anti-PD medications. Study outcomes were compared using univariate analyses, 1-sample paired t-tests, and 2-sample t-tests. RESULTS: A total of 151 patients were studied, of whom 24.5% were ≥ 70 years. The most common preoperative Hoehn and Yahr stages for both groups were 2 and 3. On average, elderly patients had more comorbidities at the time of surgery than their younger counterparts (1 vs 0, p = 0.0001) as well as a higher average LEDD (891 mg vs 665 mg, p = 0.008). Both groups experienced significant decreases in LEDD following surgery (elderly 331.38 mg, p = 0.0001; and young 108.6 mg, p = 0.0439), with a more significant decrease seen in elderly patients (young 108.6 mg vs elderly 331.38 mg, p = 0.0153). Elderly patients also experienced more significant reductions in daily doses (young 0.65 vs elderly 3.567, p = 0.0344). Both groups experienced significant improvements in motor function determined by reductions in UPDRS III scores (elderly 16.29 vs young 12.85, p < 0.0001); however, reductions in motor score between groups were not significant. Improvement in motor function was present for a mean follow-up of 3.383 years postsurgery for the young group and 3.51 years for the elderly group. The average follow-up was 40.6 months in the young group and 42.2 months in the elderly group. CONCLUSIONS: This study found long-term improvements in motor function and medication requirements in both elderly and young PD patients treated with DBS. These outcomes suggest that DBS can be successfully used in PD patients ≥ 70 years. Further studies will expand on these findings.

Impact of gender and genetics on emotion processing in Parkinson's disease - A multimodal study.

•Understanding of the phenotypic heterogeneity of Parkinson's disease is needed.•Gender and genetics determine manifestation and progression of Parkinson's disease.•Altered emotion processing in Parkinson's disease is specific to male patients.•This is influenced by endocrinal and genetic factors in both genders.•This finding may impact the diagnosis and treatment of emerging clinical features.

[18F]fallypride characterization of striatal and extrastriatal D2/3 receptors in Parkinson's disease.

Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D2/3 receptor binding in both striatal and extrastriatal regions in PD are limited. We studied 35 PD patients off-medication and 31 age- and sex-matched healthy controls (HCs) using PET imaging with [18F]fallypride, a high affinity D2/3 receptor ligand, to measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). PD patients completed PET imaging in the off medication state, and motor severity was concurrently assessed. Voxel-wise evaluation between groups revealed significant BPND reductions in PD patients in striatal and several extrastriatal regions, including the locus coeruleus and mesotemporal cortex. A region-of-interest (ROI) based approach quantified differences in dopamine D2/3 receptors, where reduced BPND was noted in the globus pallidus, caudate, amygdala, hippocampus, ventral midbrain, and thalamus of PD patients relative to HC subjects. Motor severity positively correlated with D2/3 receptor density in the putamen and globus pallidus. These findings support the hypothesis that abnormal D2/3 expression occurs in regions related to both the motor and non-motor symptoms of PD, including areas richly invested with noradrenergic neurons.

Clinical outcomes following awake and asleep deep brain stimulation for Parkinson disease.

OBJECTIVE: Recent studies have shown similar clinical outcomes between Parkinson disease (PD) patients treated with deep brain stimulation (DBS) under general anesthesia without microelectrode recording (MER), so-called "asleep" DBS, and historical cohorts undergoing "awake" DBS with MER guidance. However, few studies include internal controls. This study aims to compare clinical outcomes after globus pallidus internus (GPi) and subthalamic nucleus (STN) DBS using awake and asleep techniques at a single institution. METHODS: PD patients undergoing awake or asleep bilateral GPi or STN DBS were prospectively monitored. The primary outcome measure was stimulation-induced change in motor function off medication 6 months postoperatively, measured using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III). Secondary outcomes included change in quality of life, measured by the 39-item Parkinson's Disease Questionnaire (PDQ-39), change in levodopa equivalent daily dosage (LEDD), stereotactic accuracy, stimulation parameters, and adverse events. RESULTS: Six-month outcome data were available for 133 patients treated over 45 months (78 GPi [16 awake, 62 asleep] and 55 STN [14 awake, 41 asleep]). UPDRS-III score improvement with stimulation did not differ between awake and asleep groups for GPi (awake, 20.8 points [38.5%]; asleep, 18.8 points [37.5%]; p = 0.45) or STN (awake, 21.6 points [40.3%]; asleep, 26.1 points [48.8%]; p = 0.20) targets. The percentage improvement in PDQ-39 and LEDD was similar for awake and asleep groups for both GPi (p = 0.80 and p = 0.54, respectively) and STN cohorts (p = 0.85 and p = 0.49, respectively). CONCLUSIONS: In PD patients, bilateral GPi and STN DBS using the asleep method resulted in motor, quality-of-life, and medication reduction outcomes that were comparable to those of the awake method.

Connectivity derived thalamic segmentation in deep brain stimulation for tremor.

The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for stereotactic ablation and deep brain stimulation (DBS) in the treatment of tremor in Parkinson's disease (PD) and essential tremor (ET). It is centrally placed on a cerebello-thalamo-cortical network connecting the primary motor cortex, to the dentate nucleus of the contralateral cerebellum through the dentato-rubro-thalamic tract (DRT). The VIM is not readily visible on conventional MR imaging, so identifying the surgical target traditionally involved indirect targeting that relies on atlas-defined coordinates. Unfortunately, this approach does not fully account for individual variability and requires surgery to be performed with the patient awake to allow for intraoperative targeting confirmation. The aim of this study is to identify the VIM and the DRT using probabilistic tractography in patients that will undergo thalamic DBS for tremor. Four male patients with tremor dominant PD and five patients (three female) with ET underwent high angular resolution diffusion imaging (HARDI) (128 diffusion directions, 1.5 mm isotropic voxels and b value = 1500) preoperatively. Patients received VIM-DBS using an MR image guided and MR image verified approach with indirect targeting. Postoperatively, using parallel Graphical Processing Unit (GPU) processing, thalamic areas with the highest diffusion connectivity to the primary motor area (M1), supplementary motor area (SMA), primary sensory area (S1) and contralateral dentate nucleus were identified. Additionally, volume of tissue activation (VTA) corresponding to active DBS contacts were modelled. Response to treatment was defined as 40% reduction in the total Fahn-Tolosa-Martin Tremor Rating Score (FTMTRS) with DBS-ON, one year from surgery. Three out of nine patients had a suboptimal, long-term response to treatment. The segmented thalamic areas corresponded well to anatomically known counterparts in the ventrolateral (VL) and ventroposterior (VP) thalamus. The dentate-thalamic area, lay within the M1-thalamic area in a ventral and lateral location. Streamlines corresponding to the DRT connected M1 to the contralateral dentate nucleus via the dentate-thalamic area, clearly crossing the midline in the mesencephalon. Good response was seen when the active contact VTA was in the thalamic area with highest connectivity to the contralateral dentate nucleus. Non-responders had active contact VTAs outside the dentate-thalamic area. We conclude that probabilistic tractography techniques can be used to segment the VL and VP thalamus based on cortical and cerebellar connectivity. The thalamic area, best representing the VIM, is connected to the contralateral dentate cerebellar nucleus. Connectivity based segmentation of the VIM can be achieved in individual patients in a clinically feasible timescale, using HARDI and high performance computing with parallel GPU processing. This same technique can map out the DRT tract with clear mesencephalic crossing.

Prescribing Pattern for Parkinson's Disease in Indian Community before Referral to Tertiary Center.

BACKGROUND: Several factors determine the choice of medications in patients with Parkinson's disease (PD). We aimed to analyze the pattern of prescription of drugs in patients with PD before attending a tertiary-care center. METHODS: The study included chart review of 800 PD patients attending the Department of Neurology of the National Institute of Mental Health and Neurosciences in Bangalore, India. RESULTS: The mean age at onset was 51.1±11.8 years. The mean duration of illness was 41.7±43.6 months. At first visit, 79.4% (group 1, n=635) of patients were on medications, 10% (group 2, n=80) were on medications but later discontinued, and 10.6% (group 3, n=85) were drug-naïve. Overall, levodopa was prescribed in 94.8%, trihexyphenidyl in 40.4%, dopamine agonists in 23.2%, and amantadine in 17.2% either as monotherapy or in combination. In group 1, 37.8% were on monotherapy, with levodopa being the most commonly used agent (33.1%), followed by trihexyphenidyl (2.2%), dopamine agonists (1.6%), and amantadine (0.6%). Among those on polytherapy, levodopa plus trihexyphenidyl was the preferred combination (23.9%). In group 2, levodopa monotherapy was also most common (72.5%), followed by trihexyphenidyl monotherapy (7.5%). CONCLUSIONS: Levodopa and trihexyphenidyl were the most commonly prescribed drugs in our patients. A higher use of trihexyphenidyl could be due to its easy availability, low cost, and better tolerability in our patients, who were relatively young at the time of onset of their disease. The choice of antiparkinsonian medications at the primary and secondary care levels in India may be inappropriate, and newer guidelines tailored to the Indian context are warranted.