A pilot psychometric study of aberrant salience state in patients with Parkinson's disease and its association with dopamine replacement therapy.

An overactive striatal dopaminergic neurotransmission is described in psychosis and may be associated with a state of aberrant salience attribution. This pilot psychometric study investigated if features suggestive of an aberrant salience state, a condition of psychosis proneness, are associated with dopamine replacement therapy in patients with early Parkinson's disease (PD). 77 participants (50 medicated PD patients, 12 newly diagnosed drug-naive PD patients and 15 healthy controls) were enrolled and assessed with the Aberrant Salience Inventory (ASI). Differences between groups were found for ASI scores, and ASI scores correlated with the dopaminergic therapy, in particular levodopa. These findings preliminary suggested that the presence and the degree of an aberrant salience state may be associated with features of the dopaminergic therapy; further studies are needed to investigate which neuropsychiatric complications more common in PD patients may be characterized by an underlying aberrant salience state.

A single-center, cross-sectional prevalence study of impulse control disorders in Parkinson disease: association with dopaminergic drugs.

The current study aimed at establishing the prevalence of impulse control disorders (ICDs) in patients with Parkinson disease (PD) and their association with demographic, drug-related, and disease-related characteristics. We performed a single-center cross-sectional study of 805 PD patients. Impulse control disorders were investigated with the Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease; also comorbid neuropsychiatric complications (dementia, delusions, visual hallucinations) were investigated with clinical interviews and ad hoc instruments (Parkinson Psychosis Questionnaire and Neuropsychiatry Inventory). Impulse control disorders were identified in 65 patients (prevalence, 8.1%), with pathological gambling and hypersexuality the most frequent. Impulse control disorders were present in 57 of 593 cognitively preserved patients (prevalence, 9.6%) and in 8 of 212 demented patients (prevalence, 3.8%). Impulse control disorders were significantly associated with dopamine agonists (odds ratio [OR], 5.50; 95% confidence interval [CI], 2.60-12.46; P < 0.0001) and levodopa (OR, 2.43; 95% CI, 1.06-6.35; P = 0.034). Impulse control disorders frequency was similar for pramipexole and ropinirole (16.6% vs 12.5%; OR, 1.45; 95% CI, 0.79-2.74; P = 0.227). Additional variables associated with ICDs were male sex and younger age. These findings suggested that dopaminergic treatments in PD are associated with increased odds of having an ICD, but also other demographic and clinical variables are associated with ICDs, suggesting the multifactorial nature of the ICD phenomenon in PD.

Diagnosis, assessment and management of delusional jealousy in Parkinson's disease with and without dementia.

Patients with Parkinson's disease (PD) may present delusional jealousy (DJ). In a previous cross-sectional prevalence study we identified 15 cognitively preserved and five demented PD patients with DJ. The current study aimed at evaluating their clinical (motor and non-motor) characteristics and the pharmacological treatments associated with DJ, and its subsequent pharmacological management. Patients were assessed by neurologists and psychiatrists using the Hoehn and Yahr scale, the Unified Parkinson's Disease Rating Scale, the Brief Psychiatric Rating Scale, the Beck Depression Inventory, the Hamilton Anxiety Scale and the Neuropsychiatric Inventory. Efficacy of DJ management was evaluated in follow-up visits. All patients were in therapy with dopamine agonists. A subgroup of five cognitively preserved patients developed DJ after a short period of treatment of therapy with dopamine agonists, while other patients developed DJ after a longer period of dopaminergic treatment. Psychiatric comorbidities were common in cognitively preserved and in demented patients. The pharmacological management included the interruption of dopamine agonists in two patients and the reduction of dopamine agonist dose plus the use of antipsychotics in other patients. These clinical data suggest that the management of medicated PD patients should include investigation for the presence of DJ and the evaluation of clinical characteristics potentially relevant to the prevention or the early recognition of delusions.

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 Parkinson's 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 Parkinson's 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.

Dopamine agonists and delusional jealousy in Parkinson's disease: a cross-sectional prevalence study.

BACKGROUND: Delusional jealousy (DJ) has been described in patients with Parkinson's disease (PD) on dopaminergic therapy, but a role for dopaminergic therapy in DJ has not been established. METHODS: The current cross-sectional study on DJ investigated its association with dopaminergic therapies compared with their associations with hallucinations and its prevalence in PD patients. Eight hundred five consecutive patients with PD were enrolled between January 2009 and June 2010. RESULTS: DJ was identified in 20 patients (2.48%) and hallucinations in 193 patients (23.98%). In the multivariate logistic regression analyses, dopamine agonists were significantly associated with DJ (odds ratio, 18.1; 95% CI, 3.0-infinity; P = .0002) but not with hallucinations (odds ratio, 0.73; 95% CI, 0.49-1.10; P = .133). CONCLUSIONS: These findings suggest that dopamine agonist treatment represents a risk factor for DJ in PD independent of the presence of a dementing disorder, and the presence of this additional nonmotor side effect should be investigated in this clinical population.

Frontal assessment battery scores and non-motor symptoms in parkinsonian disorders.

Using data from the PRIAMO study, we investigated non-motor symptoms (NMS) versus frontal lobe dysfunction in patients with idiopathic Parkinson disease (PD); 808 patients with PD and 118 with atypical parkinsonisms (AP) were consecutively enrolled at 55 Centers in Italy. Twelve categories of NMS were investigated. Cognitive impairment was defined as a Mini-Mental Status Evaluation score ≤ 23.8 and frontal lobe dysfunction as a Frontal Assessment Battery (FAB) score ≤ 3.48. Multivariable logistic regression was used to identify predictor of frontal lobe dysfunction in 524 PD patients, and a generalized linear model was used for each of the six FAB items. Not only the total FAB scores but also the single FAB items were lower in AP versus PD (p ≤ 0.005). Age (OR = 1.05), cognitive impairment (OR = 9.54), lack of cardiovascular symptoms (OR = 3.25), attention or memory problems (OR = 0.59) and treatment with L: -DOPA (OR = 5.58) were predictors of frontal lobe dysfunction. MMSE was negatively associated with all FAB items (ß ≤ -0.16) and age with all FAB items but prehension behavior (ß ≤ -0.01). Previous use of L: -DOPA was negatively associated with verbal fluency (ß = -0.32) possibly acting as surrogate marker of disease duration. Cognitive impairment is a predictor of frontal lobe dysfunction. Among NMS, lack of attention or memory problems were negatively associated with frontal impairment. Further studies are nonetheless needed to better identify the predictors of frontal impairment in PD patients.

Bilateral thalamic infarct caused by spontaneous vertebral artery dissection in pre-eclampsia with HELLP syndrome: a previously unreported association.

Cerebrovascular accidents are not rare during pregnancy and the postpartum period. Pre-eclampsia is a common condition that is characterized by proteinuria and de novo hypertension that may be complicated by hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Spontaneous cervical artery dissection has been rarely reported in the postpartum period but never in association with HELLP syndrome. We describe a case of pre-eclampsia and HELLP syndrome complicated in the postpartum period by bilateral thalamic infarct as result of left vertebral artery dissection. We speculated about the possible common etiopathologic mechanisms involved in this previously unreported association.

Alexithymia may modulate decision making in patients with de novo Parkinson's disease.

The aim of this study was to investigate whether and how alexithymia may influence decision making under conditions of uncertainty, assessed using the Iowa Gambling Task, in patients with newly diagnosed, untreated (de novo) Parkinson's disease, as previously reported for healthy subjects. Twenty-four patients with de novo Parkinson's disease underwent a neuropsychological and neuropsychiatric assessment, including the Toronto Alexithymia Scale, the Geriatric Depression Scale Short Form, and the Iowa Gambling Task (IGT). The assessment showed that 12 patients were alexithymic and 12 were non-alexithymic; seven patients were found to be mildly depressed and 17 non-depressed. Alexithymic and non-alexithymic patients did not differ in the IGT total score; however, significant differences emerged across the third block of the IGT, in which the alexithymic patients outperformed the nonalexithymic patients. Depression did not influence IGT performance. Alexithymia may modulate decision making, as assessed with the IGT; alexithymia could be associated with faster learning to avoid risky choices and negative feedback, as previously reported in some studies conducted in anxious or depressed patients.

HCT116 cells deficient in p21(Waf1) are hypersensitive to tyrosine kinase inhibitors and adriamycin through a mechanism unrelated to p21 and dependent on p53.

p21(Waf1) (p21) was described as a cyclin-dependent kinase inhibitor, but other p21 activities have subsequently been described, including its ability to inhibit apoptosis in some models. Comparative work on the human colon cancer isogenic cell lines HCT116 and HCT116p21(-/-) led to the proposal that p21 protects colon cancer cells against apoptosis by genotoxic drugs. We asked whether p21 also protected from cell death induced by non-genotoxic drugs, such as tyrosine kinase inhibitors. We found that p21-deficient cells were dramatically more sensitive towards imatinib and gefitinib than parental cells. Interestingly, HCT116p21(-/-) also showed higher basal activity of protein kinases as c-Abl, c-Src, and Akt. We generated HCT116p21(-/-) sublines with inducible p21 expression and found that p21 did not rescue the hypersensitivity to imatinib. Moreover, down-regulation of p21 by enforced c-Myc expression or by p21 siRNA did not sensitize parental HCT116 cells. We found that, in HCT116p21(-/-) cells, p53 showed higher stability, higher transcriptional activity and phosphorylation in serines associated with p53 activity. Furthermore, silencing of p53 with siRNA and inactivation of p53 with a dominant negative mutant rescued the hypersensitive response to kinases inhibitors, 5-fluorouracil and adriamycin in HCT116p21(-/-) cells. Consistently, HCT116p53(-/-) cells are more resistant to imatinib than parental cells, suggesting that imatinib activity is partly dependent on p53 in colon cancer cells. We conclude that high p53 activity, rather than p21 deficiency, is the mechanism responsible for hypersensitivity to drugs of HCT116p21(-/-) cells. Therefore the role of p21 on apoptosis of HCT116 colon cancer cells should be re-evaluated.

Decision making in de novo Parkinson's disease.

The aim is to study decision making in patients with de novo Parkinson's 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.

The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease.

We performed a multicenter survey using a semistructured interview in 1,072 consecutive patients with Parkinson's disease (PD) enrolled during 12 months in 55 Italian centers to assess the prevalence of nonmotor symptoms (NMSs), their association with cognitive impairment, and the impact on patients' quality of life (QoL). We found that 98.6% of patients with PD reported the presence of NMSs. The most common were as follows: fatigue (58%), anxiety (56%), leg pain (38%), insomnia (37%), urgency and nocturia (35%), drooling of saliva and difficulties in maintaining concentration (31%). The mean number of NMS per patient was 7.8 (range, 0-32). NMS in the psychiatric domain were the most frequent (67%). Frequency of NMS increased along with the disease duration and severity. Patients with cognitive impairment reported more frequently apathy, attention/memory deficit, and psychiatric symptoms. Apathy was the symptom associated with worse PDQ-39 score but also presence of fatigue, attention/memory, and psychiatric symptoms had a negative impact on QoL. These findings further support a key role for NMS in the clinical frame of PD and the need to address them specifically in clinical trials using dedicated scales.

Long-term clinical evaluation in patients with Parkinson's disease and early autonomic involvement.

OBJECTIVE: To evaluate in a prospective longitudinal study the evolution of functional disability and the response to dopaminergic therapy in PD patients with and without autonomic involvement. METHODS: Sixty untreated consecutive patients with PD underwent autonomic cardiovascular function evaluation using the five autonomic tests of Ewing. An integrated index (Autonomic Score=AS), taking in account the results of all subtests, was calculated. Patients were treated with pergolide and bromocriptine during a 5-year follow-up until the level of functional disability was sufficient to warrant the initiation of levodopa therapy. RESULTS: Results of autonomic testing were compared with those of a group of age-matched healthy subjects. A value of AS>2 was considered as indicative of autonomic failure. Eighteen patients with PD (35%) showed AS>2 (autonomically impaired group=AI), the remaining 33 (65%) had AS<2 (nonautonomically impaired group=non-AI). During the follow-up levodopa was added to the treatment regimen of 10/18 (55%) patients in AI group, and 6/33 (18%) patients in non-AI group (p<.01). CONCLUSIONS: The increased occurrence of levodopa adjunct in autonomically impaired PD suggests that there is a more rapid deterioration of functional performance in parkinsonian patients with early autonomic involvement.

Orthostatic hypotension in de novo Parkinson disease.

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.

Clinical pharmacokinetics of cabergoline.

Cabergoline is a synthetic ergoline dopamine agonist with a high affinity for D(2) receptors indicated for use in both early and advanced Parkinson'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 Parkinson'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.

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 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.