Dopamine agonist modifies cortical activity in Parkinson disease: a functional neuroimaging study.

OBJECTIVES: To investigate, using functional magnetic resonance imaging, the influence of a long-term dopaminergic therapy on brain activation during a simple motor task in early, previously untreated patients with Parkinson disease. METHODS: Thirteen patients with Parkinson disease in Hoehn-Yahr stage 1 or 2, with a right predominance of the disease, underwent functional magnetic resonance imaging during self-paced continuous right-hand tapping before and after 6 months of therapy with ropinirole 15 mg/d. The task was monitored online with a dedicated device, which measures the strength and frequency of the tapping. RESULTS: All patients with Parkinson disease on ropinirole treatment showed a clinically significant improvement, and their functional magnetic resonance imaging pattern after treatment showed a reduced activation in the right postcentral (primary sensory-motor area), supramarginal and inferior parietal gyri compared with the activation pattern before treatment. No area of increased activation was observed after therapy. CONCLUSIONS: In line with the classical functional deafferentation hypothesis, dopaminergic stimulation should increase motor cortex activity as a result of restoration of the striatocortical loops. On the contrary, our results challenge this hypothesis as we found decreased cerebral activity after a short-term chronic dopaminergic treatment. We suggest that the recruitment of cortical motor circuits aimed to overcome the functional deficit of the striatocortical loops lessens after dopaminergic treatment.

Concomitant development of hypersexuality and delusional jealousy in patients with Parkinson's disease: a case series.

BACKGROUND: Both impulse-control disorders and delusional jealousy (DJ) may be considered non-motor side-effects of dopamine agonist therapy in Parkinson's disease (PD). We aimed to investigate the possible concomitant development of these features in PD and their clinical correlates. METHODS: We performed a cross-sectional investigation in 1063 consecutive PD patients with the Questionnaire for Impulsive Compulsive Disorders in Parkinson's disease and the Parkinson's Psychosis Questionnaire. RESULTS: 81 patients presented ICDs (prevalence 7.61%) and 23 patients presented DJ (17 males, 6 females; prevalence 2.16%). 9 male PD patients presented both DJ and ICDs (39.13% of patients with DJ, 11.11% of patients with ICDs; prevalence of 0.84% in the whole PD sample), with a concomitant onset of delusional jealousy and hypersexuality in 8 cases and a concomitant onset of delusional jealousy and pathological gambling in 2 cases. DISCUSSION: Hypersexuality and delusional jealousy may occur independently in PD patients "on" dopamine agonist therapy, but may develop together probably reflecting a common alteration of sexuality (sexual arousal and jealousy) The presence of both of these clinical features and sexuality more in general should be investigated when features of either one of them appear. Further confirmation is needed in larger samples of patients.

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.

The relationship between motor symptom lateralization and cognitive performance in newly diagnosed drug-naïve patients with Parkinson's disease.

The side of motor symptom predominance may influence cognitive performance in patients with Parkinson's disease (PD): PD patients with right-side motor symptom predominance typically present difficulties in tasks of language and verbal memory, whereas PD patients with left-side motor symptom predominance typically present difficulties in visuospatial tasks. The current study aimed at investigating the relationship between motor symptom lateralization and cognitive performance in PD patients without the possible confounding effect of dopaminergic drugs, which may enhance or impair cognition on the basis of assessed function and disease stage. From the initial sample of 137 consecutive newly diagnosed drug-naïve (de novo) PD patients, clinical follow-ups and neurological examinations identified 108 right-handed patients with a unilateral motor presentation or a clear motor asymmetry (59 right-PD: 54.6%; 49 left-PD: 45.4%). Any cognitive difference emerged between right-PD patients and left-PD patients at this disease stage. Scores of lateralized motor impairment severity correlated with some cognitive performances: Right motor impairment correlated with a measure of set shifting (Trail Making Test B-A), and left motor impairment correlated with phonemic fluency and tasks with visuospatial material (Colored Progressive Matrices of Raven, Rey-Osterrieth Complex Figure Copy and Immediate Recall). Findings of the current study supported the conclusion that the side of clinical motor predominance scarcely influences cognition in the early untreated stages of PD, suggesting that cognitive differences between subgroups of lateralized PD patients probably may appear in more advanced disease 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.

The progression of non-motor symptoms in Parkinson's disease and their contribution to motor disability and quality of life.

Non-motor symptoms are gaining relevance in Parkinson's disease (PD) management but little is known about their progression and contribution to deterioration of quality of life. We followed prospectively 707 PD patients (62 % males) for 2 years. We assessed non-motor symptoms referred to 12 different domains, each including 1-10 specific symptoms, as well as motor state (UPDRS), general cognition, and life quality. Hoehn & Yahr (H&Y) stage was used to categorize patient status (I-II mild; III moderate; IV-V severe). We found that individual non-motor symptoms had variable evolution over the 2-year follow-up with sleep, gastrointestinal, attention/memory and skin disturbances (hyperhidrosis and seborrhea) becoming more prevalent and psychiatric, cardiovascular, and respiratory disorders becoming less prevalent. Development of symptoms in the cardiovascular, apathy, urinary, psychiatric, and fatigue domains was associated with significant life-quality worsening (p < 0.0045, alpha with Bonferroni correction). During the observation period, 123 patients (17 %) worsened clinically while 584 were rated as stable. There was a fivefold greater increase in UPDRS motor score in worse compared with stable patients over 24 months (p < 0.0001 vs. baseline both in stable and worse group). The total number of reported non-motor symptoms increased over 24 months in patients with motor worsening compared to stable ones (p < 0.001). Thirty-nine patients died (3.4 % of patients evaluable at baseline) with mean age at death of 74 years. Deceased patients were older, had significantly higher H&Y stage and motor score, and reported a greater number of non-motor symptoms at baseline. In conclusion, overall non-motor symptom progression does not follow motor deterioration, is symptom-specific, and only development of specific domains negatively impacts quality of life. These results have consequences for drug studies targeting non-motor features.

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.

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.

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.

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.

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.

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.

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 Parkinson's 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.

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 Parkinson's 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 subject's 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.