Improvement of impulse control disorders associated with levodopa-carbidopa intestinal gel treatment in advanced Parkinson's disease.

Impulse control behaviors are a frequent comorbidity for patients with Parkinson's disease (PD). The objective of the present study was to evaluate the effectiveness levodopa-carbidopa intestinal gel (LCIG) therapy on impulse control disorders (ICDs) in patients with advanced PD. We conducted a multicenter, observational, and prospective (6 months follow-up) study that included consecutive PD patients assigned to LCIG through routine medical practice. Patients completed visits at baseline, 1, 3, and 6 months after percutaneous endoscopic gastrostomy procedure. The following outcomes were evaluated: presence and severity of ICDs and other neuropsychiatric disorders, sleep disturbances, patients' quality of life, and caregivers' burden. Sixty-two patients were included at baseline: mean age 72.2 years (SD ± 7.0), 42% women. Median duration of PD symptoms was 13.5 years (IQR 5.5-21.5) and median time with motor fluctuations was 5.0 years (IQR 1.0-9.0). Treatment with LCIG infusion was associated with progressive and significant improvements in ICDs symptoms over the study period (64.4% reduction in the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease-Rating Scale score). Psychotic and other neuropsychiatric symptoms were also significantly reduced, and patients' sleep quality and psychosocial function improved. Caregivers' burden remained unchanged. There was a significant improvement in the daily "Off" time [7.4 h (SD ± 4.0) vs 1.5 h (SD ± 1.8); p < 0.0001] at the end of follow-up, whereas duration of dyskinesias was not affected. ICDs significantly improved after 6-month LCIG treatment in a group of PD patients with mild-to-moderate neuropsychiatric disturbances.

In vivo neurometabolic profiling in orthostatic tremor.

The pathogenesis of orthostatic tremor (OT) remains unclear, although some evidence points to dysfunction in the brainstem or cerebellum. We used single voxel proton magnetic resonance spectroscopy (1H-MRS) (3 T) to investigate whether neurochemical changes underlie abnormal cerebellar or cortical function in OT. Fourteen OT patients and 14 healthy controls underwent 1H-MRS studies with voxels placed in midparietal gray matter and cerebellum (vermis and central white matter). Spectral analysis was analyzed using the software package LCModel (version 6.3). The absolute metabolite concentrations and ratios of total N-acetylaspartate + N-acetylaspartyl glutamate (NAA), choline-containing compounds, myoinositol, and glutamate + glutamine to creatine were calculated. In midparietal gray matter spectra, we found a significant decrease in the absolute concentration of NAA in OT patients versus healthy controls (7.76 ±â€Š0.25 vs 8.11 ±â€Š0.45, P = 0.017). A similar decrease in NAA was seen in the cerebellar vermis (7.33 ±â€Š0.61 vs 8.55 ±â€Š1.54, P = 0.014) and cerebellar white matter (8.54 ±â€Š0.79 vs 9.95 ±â€Š1.57, P = 0.010). No differences in the other metabolites or their ratios were observed. Reductions in both cerebral cortical and cerebellar NAA suggest that there is neuronal damage or loss in OT, raising the intriguing question as to whether OT is a neurodegenerative disease. Along with clinical history and electrophysio0logical examination, 1H-MRS could serve as a useful diagnostic aid for OT.

Resting state functional MRI reveals abnormal network connectivity in orthostatic tremor.

Very little is known about the pathogenesis of orthostatic tremor (OT). We have observed that OT patients might have deficits in specific aspects of neuropsychological function, particularly those thought to rely on the integrity of the prefrontal cortex, which suggests a possible involvement of frontocerebellar circuits. We examined whether resting-state functional magnetic resonance imaging (fMRI) might provide further insights into the pathogenesis on OT. Resting-state fMRI data in 13 OT patients (11 women and 2 men) and 13 matched healthy controls were analyzed using independent component analysis, in combination with a "dual-regression" technique, to identify group differences in several resting-state networks (RSNs). All participants also underwent neuropsychological testing during the same session. Relative to healthy controls, OT patients showed increased connectivity in RSNs involved in cognitive processes (default mode network [DMN] and frontoparietal networks), and decreased connectivity in the cerebellum and sensorimotor networks. Changes in network integrity were associated not only with duration (DMN and medial visual network), but also with cognitive function. Moreover, in at least 2 networks (DMN and medial visual network), increased connectivity was associated with worse performance on different cognitive domains (attention, executive function, visuospatial ability, visual memory, and language). In this exploratory study, we observed selective impairments of RSNs in OT patients. This and other future resting-state fMRI studies might provide a novel method to understand the pathophysiological mechanisms of motor and nonmotor features of OT.

Cognitive and neuropsychiatric features of orthostatic tremor: A case-control comparison.

INTRODUCTION: Evidence suggests that the cerebellum could play a role in the pathophysiology of orthostatic tremor. The link between orthostatic tremor and the cerebellum is of interest, especially in light of the role the cerebellum plays in cognition, and it raises the possibility that orthostatic tremor patients could have cognitive deficits consistent with cerebellar dysfunction. Our aim was to examine whether orthostatic tremor patients had cognitive deficits and distinct personality profiles when compared with matched controls. METHODS: Sixteen consecutive orthostatic tremor patients (65.7 ± 13.3 years) and 32 healthy matched controls underwent a neuropsychological battery and the Personality Assessment Inventory. In linear regression models, the dependent variable was each one of the neuropsychological test scores or the Personality Assessment Inventory subscales and the independent variable was orthostatic tremor vs. RESULTS: Adjusted for age in years, sex, years of education, comorbidity index, current smoker, and depressive symptoms, diagnosis (orthostatic tremor vs. healthy control) was associated with poor performance on tests of executive function, visuospatial ability, verbal memory, visual memory, and language tests, and on a number of the Personality Assessment Inventory subscales (somatic concerns, anxiety related disorders, depression, and antisocial features). Older-onset OT (>60 years) patients had poorer scores on cognitive and personality testing compared with their younger-onset OT counterparts. CONCLUSION: Orthostatic tremor patients have deficits in specific aspects of neuropsychological functioning, particularly those thought to rely on the integrity of the prefrontal cortex, which suggests involvement of frontocerebellar circuits. Cognitive impairment and personality disturbances could be disease-associated nonmotor manifestations of orthostatic tremor.

In vivo gastric detection of α-synuclein inclusions in Parkinson's disease.

α-Synuclein inclusions have been identified in the brain and some parts of the enteric nervous system in Parkinson's disease cases. We aimed to assess these inclusions in gastric mucosa samples from patients with symptomatic Parkinson's disease. Random biopsies were performed by gastroscopy in 28 patients with Parkinson's disease and in 29 age- and sex-matched controls. Gastroscopy was performed to start enteral levodopa (L-dopa) therapy in cases and for diagnostic purposes in controls (gastroesophageal reflux, anemia, and abdominal pain were the main indications). The clinical definition of cases and controls was made a priori. Six controls had data suggestive of "mild presymptomatic parkinsonism". Biopsy specimens were immunostained for α-synuclein. The neuropathological diagnosis was established post hoc. No differences were found in the baseline characteristics of the groups. Positive fibers for the α-synuclein protein were observed in 17 of 28 (60.7%) Parkinson's disease patients, 1 of 23 controls (4.3%), and 1 of 6 (16.7%) cases of incident "mild presymptomatic parkinsonism." Neuropathological diagnosis based on α-synuclein immunostaining showed a sensitivity of 85% (95% confidence interval [CI] 62.1-96.8), specificity of 95% (95% CI 76.2-99.9) and area under the receiver operating characteristics curve (AUC) of 0.90 (95% CI 0.80-1.00). No adverse events occurred. Detection of α-synuclein inclusions in the gastric mucosa is a useful and safe tool providing in vivo evidence of the underlying neurodegenerative peripheral involvement linked to Parkinson's disease. Further studies are warranted to determine its pathophysiological implications.

Rate of cognitive decline in premotor Parkinson's disease: a prospective study (NEDICES).

Previous research has documented cognitive impairment in the early stages of Parkinson's disease (PD). It is not known when this decline starts or if decline progresses at an accelerated rate during the premotor period of the disorder. In this population-based prospective study of older people (≥65 years) from the Neurological Disorders in Central Spain (NEDICES) cohort, we compared the rates of cognitive decline in 3 groups: (1) non-PD elderly controls; (2) prevalent PD patients (those diagnosed with the disease at baseline, 1994-95); and (3) premotor PD subjects (those diagnosed with the disease at follow up, 1997-98, but not at baseline). A 37-item version of the Mini-Mental State Examination (37-MMSE) was administered in the 2 visits of the study. From 2487 participants (age, 72.8 ± 6.0 years), including 2429 controls, we recruited 21 premotor PD cases, and 37 prevalent PD cases. At baseline, the mean 37-MMSE score was 28.5 ± 4.7 in prevalent cases, 28.1 ± 4.6 in premotor cases, and 29.9 ± 5.0 in controls (P = .046). During the 3-year follow-up period, there was a significant score decline of 2.4 ± 4.6 points in prevalent cases versus 0.2 ± 4.1 points in premotor cases and 0.3 ± 4.0 points in controls (Kruskal-Wallis test, P = .03). In the NEDICES cohort, cognitive test scores of prevalent PD cases declined at a rate above and beyond that observed in premotor PD cases and in controls. The rate of cognitive decline in premotor PD and controls was similar. Our data suggest that a decline in global cognitive function does not occur in premotor PD.