Gender differences in microRNA expression in levodopa-naive PD patients.

Gender is an important factor influencing epidemiological and clinical features of Parkinson's disease (PD). We aimed to evaluate gender differences in the expression of a panel of miRNAs (miR-34a-5p, miR-146a, miR-155, miR-29a, miR-106a) possibly involved in the pathophysiology or progression of disease. Serum samples were obtained from 104 PD patients (58 men and 46 women) never treated with levodopa. We measured levels of miRNAs using quantitative PCR. Correlations between miRNA expression and clinical data were assessed using the Spearman's correlation test. We used STRING to evaluate co-expression relationship among target genes. MiR-34a-5p was significantly upregulated in PD male patients compared to PD female patients (fc: 1.62; p < 0.0001). No correlation was found with age, BMI, and disease severity, assessed by UPDRS III scale, in male and female patients. MiR-146a-5p was significantly upregulated in female as compared to male patients (fc: 3.44; p < 0.0001) and a significant correlation was also observed between disease duration and mir-146a-5p. No differences were found in the expression of miR-29a, miR-106a-5p and miR-155 between genders. Predicted target genes for miR-34a-5p and miR-146-5p and protein interactions in biological processes were reported. Our study supports the hypothesis that there are gender-specific differences in serum miRNAs expression in PD patients. Follow-up of this cohort is needed to understand if these differences may affect disease progression and response to treatment.

Cognitive disorders in normal pressure hydrocephalus with initial parkinsonism in comparison with de novo Parkinson's disease.

BACKGROUND AND PURPOSE: The clinical differentiation between parkinsonism in idiopathic normal pressure hydrocephalus (iNPH) and Parkinson's disease (PD) remains challenging in the initial phase. Whether an early cognitive profiling might support the differential diagnosis of early iNPH and PD was addressed. METHODS: Neuropsychological tests of 40 iNPH subjects with early symptoms resembling parkinsonism were retrospectively evaluated together with 47 de novoPD patients (dnPD). Only neuropsychological tests performed within 1 year from the first motor symptom were included. The cognitive spectrum of iNPH and dnPD was also compared with a sample of 70 normal controls. RESULTS: A clear difference in the cognitive profile of iNPH, dnPD patients and normal controls was shown. 65% of iNPH subjects showed a diffuse cognitive impairment, including memory, visuospatial abilities, fronto-executive functioning and attention, whereas only 25.5% of the dnPD patients presented an executive dysfunction. 35% of iNPH and 74.5% of PD patients performed within the normal range (P < 0.05). CONCLUSION: Subjects with iNPH showed an early and diffuse alteration of cognition with respect to dnPD patients. Performing a prompt and accurate neuropsychological evaluation might support the differential diagnosis of these two conditions of parkinsonism.

Specific patterns of laryngeal electromyography during wakefulness are associated to sleep disordered breathing and nocturnal stridor in multiple system atrophy.

BACKGROUND: Nocturnal stridor and respiratory abnormalities are important features of multiple system atrophy (MSA) with relevance to patient survival, and they are detected and evaluated mainly through video-polysomnography (video-PSG). Diurnal laryngoscopy seems to yield abnormal findings only in the presence of significant vocal cord (VC) dysfunction. AIM: To assess whether specific electrophysiological patterns of diurnal EMG of VC muscles may indicate nocturnal stridor or respiratory dysfunctions in MSA patients. MATERIALS AND METHODS: Seventeen patients with probable MSA were examined. A full-night video-PSG to collect standard breathing parameters (apnea/hypopnea index, mean HbSAO2, oxygen desaturation index, total sleep time with HbSaO2 below 90%) was performed in all the patients. Laryngoscopy and EMG investigation of adductor (thyroarytenoid-TA) and abductor (posterior cricoarytenoid-PCA) muscles of the VCs were also performed. RESULTS: Both the laryngeal EMG abnormalities (based on MUAP analysis and kinesiologic EMG investigation of VC muscles) and the laryngoscopic alterations correlated with video-PSG respiratory abnormalities. Specific patterns of EMG findings were consistently found in MSA subjects with nocturnal stridor detected at PSG. In particular, the following EMG findings were related to the severity of breathing abnormalities and the presence of stridor on video-PSG: neurogenic pattern on MUAP analysis of the PCA, paradoxical activation of the TA during inspiration and tonic EMG activity of the TA during quiet breathing. CONCLUSIONS: Electromyographic/kinesiologic investigation of VC muscles during wakefulness provides additional information on the pathophysiology of the respiratory abnormalities in MSA patients that could be useful for guiding the choice of the best appropriate treatment and care.

How parkinsonism influences life: the patients' point of view.

To explore the experience of living with parkinsonism, a survey form was sent to the members of a patients' association; 1,256 forms were analysed. The mean age was 65.75 ± 9.29 years; 64.4% males. A family history was reported by 19.2%. Basic abilities were preserved in 75% of the responders; the ability to do indoor and outdoor activities was preserved in 42 and 28%, respectively. 70% of the responders liked to meet other people and about 50% liked discussing their condition. 80.3% of the responders lived with partner, while 7.8% did not live with family. Of the patients' partners, 38.9% took drugs, and 9.4% themselves needed assistance. Care programmes for parkinsonians should take into account the disease duration, the degree of disability, the presence of caregiver/s, and the level of caregiver burden; but it should also be appreciated that social habits, need of help, and severity of symptoms influence disability.

Peripheral expression of key regulatory kinases in Alzheimer's disease and Parkinson's disease.

Alteration of key regulatory kinases may cause aberrant protein phosphorylation and aggregation in Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we investigated expression and phosphorylation status of glycogen synthase kinase 3 (GSK-3), protein kinase B (Akt) and tau protein in peripheral blood lymphocytes of 20 AD, 25 PD patients and 20 healthy controls. GSK-3 was increased in AD and PD patients. In these latter, GSK-3 levels were positively correlated with daily L-Dopa intake. Phosphorylated Akt expression was augmented in both groups; total Akt levels were increased only in AD patients and were positively correlated with disease duration and severity. Total and phosphorylated tau were increased only in AD, with phospho-tau levels being positively correlated with levels of total tau, Akt, and disease duration. No correlations between protein levels and clinical variables were found in PD patients. Investigation of peripheral changes in the expression of specific kinases may, therefore, lead to the development of innovative biomarkers of neurodegeneration, particularly for AD.

BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson's disease.

BACKGROUND AND PURPOSE: A possible association between Parkinson's disease (PD) and the polymorphism of Brain Derived Neurotrophic Factor (BDNF) G196A (Val66Met) has been suggested by different studies that nevertheless yielded-contrasting result. The purpose of this study was to analyze such possible association in a cohort of Italian PD patients. METHODS: The BDNF polymorphisms were analyzed in 294 Italian patients with PD; results were compared to those obtained in 233 age- and sex-matched healthy controls (HC) enrolled from two tertiary centres in Italy. Polymorphisms were determined by Restriction Fragment Length Polymorphism (RFLP) analysis; correlations between BDNF G196A polymorphism, and cognitive function were established by sub analyzing the results upon dividing PD patients based on their Mini Mental State Examination (MMSE) score. RESULTS: Univariate analysis showed a highly significant correlation between the BDNF(AA) genotype and a MMSE score < or =24. Hence, the distribution of this genotype in PD individuals with a MMSE score < or =24 was significantly increased compared to PD patients with an MMSE score >24 and HC (P < 0.001 in both cases). Multivariate analyses showed that BDNF (AA) genotype was associated to a sixfold risk of cognitive impairment. CONCLUSIONS: The BDNF(AA) homozygote genotype is over-represented in PD patients compared with normal individuals; this genotype was significantly correlated to cognitive impairment, age and disease severity. These results, although preliminary, could be important in establishing novel diagnostic and therapeutic approaches to PD.

Duodenal levodopa infusion improves quality of life in advanced Parkinson's disease.

BACKGROUND: A significant percentage of patients with Parkinson's disease (PD) continue to experience motor fluctuations and dyskinesias despite the association of dopamine agonists and levodopa with COMT or MAO-B inhibitors. The use of apomorphine infusion is limited by compliance while deep brain stimulation is feasible only for a small number of patients mostly because of age constraints. OBJECTIVE: To assess prospectively the effectiveness of duodenal levodopa infusion on quality of life as well as motor features in patients with advanced PD. In all but 1 case levodopa infusion was stopped at nighttime. METHODS: We report the outcome of 22 PD patients, followed for up to 2 years, who were on continuous duodenal levodopa/carbidopa infusion through percutaneous endoscopic gastrostomy. RESULTS: We found a significant reduction in 'off' period duration as well as dyskinesia severity (Unified Parkinson's Disease Rating Scale part IV, items 33 and 39). There was significant improvement in the 39-item Parkinson's Disease Quality of Life Questionnaire as well as in the Unified Parkinson's Disease Rating Scale part II up to the 2-year follow-up. Five patients withdrew: 2 for poor compliance and 3 for adverse events (1 was related to percutaneous endoscopic gastrostomy). CONCLUSIONS: These results demonstrate significant clinical improvements in quality of life and activities of daily living consistent with the occurrence of a satisfactory therapeutic response and a reduction in dyskinesia severity.

Homocysteine and Parkinson's disease: a dangerous liaison?

Homocysteine, a sulphur-containing amino acid formed by demethylation of methionine, is involved in numerous processes of methyl group transfer, all playing pivotal roles in the biochemistry of the human body. Increased levels of plasma homocysteine (hyperhomocysteinemia) - which may result from a deficiency of folate, vitamin B6 or B12 or mutations in enzymes regulating the catabolism of homocysteine - are associated with a wide range of clinical manifestations, mostly affecting the central nervous system (e.g., mental retardation, cerebral atrophy and epileptic seizures). Recent evidence suggests that changes in the metabolic fate of homocysteine, leading to hyperhomocysteinemia, may also play a role in the pathophysiology of neurodegenerative disorders, particularly Parkinson's disease (PD). The nervous system might be particularly sensitive to homocysteine, due to the excitotoxic-like properties of the amino acid. However, experimental findings have shown that homocysteine does not seem to posses direct, cytotoxic activity, while the amino acid has proven able to synergize with more specific neurotoxic insults. Hyperhomocysteinemia has been repeatedly reported in PD patients; the increase, however, seems mostly related to the methylated catabolism of l-Dopa, the main pharmacological treatment of PD. Therefore, hyperhomocysteinemia may not be specific to movement disorders or other neurological diseases, the condition being, in fact, rather the result of the combinations of different factors, mainly metabolic, but also genetic and pharmacological, intervening in the neurodegenerative process.

Peripheral proteasome and caspase activity in Parkinson disease and Alzheimer disease.

BACKGROUND: Defects of the ubiquitin-proteasome (UP) system, a multicatalytic complex degrading polyubiquitinated proteins, may intervene in the pathogenesis of neurodegenerative disorders characterized by intracellular formation of protein aggregates such as Parkinson disease (PD) and Alzheimer disease (AD) by inducing proapoptotic conditions. METHODS: The authors measured the activity of proteolytic UP core, proteasome 20S, and of proapoptotic caspase-3 and -9 in peripheral blood lymphocytes (PBLs) of PD and AD patients to establish whether changes in these systems are detectable peripherally. RESULTS: Proteasome 20S activity was reduced in PBLs of treated PD patients vs healthy controls (mean +/- SEM: 1.0 +/- 0.1 vs 2.3 +/- 0.2 nmol 7-amino-4-methylcoumarin (AMC)/10(6) cells, p < 0.001), whereas marked increases in caspase-3 activity (1370 +/- 153 vs 586 +/- 104 pmol AMC/10(6) cells, p < 0.001) and caspase-9 activity (873 +/- 86 vs 304 +/- 27 U/10(6) cells, p < 0.001) were found. Increased caspase-9 activity was also detected in PBLs of untreated PD patients (900 +/- 193 U/10(6) cells). PD duration and severity (Unified Parkinson's Disease Rating Scale score) were inversely correlated with proteasome 20S activity and directly correlated with caspase-3 activity. An inverse correlation was also observed in PD patients between caspase-3 activity and proteasome 20S activity. No significant changes in proteasome 20S or caspase activity or correlations between biochemical and clinical variables were found in patients with AD. CONCLUSIONS: A decrease in proteasome activity, possibly related to caspase activation, is detectable in peripheral blood lymphocytes of patients with Parkinson disease but not patients with Alzheimer disease, suggesting that these variables may be considered for the development of peripheral biomarkers of Parkinson disease.

Comorbid disorders and hospitalisation in Parkinson's disease: a prospective study.

Parkinson's disease (PD) is often associated with other disorders, typical of the disease or of the age of PD patients, that can lead to hospitalisation, sometimes as emergencies. In this one-year prospective, longitudinal study, we investigated the comorbid events prompting the hospitalisation, or occurring during the planned hospitalisation, of an unselected group of 180 PD patients, admitted to 9 general hospitals in the course of the study. The most frequent acute comorbid events were trauma (30.5%), mostly due to falls, and vascular disorders (29.3%). Comorbidities were closely related to PD in 50% of cases. More than 50% of patients did not require (in addition to PD therapy) specific treatment for the acute comorbid event. Older age was associated with increased risk of complications. The setting up of multidisciplinary networks covering entire territories could help to improve the way in which we tackle the clinical and social problems generated by PD and its comorbidities.

Sleep attacks in Parkinson's disease: a clinical and polysomnographic study.

The objective of the study was to evaluate daytime sleepiness, (the features of episodes of sudden sleep onset), i. e., so-called sleep attacks (SAs), in three male Parkinson's disease (PD) patients (mean age 66 years) on chronic therapy with ropirinole or pramipexole. A structured clinical interview, the Epworth Sleepiness Scale, and continuous 24-h ambulatory polysomnography were used to assess the features of SAs occurring in the patients in their normal home environments. The polysomnographic patterns characterizing SAs (sleep occurring against a background of wakefulness, and not preceded by a feeling of sleepiness or by other heralding symptoms) were analyzed. The results showed that SAs can be clearly documented through polysomnographic monitoring and really, but rarely, occur in PD. SAs seem to represent the extreme of the continuum of daytime sleepiness observed in PD patients.

High-dose ropinirole in advanced Parkinson's disease with severe dyskinesias.

Levodopa (LD) is the gold standard of therapy for Parkinson's disease, but it is commonly associated with motor fluctuations and dyskinesias. Dopamine agonists are often used as adjuncts to LD in an attempt to reduce these complications. In this open-label study the authors investigated the effects of high doses of adjunctive ropinirole in 36 patients with advanced Parkinson's disease and normal cognitive status. The daily dose of ropinirole was increased from 18.4 +/- 3.5 mg to 34.7 +/- 5.5 mg, generally in four separate doses. The daily LD dose was decreased from 734.1 +/- 254.8 mg to 502.8 +/- 228.4 mg. After 12 months 25 patients were still on high doses of ropinirole whereas 11 patients had, after either the emergence of side effects or a worsening of their clinical conditions, decreased or interrupted ropinirole. At 12 months, the daily doses of LD and ropinirole were 489 +/- 243 mg and 34.6 +/- 4.6 mg respectively. There was a significant reduction in the Dyskinesia Rating Scale scores during both ON and OFF periods, indicating a reduction in dyskinesias during ON periods and a reduction in dystonias during OFF periods (p < 0.001). Both the intensity and the hours spent during OFF periods were reduced significantly (p < 0.001). Even though these results need to be confirmed through extended controlled studies, the high-dose dopamine agonist strategy is safe for patients with advanced PD in whom a marked motor response to LD (even at very low doses) is associated with severe dyskinesias, and may be used as a means of delaying surgery or as an alternative to continuous apomorphine infusion.

Parkinson's disease and reproductive life events.

Onset, progression and duration of Parkinson's disease (PD) seem to be similar in men and women but gender differences have been suggested concerning clinical aspects, such as more severe disease in men and more dyskinesia in women. Taking into account the multiple influences of sex hormones, estrogens in particular, on basal ganglia function, the present work compared the characteristics of reproductive events in PD subjects and in healthy women, with regard to onset and clinical aspects of the disease with respect to the milestones of reproductive life. A total of 150 PD women and 200 healthy women matched for age were interviewed about reproductive life and disease characteristics (if patients). As a group, the women with PD had menarche later than the controls, but in the normal range. Menopause was similar to the controls for time, type (natural) and onset (slow), but with less hormonal therapies. Women with PD had fewer children, while breast feeding and gynecological diseases were comparable to controls. The characteristics of menses were similar as far as dysmenorrhea and premenstrual syndrome (PMS). The women with PD onset before menopause had a longer disease duration, with a more frequent fluctuating stage, and longer treatment with both levodopa and dopamine agonists. They had more dysmenorrhea and PMS when compared with women with PD onset after menopause and controls.

Botulinum toxin treatment for functional disability induced by essential tremor.

This study aimed to improve botulinum toxin's (BTX) efficacy and to reduce its unwanted effects in the treatment of functional disability due to essential tremor (ET) of the hand. Twenty patients with disabling ET, not responding to conventional pharmacological therapy, were enrolled in this open-label study. Activities of daily living self-questionnaire (ADLS) and severity tremor scale (STS) were used to establish patients' functional disability and tremor severity. Accelerometry and surface electromyography were used to identify the arm muscles with tremorogenic activity during impaired positions. Global rating was used to measure treatment efficacy and unwanted effects. BTX type A was injected into the muscles principally responsible for impaired positions. After BTX treatment, there was a significant reduction in both severity and functional rating scales scores (ADLS and STS) and of tremor amplitude as measured with accelerometry and EMG. Adverse effects were limited to a slight third finger extension weakness in 15% of patients. BTX injections are effective and safe in reducing disability due to ET, if based on the criterion of functional selection.