Paolo Del Dotto

Pain as a nonmotor symptom of Parkinson disease: evidence from a case-control study

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.

Intravenous amantadine improves levadopa-induced dyskinesias: an acute double-blind placebo-controlled study.

Experimental evidence suggests that glutamatergic receptor blockade may improve the motor response complications associated with long‐term levodopa treatment in Parkinsons 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 Parkinsons 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.

Mild cognitive impairment and cognitive-motor relationships in newly diagnosed drug-naive patients with Parkinson's disease

Background and aims (1) To establish the prevalence of mild cognitive impairment (MCI) in newly diagnosed drug-naive patients with Parkinsons disease adopting recently proposed and more conservative preliminary research criteria. (2) To investigate the relation between cognitive performances, MCI and motor dysfunction. Methods 132 consecutive newly diagnosed drug-naive PD patients and 100 healthy controls (HCs) underwent a neuropsychological evaluation covering different cognitive domains. Moreover, on the basis of the Unified Parkinsons Disease Rating Scale II/III, different motor scores were calculated and patients were classified in motor subtypes. 11 patients were excluded from the analysis during clinical follow-up which was continued at least 3 years from the diagnosis; therefore, the final sample included 121 patients. Results MCI prevalence was higher in PD (14.8%) patients than in HCs (7.0%). PD patients reported lower cognitive performances than HCs in several cognitive domains; HCs also outperformed cognitively preserved PD patients in tasks of episodic verbal memory and in a screening task of executive functions. MCI-PD patients presented a more severe bradykinesia score than non-MCI PD patients and patients mainly characterised by tremor had better performances in some cognitive domains, and specific cognitive-motor relationships emerged. Conclusions Although the adoption of more conservative diagnostic criteria identified a lower MCI prevalence, we found evidence that newly diagnosed drug-naive PD patients present a higher risk of MCI in comparison with HCs. Axial symptoms and bradykinesia represent risk factors for MCI in PD patients and a classification of PD patients that highlights the presence/absence of tremor, as proposed in this study, is probably better tailored for the early stages of PD than classifications proposed for more advanced PD stages.

Decision making in de novo Parkinson's disease

The aim is to study decision making in patients with de novo Parkinsons disease (PD). Recent studies reported that medicated patients with PD have poor performances compared with age‐matched healthy controls in decision making tasks, specially in the Iowa Gambling Task. Two principal causal hypotheses have been proposed to explain this phenomenon: the overdosing effects of dopaminergic therapy on the orbital frontostriatal circuit that is involved in reward processing, or an amygdala dysfunction, as suggested by similar Skin Conductance Responses of patients with PD and amygdala‐damaged patients while performing this task. The assessment of decision making with the Iowa Gambling Task was conducted in 30 nondemented and nondepressed patients with de novo PD and in 25 age‐matched healthy controls. No statistically significant difference emerged between performances of de novo PD patients and performances of healthy controls. De novo PD patients have performances in the Iowa Gambling Task similar to those of age‐matched healthy controls, suggesting that difficulties in decision making emerge, at least in de novo PD patients, by dopaminergic overstimulation of the orbital frontostriatal circuits.

Clinical Pharmacokinetics of Cabergoline

Cabergoline is a synthetic ergoline dopamine agonist with a high affinity for D2 receptors indicated for use in both early and advanced Parkinsons’s disease and in hyperprolactinaemic disorders.Following oral administration, peak plasma concentrations of cabergoline are reached within 2–3 hours. Over the 0.5–7mg dose range, cabergoline shows linear pharmacokinetics in healthy adult volunteers and parkinsonian patients. Cabergoline is moderately bound (around 40%) to human plasma proteins in a concentration-independent manner; concomitant administration of highly protein-bound drugs is unlikely to affect its disposition. The absolute bioavailability of cabergoline is unknown.Cabergoline is extensively metabolised by the liver, predominantly via hydrolysis of the acylurea bond of the urea moiety. Cytochrome P450-mediated metabolism appears to be minimal. The major metabolites identified thus far do not contribute to the therapeutic effect of cabergoline. A significant fraction of the administered dose undergoes a first-pass effect. Less than 4% is excreted unchanged in the urine. The elimination half-life of cabergoline estimated from urinary data of healthy subjects ranges between 63 and 109 hours. Mild to moderate renal and hepatic impairment, administration of food and the use of concomitant antiparkinsonian medications, such as levodopa and Selegiline, have no effect on the pharmacokinetics of cabergoline.The pharmacokinetic properties of cabergoline allow once daily administration in patients with Parkinsons’s disease and twice weekly administration in patients with hyperprolactinaemia, making this drug advantageous over other dopaminergic agents in term of both therapeutic compliance and better symptom control.

Decreased and increased cortical activation coexist in de novo Parkinson's disease

Previous fMRI studies using motor tasks yielded conflicting results concerning the activation pattern in Parkinsons disease (PD) patients. Possible explanations of these discrepancies include differences in the clinical features of the examined patients and in the executed tasks and incomplete task monitoring. We evaluated with fMRI 20 patients with untreated de-novo PD and 11 healthy controls with a simple motor task consisting of self-paced continuous right hand-tapping. The task was monitored on-line with a dedicated device which measures the strength and frequency of the tapping. Fifteen patients performed the task correctly. The frequency was not significantly different, whereas force was slightly different between patients (26.4+/-3.0 N) and controls (28.5+/-2.4 N) (p=0.046, Mann-Whitney U-test). After insertion of the subjects frequency and force as covariate variables in the model, PD patients compared to controls showed areas of significantly [Z statistic image>5.1 and p< or =0.05 (corrected) cluster significance] lower activation in the left primary sensorimotor (SM1) cortex and cerebellum and higher activation in the left temporal-parietal cortex adjacent to the SM1 and in right SM1. Furthermore in PD patients the disease severity evaluated with the Hoehn and Yahr staging system correlated significantly [Z statistic image>2.3 and p< or =0.05 (corrected) cluster significance] with activation of left SM1 and supplementary motor area and cingulum, bilaterally. The mixed pattern of decreased and increased cortical activation in de novo PD patients possibly reflects the coexistence of cortical deafferentation, and compensatory phenomena by cortico-cortical circuits.

Pergolide in the treatment of patients with early and advanced Parkinson's disease.

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 Parkinsons 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.

Levodopa response in dementia with lewy bodies: A 1-year follow-up study

PURPOSE To evaluate levodopa responsiveness in patients with probable dementia with Lewy bodies (DLB) compared to early Parkinsons disease (PD) patients. METHODS Twenty four cases with DLB and 21 with PD underwent a baseline assessment with UPDRS (sub-item II and III) and an acute levodopa challenge test. Positive response to acute levodopa test was defined as an improvement of at least 15% in the tapping test, and at least 25% in the walking test and rigidity or tremor score. Subsequently, all patients were treated continuously with levodopa and evaluated after 6 and 12 months by means of UPDRS II/III. RESULTS Positive response to the acute levodopa test was observed in 55% of DLB patients (acute DLB responders), and in 90% of PD patients (acute PD responders). Acute DLB responders showed increased latency, and reduction of both duration and amplitude of response to acute levodopa in comparison with acute PD responders. At the 6-month follow-up visit, acute DLB responders showed a greater motor benefit compared with acute DLB non-responders. This improvement was similar to that observed in PD patients. However, at 1-year follow-up acute DLB responders showed a faster worsening of UPDRS III scores compared with acute PD responders, implying a reduction of levodopa efficacy. CONCLUSIONS Positive response to acute levodopa test can occur in DLB patients and may be predictive of long-term benefit of chronic levodopa therapy, although the motor improvement is less impressive than in PD patients.

Alexithymia is associated with depression in de novo Parkinson's disease

drocephalus, moderate-to-severe vascular abnormalities, and tumors. Exclusion criteria were the presence of a comorbid psychiatric mental disorder or a history of drug abuse. In all de novo PD patients we recorded gender, age, years of education, and the side and the type of motor symptoms’ onset. The severity of motor symptoms was measured by the Unified Parkinson’s Disease Rating Scale (UPDRS II and III) [13] . In all enrolled subjects the global cognitive status was assessed with the Mini-Mental State Examination (MMSE) [14] . Informed consent was obtained in compliance with research standards for human research for all participating institutions and in accordance with the Helsinki Declaration. The TAS-20 is an extensively validated self-report questionnaire comprised of three subscales that investigate the following factors: F1 = difficulty identifying feelings, F2 = difficulty describing feelings, and F3 = difficulty focusing on inner affective experience. The total score on the questionnaire allows categorizing subjects as nonalexithymic (scores ranging from 20 to 51), borderline alexithymic (scores ranging from 52 to 60), or alexithymic (scores 6 61). A 2 test was used for the comparison between qualitative characteristics of the de novo PD subgroups; the Wilcoxon test was used for the comparison of quantitative variables for independent data. All de novo PD patients and all HC were cognitively preserved. Demographic and clinical characteristics of de novo PD patients and HC are reported in table 1 . No differences were found for age, education, cognitive status (MMSE), alexithymia (TAS-20 score) and depression (GDS-15 score) between de novo PD patients and HC. A statistically significant difference was approached for the subscale F2 (p = 0.07). In the group of de novo PD patients, cutoff scores of the TAS-20 identified 10 alexithymic patients (23.80%), 11 borderline alexithymic patients (26.19%) and 21 nonalexithymic patients (50.01%). In the group of HC, 5 subjects were alexithymic (16.6%), 7 subjects were borderline alexithymic (23.3%) and 18 were nonalexithymic (60.1%) ( table 1 ). The difference between frequencies of alexithymia in de novo PD patients (23.80%) and HC (16.6%) was not statistically different (p = 0.33). In the group of de novo PD patients, any difference was found for age, education, cognitive status (MMSE) and motor severity (UPDRS II and III) between alexithymic, borderline alexithymic and nonalexithymic de novo PD patients. Either in the sample of de novo PD patients or in the sample of HC, alexithymic subjects were more depressed at the GDS-15 than nonalexithymic or borderline alexithymic subjects (p ! 0.01) and borderline alexithymic subjects were more depressed than nonalexithymic subjects (p ! 0.01). In the sample of de novo PD patients, the TAS-20 significantly correlated with age (r = 0.343; p = 0.026), with education (r = Alexithymia is a phenomenon related to an alteration in affect regulation. Its characteristics include the inability to identify and describe feelings, difficulty distinguishing feelings from bodily sensations of emotional arousal, impaired symbolization and an externally oriented cognitive style [1] . Alexithymia has been found to be strongly associated with depression in both general [2] and clinical populations [3] . Alexithymic and depressive symptoms may be partially overlapping, but not all are correlated with depressive symptoms, thus underlining the relative independence of the two disorders [4] . Parkinson’s disease (PD) is a clinical condition often characterized by depression and an altered emotional processing [5] . In medicated PD patients alexithymia has a prevalence of 21% [6, 7] and is related to depression [7] . To our knowledge, alexithymia has never been investigated in newly diagnosed untreated (de novo) PD patients before the administration of dopaminergic therapy; this topic is of particular clinical interest considering that affective symptoms may precede the clinical motor onset of PD [8, 9] . This study was aimed at investigating the prevalence of alexithymia in de novo PD patients and its relation to depression. To estimate the prevalence of alexithymia and its relation to depression in de novo PD patients we administered the TwentyItem Toronto Alexithymia Scale (TAS-20) [10] and the Geriatric Depression Scale Short Form (GDS-15) [11] to 42 de novo PD patients and 30 age-matched healthy controls (HC). The de novo PD patients were enrolled in two Italian movement disorder tertiary clinics (Versilia Hospital, Viareggio; Neurological Clinic, University of Pisa). All enrolled patients fulfilled research diagnostic criteria for idiopathic PD [12] . Patients who had clinical features suggestive of primary atypical parkinsonism, such as multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, and those with diagnosis of dementia according to DSM-IV criteria were not included. Magnetic resonance imaging showed no signs of atypical parkinsonism, normal pressure hyReceived: April 15, 2010 Accepted after revision: October 6, 2010 Published online: May 4, 2011

The association between motor subtypes and alexithymia in de novo Parkinson’s disease

This study aimed at investigating the association between motor subtypes and alexithymic features in patients with newly diagnosed untreated (de novo) Parkinson’s disease. This objective derived from empirical findings about an association between the postural instability/gait difficulty motor subtype of Parkinson’s disease and more marked symptoms of depression, an affective disorder strongly related to alexithymia. A total of 42 patients with de novo Parkinson’s disease underwent neuropsychiatric assessment, including the toronto alexithymia scale (TAS-20) and the geriatric depression scale (GDS-15). On the basis of scores reported at the unified Parkinson’s disease rating scale III section, patients were classified within postural instability/gait difficulty motor subtype tremor dominant motor subtype and mixed motor subtype. Patients of the postural instability/gait difficulty motor subtype reported significantly higher alexithymic features compared to patients of the other motor subtypes. Considering the strong association between alexithymia and depression, this finding is in line with previous findings reporting that the postural instability/gait difficulty subtype of Parkinson’s disease is associated to more marked psychopathological features, especially affective features (depression and apathy). In conclusion this brief report suggests the usefulness of an early neuropsychiatric assessment of affect regulation difficulties in PD patients, especially in those with a prevalence of akinetic/rigid symptoms.