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Little is known about the anatomical progression over the body segments of extrapyramidal signs in Parkinson's disease (PD); furthermore a great unmet need is the availability of instruments able to detect disease progression, even in the early phase. The purpose of this study is to demonstrate that assessing topographical distribution of the cardinal motor features of PD may significantly improve the evaluation of disease progression in the early stages. Forty-four drug-naïve PD patients were included in the study. Presence or absence of bradykinesia, rest tremor and rigidity was derived from Unified Parkinson's disease rating scale part III (UPDRS-III) in five different anatomical segments: axial, right and left upper- and lower-limbs. Based on this approach, four new scores were computed evaluating the anatomical spread of the cardinal motor symptoms of PD on the five body segments over a 18-month follow-up period. The four new scores included: the Bradykinesia Segmental Score, the Tremor Segmental Score, the Rigidity Segmental Score, measuring the occurrence of each motor symptom in different segments and the Combined Segmental Score evaluating the occurrence of any motor symptom in different anatomical regions. Data were analyzed using a repeated measures analysis of variance. The Combined Segmental Score showed a significant progression over time whereas the Hoehn and Yahr and the UPDRS-III scores did not. We suggest that a simple approach evaluating the anatomical distribution of motor symptoms and their progression over the body segments may be a useful complement to the classical rating tools to assess progression in early PD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson's disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naïve PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the χ (2) exact test; multiple comparisons were corrected with the Benjamini-Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naïve PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients.

Background: The variability in the clinical phenotype of Parkinson's disease seems to suggest the existence of several subtypes of the disease. To test this hypothesis we performed a cluster analysis using data assessing both motor and non-motor symptoms in a large cohort of newly diagnosed untreated PD patients., Methods: We collected data on demographic, motor, and the whole complex of non-motor symptoms from 100 consecutive newly diagnosed untreated outpatients. Statistical cluster analysis allowed the identification of different subgroups, which have been subsequently explored., Results: The data driven approach identified four distinct groups of patients, we have labeled: 1) Benign Pure Motor; 2) Benign mixed Motor-Non-Motor; 3) Non-Motor Dominant; and 4) Motor Dominant., Conclusion: Our results confirmed the existence of different subgroups of early PD patients. Cluster analysis revealed the presence of distinct subtypes of patients profiled according to the relevance of both motor and non-motor symptoms. Identification of such subtypes may have important implications for generating pathogenetic hypotheses and therapeutic strategies.

Much pre-clinical evidence show that insulin-like growth factor 1 (IGF-1) provides protection against loss of dopaminergic neurons. Recently, IGF-1 has been proposed as a possible biomarker for early diagnosis of Parkinson's disease (PD). We aimed to assess the relationship between serum IGF-1 levels and progression of motor symptoms in a cohort of drug-naïve PD patients. Serum IGF-1 was measured at baseline in 37 early, drug-naive PD patients; subsequently, patients were evaluated "on drug" by means of UPDRS-III, UPDRS dopa-resistant score and dopaminergic score at 12, 18 and 24 month follow-up. Repeated measures ANOVA was used both to evaluate progression of motor scores within time and differences between serum IGF-1 quartiles, age at onset and motor phenotype. Patients at the highest IGF-1 quartile were found to have significantly higher UPDRS-III (p < 0.001) and dopaminergic score (p < 0.001), as compared to patients at other quartiles. Mean serum IGF-1 level was moderately increased in PD as compared to healthy controls (p < 0.011). IGF-1 levels are related to those symptoms predominantly responsive to dopaminergic treatment. This is the first study to demonstrate a relationship between serum IGF-1 and progression of motor symptoms in the early stage of disease.

Epidermal growth factor (EGF) has been proposed as a candidate biomarker for cognitive impairment in Parkinson's disease (PD). We aimed to assess the relationship between serum EGF and cognitive functions in early, drug-naive PD patients and evaluate the predictive value of EGF on cognitive functions in a 2-year follow-up study. Serum EGF was measured in 65 early, drug-naive PD patients, that underwent a comprehensive neuropsychological battery. Motor symptoms were assessed by means of the Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III). Neuropsychological evaluation was repeated after 2 years. Spearman's rank correlation was used to assess the relationship between serum EGF levels and neuropsychological variables. Linear regression analysis was used to evaluate the relationship between EGF and neuropsychological scores as well as other variables (age, gender, UPDRS-III, levodopa equivalent dose, and type of treatment at follow-up) potentially affecting cognitive performance. Variation over time in cognitive scores was analyzed using repeated-measures ANOVA. At baseline, EGF was the only significant variable associated with performance on semantic fluency (R (2) = 0.131; p = 0.005). EGF levels (p = 0.025), together with UPDRS-III (p = 0.009) and age (p = 0.011), were associated with performance on frontal assessment battery (R (2) = 0.260). At 2-year follow-up, EGF was the only significant variable to predict performance on semantic fluency (R (2) = 0.147; p = 0.025) and color naming task of Stroop color-word test (R (2) = 0.121; p = 0.044). Serum EGF levels are related to frontal and temporal cognitive functions in early, drug-naive PD patients and predict performance on frontal and posterior cognitive functions at 2-year follow-up. EGF is proposed as a potential serum biomarker for early cognitive impairment in PD.

Background: A relation between the side of motor onset and cognitive impairment in early PD has been reported, suggesting that the asymmetric degeneration affecting subcortical regions may play a pivotal role in lateralized cognitive function. However, evidences are controversial and all previous studies were performed on treated patients, though it is known that dopaminergic therapy can affect cognition in PD., Methods: Sixty-nine early untreated PD patients underwent an extensive neuropsychological battery exploring memory, visuospatial and attention/executive functions. Patients were divided with respect of the side of onset (right vs. left) and further grouped according to motor phenotype (tremor vs. rigidity-bradykinesia). Multivariate analysis of variance has been carried out to compare clinical and neuropsychological data between subgroups., Results: There were no differences in any neuropsychological task between right-sided and left-sided onset subgroups, irrespective of tremor dominant or rigid-bradykinetic phenotype. Age at onset was significantly higher in patients with any cognitive impairment as compared with patients without (66.7 ± 3.2 vs. 56.3 ± 6.8 years, p = 0.001)., Conclusion: Side of motor onset is not a major determinant for developing lateralized cognitive deficits in newly diagnosed untreated PD patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Non-motor symptoms are very common among patients with Parkinson's disease since the earliest stage, but little is known about their progression and their relationship with dopaminergic replacement therapy., Methods: We studied non-motor symptoms before and after 2 years from dopaminergic therapy introduction in ninety-one newly diagnosed previously untreated PD patients., Results: At baseline, nearly all patients (97.8%) referred at least one non-motor symptom. At follow-up, only few non-motor symptoms significantly changed. Particularly, depression and concentration became less frequent, while weight change significantly increased after introduction of dopamine agonists., Conclusions: We reported for the first time a 2-year prospective study on non-motor symptoms before and after starting therapy in newly diagnosed PD patients. Even if non-motor symptoms are very frequent in early stage, they tend to remain stable during the early phase of disease, being only few non-motor symptoms affected from dopaminergic therapy and, specifically, by the use of dopamine agonists.

Background: Anxiety is a common non-motor symptom among patients with Parkinson's disease (PD). Although the etiology of anxiety in PD is likely to be multifactorial, a dysfunction in the dopaminergic system might be implicated in its pathogenesis. The aim of our study was to investigate a possible dopaminergic mechanism involved in anxiety in newly diagnosed never-medicated PD patients using SPECT and ¹²³I-FP-CIT as the dopamine transporter ligand., Methods: Thirty-four newly diagnosed, untreated PD patients with asymmetric motor symptoms were included in the study: 17 patients with right- and 17 with left-motor onset, matched for age, disease duration and motor disability constituted the group. They were all evaluated for anxiety and depression and underwent an SPECT with ¹²³I-FP-CIT. Dopamine transporter (DAT) availability values for right and left caudate and putamen were calculated and compared between patients with and without anxiety. Regression analyses were also performed in order to correlate DAT availability with the severity of the anxiety symptoms., Results: Comparison between PD patients with and those without anxiety revealed significant differences of DAT availability in all the examined regions except the right putamen. In the group of patients considered as a whole, a significant correlation was found between increased anxiety severity and decreased DAT availability in right caudate., Conclusions: We reported an association between nigrostriatal DAT availability deficits and anxiety symptoms in newly diagnosed, untreated PD patients. Our results suggest that hypofunction of the nigrostriatal dopaminergic system may represent one of the functional anomalies involved in anxiety in PD from the earliest stages of disease and irrespective of any therapy., (© 2012 Elsevier Ltd. All rights reserved.)

The objective of this study was to evaluate hearing impairment in patients affected by Parkinson's disease compared with hearing scores observed in normal age- and sex-matched controls. One hundred eighteen consecutive patients with a clinical diagnosis of Parkinson's disease were screened. Severity of motor symptoms and staging were measured with the Unified Parkinson's Disease Rating Scale (section III) and the Hoehn and Yahr scale. Audiometric evaluation consisted of a comprehensive audiologic case history and questionnaire, visual otoscopic examination, acoustic immittance measures (tympanogram and acoustic reflexes), pure tone audiometry, and measurement of brain stem auditory-evoked potentials. Healthy age- and sex-matched subjects were selected as the control group. One hundred six of 118 patients were enrolled. Pure tone audiometry revealed age-dependent high-frequency hearing loss in patients with Parkinson's disease compared with both normative values and values for healthy age- and sex-matched controls (75/106 [71%], χ(2) = 5.959, P = .02; 92/106 [86.8%] vs 60/106 [56.6%], χ(2) = 23.804, P < .001, respectively). Pure tone audiometry scores correlated with Hoehn and Yahr scale scores (P < .05). Brain stem auditory-evoked potentials were normal in all patients. Our patients with Parkinson's disease showed age-dependent peripheral, unilateral, or bilateral hearing impairment. Whether these auditory deficits are intrinsic to Parkinson's disease or secondary to a more complex impaired processing of sensorial inputs occurring over the course of illness remains to be determined. Because α-synuclein is located predominately in the efferent neuronal system within the inner ear, it could affect susceptibility to noise-induced hearing loss or presbycusis. It is feasible that the natural aging process combined with neurodegenerative changes intrinsic to Parkinson's disease might interfere with cochlear transduction mechanisms, thus anticipating presbycusis., (Copyright © 2012 Movement Disorder Society.)

Little is known about the relationship between cognitive dysfunctions and the non-motor complex in subjects with newly diagnosed untreated Parkinson's disease (PD). The aim of this study was to explore the association between non-motor symptoms (NMS) and cognitive dysfunctions in an incident cohort of de novo, drug-naive, PD patients. Sixty-six non-demented, early, untreated PD patients completed a semi-structured interview on NMS and a battery of neuropsychological tests that assess verbal memory, visuospatial abilities, and attention/executive functions. Scores were age- and education-corrected. Patients who failed at least two tests for each cognitive domain were diagnosed as having mild cognitive impairment (MCI). All but three (95.4%) PD patients complained of at least one NMS. A total of 37.8% was diagnosed with MCI. There was a relationship between sleep-NMS and cognitive dysfunctions. Specifically, both REM behavioral sleep disorders (RBD) and insomnia were associated with lower scores on several cognitive tests. Moreover, RBD was closely related to MCI. NMS and MCI are very common even in the early phase of PD, before patients are treated. Given the correlation between sleep disturbances and cognitive impairment, it is possible that sleep symptoms in PD patients might be considered as an early marker of dementia.

Objective: To characterize brain metabolic changes associated with mild cognitive impairment (MCI) in drug-naive patients with Parkinson disease (PD) using (18)F-fluorodeoxyglucose (FDG) and PET (FDG-PET)., Methods: This cross-sectional study included newly diagnosed patients with PD with MCI in single or multiple domain (PD-MCI; n =12) and without MCI (PD-nMCI; n =12), and healthy controls (n =12). The groups were matched for age. Moreover, the patient groups were matched for motor disability. All subjects underwent a FDG-PET study. Cerebral regional relative metabolic maps were compared in PD-MCI, PD-nMCI, and controls using regions of interest analysis (ROIs) and voxel-based analysis with statistical parametric mapping., Results: ROIs and voxel-based analyses revealed significant relative hypometabolism in the prefrontal, superior/inferior parietal, and associative occipital cortices as well as in the striatum in patients with PD-MCI relative to controls (p < 0.05) and to a lesser extent in patients with PD-nMCI. In contrast, patients with PD-nMCI did not show significant metabolic changes as compared to controls., Conclusion: MCI in patients with PD is associated with cortical hypometabolism since the earliest stage, independent of therapy or motor disability. The early involvement of posterior cortical region, a pattern shared by advanced stages of PD-MCI and PD with dementia, could represent an early marker of dementia. The relevance of this pattern in predicting prodromal dementia has to be evaluated in longitudinal studies.

The "eye of the tiger" is a neuroradiologic sign due to iron deposition in the globus pallidus: it appears as diffuse low signal intensity with a central area of high signal intensity confined to the globus pallidus. The "eye of the tiger" sign has been associated with neurodegeneration with brain iron accumulation type 1 (NBIA1), a condition caused by mutations in the gene encoding pantothenate kinase 2 (PANK2). However, the specificity of this neuroradiologic sign has been already challenged and it has been described in other neurodegenerative diseases. Here, we report the first case of a patient suffering from pure akinesia with gait freezing with the "eye of the tiger" sign in T2-weighted MRI sequences. All clinical, laboratory and radiologic data excluded other diagnosis and genetic testing excluded PANK2 mutations suggesting that the "eye of the tiger" is not specific for NBIA1 and may also occur in other movement disorders.

Lateral trunk flexion is a very common clinical observation in patients affected by Parkinson's disease. Postural control is known to depend on vestibular, visual, and somatosensory information. The aim of this study was to investigate whether impairment of vestibular function can account for the postural alterations observed in parkinsonian patients with lateral trunk flexion. We evaluated vestibular function in 11 parkinsonian patients with lateral trunk flexion and in 11 age-, sex-, and disease duration-matched patients without lateral trunk flexion. The following vestibular tests were performed: infrared videonystagmography including fast and slow ocular movements, spontaneous-positional and evoked nystagmus search with and without visual fixation, fast positioning maneuvers, the bithermal caloric test, and the vibration test. A peripheral, unilateral vestibular hypofunction was identified in all patients with lateral trunk flexion. The vestibular hypofunction was ipsilateral to the leaning side and contralateral to the most affected parkinsonian side in all patients. In the control group, 7 subjects had no vestibular signs; 4 subjects had unilateral vestibular hypofunction without clinically evident lateral trunk flexion. Two of the latter patients subsequently developed lateral trunk flexion ipsilateral to the vestibular deficit and contralateral to the side most affected by Parkinson's disease. The processing of vestibular information was impaired in parkinsonian patients affected by lateral trunk flexion. The impairment was at least in part responsible for the patients' postural abnormality. We propose that the acronym PISA (Postural Imbalance Syndrome with vestibular Alterations) be used to describe the specific postural change observed in parkinsonian patients affected by a vestibular defect and lateral trunk flexion., (Copyright © 2011 Movement Disorder Society.)

Diffusion-weighted imaging has been largely used to detect and quantify early degenerative changes in patients with multiple system atrophy, but progression of neurodegeneration has been poorly investigated. We performed a serial diffusion-weighted imaging study in a population of multiple system atrophy patients and analyzed the evolution of diffusion properties in striatal and extrastriatal brain regions. Diffusion-weighted imaging was obtained in 11 multiple system atrophy patients at baseline and after a follow-up of 11.7 ± 1.2 months, and Trace (D) changes in different brain regions were correlated with disease duration and severity. A significant increase in Trace (D) was observed at follow-up in the putamen (P < .001), pons (P = .003), cerebellar white matter (P = .03), thalamus (P = .013), and frontal white matter (P = .021). Both Unified Multiple System Atrophy Rating Scale Part II and Unified Parkinson's Disease Rating Scale Part III scores significantly increased at follow-up (P = .003), but percent changes of Unified Parkinson's Disease Rating Scale Part III and Unified Multiple System Atrophy Rating Scale Part II did not correlate with percent changes of Trace (D) values in any brain region. This longitudinal study provides new insights into the progression of neurodegeneration in different brain regions in multiple system atrophy. Our results confirm that abnormal diffusivity in the putamen is sensitive to change over time in multiple system atrophy patients and show for the first time a progression of Trace (D) alterations in specific extrastriatal regions. Diffusivity changes in these regions may be useful for monitoring disease progression even after a short follow-up period. © 2011 Movement Disorder Society., (Copyright © 2011 Movement Disorder Society.)

Insulin-like growth factors (IGF-I and IGF-II) have been shown to have several neurotrophic actions and IGF system may be impaired in neurodegenerative disorders. The aim of this study was to investigate the IGF system in patients with MSA and to evaluate correlations between this endocrine system and clinical features of the disease. Serum levels of IGF-I, IGF-II, insulin, IGF-binding protein 1 (BP1), and IGF-binding protein 3 (BP3) were measured in 25 patients with probable MSA and 25 age, sex and BMI-matched healthy controls. Clinical status of each patient was evaluated with the Unified Multiple System Atrophy Rating Scale (UMSARS) Part II and the Hoehn and Yahr rating scale. IGF-I levels were significantly higher in MSA (164.1 + 66.2 μg/L) than in healthy controls (111.7 + 60.3 μg/L; p = 0.001). Insulin levels were significantly higher in MSA patients (21.9 ± 14.4 μU/mL) than in healthy controls (13.3 ± 5.1 μU/mL, p = 0.048). No significant difference was found in serum IGF-II, IGF-BP1, and IGF- BP3 levels between patients with MSA and healthy controls. There was a trend toward significantly higher IGF-II levels in MSA patients with UMSARS score <26 (1026.3 ± 442.6 μg/L) than MSA patients with UMSARS score >26 (796.1 ± 234 μg/L, p = 0.055). The results of this study demonstrated that IGF system is altered in MSA. The degenerative process in MSA could lead to a compensatory increase in IGF-I and insulin in an attempt to provide additional support to degenerating neurons., (© 2010 Movement Disorder Society.)

Background and Purpose: The growth hormone (GH) and insulin-like growth factor (IGF) system may be involved in neurodegenerative processes, and some abnormalities have been reported in amyotrophic lateral sclerosis (ALS). Our aim was to investigate the GH-IGF axis in patients with ALS and evaluate correlations between this endocrine system and clinical features., Methods: Serum levels of GH, IGF-I, IGF-II, insulin, IGF-binding protein 1 (IGF-BP1), and IGF-binding protein 3 (IGF-BP3) were measured in 25 patients with ALS and 25 age-, gender-, and BMI-matched healthy controls. A GHRH plus arginine test was performed in patients and controls. Clinical status of patients was evaluated with the ALS Functional Rating Scale - Revised (ALSFRS-R) and upper motor neuron (UMN) score., Results: GHRH plus arginine test showed GH deficiency (GHD) in 13 (52%) patients with ALS; severe GHD was found in 6 (24%) and partial GHD in 7 (28%) patients. IGF-I levels were significantly higher in patients with ALS than in healthy controls (182.9 +/- 90.8 vs. 139.4 +/- 58.1 ng/ml; P = 0.015). IGF-I levels were higher in patients with ALS with UMN score >10 than those with UMN score <10 (217.8 +/- 100.8 vs. 155.5 +/- 74.6 ng/ml, P = 0.05). IGF-II levels were significantly lower in patients with ALS than in healthy controls (720.9 +/- 215 vs. 1001.9 +/- 475.4 ng/ml; P = 0.03)., Conclusions: The results demonstrate an impairment of the GH-IGFs system in ALS. The degenerative process in ALS might lead to a compensatory increase in IGF-I in an attempt to provide additional support to motor neurons or degenerating muscle fibers. The decrease in IGF-II levels may also be of pathological significance.

The objective of the study is to evaluate the effect of the daily variation in concentrations of fine particulate matter (diameter less than 2.5 microm--PM2.5) resulting from the burning of biomass on the daily number of hospitalizations of children and elderly people for respiratory diseases, in Alta Floresta and Tangará da Serra in the Brazilian Amazon in 2005. This is an ecological time series study that uses data on daily number of hospitalizations of children and the elderly for respiratory diseases, and estimated concentration of PM2.5. In Alta Floresta, the percentage increases in the relative risk (%RR) of hospitalization for respiratory diseases in children were significant for the whole year and for the dry season with 3-4 day lags. In the dry season these measurements reach 6% (95%CI: 1.4-10.8). The associations were significant for moving averages of 3-5 days. The %RR for the elderly was significant for the current day of the drought, with a 6.8% increase (95%CI: 0.5-13.5) for each additional 10 microg/m3 of PM2.5. No associations were verified for Tangará da Serra. The PM2.5 from the burning of biomass increased hospitalizations for respiratory diseases in children and the elderly.

Hyperhomocysteinaemia was reported in patients with Parkinson's disease (PD) treated with l-Dopa. The increase in plasma concentration of this sulfur compound arises from the massive methylation of the drug operated by the enzyme catechol-O-methyltransferase (COMT), which acts as a powerful sink of methyl groups. The contemporary occurrence of C677T polymorphism in homozygosity, leading to a temperature-labile variant of the MTHFR enzyme, induces an even more marked increase in tHcy. Here we show that l-Dopa administration in hyperhomocysteinemic PD patients is able to lower intracellular concentration of S-Adenosylmethionine (AdoMet) in erythrocytes (RBC), while the occurrence of hyperhomocysteinaemia causes a significant increase in S-Adenosylhomocysteine (AdoHcy) level. In patients with PD treated with l-Dopa and hyperhomocysteinemic, the remarkable decrease in AdoMet and the concurrent increase in AdoHcy concentration both contribute to significantly lower the transmethylation potential ([AdoMet]/[AdoHcy]), a useful index of the effectiveness of methyl group transfer by methyltransferases. This decrease could indeed contribute to partly attenuate, through a self-limiting kinetic mechanism, the tendency of developing drug resistance, partly mediated in these patients by COMT upregulation. Our results also support the conclusion that COMT inhibitors (entacapone or tolcapone), when administered in PD patients treated with l-Dopa, may potentiate the endogenous AdoHcy-dependent COMT inhibition mechanism already operative in a variable fashion., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Objective: Antiparkinsonian pharmacotherapy is costly and the determinants of drug costs in Parkinson's disease (PD) have been poorly investigated. The objective of this study was to investigate the costs of PD and antiparkinsonian drugs in an Italian cohort of patients and identify cost-driving factors of drug therapy., Methods: Seventy outpatients with idiopathic PD were recruited in the Department of Neurology, Napoli University, Italy. Data on resource utilization were collected for 6 months using a bottom-up approach. Clinical status was evaluated using the Unified Parkinson's Disease Rating Scale. Direct and indirect costs were calculated from the societal perspective (figures of year 2009). Independent determinants of total costs and costs of antiparkinsonian drugs were identified using multivariate regression analysis., Results: The total costs of PD were EUR 8,640 (95% CI: EUR 6,700-11,240) per patient over a 6-month period. Direct costs accounted for 70% of the total costs. Antiparkinsonian drugs (EUR 1,450; 95% CI: EUR 1,220-1,760) were the primary component of costs paid by the health insurance (39.6%) and one of the most expensive components of the direct costs (24.0%). The highest copayments made by patients were for antiparkinsonian drugs and medical equipment (58%). Independent determinants of the increased costs of antiparkinsonian pharmacotherapy were younger age and occurrence of motor fluctuations., Conclusions: Antiparkinsonian pharmacotherapy is one of the major cost components of PD-related costs for health insurance. It imposes a considerable economic burden on patients and their families as well., (Copyright © 2010 S. Karger AG, Basel.)

Multiple system atrophy can be classified into two main types, a Parkinsonian (MSA-P) and a cerebellar (MSA-C) variant based on clinical presentation. We obtained diffusion-weighted magnetic resonance imaging (DWI) in 9 MSA-P and 12 MSA-C patients and 11 controls, and correlated DWI changes with disease duration and severity. We found that Trace (D) values in the entire and anterior putamen were significantly higher in MSA-P than in MSA-C patients and controls, whereas Trace (D) values in the cerebellum and middle cerebellar peduncle (MCP) were significantly higher in MSA-C than in MSA-P patients and controls. Increased disease duration was significantly correlated with increased Trace (D) values in pons of MSA-P patients, and in cerebellum and MCP of MSA-C patients. Both UMSARS and UPDRS motor scores positively correlated with entire and posterior putaminal Trace (D) values in MSA-P patients. The diffusivity changes parallel phenotypical and pathologic differences between MSA-P and MSA-C patients, suggesting that DWI is a feasible tool for in vivo evaluation of neurodegeneration in MSA. Based on our findings, Trace (D) measurements in the putamen and pons in MSA-P patients and in the cerebellum and MCP in MSA-C patients could serve as quantitative markers for microstructural damage in the course of disease.

To explore the relationship between depression and cognitive impairment in non-demented PD patients, we evaluated neurological and neuropsychological asset in 65 patients with a diagnosis of major depressive disorder (dPD) according to DSM-IV criteria and 60 patients without depression (nPD). Compared with nPD patients, dPD patients had significantly higher scores on behavioral rating scales and performed worse on the Frontal Assessment Battery (FAB), Semantic Fluency Task, Copying Task (CT), and Stroop Test. Three dPD subgroups were identified based on the first two DSM-IV criteria: patients fulfilling criterion 1 (depressed mood; group 1); patients fulfilling criterion 2 (apathy/anhedonia; group 2); patients fulfilling criteria 1 and 2 (group 3). Patients of group 2 scored significantly lower than patients of group 1 on the CT, FAB and phonological fluency task. Patients of groups 2 and 3 scored significantly lower than nPD patients on visuoconstructional and frontal tasks. Similar results were obtained in dPD patients stratified in four subgroups based on cut-off scores of the Apathy Evaluation Scale and the Snaith Hamilton Pleasure Scale. In summary, PD patients with concomitant apathy and anhedonia may show more severe cognitive impairments. Since such patients are diagnosed to be affected by depression according to clinical DSM-IV criteria, we suggest that DSM-IV criteria may not distinguish an affective from a cognitive disorder in PD.

Freezing of gait (FOG) is a frequent, disabling symptom of Parkinson's disease (PD). FOG usually lasts a few seconds. It refers to brief paroxysmal events during which a subject is unable to start or continue locomotion. Despite its frequency, FOG pathophysiology is unclear. Because a frontal lobe dysfunction or a disconnection between the frontal lobe and basal ganglia has been implicated in FOG, we explored frontal functions in PD patients using neuropsychological tests. Thirteen early-stage PD patients [Hoehn & Yahr score (H&Y) < or = 2.5] with freezing during "on " state (FOG+), and 15 age-, H&Y score-, and disease-duration-matched PD patients without freezing (FOG-) were investigated. No patient was demented or depressed. Assessment included the Unified Parkinson's Disease Rating Scale (UPDRS), FOG questionnaire, Mini Mental State Examination (MMSE), frontal assessment battery (FAB), phonemic verbal fluency, Stroop test (parts II and III), and ten-point clock test (TPCT). UPDRS and MMSE scores did not differ between the two groups. FAB, verbal fluency, and TPCT scores were significantly lower in FOG+ patients than in FOG- patients (FAB: P = 0.008; phonemic verbal fluency: P = 0.011; TPCT: P = 0.024). FOG correlated with lower scores at frontal tests in patients with early-stage PD., (2007 Movement Disorder Society)

The arginine growth hormone (GH) stimulation test differentiates the Parkinsonian variant of multiple system atrophy (MSA-P) from idiopathic Parkinson's disease (PD). Our aim was to evaluate the accuracy of the arginine GH stimulation test in distinguishing between PSP, MSA-P, and PD. We measured the GH response to arginine in serum samples of 26 MSA-P, 23 PSP, and 26 PD patients, and in 80 healthy controls. We used ANOVA followed by the Bonferroni test to compare GH values and peaks among groups. We used receiver operating characteristic curve analysis to establish the arginine cut-off level that best differentiated between MSA-P, PSP, and PD. The GH peak was significantly lower (P < 0.01) in MSA-P (1.46 +/- 0.29 microg/L) than in both PD (8.74 +/- 0.98 microg/L) and PSP (6.64 +/- 0.82 microg/L) patients, and controls (8.59 +/- 0.44 microg/L). Growth hormone peaked later in PSP patients than in PD patients and controls. At a cut-off level of 4 microg/L, arginine test distinguished MSA-P from PD with a sensitivity of 92% and a specificity of 96%, and MSA-P from PSP with a sensitivity of 78% and a specificity of 96%. The GH response to arginine differentiates MSA-P from PD and PSP with a good diagnostic accuracy. The neuroendocrine response to arginine of PSP patients differed from that of MSA-P patients, but was not identical to that of normal controls and PD patients. Our results suggest that the impairment of the central mechanisms modulating GH release differs between PSP and MSA-P., (2007 Movement Disorder Society)

We evaluated tolerability and the efficacy of continuous infusion of apomorphine hydrochloride on involuntary movements and mood disorder in Huntington's disease (HD) patients in a pilot, single center, double-blind, randomized, crossover, and controlled versus placebo study. Nine patients with a molecular diagnosis of HD were screened for response to acute apomorphine injection. Four of them, not ameliorating at the acute test, were discontinued. Five patients, responding to acute apomorphine, received continuous infusion of either apomorphine or placebo for 5 days. After 2 days of washout, the alternative treatment was administered. Primary endpoint measures were scores of the Unified Huntington's Disease Rating Scale (UHDRS "motor section") and of the Abnormal Involuntary Movement Scale (AIMS). Secondary endpoint measures were the Hamilton Depression Rating Scale (HAD) score and safety parameters. Both UHDRS and AIMS scores significantly decreased in all patients after apomorphine. The beneficial effect of apomorphine was recorded throughout the 5 treatment days. The HAD score did not change after infusion of either treatment. No serious adverse events were reported by either group during the study. Our results suggest that continuous infusion of apomorphine might be considered for the treatment of involuntary movements in some HD patients., (2007 Movement Disorder Society)

Spastic paraplegia type 4 is caused by mutations in the gene that encodes spastin (SPG4), a member of the AAA protein family. A cohort of 34 unrelated Italian patients with pure spastic paraplegia, of which 18 displayed autosomal dominant inheritance and 16 were apparently sporadic, were screened for mutations in the SPG4 gene by denaturing high performance liquid chromatography. We identified a previously reported mutation in a sporadic patient with pure hereditary spastic paraplegia. We also identified eight unrelated patients with pure autosomal dominant hereditary spastic paraplegia carrying five novel mutations in the SPG4 gene (one missense mutation, c.1304 C>T; one nonsense mutation, c.807C>A; two frameshift mutations, c.1281dupT, c.1514&#95;1515insATA; and one splicing mutation, c.1322-2A>C). The frequency for SPG4 mutations detected in autosomal dominant hereditary spastic paraplegia was 44.4%. This study contributes to expand the spectrum of SPG4 mutations in Italian population.

Objective: Restless legs syndrome (RLS) is a common neurologic condition characterized by uncomfortable and unpleasant sensations in the legs, occurring primarily at rest, which are usually worse in the evening and are alleviated by movement. RLS is present in 20-40% of patients with renal failure. This study was a 14-week open, randomized, crossover trial of ropinirole vs. levodopa sustained release (SR) in 11 patients with RLS on chronic hemodialysis., Methods: Eleven patients (7 men, 4 women) were enrolled in the study. They received either levodopa SR or ropinirole for 6 weeks, followed by a washout week, then the alternate treatment for 6 weeks. Patients rated the severity of RLS by means of a 6-item questionnaire developed by the International Restless Legs Study Group (6-item IRLS), by the Clinical Global Impression (CGI) scale, and by sleep diaries., Results: Under treatment with levodopa SR, 1 patient presented severe vomiting, leading to study discontinuation. The 10 patients who completed the study reported a 33.5% improvement (from 16.7 +/- 3.2 to 11.1 +/- 4; P < 0.001) of the 6-item IRLS scores during levodopa SR treatment and a 73.5% improvement (from 16.6 +/- 2.8 to 4.4 +/- 3.8; P < 0.001) during ropinirole treatment. By the end of the study the mean levodopa SR dosage was 190 mg/d and the mean ropinirole dosage was 1.45 mg/d. Ropinirole was superior to levodopa SR in reducing 6-item IRLS scores (P < 0.001) and in increasing sleep time (P < 0.001). The patient CGI scale showed a significant difference favoring ropinirole (P < 0.01). There was no significant carryover or period effect for any outcome measure. Four patients reported a complete reversion of RLS symptoms during ropinirole treatment at doses ranging from 0.25-2 mg/d., Conclusions: These results suggest that ropinirole is more effective than levodopa SR in the treatment of RLS in patients on chronic hemodialysis.

Heavy smoke from forest fires in the Amazon was observed to reduce cloud droplet size and so delay the onset of precipitation from 1.5 kilometers above cloud base in pristine clouds to more than 5 kilometers in polluted clouds and more than 7 kilometers in pyro-clouds. Suppression of low-level rainout and aerosol washout allows transport of water and smoke to upper levels, where the clouds appear "smoking" as they detrain much of the pollution. Elevating the onset of precipitation allows invigoration of the updrafts, causing intense thunderstorms, large hail, and greater likelihood for overshooting cloud tops into the stratosphere. There, detrained pollutants and water vapor would have profound radiative impacts on the climate system. The invigorated storms release the latent heat higher in the atmosphere. This should substantially affect the regional and global circulation systems. Together, these processes affect the water cycle, the pollution burden of the atmosphere, and the dynamics of atmospheric circulation.

Wnts are secreted signaling proteins that regulate developmental processes. Here we show that Wnt signaling, likely mediated by Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors CCAAT/enhancer binding protein alpha (C/EBPalpha) and peroxisome proliferator- activated receptor gamma (PPARgamma). When Wnt signaling in preadipocytes is prevented by overexpression of Axin or dominant-negative TCF4, these cells differentiate into adipocytes. Disruption of Wnt signaling also causes transdifferentiation of myoblasts into adipocytes in vitro, highlighting the importance of this pathway not only in adipocyte differentiation but also in mesodermal cell fate determination.

Research suggests that oxytocin acts as a growth modulating agent for breast cancer cells. However, the signaling mechanisms responsible for these modulatory effects have not been fully elucidated. In the physiological setting oxytocin is known to stimulate contraction of myometrial cells in the uterus and myoepithelial cells in the breast by increasing intracellular free calcium ([Ca2+]i). The expression of oxytocin receptor mRNA in T-47D breast cancer cells, and four additional breast cancer cell lines (BT-549, MCF-7, MDA-MB- 231, ZR-75-1), was confirmed by RT-PCR analysis. Oxytocin-induced changes in [Ca2+]i in indo-1 AM loaded T-47D breast cancer cells were monitored using flow cytometric analysis. In this cell line, oxytocin (0, 1, 10, 100, and 1,000 nM) did not induce a dose-dependent increase in the mean 405 nm/485 nm emission ratio. These results indicate that oxytocin signaling in T-47D breast cancer cells does not appear to involve an increase in [Ca2+]i.

Vasopressin is one of several small neuropeptides that are reported to be autocrine growth factors for small cell carcinoma of the lung (SCCL). It has been assumed that this peptide exercises its mitogenic influences through the vasopressin V1a receptor, and we have previously demonstrated that this receptor is expressed by classical and variant SCCL. Activation of the vasopressin V1a receptor produces changes in phospholipases C, D, and A2, in protein kinase C, and in Ca2+ mobilization. This study demonstrates that SCCL cells express not only vasopressin V1a receptors but also mRNAs and proteins representing normal V1b receptors and V2 receptors. They were also shown to express mRNA for a human form of the putative receptor rabbit vasopressin-activated calcium-mobilizing receptor (VACM-1). Additionally, SCCL tumor cells were found to express mRNA and protein representing a possible nonfunctional, shortened, "diabetic" form of the vasopressin V2 receptor that is the product of incomplete posttranscriptional splicing. At least four of these five vasopressin receptors were produced by cell lines exemplifying classical and variant forms of SCCL. No differences in the sequences for the V1 receptors between classical and variant SCCL were found. However, although the nature and expression of both vasopressin V1 receptors and human VACM are apparently unaffected by dedifferentiation in SCCL, only the abnormal (and probably nonfunctional) form of the V2 receptor could be demonstrated in variant cell line NCI H82. Functional engagement of vasopressin V2 receptors is reported to produce rises in cAMP and activation of protein kinase A, whereas stimulation of V1b receptors is believed to produce similar changes to those produced by V1a receptors, i.e., activation of phospholipases and of protein kinase C. Stimulation of VACM receptors raises intracellular free Ca2+ through currently unknown but phosphoinositide-independent mechanisms. The presence of all known vasopressin receptors that are, together, potentially capable of inducing several different transduction cascades in small cell tumor cells suggests that this peptide serves a multifaceted role in tumor physiology.

The immortalized GT1-7 cell line synthesizes and secretes GnRH, the key hormone of reproduction. However, GT1-7 cells lack the normal inputs from neurotransmitters, growth factors, and steroids, which are involved in the maturation and maintenance of GnRH neurons in the brain. We examined the effects of the neurotrophic factor insulin-like growth factor-I (IGF-I) on GnRH gene expression and the mechanism for these changes. Initially, effects of IGF-I on GnRH gene expression were determined by ribonuclease protection assay. In time-course experiments, IGF-I treatment caused significant increases in nuclear GnRH primary transcript levels, an index of GnRH gene transcription, 4 and 8 h after initiation of IGF-I treatment. GnRH messenger RNA (mRNA) levels in the cytoplasm were stimulated by IGF-I at 24 h of treatment. IGF-I also affected GT1-7 cell morphology, with an increase in process extension and cell-cell contacts. In contrast, GnRH peptide levels in the medium were initially stimulated and then suppressed by IGF-I, indicating an uncoupling of biosynthesis and secretion. The increase in GnRH mRNA levels induced by IGF-I is probably caused by a transcriptional mechanism, as evidenced by the increase in GnRH primary transcript levels before a change in GnRH mRNA levels, as well as our finding of a similar GnRH mRNA half-life for both control and IGF-I-treated cells. Interestingly, GT1-7 cells themselves were observed to express IGF-I immunoreactivity, suggesting the possibility of autoregulation by this neurotrophic factor. It is concluded that IGF-I is an important modulator of GnRH gene expression and release in the GT1-7 cell line. The reported stimulatory effects of IGF-I in vivo, and its hypothesized role in the development of GnRH neurons in the brain, suggest that IGF-I may make the GT1-7 cells line more like a mature GnRH neuron, as a model for future studies.

The synthesis and structure-activity relationships of a series of aza-tricyclic analogs of the quinuclidine substance P (SP) antagonist 1 are described. The SP receptor affinity of these compounds was found to vary according to the size of the new ring fused to the quinuclidine and the mode of fusion. Correlations between receptor affinity and (1) the steric bulk of the newly introduced ring fusion and (2) the dihedral angle between the benzhydryl and benzylamino substituents of these aza-tricyclic compounds were explored.

The authors of this section represent a broad range of practice experience with horses that perform in rigorous and varied sport competitions. Each breed and performance application represent unique challenges of diagnosis and uncompromising demands on rehabilitated tendon injuries. This article will serve to guide, stimulate, and encourage veterinarians to apply scientific criteria to the evaluation of tendinitis therapy in the years to come so that we can arrive at a more valid consensus as to the "best" means of tendon and ligament injury management.

We describe the structure-activity relationship development of a series of quinuclidines which culminated in the first potent, selective, nonpeptide substance P (SP) antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-phenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine, 3 (CP-96,345). Compound 3 is a potent displacer of [3H]SP binding in human IM-9 cells and blocks SP-induced and capsaicin-induced plasma extravasation, as well as SP-induced salivation in the rat in vivo. This compound may both help to further our understanding of the interactions of small molecules with peptide receptors and serve to evaluate the therapeutic potential of a SP antagonist.

CP-96,345 [(2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)- methyl]-1-azabicyclo[2.2.2]octan-3-amine] is a potent nonpeptide antagonist of the substance P (NK1) receptor. CP-96,345 inhibited 3H-labeled substance P binding and was a classical competitive antagonist in the NK1 monoreceptor dog carotid artery preparation. CP-96,345 inhibited substance P-induced salivation in the rat, a classical in vivo bioassay, but did not inhibit NK2, NK3, or numerous other receptors; it is thus a selective NK1 antagonist. This compound may prove to be a powerful tool for investigation of the physiological properties of substance P and exploration of its role in diseases.