Parkinson Disease: Bonuccelli U

Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P, Larsen JP, Lees A, Oertel W, Poewe W, Rascol O, Sampaio C, Anonymous00036, Anonymous00037. · Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands. · Eur J Neurol. · Pubmed #17038032 No free full text.

Abstract: To provide evidence-based recommendations for the management of late (complicated) Parkinson's disease (PD), based on a review of the literature. Complicated PD refers to patients suffering from the classical motor syndrome of PD along with other motor or non-motor complications, either disease-related (e.g. freezing) or treatment-related (e.g. dyskinesias or hallucinations). MEDLINE, Cochrane Library and INAHTA database literature searches were conducted. National guidelines were requested from all EFNS societies. Non-European guidelines were searched for using MEDLINE. Part II of the guidelines deals with treatment of motor and neuropsychiatric complications and autonomic disturbances. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement ('good practice point') is made.

Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P, Larsen JP, Lees A, Oertel W, Poewe W, Rascol O, Sampaio C, Anonymous00034, Anonymous00035. · Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands. · Eur J Neurol. · Pubmed #17038031 No free full text.

Abstract: The aim of the study was to provide evidence-based recommendations for the management of early (uncomplicated) Parkinson's disease (PD), based on a review of the literature. Uncomplicated PD refers to patients suffering from the classical motor syndrome of PD only, without treatment-induced motor complications and without neuropsychiatric or autonomic problems. MEDLINE, Cochrane Library and International Network of Agencies for Health Technology Assessment (INAHTA) database literature searches were conducted. National guidelines were requested from all European Federation of Neurological Societies (EFNS) societies. Non-European guidelines were searched for using MEDLINE. Part I of the guidelines deals with prevention of disease progression, symptomatic treatment of motor features (parkinsonism), and prevention of motor and neuropsychiatric complications of therapy. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement (good practice point) is made.

Bonuccelli U, Ceravolo R. · University of Pisa, Department of Neuroscience, Via Roma, 67 56100 Pisa, Italy. · Expert Opin Drug Saf. · Pubmed #18324875 No free full text.

Abstract: Dopamine agonists are highly effective as adjunctive therapy to levodopa in advanced Parkinson's disease. These drugs have rapidly gained popularity as a monotherapy in the early stages of Parkinson's disease for patients < 65-70 years old, because they are about as effective as levodopa, but patients demonstrate a lower tendency to develop motor complications. However, dopamine agonists could have peripheral and central side effects, which are often the reason for the discontinuation of the treatment. This review focuses on the potential negative effects related to the use of dopamine agonists in the treatment of Parkinson's disease.

Bonuccelli U, Pavese N. · University of Pisa, Department of Neuroscience, Via Roma 67 (56126), Pisa, Italy. · Expert Rev Neurother. · Pubmed #17939774 No free full text.

Abstract: At present, dopamine agonists play an important role in antiparkinsonian therapy since they were proved effective in the management of both advanced- and early-stage Parkinson's disease. In the latter, they are often regarded as first-choice medication to delay the introduction of levodopa therapy. Despite sharing the capacity to directly stimulate dopamine receptors, dopamine agonists show different pharmacological properties as they act on different subsets of dopamine receptors. This, in theory, provides the advantage of obtaining a different antiparkinsonian activity or safety profile with each agent. However, there is very little evidence that any of the marketed dopamine agonists should be consistently preferred in the management of patients with Parkinson's disease. Pergolide and cabergoline are now considered a second-line choice after the proven association with valvular fibrosis. Transdermal administration (rotigotine) and subcutaneous infusion (apomorphine) of dopamine receptor agonists are now available alternatives to oral administration and provide continuous dopaminergic stimulation. Continuous subcutaneous apomorphine infusion during waking hours leads to a large reduction in daily 'off' time, dyskinesias and levodopa daily dose. Almost all currently used dopamine agonists are able to provide neuroprotective effects towards dopaminergic neurons during in vitro and in vivo experiments. This neuroprotection may be the result of different mechanisms including antioxidation, scavenging of free radicals, suppression of lipid peroxidation and inhibition of apoptosis. However, the disease-modifying effect of these agents in Parkinson's disease remains to be ascertained.

Bonuccelli U, Del Dotto P. · Department of Neuroscience, University of Pisa, Italy. · Neurology. · Pubmed #17030738 No free full text.

Abstract: Many of the motoric features that define Parkinson's disease (PD) result primarily from the loss of dopaminergic neurons of the substantia nigra. l-dopa remains at present the most powerful symptomatic drug for the treatment of this condition. However, motor complications of chronic l-dopa treatment have emerged as a major limitation of this therapy. Slowing or delaying the progression of the disease with neuroprotective therapies may delay the need for l-dopa. In the past few years, novel insight into the pathogenetic mechanisms of neurodegeneration in PD has been provided. Mitochondrial function deficiency, increased oxidative stress, apoptosis, excitotoxicity, and inflammation are part of the processes that ultimately result in neurodegeneration. Drugs that are now under clinical scrutiny as neuroprotectant include molecules that combine one or more of the following properties: (1) monoamine oxidase inhibition (rasagiline, safinamide); (2) mitochondrial enhancement (coenzyme Q10, creatine); (3) antiapoptotic activity; (4) anti-inflammatory activity; (5) protein aggregation inhibition; (6) neurotrophic activity. In advanced Parkinson's disease, the combination of disease progression and l-dopa therapy leads to the development of motor response complications, particularly wearing off, on off, dyskinesias and dystonias. The nonphysiologic pulsatile stimulation of striatal dopamine receptors, produced by the currently available dopaminergic drugs, may trigger a dysregulation of many neurotransmitter systems within the basal ganglia, mainly localized on medium spiny striatal neurons. These include alterations of glutamatergic, serotonergic, adrenergic and adenosine A(2A) receptors. Novel strategies for pharmacological intervention with nondopaminergic treatments hold the promise of providing effective control or reversal of motor response complications. Of particular interest are NMDA and AMPA antagonists or drugs acting on 5-HT subtype 2A, alpha2-adrenergic, and adenosine A(2) receptors. Future strategies may also target pre- and postsynaptic components that regulate firing pattern of basal ganglia neurons, such as synaptic vesicle proteins, nonsynaptic gap junction communication mechanisms, or signal transduction systems that modulate the phosphorylation state of glutamatergic receptors.

Bonuccelli U, Pavese N. · Department of Neuroscience, University of Pisa, (56126) Pisa, Italy. · Expert Rev Neurother. · Pubmed #16466315 No free full text.

Abstract: Dopamine agonists are highly effective as adjunctive therapy to levodopa in advanced Parkinson's disease and have rapidly gained popularity as a monotherapy in the early stages of Parkinson's disease for patients less than 65-70 years old. In the latter case, dopamine agonists are about as effective as levodopa but patients demonstrate a lower tendency to develop motor complications. However, dopamine agonists lose efficacy over time and the number of patients remaining on agonist monotherapy decreases to less than 50% after 3 years of treatment. Thus, after a few years of treatment the majority of patients who started on dopamine agonists will be administered levodopa, in a combined dopaminergic therapy, in order to achieve a better control of motor symptoms.

Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Bonucelli U, Damier P, De Yebenes J, Gershanik O, Guttman M, Grandas F, Hallett M, Hornykiewicz O, Jenner P, Katzenschlager R, Langston WJ, LeWitt P, Melamed E, Mena MA, Michel PP, Mytilineou C, Obeso JA, Poewe W, Quinn N, Raisman-Vozari R, Rajput AH, Rascol O, Sampaio C, Stocchi F. · Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. · Mov Disord. · Pubmed #15372588 No free full text.

Abstract: Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

Bonuccelli U. · Department of Neuroscience, University of Pisa, Pisa, Italy. · Curr Opin Neurol. · Pubmed #15180133 No free full text.

Abstract: Dopamine agonists are effective in the management of both advanced and early-stage Parkinson's disease. Unfortunately, randomized head-to-head comparative studies between the many different dopamine agonists now available are sparse. Indirect comparisons of dopamine agonists show that ergot derivatives, such as pergolide and cabergoline, are as effective as non-ergot derivatives, such as ropinirole and pramipexole, in ameliorating Parkinson's disease symptoms in patients in early or advanced stages of the condition. As far as safety and tolerability are concerned, no significant differences between dopamine agonists are found. However, some specific adverse events, such as somnolence and sleep attacks, seem less frequent in monotherapy studies with pergolide than in those with the non-ergot dopamine agonists; however, because of the lack of direct-comparison studies this cannot be proved conclusively. Randomized, controlled comparative studies between dopamine agonists are necessary to verify any possible differences in their effectiveness and tolerability in the treatment of Parkinson's disease.

Bonuccelli U, Colzi A, Del Dotto P. · Department of Neuroscience, University of Pisa, Pisa, Italy. · Clin Neuropharmacol. · Pubmed #11852289 No free full text.

Abstract: Introduced on the market in 1989, pergolide, a D1/D2 dopamine receptor agonist, is still widely prescribed for the treatment of patients with early and advanced Parkinson's disease (PD). Initially, pergolide was introduced as an adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor responses and dyskinesias. Results of recent randomized controlled clinical trials in de novo patients with PD show that pergolide is able to improve parkinsonian symptoms when used as monotherapy. Moreover, preliminary results of a long-term monotherapy study in early PD suggest that pergolide is as effective as levodopa, and that a significant delay in the time of the onset of levodopa-induced motor complications can be obtained. A number of randomized studies have shown that pergolide is more effective than bromocriptine as adjunct therapy to levodopa in patients with advanced PD; the greater benefit found with pergolide could be ascribed to its action on both D1 and D2 dopamine receptors. However, controlled comparative studies with new dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not been performed yet. Interestingly, few open studies in patients with complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to improve motor fluctuations and dyskinesias through a dramatic reduction of levodopa dosage. The side-effect profile of pergolide is similar to that of other dopamine agonists, and complications such as sleep attack and serosal fibrosis have been rarely reported.

Lucetti C, Del Dotto P, Gambaccini G, Ceravolo R, Logi C, Berti C, Rossi G, Bianchi MC, Tosetti M, Murri L, Bonuccelli U. · Department of Neuroscience, University of Pisa, Pisa, Italy. · Mov Disord. · Pubmed #17722082 No free full text.

Abstract: The objective of this study was to investigate neurochemical and metabolic changes in the motor cortex in a group of de novo Parkinson's disease (PD) patients before and after 6 mo treatment with the dopamine agonist pergolide. Proton magnetic resonance spectroscopy (1H-MRS) has been used to study striatal and cortical metabolism in PD and other parkinsonisms. So far, no studies evaluating possible brain metabolic changes in PD patients before and after dopaminergic therapy have been reported. De novo PD patients (11) and controls (11) underwent clinical evaluation (UPDRS-III motor evaluation) and a first single-voxel 1H-MRS of the motor cortex. 1H-MRS studies were performed using the PROBE-SV System implemented on a 1.5 Tesla Scanner (GE Medical System, Milwaukee, WI). Pergolide was administered up to a dose of 1 mg t.i.d. After 6 mo follow-up, all patients were clinically evaluated and a second single-voxel 1H-MRS was performed. Lower values of Cho/Cr and NAA/Cr ratios were observed in the motor cortex of PD patients compared with controls (P < 0.02 and P < 0.01, respectively). After 6 mo therapy with pergolide (1 mg t.i.d), PD patients showed an improvement in motor performances (P < 0.05) and an increase in Cho/Cr ratios in the motor cortex at the second 1H-MRS evaluation (P < 0.05) was reported. In conclusion, cortical NAA/Cr and Cho/Cr ratios may be impaired in de novo PD. Dopaminergic therapy capable of improving motor function may restore the Cho/Cr ratio in the motor cortex.

Ceravolo R, Volterrani D, Frosini D, Bernardini S, Rossi C, Logi C, Manca G, Kiferle L, Mariani G, Murri L, Bonuccelli U. · Department of Neuroscience, Neurology Section, University of Pisa, Pisa, Italy. · J Neural Transm. · Pubmed #16758132 No free full text.

Abstract: Several evidences suggest that cholinergic deficits may significantly contribute to dementia in Parkinson's disease (PDD) and acetylcholinesterase inhibitors (ChEIs) have been reported to improve cognitive symptoms in PDD, without worsening parkinsonism. Nineteen PDD patients underwent brain perfusion SPECT with (99m)Tc-ethyl cysteinate dimer after 6 months ChEIs treatment in order to evaluate the functional correlates of clinical improvement. A clear-cut cognitive improvement was reported in PDD patients with a significant improvement of ADAS-cog total score as well as of subscores exploring executive functions (p<0.01). MMSE total score did not significantly change after ChEIs but the subscore of attention significantly improved after therapy (p<0.01). No difference in motor performance as evaluated by UPDRS was reported. SPM analysis showed a significant increase of perfusion (p < 0.0001) in bilateral cingulate, and frontal regions after ChEIs. Our data confirm the efficacy of ChEIs in the treatment of dementia associated with PD mainly on attention and executive functions, and the functional findings indicate that this cognitive improvement could be associated with a sort of pharmacological frontal "re-afferentation".

Stocchi F, Arnold G, Onofrj M, Kwiecinski H, Szczudlik A, Thomas A, Bonuccelli U, Van Dijk A, Cattaneo C, Sala P, Fariello RG, Anonymous00085. · Department of Neuroscience and IRCCS Neuromed Pozzilli (IS), Disorders Centre, Department of Neuroscience, Universita' G. D'Annunzio, Chieti-Pescara, Pescara, Italy. · Neurology. · Pubmed #15326260 No free full text.

Abstract: A median safinamide (SAF) dose of 70 mg/day (range 40 to 90 mg/day) increased the percentage of parkinsonian patients improving their motor scores by > or =30% from baseline (responders) after 3 months from 21.4% (placebo) to 37.5% (p < 0.05, calculated by logistic regression analysis). In a subgroup of 101 patients under stable treatment with a single dopamine agonist, addition of SAF magnified the response (47.1% responders, mean 4.7-point motor score decrease; p > or = 0.05). These results suggest that doses of SAF exerting ion channel block and glutamate release inhibition add to its symptomatic effect and warrant exploration of higher doses.

Ceravolo R, Volterrani D, Gambaccini G, Bernardini S, Rossi C, Logi C, Tognoni G, Manca G, Mariani G, Bonuccelli U, Murri L. · Department of Neuroscience, University of Pisa, Italy. · J Neural Transm. · Pubmed #15254794 No free full text.

Abstract: The occurrence of parkinsonism in Alzheimer's disease (AD) is quite common, however the molecular and neurochemical changes underlying such extrapyramidal features in AD have been not fully understood. Post-mortem as well as in vivo imaging study have produced conflicting results as regards the existence of dopaminergic changes in AD. Aim of the present study was to investigate in vivo the nigro-striatal dopaminergic function in a group of AD patients with parkinsonism. Thirteen patients with AD and extrapyramidal features not related to past neuroleptic use (AD-P) underwent SPECT with 123I-FP-CIT, a ligand of dopamine transporter, and the data were compared with those obtained in 15 patients with Diffuse Lewy Body Dementia (DLBD), 20 patients with Parkinson's disease (PD), and 8 healthy elderly controls. The analysis of the data was performed by regions-of-interest approach and calculations of the striatal-to-non specific (occipital lobes) radioactivity ratios were made. The 123I-FP-CIT striatal uptake in patients with AD-P was similar to that obtained in the control population. Both the DLBD and PD groups showed significantly lower 123I-FP-CIT uptake in all striatal areas with respect to AD-P and control groups (p < 0.005). The lack of dopamine transporter changes in our series of AD-P patients can indicate that dopaminergic presynaptic function is preserved in this population and that different dopaminergic changes such as postsynaptic ones, or different neurotransmitter alterations might underlie the extrapyramidal features in AD.

Marinus J, Visser M, Stiggelbout AM, Rabey JM, Martínez-Martín P, Bonuccelli U, Kraus PH, van Hilten JJ. · Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #14966153 links to  free full text

Abstract: OBJECTIVES: To evaluate the reliability and validity of the Short Parkinson's Evaluation Scale (SPES)/SCales for Outcomes in Parkinson's disease (SCOPA)-a short scale developed to assess motor function in patients with Parkinson's disease (PD). METHODS: Eighty five patients with PD were assessed with the SPES/SCOPA, Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (H&Y) scale, and Schwab and England (S&E) scale. Thirty four patients were examined twice by two different assessors who were blinded to each other's scores and test executions. Additionally, six items of the motor section of the SPES/SCOPA were assessed in nine patients and recorded on videotape to evaluate inter-rater and intra-rater reliability. RESULTS: The reproducibility of the sum scores in the clinical assessments was high for all subscales of the SPES/SCOPA. Inter-rater reliability coefficients for individual items ranged from 0.27-0.83 in the motor impairment section, from 0.58-0.82 in the activities of daily living section, and from 0.65-0.92 in the motor complications section. Inter-rater reliability of the motor items in the video assessments ranged from 0.70-0.87 and intra-rater reliability ranged from 0.81-0.95. The correlation between related subscales of the SPES/SCOPA and UPDRS were all higher than 0.85, and both scales revealed similar correlations with other measures of disease severity. The mean time to complete the scales differed significantly (p<0.001) and measured 8.1 (SD 1.9) minutes for the SPES/SCOPA and 15.6 (SD 3.6) minutes for the UPDRS. CONCLUSION: The SPES/SCOPA is a short, reliable, and valid scale that can adequately be used in both research and clinical practice.

Bonuccelli U, Lucetti C, Del Dotto P, Ceravolo R, Gambaccini G, Bernardini S, Rossi G, Piaggesi A. · Department of Neuroscience, Section of Neurology, Movement Disorders Unit, University of Pisa, Pisa, Italy. · Arch Neurol. · Pubmed #14568810 links to  free full text

Abstract: BACKGROUND: It is accepted that orthostatic hypotension is a clinical marker for the diagnosis of multiple system atrophy, but conflicting data indicate that it may also be present in Parkinson disease (PD). OBJECTIVES: To evaluate the prevalence of autonomic cardiovascular impairment and orthostatic hypotension in a large group of patients with de novo PD, followed up for at least 7 years, to clinically confirm the diagnosis of the disease. METHODS: During a 2-year recruiting period, 60 untreated patients diagnosed as having idiopathic PD underwent autonomic cardiovascular function evaluation using the Ewing test. Patients subsequently received dopaminergic therapy and their condition was followed up for at least 7 years. RESULTS: Nine (15%) of 60 patients were excluded from the study because during the follow-up period a parkinsonian syndrome was diagnosed (5 had multiple system atrophy and 4 had progressive supranuclear palsy). Data from 51 patients with PD underwent final statistical analysis and the results were compared with those of 51 age-matched healthy control subjects who had taken the same battery of autonomic tests. A statistically significant difference was found in postural hypotension (P =.02) and deep breathing test results (P =.03) between patients and controls. Seven (14%) of 51 patients with PD and 3 (60%) of 5 patients with multiple system atrophy had a decrease of more than 20 mm Hg in systolic blood pressure on standing. CONCLUSIONS: Data from this study indicate a high prevalence of sympathetic and parasympathetic failure in patients with de novo PD, and when using a decrease of at least 20 mm Hg in systolic blood pressure, manometric orthostatic hypotension was found in 7 (14%) of the 51 patients with de novo PD.

Bonuccelli U, Napolitano A, Del Dotto P, Quattrone A. · Department of Neuroscience, University of Pisa, Pisa, Italy. · Clin Neuropharmacol. · Pubmed #11981241 No free full text.

Abstract: The authors studied the motor response to apomorphine before and 1 year after levodopa therapy in 12 patients with Parkinson's disease. At the 1-year evaluation, the basal tapping score, recorded after a 12-hour levodopa withdrawal, was higher compared with the test performed while patients were de novo, indicating the presence of a long-duration response to levodopa. The amplitude (net increase) of the motor response to apomorphine was similar before and during levodopa therapy. However, because of the better baseline, the maximal tapping score was higher during levodopa therapy. The duration and the latency of the motor response to apomorphine did not change. The presence of a short-duration response to apomorphine, in the presence of a long-duration response to levodopa, may imply that either different compartment (i.e., postsynaptic versus presynaptic) or transduction pathways are involved in such responses.

Gabrielli L, Nocita P, Pasetti C, Bonuccelli U, Dell'Agnello G, Chiara Carboncini M, Rossi B. · Section of Neurology, Department of Neuroscience, University of Pisa, Via Roma 67, 56100 Pisa, Italy. · Int J Psychophysiol. · Pubmed #11852159 No free full text.

Abstract: PURPOSE: the aim of this experimental study was to evaluate the attention modulating actions on the polysynaptic component of blink reflex responses and especially of the R3 component in patients suffering from Parkinson's Disease (PD). To this end, a non-task warning paradigm was adopted. METHODS: attention processing was evaluated by means of a non-task paradigm in 55 patients suffering from PD. Subjects were presented with a visual 'warning' prestimulus and the blink reflex (BR) analyzed with special regard for any modulation of its polysynaptic components (R2-R3). RESULTS: The mean amplitude of the post-warning R3 component (PW-R3c) of 'de novo' PD patients was 62% of the corresponding component following unannounced stimuli, a figure which differs significantly from both treated PD patients (18.9%) and control subjects (15.4%). De novo patients subsequently started on L-dopa therapy exhibited a more pronounced inhibition of the R3 component after warning stimulus, as the PW-R3c percentage decreased. Inversely, treated patients whose therapy was withheld showed decreased inhibition of this component. Regarding R2, the mean PW-R2c in the de novo patients differed slightly from that of the treated patients (P<0.05), but not from that of the control subjects. Such a finding may be attributable to a specific effects on the excitability of the polysynaptic responses. CONCLUSIONS: Attention disorders in PD have been well documented by means of this kind of non-task warning paradigm, which appears to probe the modulation of the BR R3 component, even if the interpretation of this R3 changes suggesting a specific alteration of attention processing must be put forward extremely carefully, because something similar, but less evident, appears also for R2.

Del Dotto P, Pavese N, Gambaccini G, Bernardini S, Metman LV, Chase TN, Bonuccelli U. · Department of Neuroscience, Neurology Section, University of Pisa, Via Roma 67, 56100 Pisa, Italy. · Mov Disord. · Pubmed #11391748 No free full text.

Abstract: Experimental evidence suggests that glutamatergic receptor blockade may improve the motor response complications associated with long-term levodopa treatment in Parkinson's disease (PD) patients. Our objective was to evaluate the acute effect of amantadine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, on levodopa-induced dyskinesias, and to gain further insights into the antidyskinetic mechanism of this drug. Nine PD patients with motor fluctuations and severely disabling peak of dose dyskinesias received their first morning levodopa dose, followed by a 2-hour intravenous amantadine (200 mg) or placebo infusion, on two different days. Parkinsonian symptoms and dyskinesias were assessed every 15 minutes during the infusion and for 3 hours thereafter, while patients were taking their usual oral antiparkinsonian therapy, by means of Unified Parkinson's Disease Rating Scale (UPDRS, motor examination), tapping test, and a modified Abnormal Involuntary Movement Scale (AIMS). Intravenous amantadine acutely improved levodopa-induced dyskinesias by 50%without any loss of the anti-parkinsonian benefit from levodopa. This study confirms the antidyskinetic effect of amantadine and strengthens the rationale for using antiglutamatergic drugs in the treatment of parkinsonian motor fluctuations.

Bonuccelli U, Del Dotto P, Lucetti C, Petrozzi L, Bernardini S, Gambaccini G, Rossi G, Piccini P. · Department of Neuroscience, University of Pisa, Italy. · Clin Neuropharmacol. · Pubmed #10682228 No free full text.

Abstract: Patients with Parkinson's disease (PD) in long-term levodopa therapy often complain of worsening of motor symptoms in the afternoon and evening. The pathophysiology of this phenomenon is not known. We evaluated the motor response to repeated doses of levodopa during a 12-hour period in 52 parkinsonian patients (19 de novo, 20 stable, and 13 wearing-off). On the day of the study, all patients received standard doses of levodopa/carbidopa at 8:00 a.m., 12:00 noon, and 4:00 p.m. Motor measurements such as tapping test, walking time, and tremor score, and blood samples for levodopa and 3-O-methyldopa (3OMD) plasma analysis, were performed hourly. Mean motor scores and pharmacokinetic data, evaluated for a period of 3 hours after each levodopa dose, were compared. In de novo patients, we did not observe diurnal changes in motor score, whereas a progressive daytime worsening was visible in stable and wearing-off patients. No significant difference in levodopa pharmacokinetics after each levodopa dose was observed within each patient group, whereas 3OMD plasma levels significant increased with repeated levodopa administrations. However, no significant correlation between motor scores and 3OMD plasma levels was observed, suggesting that the diminishing motor response to afternoon and evening doses of levodopa in patients in long-term levodopa therapy does not relate to the pharmacokinetics of the drug. It is possible that this phenomenon may be an expression of the occurrence of tolerance to repeated doses of levodopa.

Borroni B, Malinverno M, Gardoni F, Alberici A, Parnetti L, Premi E, Bonuccelli U, Grassi M, Perani D, Calabresi P, Di Luca M, Padovani A. · Centre for Aging Brain and Dementia, Department of Neurology, University of Brescia, Italy. · Neurology. · Pubmed #18971445 No free full text.

Abstract: OBJECTIVE: In CSF, extended (55 kDa) and truncated (33 kDa) tau forms have been previously recognized, and the tau 33 kDa/55 kDa ratio has been found significantly reduced in progressive supranuclear palsy (PSP) vs in other neurodegenerative disorders. The aim of this study was to evaluate the diagnostic value of the CSF tau form ratio as a biomarker of PSP and to correlate the structural anatomic changes as measured by means of voxel-based morphometry (VBM) to CSF tau form ratio decrease. METHODS: A total of 166 subjects were included in the study (21 PSP, 20 corticobasal degeneration syndrome, 44 frontotemporal dementia, 29 Alzheimer disease, 10 Parkinson disease, 15 dementia with Lewy bodies, and 27 individuals without any neurodegenerative disorder). Each patient underwent a standardized clinical and neuropsychological evaluation. In CSF, a semiquantitative immunoprecipitation was developed to evaluate CSF tau 33 kDa/55 kDa ratio. MRI assessment and VBM analysis was carried out. RESULTS: Tau form ratio was significantly reduced in patients with PSP (0.504 +/- 0.284) when compared to age-matched controls (0.989 +/- 0.343), and to patients with other neurodegenerative conditions (range = 0.899-1.215). The area under the curve (AUC) of the receiver operating characteristic analysis in PSP vs other subgroups ranged from 0.863 to 0.937 (PSP vs others, AUC = 0.897, p < 0.0001). VBM study showed that CSF tau form ratio decrease correlated significantly with brainstem atrophy. CONCLUSIONS: Truncated tau production, which selectively affects brainstem neuron susceptibility, can be considered a specific and reliable marker for PSP. Tau form ratio was the lowest in progressive supranuclear palsy with no overlap with any other neurodegenerative illness.

Defazio G, Berardelli A, Fabbrini G, Martino D, Fincati E, Fiaschi A, Moretto G, Abbruzzese G, Marchese R, Bonuccelli U, Del Dotto P, Barone P, De Vivo E, Albanese A, Antonini A, Canesi M, Lopiano L, Zibetti M, Nappi G, Martignoni E, Lamberti P, Tinazzi M. · Department of Neurology and Psychiatry, University of Bari, Piazza Giulio Cesare 11, I-70124 Bari, Italy. · Arch Neurol. · Pubmed #18779422 No free full text.

Abstract: OBJECTIVE: To determine whether pain is more frequent among people with Parkinson disease (PD) than among age-matched controls. DESIGN: Case-control study. Patients and METHODS: Logistic regression models taking into account type of pain, time between pain and PD onset, and possible confounders were used to compare 402 PD patients with 317 age-matched healthy control subjects. RESULTS: The overall frequency of pain was significantly greater in PD patients than in controls (281 [69.9%] vs 199 [62.8%]; P = .04), mainly because the healthy control group lacked dystonic pain. Conversely, the frequency of nondystonic pain was similar among PD patients and controls (267 [66.4%] vs 199 [62.8%]; P = .28). Nevertheless, we observed a significant association between PD and nondystonic pain, beginning after the onset of parkinsonian symptoms (odds ratio, 2.1; 95% confidence interval, 1.4-2.9). Cramping and central neuropathic pain were more frequent among PD patients than controls. About one-quarter of patients who experienced pain reported pain onset before starting antiparkinsonian therapy. CONCLUSION: These data support the hypothesis that pain begins at clinical onset of PD or thereafter as a nonmotor feature of PD.

Antonini A, Abbruzzese G, Barone P, Bonuccelli U, Lopiano L, Onofrj M, Zappia M, Quattrone A. · Parkinson Institute, Istituti Clinici di Perfezionamento Milan, Italy. · Neuropsychiatr Dis Treat. · Pubmed #18728767 links to  free full text

Abstract: Levodopa is the most effective treatment in Parkinson's disease and the association with COMT inhibitors widens its plasma bioavailability and effectiveness. Tolcapone is a potent COMT inhibitor whose utilization in PD is limited due to safety concerns on liver toxicity. However, recent data indicate that if liver function is actively monitored, tolerability is no worse than other currently available therapies. By contrast, administration of tolcapone is associated with significant clinical improvement and benefit involves also non-motor features. In this review we discuss the rationale for the use of tolcapone in association with levodopa and other treatments in PD, and we provide an indirect comparison of current strategies to reduce "off" time. We propose that future guidelines include a trial with tolcapone in all PD patients who continue to complain about motor fluctuations despite treatment with entacapone and/or MAO-B inhibitors. Moreover, we suggest that tolcapone should be considered before surgical or infusional strategies are applied.

Morgante L, Nicoletti A, Epifanio A, Contrafatto D, Savica R, Lanzafame S, Musolino R, La Spina P, Bonuccelli U, Marconi R, D'Amelio M, Savettieri G, Zappia M. · Dipartimento di Neuroscienze, Scienze Psichiatriche ed Anestesiologiche, Università di Messina, Messina, Italy. · Parkinsonism Relat Disord. · Pubmed #18325817 No free full text.

Abstract: OBJECTIVE: To estimate prevalence of Parkinson's disease (PD) and other types of parkinsonism in the Aeolian Archipelago, Sicily. METHODS: We studied the frequency of PD and other types of parkinsonism in the Aeolian Archipelago (population 13,431). All potential cases were identified from available medical information sources. To ensure the completeness of the case-findings, a screening questionnaire was also mailed to residents aged 40 years and over. Subjects were considered prevalent if they fulfilled the SNES diagnostic criteria for PD, on prevalence day (January 1, 2001). RESULTS: We identified 17 patients with parkinsonism from medical sources, and 4 from mail-survey. Prevalence for all types of parkinsonism was 156.3/100,000 (95% CI 99.4-234.8). Fourteen subjects fulfilled diagnostic criteria for PD giving a crude prevalence of 104.2/100,000 (95% CI 59.4-170.7) and 422.5/100,000 in the population aged 60 years and over. CONCLUSIONS: Prevalence of all types of parkinsonism and PD found in the Aeolian Archipelago is lower than that previously reported in Sicily.

Tessa C, Giannelli M, Della Nave R, Lucetti C, Berti C, Ginestroni A, Bonuccelli U, Mascalchi M. · Radiology Unit, Versilia Hospital, Lido di Camaiore, Lucca, Italy. · AJNR Am J Neuroradiol. · Pubmed #18184843 links to  free full text

Abstract: BACKGROUND AND PURPOSE: Widespread cerebral changes are observed in advanced stages of Parkinson disease (PD), suggesting that PD is a multisystem disorder. We investigated with MR imaging whether global brain changes are present in early clinical stages of PD and correlated the findings with the type of clinical presentation. MATERIALS AND METHODS: T1-weighted images and mean diffusivity and fractional anisotropy (FA) maps calculated from diffusion tensor imaging (DTI) were obtained in 27 patients with de novo drug-naïve PD, who were classified according to the clinical features in tremor-dominant type (n = 13), akinetic-rigid type (n = 11), and mixed type (n = 3). Sixteen healthy subjects provided control data. With SIENAX software, total brain, gray matter (GM), and white matter (WM) volumes were computed from T1-weighted images, whereas brain histograms were obtained from mean diffusivity and FA maps. RESULTS: Total brain, GM and WM volumes were not significantly different in patients as a whole or subgroups and controls. As compared with controls, patients with PD as a whole and patients with the akinetic-rigid type showed an increase (P </= .01) of the twenty-fifth percentile of the FA histogram. In patients with the akinetic-rigid type, there also was a trend toward an increase of the mean and fiftieth and seventy-fifth percentiles, and a reduction of the skewness of the FA histogram. Patients with tremor-dominant type showed a trend toward an increase of the twenty-fifth percentile of the FA histogram. CONCLUSIONS: In patients with de novo PD, there is an increase of FA values, more pronounced in patients with the akinetic-rigid type, probably reflecting diffuse subtle GM loss. This is in line with the hypothesis that widespread neurodegeneration is already present at the time of the clinical onset.

Pellecchia MT, Longo K, Manfredi M, Lucetti C, Cossu G, Petrone A, Marconi R, Sensi M, Epifanio A, Eleopra R, Marchese R, Scaravilli T, Morgante L, Abbruzzese G, Bonuccelli U, Donati E, Pivonello R, Colao A, Barone P. · Department of Neurological Sciences, University of Naples Federico II, Naples, Italy. · Mov Disord. · Pubmed #18044703 No free full text.

Abstract: 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.