Evaluation of morning bradykinesia in Parkinson's disease in a United States cohort using continuous objective monitoring.

Introduction: Bradykinesia in Parkinson's disease is a marker for clinical levodopa responsiveness, with persistent bradykinesia reflecting suboptimal response. We objectively measured prevalence and severity of morning bradykinesia using the Personal KinetiGraph® (PKG®). Methods: Retrospective evaluation of a large global database of de-identified PKG assessments from individuals (N=12,840) in routine clinical care in the United States (US; n=3288). Median bradykinesia scores (mBKS) and median dyskinesia scores (mDKS) were calculated using a validated algorithm and previously established targets to evaluate percent time in bradykinesia, levodopa responsiveness, and prevalence and severity (0-5; 5=highest severity) of morning bradykinesia. Results: mBKS was above target (≥26) in 65% of all individuals, and mDKS was above target (≥7) in 3%. Elevated percent time in bradykinesia occurred in 79%. Among individuals where levodopa responsiveness could be evaluated (n=1933), 31% had a significant response (≥1.15 postdose decrease in severity). Morning bradykinesia was identified in 85% of individuals with available morning data (1298/1524), and 64% (954/1501) experienced continued bradykinesia after the first daily levodopa dose. Morning bradykinesia was severe (4.0-4.7) in levodopa-responsive individuals regardless of percent time spent in bradykinesia. Conclusion: Elevated mBKS was very common in the US. Most individuals taking levodopa had morning bradykinesia that persisted even after the first daily dose, and severity was high, indicating a need for additional treatment options.

Dopaminergic Basis of Spatial Deficits in Early Parkinson's Disease.

Dopaminergic mechanisms regulating cognitive and motor control were evaluated comparing visuoperceptual and perceptuomotor functions in Parkinson's disease (PD). The performance of PD patients (n = 40) was contrasted with healthy controls (n = 42) across two separate visits (on and off dopaminergic medications) on computerized tasks of perception and aiming to a target at variable stimulus lengths (4, 8, 12 cm). Novel visuoperceptual tasks of length equivalence and width interval estimations without motor demands were compared with tasks estimating spatial deviation in movement termination. The findings support the presence of spatial deficits in early PD, more pronounced with increased discrimination difficulty, and with shorter stimulus lengths of 4 cm for both visuoperceptual and perceptumotor functions. Dopaminergic medication had an adverse impact on visuoperceptual accuracy in particular for length equivalence estimations, in contrast with dopaminergic modulation of perceptuomotor functions that reduced angular displacements toward the target. The differential outcomes for spatial accuracy in perception versus movement termination in PD are consistent with involvement of the direct pathway and models of progressive loss of dopamine through corticostriatal loops. Future research should develop validated and sensitive standardized tests of perception and explore dopaminergic selective deficits in PD to optimize medication titration for motor and cognitive symptoms of the disease.

The effect of the accessory proteins, soluble CD14 and lipopolysaccharide-binding protein on Toll-like receptor 4 activity in human monocytes and adipocytes.

BACKGROUND: There is a growinge body of evidence pointing towards an important role for Toll-like receptors (TLR) especially TLR4 in obesity and metabolic syndrome. OBJECTIVE: Owing to the paucity of data on the effect of the accessory proteins, lipopolysaccharide (LPS)-binding protein (LBP) and soluble CD14 (sCD14) on TLR4 activation, the present study was undertaken to examine the effect of sCD14 and LBP on TLR4 activation in pivotal cells of meta-inflammation, monocytes and adipocytes. METHODS: The dose-response effects of sCD14 and LBP on TLR4 protein abundance in monocytes obtained from normal human volunteers was determined by flow cytometry and in human-differentiated adipocytes by western blotting. Additionally, the nuclear factor-kappaB (NF-κB) p65 and downstream biomediators interleukin (IL)-1ß, IL-8, IL-6 and tumor necrosis factor (TNF)-α were measured in the cell culture supernatants by ELISA (enzyme-linked immunosorbent assay). RESULTS: In LPS-primed monocytes, sCD14 but not LBP, augments both TLR4 abundance and inflammatory biomediators (IL-1ß, IL-8, IL-6 and TNF-α).sCD14 also showed a similar effect in LPS-primed human adipocytes by augmenting TLR4 protein expression and activity in terms of NF-κB p65 and downstream biomediators (IL-1ß, IL-8, IL-6 and TNF-α). LBP at the highest concentration only promoted secretion of IL-8 and TNF-α. However in both monocytes and adipocytes, the effect of sCD14 was superior to LBP. CONCLUSIONS: In the present report, we make the novel observation that sCD14 compared with LBP, offers a preferred target to ameliorate TLR especially TLR4-induced inflammation and insulin resistance in human obesity and metabolic syndrome.

Insulin resistance and gray matter volume in neurodegenerative disease.

The goal of this study was to compare insulin resistance in aging and aging-related neurodegenerative diseases, and to determine the relationship between insulin resistance and gray matter volume (GMV) in each cohort using an unbiased, voxel-based approach. Insulin resistance was estimated in apparently healthy elderly control (HC, n=21) and neurodegenerative disease (Alzheimer's disease (AD), n=20; Parkinson's disease (PD), n=22) groups using Homeostasis Model Assessment of Insulin Resistance 2 (HOMA2) and intravenous glucose tolerance test (IVGTT). HOMA2 and GMV were assessed within groups through General Linear Model multiple regression. We found that HOMA2 was increased in both AD and PD compared to the HC group (HC vs. AD, p=0.002, HC vs. PD, p=0.003), although only AD subjects exhibited increased fasting glucose (p=0.005). Furthermore, our voxel-based morphometry analysis revealed that HOMA2 was related to GMV in all cohorts in a region-specific manner (p<0.001, uncorrected). Significant relationships were observed in the medial prefrontal cortex (HC), medial temporal regions (AD), and parietal regions (PD). Finally, the directionality of the relationship between HOMA2 and GMV was disease-specific. Both HC and AD subjects exhibited negative relationships between HOMA2 and brain volume (increased HOMA2 associated with decreased brain volume), while a positive relationship was observed in PD. This cross-sectional study suggests that insulin resistance is increased in neurodegenerative disease, and that individuals with AD appear to have more severe metabolic dysfunction than individuals with PD or PD dementia.

Long-term evaluation of gait initiation in six Parkinson's disease patients with bilateral subthalamic stimulation.

Defined as the transient state between standing and walking, gait initiation is negatively affected in Parkinson's disease (PD), which often results in significant disability. Although deep brain stimulation (DBS) is the most common surgical procedure for PD, the long-term effects of DBS on gait initiation are not well studied. The present study evaluated the long-term effects of subthalamic nucleus (STN) DBS on the preparation phase of gait initiation using principal component (PC) analysis. Six patients with PD who had undergone STN DBS and 24 healthy control subjects were evaluated. PD subjects were assessed 11.3±10.3 (P1) and 78.9±10.6 (P2) months after surgery. PD subjects were tested with STN DBS in two conditions: without medication and with medication. PC analysis was applied separately for the vertical, anterior-posterior and medial-lateral components of ground reaction force (GRF) recorded during gait initiation. Three PC scores were chosen by the scree test for each GRF component and all these PC scores were used for calculating a standard distance between healthy controls and PD subjects. The Friedman test showed a significant difference in standard distance among conditions (P=0.004), with the post-hoc test recognizing differences among P1 conditions and P2 medication-on condition. The eigenvector loading factors pointed to major differences between PD conditions surrounding the maximum amplitude of vertical and anterior-posterior GRF. For the studied sample, all distances increased in the follow-up evaluation (P2) with and without medications, indicating a worsening in gait initiation after seven years.

Quinazolinone analogs as potential therapeutic agents.

Quinazolinone scaffold has been considered as a magic moiety possessing myriad spectrum of medicinal activities. Diversity of biological response profile has attracted considerable interest of several researchers across the globe to explore this skeleton for its assorted therapeutic significance. Various novel classes of structurally different quinazolinones have been designed and synthesized depicting potential interventions such as antibacterial, antifungal, antiviral, anticonvulsant, CNS depressant, antiinflammatory, antihistaminic, anticancer and so on. Moreover, the nucleus constitutes an integral structural component in a number of drugs currently employed in several clinical therapies. The present paper is an earnest attempt to provide an insight view on the current medicinal aspects of quinazolinone heterocycles alongwith brief discussion of their chemistry.

Gait initiation evaluation after deep brain stimulation for Parkinson's disease: A 7-year follow-up.

This study evaluated the long-term effects of deep brain stimulation of the subthalamic nucleus (DBS-STN) on gait initiation. Six Parkinson's disease (PD) patients who had undergone DBS-STN and 31 control subjects were evaluated. PD subjects were assessed at two different time periods: 11.3 ± 10.3 (P1) and 78.9 ± 10.6 (P2) months after surgery. Subjects under stimulation were tested in two conditions: without medication and with medication. Principal components (PC) analysis was separately applied on vertical, anterior-posterior and medial-lateral ground reaction force (GRF) from gait initiation, during the anticipatory postural adjustment (APA) phase. Three PC scores were chosen by the scree test for each GRF component. The higher loading factors pointed to major differences between controls and PD patients on maximum APA amplitude for vertical and anterior-posterior GRF. Friedman test showed a significant difference in standard distance among conditions (P = 0.006), with the post-hoc test recognizing differences only between P1 and P2 in the medication-on condition. All distances increased in the follow-up evaluation (P2), when considering the same medication condition, indicating a worsening in gait initiation after 7 years of follow-up.

Quantitative evaluation of the effects of subthalamic stimulation on gait in Parkinson's disease patients using principal component analysis.

BACKGROUND: Principal component analysis (PCA) was applied to the ground reaction force (GRF) for evaluating the deep brain stimulation of the subthalamic nucleus (DBS-STN) effects in Parkinson's disease (PD) subjects with and without medication. METHODS: Ten subjects who underwent DBS-STN were evaluated under the following four conditions: without treatment (mof-sof), with stimulation (mof-son), with medication (mon-sof), and with both treatments (mon-son). A control group of 30 subjects was also evaluated. PCA was applied separately on each GRF component. Broken stick criterion selected eight principal components (PC) from vertical GRF and one from each horizontal GRF. A standard distance was calculated using these 10 PCs and the gait speed to measure how far the PD group's gait was from the normal pattern. RESULTS: The standard distance allowed classifying normal and PD subjects in the mof-sof condition with 100% accuracy, sensitivity, and specificity. The same distance was calculated for mon-sof, mof-son, and mon-son conditions. The smallest mean standard distance was found in the mon-son condition, which was significantly different from mof-sof (Friedman test with Dunn post-hoc, p < .05). CONCLUSION: PCA allowed the quantitative evaluation of treatment effects, indicating that DBS-STN improves the GRF pattern in PD subjects, primarily in the medication on state.

Utility of the NeuroTrax computerized battery for cognitive screening in Parkinson's disease: comparison with the MMSE and the MoCA.

To determine the utility of a computerized assessment in Parkinson's disease (PD), we compared the cognitive performance of 50 PD patients on the NeuroTrax computerized battery relative to the mini-mental state examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The results revealed fair agreement between impairment on the NeuroTrax and the MMSE (kappa=.291, p=.031) but only slight agreement between the NeuroTrax and the MoCA (kappa=.138, p = .054) and between the MoCA and the MMSE (kappa = .168, p = .069). The NeuroTrax identified 52% of the sample as average or above, 40% as below average, and 8% as impaired. The MoCA identified 54% of the sample as impaired (28% average or above and 18% below average), while the MMSE identified 66% as average or above (20% below average and 14% impaired). Several stepwise regressions revealed that executive and verbal functions were the best predictors of cognitive functioning on the NeuroTrax, while memory recall, serial sevens, naming, and abstraction were the best predictors on the MoCA. These results suggest that although the NeuroTrax may be useful in identifying executive cognitive deficits in PD, similar to the MMSE the NeuroTrax may lack optimal sensitivity. While the MoCA is sensitive, it may be too stringent in overclassifying PD patients as impaired.

Comparison among probabilistic neural network, support vector machine and logistic regression for evaluating the effect of subthalamic stimulation in Parkinson disease on ground reaction force during gait.

Deep brain stimulation of the subthalamic nucleus (DBS-STN) is an approved treatment for advanced Parkinson disease (PD) patients; however, there is a need to further evaluate its effect on gait. This study compares logistic regression (LR), probabilistic neural network (PNN) and support vector machine (SVM) classifiers for discriminating between normal and PD subjects in assessing the effects of DBS-STN on ground reaction force (GRF) with and without medication. Gait analysis of 45 subjects (30 normal and 15 PD subjects who underwent bilateral DBS-STN) was performed. PD subjects were assessed under four test conditions: without treatment (mof-sof), with stimulation alone (mof-son), with medication alone (mon-sof), and with medication and stimulation (mon-son). Principal component (PC) analysis was applied to the three components of GRF separately, where six PC scores from vertical, one from anterior-posterior and one from medial-lateral were chosen by the broken stick test. Stepwise LR analysis employed the first two and fifth vertical PC scores as input variables. Using the bootstrap approach to compare model performances for classifying GRF patterns from normal and untreated PD subjects, the first three and the fifth vertical PCs were attained as SVM input variables, while the same ones plus the first anterior-posterior were selected as PNN input variables. PNN performed better than LR and SVM according to area under the receiver operating characteristic curve and the negative likelihood ratio. When evaluating treatment effects, the classifiers indicated that DBS-STN alone was more effective than medication alone, but the greatest improvements occurred with both treatments together.

Assessment of the effects of subthalamic stimulation in Parkinson disease patients by artificial neural network.

This study aims at using a probabilistic neural network (PNN) for discriminating between normal and Parkinson disease (PD) subjects using as input the principal components (PCs) derived from vertical component of the ground reaction force (vGRF). The trained PNN was further used for evaluating the effects of deep brain stimulation of the subthalamic nucleus (STN DBS) on PD, with and without medication. A sample of 45 subjects (30 normal and 15 PD subjects who underwent STN DBS) was evaluated by gait analysis. PD subjects were assessed under four test conditions: without treatment (mof-sof), only with stimulation (mof-son) or medication (mon-sof), and with combined treatments (mon-son). PC analysis was applied on vGRF, where six PC scores were chosen by the broken stick test. Using a bootstrap approach for the PNN model, and the area under the receiver operating characteristic curve (AUC) as performance measurement, the first three and fifth PCs were selected as input variables. The PNN presented AUC = 0.995 for classifying controls and PD subjects in the mof-sof condition. When applied to classify the PD subjects under treatment, the PNN indicated that STN DBS alone is more effective than medication, and further vGRF enhancement is obtained with combined therapies.

Assessment of the effects of subthalamic stimulation in Parkinson disease patients by artificial neural network.

This study aims at applying an artificial neural network for the evaluation of the effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on Parkinson disease (PD) patients with and without medication. A sample of 15 PD patients who have undergone STN DBS were evaluated under four test conditions: medication off and stimulation off (mof-sof), medication off and stimulation on (mof-son), medication on and stimulation off (mon-sof) and medication on and stimulation on (mon-son). A control group with 30 subjects was also evaluated. Principal component analysis (PCA) was applied on vertical ground reaction force (vGRF) and the first six principal component scores (PC score) were obtained in both groups. Those PCs scores were used as input in a probabilistic neural network (PNN). PNN presented satisfactory classification performance in the separation of controls and PD with 90.1% accuracy, 69.2% sensitivity and 100% specificity. The stimulation mof-son and mon-son conditions presented better results compared to mon-sof. In the mof-son condition, 41.7% were classified as normal, while further enhancement (63.3%) was given by the mon-son condition. These results indicated the potentiality of PNN to quantitatively evaluate treatment effects. Furthermore, STN DBS shows improvement on vGRF pattern in PD patients, most substantially when used with medication.

Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease.

OBJECTIVE: To evaluate the efficacy of ropinirole 24-hour prolonged release (ropinirole 24-hour) as an adjunct to levodopa in patients with Parkinson disease (PD) and motor fluctuations. METHODS: In a double-blind, placebo-controlled, 24-week study, 393 subjects with PD were randomized to ropinirole 24-hour (n = 202) or placebo (n = 191). The primary outcome measure was reduction in hours of daily "off" time. RESULTS: At week 24, the mean dose of ropinirole 24-hour was 18.8 mg/day with a mean reduction in daily levodopa of 278 mg. There was a mean reduction in daily "off" time of 2.1 hours in the ropinirole 24-hour group and 0.3 hours with placebo. Secondary outcome measures including change in hours and percent of daily "on" time and "on" time without troublesome dyskinesia, Unified PD Rating Scale motor and activities of daily living subscales, Beck Depression Inventory-II, PDQ-39 subscales of mobility, activities of daily living, emotional well-being, stigma and communication, and PD Sleep Scale were significantly improved at week 24 with ropinirole 24-hour. The most common adverse events (AE) with ropinirole 24-hour were dyskinesia, nausea, dizziness, somnolence, hallucinations, and orthostatic hypotension and AEs led to study withdrawal in 5% of both the active and placebo groups. CONCLUSION: Ropinirole 24-hour was effective and well tolerated as adjunct therapy in patients with Parkinson disease (PD) not optimally controlled with levodopa. Ropinirole 24-hour demonstrated an improvement in both motor and non-motor PD symptoms, while permitting a reduction in adjunctive levodopa dose.

Neuropathologic findings in essential tremor.

Pathologic findings, including cerebellar changes and brainstem Lewy bodies, distinguished 10 essential tremor (ET) cases from 12 controls. Numbers of torpedoes (p = 0.009) and Bergmann glia (p = 0.046) were increased in cases. Six cases (60%) had Lewy bodies vs 2 controls (16.7%) (odds ratio 7.5, 95% CI 1.04 to 54.1; p = 0.035). Four of these six had an atypical distribution of brainstem Lewy bodies. ET may be pathologically heterogeneous.

Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To make evidence-based treatment recommendations for the medical and surgical treatment of patients with Parkinson disease (PD) with levodopa-induced motor fluctuations and dyskinesia. To that end, five questions were addressed. 1. Which medications reduce off time? 2. What is the relative efficacy of medications in reducing off time? 3. Which medications reduce dyskinesia? 4. Does deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus interna (GPi), or ventral intermediate (VIM) nucleus of the thalamus reduce off time, dyskinesia, and antiparkinsonian medication usage and improve motor function? 5. Which factors predict improvement after DBS? METHODS: A 10-member committee including movement disorder specialists and general neurologists evaluated the available evidence based on a structured literature review including MEDLINE, EMBASE, and Ovid databases from 1965 through June 2004. RESULTS, CONCLUSIONS, AND RECOMMENDATIONS: 1. Entacapone and rasagiline should be offered to reduce off time (Level A). Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B). Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level C). 2. The available evidence does not establish superiority of one medicine over another in reducing off time (Level B). Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C). 3. Amantadine may be considered to reduce dyskinesia (Level C). 4. Deep brain stimulation of the STN may be considered to improve motor function and reduce off time, dyskinesia, and medication usage (Level C). There is insufficient evidence to support or refute the efficacy of DBS of the GPi or VIM nucleus of the thalamus in reducing off time, dyskinesia, or medication usage, or to improve motor function. 5. Preoperative response to levodopa predicts better outcome after DBS of the STN (Level B).

Topiramate in essential tremor: a double-blind, placebo-controlled trial.

BACKGROUND: Essential tremor is most prevalent and most disabling in older patients. Additional therapies are required for patients with an inadequate response or intolerable side effects. In small trials, topiramate appeared to be beneficial in essential tremor. METHODS: In this multicenter, double-blind, placebo-controlled, parallel-design trial, patients with moderate to severe essential tremor of the upper limbs were randomized to 24 weeks of treatment with placebo or topiramate (target dose, 400 mg/day) as monotherapy or as an adjunct to one antitremor medication. The primary efficacy variable was the final visit tremor score based on the Fahn-Tolosa-Marin Tremor Rating Scale (TRS). RESULTS: The intent-to-treat population was 208 patients (topiramate, 108; placebo, 100). The final visit score (last observation carried forward) was lower in the topiramate group than with placebo (p < 0.001). Mean percentage improvement in overall TRS scores was 29% with topiramate at a mean final dose of 292 mg/day and 16% with placebo (p < 0.001). Topiramate was associated with greater improvement in function and disability (p = 0.001). A between-group difference (p < 0.001) was observed at the first on-treatment visit at 4 weeks when the target topiramate dose was 100 mg/day (mean achieved dose, 62 +/- 9 mg/day). The most common treatment-limiting adverse events in topiramate-treated patients were paresthesia (5%), nausea (3%), concentration/attention difficulty (3%), and somnolence (3%). Adverse events were treatment limiting in 31.9% of topiramate patients and 9.5% of placebo patients. CONCLUSIONS: Topiramate was effective in the treatment of moderate to severe essential tremor. Tremor reduction was accompanied by functional improvements, such as in motor tasks, writing, and speaking.

Bilateral subthalamic stimulation improves gait initiation in patients with Parkinson's disease.

Impaired gait initiation is one of the typical sign of advanced Parkinson's disease (PD). This is the first study to examine quantitatively the effect of deep brain stimulation of the subthalamic nucleus on the performance of gait initiation for patients with advanced PD. A total of 11 patients after surgery of bilateral deep brain stimulation of the subthalamic nucleus (STN) were tested in both the deep brain stimulation (DBS) ON and OFF conditions and/or in both the medication ON (i.e., with the usual dosage of antiparkinsonian medications administered) and OFF (i.e., with the usual dosage of antiparkinsonian medications withheld) conditions. DBS had no effect on the onset of anticipatory postural adjustment (APA). The effect of DBS approached significant level for the onset of swing foot lifting, but reached significant level for the delay of swing foot lifting. DBS significantly increased the amplitude of the APA, amplitude of reactive shear forces on both feet, and amplitude of COP in both anterior-posterior and medial-lateral directions. It is concluded that DBS significantly improved the performance of patients with advanced PD in gait initiation.

Quantitative assessments of the effect of bilateral subthalamic stimulation on multiple aspects of sensorimotor function for patients with Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective for the treatment of advanced Parkinson's disease. Most studies have evaluated the effectiveness of DBS of the STN using clinical motor scores or simple timed tests of motor function. There have been few studies that quantitatively assessed the outcome of STN DBS using multiple testing paradigms. In the current study, 11 patients who had bilateral STN DBS were quantitatively evaluated under four conditions using gait, postural control, and gait initiation. The four conditions included the medication on/stimulation on (M_on/S_on), medication on/stimulation off (M_on/S_off), medication off/stimulation on (M_off/S_on), and medication off/stimulation off (M_off/S_off) conditions. DBS of the STN significantly increased walking speed with and without levodopa, but had no influence on the cadence. The addition of levodopa had a minimal additional effect on walking speed. The effect of STN DBS on gait initiation approached the significant level. The mean values of lateral body sway during quiet standing increased moderately with medication and/or DBS, but the changes were not statistically significant. Future studies need to determine whether or not there is a potential negative effect of STN DBS on the postural control.

Development and initial validation of a screening tool for Parkinson disease surgical candidates.

As there is currently no standardized assessment tool for evaluating Parkinson disease (PD) patients for deep brain stimulation (DBS), the authors developed the Florida Surgical Questionnaire for Parkinson Disease (FLASQ-PD). Part I of the study was a retrospective analysis of 174 patients presenting for a surgical screening. Part II was a multicenter study to assess the correlation of FLASQ-PD scores. The results of this study suggest that the FLASQ-PD may be a useful triage tool for screening PD patients for DBS surgery.