Minor hallucinations occur in drug-naive Parkinson's disease patients, even from the premotor phase.

OBJECTIVES: The description of minor hallucinatory phenomena (presence, passage hallucinations) has widened the spectrum of psychosis in Parkinson's disease (PD). Minor hallucinatory phenomena seem to antedate the development of more severe hallucinations. Early detection of minor hallucinations may be useful for screening patients with more severe endophenotypes. Motivated by the observation of "de novo," drug-naive PD patients reporting minor hallucinations, we aimed to prospectively identify "de novo" untreated PD patients experiencing hallucinatory phenomena, and to compare their clinico-demographic characteristics with those of untreated PD patients without hallucinations and healthy controls. METHODS: Screening and description of psychosis was assessed by the Movement Disorders Society Unified Parkinson's Disease Rating Scale-Part I and a structured interview covering all types of psychotic phenomena reported in PD. Clinical, neuropsychological, and demographic data of PD patients with and without psychotic phenomena were compared with those of age- and education-matched healthy controls. RESULTS: Fifty drug-naive, "de novo" PD patients and 100 controls were prospectively included. Minor hallucinations were experienced in 42% (21 of 50) PD patients and 5% controls (P < 0.0001). Coexistence of passage and presence hallucinations was the most common finding. Unexpectedly, 33.3% of patients with minor hallucinations manifested these as a pre-motor symptom, starting 7 months to 8 years before first parkinsonian motor symptoms. The presence of minor hallucinations was significantly associated with presence of rapid eye movement sleep behavior disorder. CONCLUSIONS: In this first study to prospectively analyze the frequency of minor hallucinatory phenomena in incident, untreated PD patients, hallucinations appeared as a frequent early non-motor symptom that may even predate the onset of parkinsonism.

Parkinson's disease-cognitive rating scale: psychometrics for mild cognitive impairment.

Lack of validated data on cutoff scores for mild cognitive impairment (MCI) and sensitivity to change in predementia stages of Parkinson's disease (PD) limit the utility of instruments measuring global cognition as screening and outcome measures in therapeutic trials. Investigators who were blinded to PD-Cognitive Rating Scale (PD-CRS) scores classified a cohort of prospectively recruited, nondemented patients into a PD with normal cognition (PD-NC) group and a PD with MCI (PD-MCI) group using Clinical Dementia Rating (CDR) and the Mattis Dementia Rating Scale-2 (MDRS-2). The discriminative power of the PD-CRS for PD-MCI was examined in a representative sample of 234 patients (145 in the PD-NC group; 89 in the PD-MCI group) and in a control group of 98 healthy individuals. Sensitivity to change in the PD-CRS score (the minimal clinically important difference was examined with the Clinical Global Impression of Change scale and was calculated with a combination of distribution-based and anchor-based approaches) was explored in a 6-month observational multicenter trial involving a subset of 120 patients (PD-NC, 63; PD-MCI, 57). Regression analysis demonstrated that PD-CRS total scores (P < 0.001) and age (P = 0.01) independently differentiated PD-NC from PD-MCI. Area under the receiver operating characteristic curve (AUC) analysis (AUC, 0.85; 95% confidence interval, 0.80-0.90) indicated that a score ≤ 81 of 134 was the optimal cutoff point on the total score for the PD-CRS (sensitivity, 79%; specificity, 80%; positive predictive value, 59%; negative predictive value, 91%). A range of change from 10 to 13 points on the PD-CRS total score was indicative of clinically significant change. These findings suggest that the PD-CRS is a useful tool to identify PD-MCI and to track cognitive changes in nondemented patients with PD.

Apathy in Parkinson's disease: more than just executive dysfunction.

Apathy is a frequent syndrome in Parkinson's disease (PD) usually associated with depression, cognitive impairment (CI), and dementia. Whereas executive dysfunction seems to play a major causative role in the development of apathy in PD, recent findings pointed for the possible participation of other underlying mechanisms in the development of clinically meaningful symptoms of apathy. By means of neuropsychological testing focused over global cognitive functioning, set-shifting, decision making, and cognitive effort, we compared to a control group, a carefully selected sample of PD patients presenting apathy as the only neuropsychiatric symptom and without clinically relevant signs of cognitive impairment. In addition to the previously reported executive dysfunction, apathetic patients also exhibited significant difficulties in tasks assessing for cortical functioning, such as naming and clock drawing. Moreover, apathetic patients performed significantly better on a decision-making task, although any of these differences appeared linked to a lack of effort when performing the tasks. On the basis of our findings, we discuss the possible implication of added mechanisms rather than just executive dysfunction in the development of apathy in PD.

Secondary nonmotor negative symptoms in healthy volunteers after single doses of haloperidol and risperidone: a double-blind, crossover, placebo-controlled trial.

OBJECTIVE: The effect of antipsychotics (APs) on negative symptoms is controversial. The present study assessed negative symptoms in healthy volunteers without any source of primary negative symptoms after single doses of haloperidol and risperidone. METHODS: Twenty-five healthy subjects were included in this randomized, placebo-controlled, single-dose (haloperidol 5 mg and risperidone 2.5 mg) crossover and double-blind clinical trial. Negative symptoms were assessed by observer-rated scales and with a self-report scale. Possible confounding effects considered were extrapyramidal symptoms (EPS) and sedative effects. The occupation of striatal dopamine D2 receptors was also determined. RESULTS: Risperidone induced a wide range of negative symptoms such as alogia, blunted affect, avolition/apathy, and attention impairment, whereas haloperidol only induced the avolition/apathy subdomain. Most of the effects of risperidone in healthy volunteers, with the exception of its effects on avolition/apathy, were attributable to AP-induced EPS. Haloperidol did not cause significant EPS after administration. No effect of sedation or psychomotor performance was observed on negative symptoms. CONCLUSIONS: Single doses of both haloperidol and risperidone induced nonmotor secondary negative symptoms in healthy volunteers. The clinical findings are especially relevant in view of the impact of negative symptoms on poor functioning. They may help to guide clinicians in their choice of APs (http://clinicaltrials.gov/ct2/show/NCT01259973).

Parkinson's Disease: Impulsivity Does Not Cause Impulse Control Disorders but Boosts Their Severity.

Introduction: Impulse control disorders (ICDs) are a common complication of Parkinson's disease (PD) receiving dopamine agonist (DAA) Impulsivity is considered an underlying mechanism but evidence of this relationship is scarce. To explore the relationship between impulsivity and the presence and severity of ICD in PD. Methods: Prospective cross-sectional study of consecutive PD outpatients. Patients with dementia or previously known ICDs were excluded. Two measures of impulsivity were assessed: Barratt Impulsiveness Scale (BIS-11) for impulsiveness trait (main exposure) and commission errors in the Continuous Performance Test (CE) for motor inhibition. Main outcomes were diagnosis of ICD based on a comprehensive clinical interview and severity of ICD based on the Questionnaire for Impulsive-Compulsive Disorders. Results: Of 100 patients (mean [SD] age, 67.2 [8.8], 54 male), 31 had ICD. Patients with ICDs were 5.3 years younger (p = 0.01), used more frequently dopamine agonist (p = 0.02), alcohol (p = 0.009) and tobacco (p = 0.02). They were not more impulsive on BIS-11 (56 vs. 58, p = 0.23, adjusted p = 0.46) and CE (p = 0.96). No relationship was found between dopaminergic medications and impulsivity or ICD severity. Among patients with ICD, impulsivity was correlated with ICD severity (BIS-11 r = 0.33, p = 0.001, adjusted p = 0.002, CE r = 0.53, p = 0.006). Multivariate regression analysis confirmed the independent predictive role of both measures. Conclusions: Impulsivity is not associated with increased prevalence of ICD in PD but it is strongly linked to ICD severity. When considering dopamine replacement therapy, assessment of impulsivity may be a useful approach to detect those patients at risk of severe forms of ICD.

Alterations in cerebral white matter and neuropsychology in patients with cirrhosis and falls.

BACKGROUND & AIM: Falls are frequent in patients with cirrhosis but underlying mechanisms are unknown. The aim was to determine the neuropsychological, neurological and brain alterations using magnetic resonance-diffusion tensor imaging (MR-DTI) in cirrhotic patients with falls. PATIENTS AND METHODS: Twelve patients with cirrhosis and falls in the previous year were compared to 9 cirrhotic patients without falls. A comprehensive neuropsychological and neurological evaluation of variables that may predispose to falls included: the Mini-Mental State Examination, Psychometric Hepatic Encephalopathy Score (PHES), Parkinson's Disease-Cognitive Rating Scale, specific tests to explore various cognitive domains, Unified Parkinson's Disease Rating Scale to evaluate parkinsonism, scales for ataxia and muscular strength, and electroneurography. High-field MR (3T) including DTI and structural sequences was performed in all patients. RESULTS: The main neuropsychological findings were impairment in PHES (p = 0.03), Parkinson's Disease-Cognitive Rating Scale (p = 0.04) and in executive (p<0.05) and visuospatial-visuoconstructive functions (p<0.05) in patients with falls compared to those without. There were no statistical differences between the two groups in the neurological evaluation or in the visual assessment of MRI. MR-DTI showed alterations in white matter integrity in patients with falls compared to those without falls (p<0.05), with local maxima in the superior longitudinal fasciculus and corticospinal tract. These alterations were independent of PHES as a covariate and correlated with executive dysfunction (p<0.05). CONCLUSIONS: With the limitation of the small sample size, our results suggest that patients with cirrhosis and falls present alterations in brain white matter tracts related to executive dysfunction. These alterations are independent of PHES impairment.

Measuring functional impact of cognitive impairment: validation of the Parkinson's disease cognitive functional rating scale.

BACKGROUND: Little is known on the impact of cognitive impairment on instrumental activities of daily living (IADL) in pre-dementia stages of Parkinson's disease (PD). OBJECTIVE: To investigate the clinimetric properties, applicability and responsiveness of a brief questionnaire (twelve-item; maximum score = 24) for rating functional abnormalities associated to cognitive impairment in non-demented PD patients (ND-PD). METHODS: Two studies were carried-out: (1) a clinimetric study validated the Parkinson's Disease-Cognitive Functional Rating Scale (PD-CFRS) against the Older Americans Resource Survey (OARS-IADL) in 53 ND-PD patients and 53 matched controls; (2) A prospective multicenter 6-month responsiveness study involving 120 ND-PD patients explored sensitivity to change. RESULTS: In the clinimetric study the PD-CFRS showed intermediate concurrent validity (ICC = 0.50), high test-retest (ICC = 0.82), inter-rater reliability (ICC = 0.80) and internal consistency (Cronbach's α = 0.79), and higher coefficient of variation to detect dysfunction in ND-PD patients (PD-CFRS 86.6% vs. OARS-IADL 8.1%). There was a strong relationship between the PD-CFRS and the global cognitive status determined with the PD-Cognitive Rating Scale (r = -0.72, p < 0.0001). The responsiveness study recruited 63 patients with normal cognition and 57 with mild cognitive impairment (MCI); an increase of 2 points in the PD-CFRS after 6 months was associated with a clinically significant worsening of the cognitive functional status. According to a discriminant analysis a PD-CFRS cut-off score of ≥3 was found to be optimal for detecting functional impairment in PD-MCI patients. CONCLUSIONS: Cognitive impairment exerts measurable impact on IADL in ND-PD patients that can be reliable measured with the PD-CFRS, a PD-validated instrument that can be useful in clinical and research settings.