Cristina Nombela

Characterizing mild cognitive impairment in incident Parkinson disease: The ICICLE-PD Study

Objective: To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers. Methods: Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria. Results: The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1–42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1–42 and 1–40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold. Conclusions: In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1–42 and 1–40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.

Into the groove: Can rhythm influence Parkinson's disease?

Previous research has noted that music can improve gait in several pathological conditions, including Parkinsons disease, Huntingtons disease and stroke. Current research into auditory-motor interactions and the neural bases of musical rhythm perception has provided important insights for developing potential movement therapies. Specifically, neuroimaging studies show that rhythm perception activates structures within key motor networks, such as premotor and supplementary motor areas, basal ganglia and the cerebellum - many of which are compromised to varying degrees in Parkinsons disease. It thus seems likely that automatic engagement of motor areas during rhythm perception may be the connecting link between music and motor improvements in Parkinsons disease. This review seeks to describe the link, address core questions about its underlying mechanisms, and examine whether it can be utilized as a compensatory mechanism.

Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study.

See Dujardin (doi:10.1093/brain/awu218) for a scientific commentary on this article. Nombela et al. present data from the ICICLE-PD study of cognition in newly diagnosed Parkinson’s disease. Consistent with the ‘Dual Syndrome’ hypothesis, impairments in executive function reflect a frontal dopaminergic syndrome modulated by COMT genotype, while visuospatial and memory deficits reflect disruption of temporo-parietal systems modulated by MAPT and APOE.

Selective serotonin reuptake inhibition modulates response inhibition in Parkinson’s disease

Impulsivity is common in Parkinson’s disease. In a double-blind, placebo-controlled study with multi-modal imaging, Ye et al. reveal improved response inhibition in some patients receiving the SSRI citalopram, including those with advanced disease. Improvements correlated with preserved frontostriatal structural connectivity and drug-induced prefrontal activity, highlighting the need for patient stratification in trials.

Cognitive Rehabilitation in Parkinson’s Disease: Evidence from Neuroimaging

Cognitive impairment in Parkinson’s disease (PD) has received little attention to date and as such, there are currently very few treatment options available. The aim of the present study was to determine whether cognitive training might alleviate these cognitive symptoms and if so, whether such changes might be correlated with altered brain patterns. The performance of 10 PD patients and 10 paired healthy controls was assessed in a modified version of the Stroop task performed in association with functional magnetic resonance imaging, and half of the PD patients were given 6 months of cognitive daily training based on Sudoku exercises. Results showed that the training program improved the cognitive performance in the Stroop test of the trained Parkinson’s patients during MRI, specifically in terms of reaction time, and of correct and missing answers. Moreover, training provoked reduced cortical activation patterns with respect to untrained patients that were comparable to the patterns of activation observed in controls. Based on these findings, we propose that cognitive training can contribute significantly to save brain resources in PD patients, maybe by readdressing the imbalance caused by the alterations to inhibitory circuitry. Furthermore, these data strongly support the development and use of standardized cognitive training programs in PD patients.

Improving Response Inhibition in Parkinson's Disease with Atomoxetine

Background Dopaminergic drugs remain the mainstay of Parkinson’s disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. Methods This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Results Patients with Parkinson’s disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. Conclusions This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson’s disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson’s disease.

Multiple Modes of Impulsivity in Parkinson's Disease

Cognitive problems are a major factor determining quality of life of patients with Parkinsons disease. These include deficits in inhibitory control, ranging from subclinical alterations in decision-making to severe impulse control disorders. Based on preclinical studies, we proposed that Parkinsons disease does not cause a unified disorder of inhibitory control, but rather a set of impulsivity factors with distinct psychological profiles, anatomy and pharmacology. We assessed a broad set of measures of the cognitive, behavioural and temperamental/trait aspects of impulsivity. Sixty adults, including 30 idiopathic Parkinsons disease patients (Hoehn and Yahr stage I–III) and 30 healthy controls, completed a neuropsychological battery, objective behavioural measures and self-report questionnaires. Univariate analyses of variance confirmed group differences in nine out of eleven metrics. We then used factor analysis (principal components method) to identify the structure of impulsivity in Parkinsons disease. Four principal factors were identified, consistent with four different mechanisms of impulsivity, explaining 60% of variance. The factors were related to (1) tests of response conflict, interference and self assessment of impulsive behaviours on the Barrett Impulsivity Scale, (2) tests of motor inhibitory control, and the self-report behavioural approach system, (3) time estimation and delay aversion, and (4) reflection in hypothetical scenarios including temporal discounting. The different test profiles of these four factors were consistent with human and comparative studies of the pharmacology and functional anatomy of impulsivity. Relationships between each factor and clinical and demographic features were examined by regression against factor loadings. Levodopa dose equivalent was associated only with factors (2) and (3). The results confirm that impulsivity is common in Parkinsons disease, even in the absence of impulse control disorders, and that it is not a unitary phenomenon. A better understanding of the structure of impulsivity in Parkinsons disease will support more evidence-based and effective strategies to treat impulsivity.

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinsons disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double‐blind randomized three‐way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinsons disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion‐weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinsons disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave‐one‐out cross‐validation (LOOCV) to predict patients’ responses in terms of improved stopping efficiency. We identified two optimal models: (1) a “clinical” model that predicted the response of an individual patient with 77–79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion‐weighted imaging scan; and (2) a “mechanistic” model that explained the behavioral response with 85% accuracy for each drug, using drug‐induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinsons disease, the individual patients response to each drug can be predicted using a pattern of clinical and neuroimaging features. Hum Brain Mapp 37:1026–1037, 2016.

Atomoxetine restores the response inhibition network in Parkinson’s disease

Impairments in response inhibition in Parkinson’s disease may reflect loss of noradrenaline and impaired fronto-subcortical connectivity. Rae et al. show that the noradrenaline reuptake inhibitor atomoxetine can restore functional connectivity in the inhibition network. Individual treatment responses depend on disease severity, plasma drug concentration and anatomical connectivity within the network.

Different decision deficits impair response inhibition in progressive supranuclear palsy and Parkinson’s disease

Both progressive supranuclear palsy and Parkinson’s disease cause impulsivity and impair executive function. Using a saccadic Go/No-Go paradigm and hierarchical Bayesian models, Zhang et al. show differential decision-making deficits in the two disorders, and that model parameters are better than common behavioural measures for single-patient classification of the diseases.