Identifying comorbidities and lifestyle factors contributing to the cognitive profile of early Parkinson's disease.

BACKGROUND: Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson's disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the design of cognitive trials. METHODS: Using a standard approach for the assessment of global cognition in PD and controlling for the effects of age, education and disease duration, we explored the associations between cognitive status, comorbidities, metabolic variables and lifestyle variables in 533 PD participants from the COPPADIS study. RESULTS: Among the overall sample, 21% of participants were classified as PD-MCI (n = 114) and 4% as PDD (n = 26). The prevalence of hypertension, diabetes and dyslipidemia was significantly higher in cognitively impaired patients while no between-group differences were found for smoking, alcohol intake or use of supplementary vitamins. Better cognitive scores were significantly associated with regular physical exercise (p < 0.05) and cognitive stimulation (< 0.01). Cognitive performance was negatively associated with interleukin 2 (Il2) (p < 0.05), Il6 (p < 0.05), iron (p < 0.05), and homocysteine (p < 0.005) levels, and positively associated with vitamin B12 levels (p < 0.005). CONCLUSIONS: We extend previous findings regarding the positive and negative influence of various comorbidities and lifestyle factors on cognitive status in early PD patients, and reinforce the need to identify and treat potentially modifiable variables with the intention of exploring the possible improvement of the global cognitive status of patients with PD.

Ablation of the tail of the ventral tegmental area compensates symptoms in an experimental model of Parkinson's disease.

Parkinson's disease is a neurodegenerative disorder partly caused by the loss of the dopamine neurons of the nigrostriatal pathway. It is accompanied by motor as well as non-motor symptoms, including pain and depression. The tail of the ventral tegmental area (tVTA) or rostromedial tegmental nucleus (RMTg) is a GABAergic mesopontine structure that acts as a major inhibitory brake for the substantia nigra pars compacta (SNc) dopamine cells, thus controlling their neuronal activity and related motor functions. The present study tested the influence of suppressing this tVTA brake on motor and non-motor symptoms in a rat model of Parkinson's disease. Using behavioral approaches, we showed that male Sprague-Dawley rats with bilateral and partial 6-hydroxydopamine SNc lesion displayed motor impairments in the rotarod test, impairments that were no more present following a co-lesion of the tVTA. Using a larger set of behavioral tests, we then showed that such SNc lesion also led to non-motor symptoms, including lower body weight, lower mechanical nociceptive thresholds in the forceps test and lower thermal nociceptive thresholds in the incremented hot-plate test, and a decreased sucrose preference in a 2-bottle choice paradigm. The excitotoxic co-lesion of the tVTA led to compensation of body weight, mechanical nociceptive thresholds and anhedonia-like behavior. These findings illustrate the major influence that the tVTA exerts on the dopamine system, modulating the motor and non-motor symptoms related to a partial loss of dopamine cells.

Remote Monitoring of Treatment Response in Parkinson's Disease: The Habit of Typing on a Computer.

OBJECTIVE: The recent advances in technology are opening a new opportunity to remotely evaluate motor features in people with Parkinson's disease (PD). We hypothesized that typing on an electronic device, a habitual behavior facilitated by the nigrostriatal dopaminergic pathway, could allow for objectively and nonobtrusively monitoring parkinsonian features and response to medication in an at-home setting. METHODS: We enrolled 31 participants recently diagnosed with PD who were due to start dopaminergic treatment and 30 age-matched controls. We remotely monitored their typing pattern during a 6-month (24 weeks) follow-up period before and while dopaminergic medications were being titrated. The typing data were used to develop a novel algorithm based on recursive neural networks and detect participants' responses to medication. The latter were defined by the Unified Parkinson's Disease Rating Scale-III (UPDRS-III) minimal clinically important difference. Furthermore, we tested the accuracy of the algorithm to predict the final response to medication as early as 21 weeks prior to the final 6-month clinical outcome. RESULTS: The score on the novel algorithm based on recursive neural networks had an overall moderate kappa agreement and fair area under the receiver operating characteristic (ROC) curve with the time-coincident UPDRS-III minimal clinically important difference. The participants classified as responders at the final visit (based on the UPDRS-III minimal clinically important difference) had higher scores on the novel algorithm based on recursive neural networks when compared with the participants with stable UPDRS-III, from the third week of the study onward. CONCLUSIONS: This preliminary study suggests that remotely gathered unsupervised typing data allows for the accurate detection and prediction of drug response in PD. © 2019 International Parkinson and Movement Disorder Society.

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.

Validation of a Spanish version of the Lille apathy rating scale for Parkinson's disease.

INTRODUCTION: To date, no rating scales for detecting apathy in Parkinson's disease (PD) patients have been validated in Spanish. For this reason, the aim of this study was to validate a Spanish version of Lille apathy rating scale (LARS) in a cohort of PD patients from Spain. PARTICIPANTS AND METHODS: 130 PD patients and 70 healthy controls were recruited to participate in the study. Apathy was measured using the Spanish version of LARS and the neuropsychiatric inventory (NPI). Reliability (internal consistency, test-retest, and interrater reliability) and validity (construct, content, and criterion validity) were measured. RESULTS: Interrater reliability was 0.93. Cronbach's α for LARS was 0.81. The test-retest correlation coefficient was 0.97. The correlation between LARS and NPI scores was 0.61. The optimal cutoff point under the ROC curve was -14, whereas the value derived from healthy controls was -11. The prevalence of apathy in our population tested by LARS was 42%. CONCLUSIONS: The Spanish version of LARS is a reliable and useful tool for diagnosing apathy in PD patients. Total LARS score is influenced by the presence of depression and cognitive impairment. However, both disorders are independent identities with respect to apathy. The satisfactory reliability and validity of the scale make it an appropriate instrument for screening and diagnosing apathy in clinical practice or for research purposes.

Levodopa infusion improves impulsivity and dopamine dysregulation syndrome in Parkinson's disease.

BACKGROUND: Impulsivity and dopamine dysregulation syndrome are frequent complications of treatment in Parkinson's disease (PD). METHODS: We assessed the effect of jejunal levodopa infusion (JLI) on behavioral symptoms in 8 PD patients with motor complications and severe impulsivity and dopamine dysregulation syndrome (DDS), which had not be controlled before by adjusting oral medications. The infusion was delivered during 15 hours (daily dose 1007.2 ± 302.5 mg) and stopped at night time. Patients were reassessed after 25 ± 9 weeks of treatment with a stable dose of jejunal l-dopa. RESULTS: Off periods and dyskinesias decreased by 27% and 20,7% respectively, compared to baseline. DDS and all types of impulse control disorders (ICDs) improved in all patients, with nearly complete symptom resolution. Punding improved in all 5 patients but disappeared completely in only 1. CONCLUSIONS: Our experience suggests that l-dopa infusion has a positive effect on both motor complications and behavioral disorders. This treatment approach deserves further controlled studies.

The rostromedial tegmental nucleus RMTg is not a critical site for ethanol-induced motor activation in rats.

RATIONALE: Opioid drugs indirectly activate dopamine (DA) neurons in the ventral tegmental area (VTA) through a disinhibition mechanism mediated by mu opioid receptors (MORs) present both on the GABA projection neurons located in the medial tegmental nucleus/tail of the VTA (RMTg/tVTA) and on the VTA GABA interneurons. It is well demonstrated that ethanol, like opioid drugs, provokes VTA DA neuron disinhibition by interacting (through its secondary metabolite, salsolinol) with MORs present in VTA GABA interneurons, but it is not known whether ethanol could disinhibit VTA DA neurons through the MORs present in the RMTg/tVTA. OBJECTIVES: The objective of the present study was to determine whether ethanol, directly microinjected into the tVTA/RMTg, is also able to induce VTA DA neurons disinhibition. METHODS: Disinhibition of VTA DA neurons was indirectly assessed through the analysis of the motor activity of rats. Cannulae were placed into the tVTA/RMTg to perform microinjections of DAMGO (0.13 nmol), ethanol (150 or 300 nmol) or acetaldehyde (250 nmol) in animals pre-treated with either aCSF or the irreversible antagonist of MORs, beta-funaltrexamine (beta-FNA; 2.5 nmol). After injections, spontaneous activity was monitored for 30 min. RESULTS: Neither ethanol nor acetaldehyde directly administered into the RMTg/tVTA were able to increase the locomotor activity of rats at doses that, in previous studies performed in the posterior VTA, were effective in increasing motor activities. However, microinjections of 0.13 nmol of DAMGO into the tVTA/RMTg significantly increased the locomotor activity of rats. These activating effects were reduced by local pre-treatment of rats with beta-FNA (2.5 nmol). CONCLUSIONS: The tVTA/RMTg does not appear to be a key brain region for the disinhibiting action of ethanol on VTA DA neurons. The absence of dopamine in the tVTA/RMTg extracellular medium, the lack of local ethanol metabolism or both could explain the present results.

Falls Predict Acute Hospitalization in Parkinson's Disease.

BACKGROUND: There is a need for identifying risk factors for hospitalization in Parkinson's disease (PD) and also interventions to reduce acute hospital admission. OBJECTIVE: To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort. METHODS: PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital encounter 1-year after the baseline visit. RESULTS: Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065-5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319-6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757-8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124-4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080-8.322; p = 0.035) was an independent predictor of AH. CONCLUSION: Falls is an independent predictor of AH in PD patients.

Fos response of the tail of the ventral tegmental area to food restriction entails a prediction error processing.

The tail of the ventral tegmental area (tVTA) or rostromedial tegmental nucleus (RMTg) receives lateral habenula inputs and projects heavily to midbrain dopamine neurons. Midbrain dopamine and lateral habenula neurons participate in learning processes predicting the outcomes of actions, placing the tVTA in a critical location into prediction error pathways. tVTA GABA neurons show electrophysiological inhibition or activation after reward and aversive stimuli, respectively, and their predictive cues. tVTA molecular recruitment, however, is not elicited by all aversive stimuli. Indeed, precipitated opioid withdrawal, repeated footshocks or food restriction raise tVTA Fos expression, whereas various other unpleasant, stressful or painful stimuli does not elicit that molecular response. However, the basis of that difference remains unknown. In the present study, we tried to disentangle whether the tVTA c-Fos induction observed after food restriction was due to the aversive state of food restriction or to procedure-related reward prediction error. To this end, male Sprague-Dawley rats were food-restricted for 7-8 days. During this period, animals were handled and weighed every day before feeding. On the test day, rats underwent several behavioral procedures to explore the impact of food restriction and food-predictive cue exposure on tVTA c-Fos expression. We showed that food restriction per se was not able to recruit c-Fos in the tVTA. On the contrary, the food-predicting cues induced c-Fos locally in the absence of feeding, whereas the food-predicting cues followed by feeding evoked lower c-Fos expression. Overall, our results support the proposed involvement of the tVTA in reward prediction error.

Long-term directional deep brain stimulation: Monopolar review vs. local field potential guided programming.

BACKGROUND: Directional subthalamic stimulation in Parkinson's disease can increase stimulation threshold for adverse effects and widen the therapeutic window. However, selection of programming settings is time consuming, requiring a thorough monopolar clinical review. To overcome this, programming may be guided by intraoperatively recording local field potential beta oscillations (13-35 Hz). OBJECTIVES: 1) Evaluate whether the power of beta oscillations recorded intraoperatively can predict the clinically most effective directional contacts; and 2) assess long-term directional stimulation outcomes between patients programmed based on clinical monopolar review and patients programmed based on beta activity. METHODS: We conducted a non-randomized, prospective study with 24 Parkinson's disease patients divided into two groups. In group A (14 patients, 2016-2018), we investigated whether beta activity in the directional contacts correlated with clinical efficacy. Stimulating parameters were selected according to clinical monopolar review and mean follow-up was 27 months. In group B (10 patients, 2018-2019), stimulating parameters were selected according to beta activity and mean follow-up was 13 months. RESULTS: Neurophysiological results showed a strong correlation between clinical efficacy and the low-beta sub-band. Contacts with highest beta peaks increased the therapeutic window by 25%. Selecting the two contacts with highest beta peaks provided an 82% probability of selecting the best clinical contact. Clinical results showed similar improvements in group A (motor score, 72% reduction; levodopa-equivalent daily dose, 65% reduction) and B (72% and 63% reduction, respectively), maintained at long-term follow-up. CONCLUSIONS: Our results validate the long-term efficacy of directional stimulation guided by intraoperative local field potential beta oscillations.

Becoming a mother shifts the activity of the social and motivation brain networks in mice.

During pregnancy hormones increase motivated pup-directed behaviors. We here analyze hormone-induced changes in brain activity, by comparing cFos-immunoreactivity in the sociosexual (SBN) and motivation brain networks (including medial preoptic area, MPO) of virgin versus late-pregnant pup-naïve female mice exposed to pups or buttons (control). Pups activate more the SBN than buttons in both late-pregnant and virgin females. By contrast, pregnancy increases pup-elicited activity in the motivation circuitry (e.g. accumbens core) but reduces button-induced activity and, consequently, button investigation. Principal components analysis supports the identity of the social and motivation brain circuits, placing the periaqueductal gray between both systems. Linear discriminant analysis of cFos-immunoreactivity in the socio-motivational brain network predicts the kind of female and stimulus better than the activity of the MPO alone; this suggests that the neuroendocrinological basis of social (e.g. maternal) behaviors conforms to a neural network model, rather than to distinct hierarchical linear pathways for different behaviors.

Patient and caregiver outcomes with levodopa-carbidopa intestinal gel in advanced Parkinson's disease.

Levodopa-carbidopa intestinal gel (LCIG) has shown to be efficacious in motor and non-motor symptoms (NMS). Nevertheless, studies with patient Quality of Life (QoL) as a primary endpoint are scarce. To assess the effect of LCIG on Advanced Parkinson's Disease (APD) patients QoL. Secondarily, the impact on motor symptoms and NMS, emotional well-being, treatment satisfaction, and caregiver QoL, stress, disease burden, anxiety, depression, and work impairment were also investigated. In this prospective, 6-month multicenter postmarketing observational study, LCIG was administered to 59 patients with APD. Endpoints were assessed using validated scales and questionnaires. LCIG significantly improved patient QoL (PDQ-39 mean change ± standard deviation from baseline, -12.8 ± 14.6; P < 0.0001), motor symptoms (UPDRS-III in "On," -6.5 ± 11.8; P = 0.0002), NMS (NMSS, -35.7 ± 31.1; P < 0.0001), mood (Norris/Bond-Lader VAS, -6.6 ± 21.1; P = 0.0297), fatigue (PFS-16, -0.6 ± 1.0; P = 0.0003), depression (BDI-II, -5.1 ± 9.4; P = 0.0002), anxiety (BAI, -6.2 ± 9.6; P < 0.0001), and patient treatment satisfaction (SATMED-Q, 16.1 ± 16.8; P < 0.0001). There were significant correlations between the change from baseline to 6 months between PDQ-39 and UPDRS-IV, NMSS, BAI, BDI-II, AS, and PFS-16 scores, and Norris/Bond-Lader alertness/sedation factor. Caregiver anxiety also improved (Goldberg anxiety scale, -1.1 ± 1.0; P = 0.0234), but the clinical relevance of this finding is questionable. The serious adverse events reported were similar to those previously described for LCIG. In patients with APD, LCIG improves QoL, motor symptoms and NMS, emotional well-being, and satisfaction with the treatment. Improvement in patient QoL is associated with improvements in motor complications, NMS, anxiety, depression, apathy and fatigue. Improvements in patients' QoL does not correspond with improvements in caregivers' QoL or burden.

Pregnancy Changes the Response of the Vomeronasal and Olfactory Systems to Pups in Mice.

Motherhood entails changes in behavior with increased motivation for pups, induced in part by pregnancy hormones acting upon the brain. This work explores whether this alters sensory processing of pup-derived chemosignals. To do so, we analyse the expression of immediate early genes (IEGs) in the vomeronasal organ (VNO; Egr1) and centers of the olfactory and vomeronasal brain pathways (cFos) in virgin and late-pregnant females exposed to pups, as compared to buttons (socially neutral control). In pup-exposed females, we quantified diverse behaviors including pup retrieval, sniffing, pup-directed attack, nest building and time in nest or on nest, as well as time off nest. Pups induce Egr1 expression in the VNO of females, irrespective of their physiological condition, thus suggesting the existence of VNO-detected pup chemosignals. A similar situation is found in the accessory olfactory bulb (AOB) and posteromedial part of the medial bed nucleus of the stria terminalis (BSTMPM). By contrast, in the medial amygdala and posteromedial cortical amygdala (PMCo), responses to pups-vs-buttons are different in virgin and late-pregnant females, thus suggesting altered sensory processing during late pregnancy. The olfactory system also shows changes in sensory processing with pregnancy. In the main olfactory bulbs, as well as the anterior and posterior piriform cortex, buttons activate cFos expression in virgins more than in pregnant females. By contrast, in the anterior and especially posterior piriform cortex, pregnant females show more activation by pups than buttons. Correlation between IEGs expression and behavior suggests the existence of two vomeronasal subsystems: one associated to pup care (with PMCo as its main center) and another related to pup-directed aggression observed in some pregnant females (with the BSTMPM as the main nucleus). Our data also suggest a coactivation of the olfactory and vomeronasal systems during interaction with pups in pregnant females.

Validation study of the Parkinson's Fatigue Scale in advanced Parkinson's disease.

Purpose: To validate the Parkinson's Fatigue Scale (PFS-16) in advanced Parkinson Disease (APD) patients using the scale's Spanish version. Patients and methods: In a clinical study for Levodopa-Carbidopa Intestinal Gel (LCIG), 59 patients were assessed over six months using the PFS-16 and other instruments. The psychometric properties of the PFS-16 were then analyzed. Results: Patients (60.7% men) were aged 68.02±7.43 years. PD duration was 12.57±5.97 years. Median Hoehn and Yahr (HY) stage of patients in "on" was 2 (range: 1-4). There were excellent data quality and acceptability for the PFS-16 as a whole, except for moderate-to-high ceiling effects in its items. Two factors explained 67% of the variance, yet parallel analysis demonstrated the unidimensional nature of the PFS-16, whose internal consistency was satisfactory (Cronbach's alpha=0.93; item homogeneity coefficient=0.19, and item total-corrected correlations=0.50-0.84). PFS-16 total score showed moderate-to-high correlations with fatigue-specific questions within clinical tools, namely item 20 of the Beck Depression Inventory (rS=0.65) and item 4 of the Non-Motor Symptoms Scale (rS=0.33). Weak-to-moderate correlations were observed between the PFS-16 and measures of anxiety, depression, apathy, and quality of life. There were no significant differences in PFS-16 total scores when grouped by age, sex, time from diagnosis, HY, and CGI-S. After treatment with LCIG, the relative change in PFS-16 total score was -17.6% and the effect size (Cohen's d) was 0.92. Moderate correlations between changes in the PFS-16 and several other clinical tools were also found. Conclusion: In APD patients, the PFS-16 showed satisfactory acceptability, internal consistency, construct validity, and responsiveness.

Psychometric Properties of the Apathy Scale in Advanced Parkinson's Disease.

OBJECTIVES: To assess the psychometric attributes of the Apathy Scale- (AS-) Spanish version in patients with advanced Parkinson's disease (APD). MATERIALS AND METHODS: Over 6 months, 61 patients participated in a clinical study of levodopa-carbidopa intestinal gel (LCIG) and were evaluated using the AS and other clinical tools. Various psychometric attributes of the AS were assessed. RESULTS: Patients (60.7% men) were aged 68.02 ± 7.43 years, with 12.57 ± 5.97 years from PD diagnosis. Median HY of patients in "on state" was 2 (range, 1-4), and mean levodopa equivalent daily dose was 1455.98 ± 456.00 mg. Overall, the parameters of feasibility/acceptability were satisfactory, except for a moderate-to-high floor effect in AS items but not in its total score (both 3.3%). Cronbach's alpha was 0.78, while item homogeneity coefficient was 0.21. Almost all items (11/14) reached acceptable item-total corrected correlations (r S = 0.16-0.50). AS total score was moderately correlated with Beck Depression Inventory (0.34) and with Non-Motor Symptoms Scale domains 2 (sleep/fatigue, 0.35), 3 (mood/apathy, 0.56), and 5 (attention/memory, 0.41). There were no significant differences between AS total scores by established groups of sex, time from diagnosis, HY, and Clinical Global Impression-Severity Scale. Following LCIG treatment, there was no significant change in the AS total score. The relative change was 5.56%, the standard error of the difference was 4.17, and Cohen's d effect was 0.10. CONCLUSIONS: The AS showed satisfactory feasibility, acceptability, scaling assumptions, internal consistency, and convergent validity. Responsiveness parameters were poor, probably due to the characteristics of the clinical study from which these data came. This trial is registered with NCT02289729.

Prospective analysis of liquid biopsies of advanced non-small cell lung cancer patients after progression to targeted therapies using GeneReader NGS platform.

BACKGROUND: In a significant percentage of advanced non-small cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses at time to progression. We prospectively analyzed the appearance of genetic alterations associated with resistance in liquid biopsies of advanced NSCLC patients progressing to targeted therapies using the NGS platform. METHODS: A total of 24 NSCLC patients were included in the study, 22 progressing to tyrosine kinase inhibitors and two to other treatments. Liquid biopsies samples were obtained and analyzed using the GeneReadTM QIAact Lung DNA UMI Panel, designed to enrich specific target regions and containing 550 variant positions in 19 selected genes frequently altered in lung cancer tumors. Previously, a retrospective validation of the panel was performed in clinical samples. RESULTS: Of the 21 patients progressing to tyrosine kinase inhibitors with valid results in liquid biopsy, NGS analysis identified a potential mechanism of resistance in 12 (57%). The most common were acquired mutations in ALK and EGFR, which appeared in 8/21 patients (38%), followed by amplifications in 5/21 patients (24%), and KRAS mutations in one patient (5%). Loss of the p.T790M was also identified in two patients progressing to osimertinib. Three of the 21 (14%) patients presented two or more concomitant alterations associated with resistance. Finally, an EGFR amplification was found in the only patient progressing to immunotherapy included in the study. CONCLUSIONS: NGS analysis in liquid biopsies of patients progressing to targeted therapies using the GeneReader platform is feasible and can help the oncologist to make treatment decisions.

Shell/core differences in mu- and delta-opioid receptor modulation of dopamine efflux in nucleus accumbens.

The mu- and delta-opioid receptors located at the terminal level in nucleus accumbens are involved in the opiate modulation of dopamine release in this brain area. However, recent studies suggest that the effects of opioid drugs on the core subregion of nucleus accumbens may completely differ from those observed in the shell. We used in vivo microdialysis to simultaneously apply selective mu- and delta-opioid receptor agonists and to measure extracellular levels of dopamine in three subregions of the accumbens, namely shell, core, and the transition zone between them. The regional analysis of these subregions of the accumbens demonstrated that basal levels of dopamine and its metabolites were higher in the core, and decreased from this subregion to the shell. Retrodialysis application to the core of both the selective mu-receptor agonist ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) (1 micromol/L)) and of the selective delta-opioid receptor agonist ([D-Pen(2), D-Pen(5)]-enkephalin (DPDPE) (50 nmol/L)) increased the dialysate levels of dopamine. However, the application of these drugs to the shell significantly reduced the dopamine levels in this subregion. Local application of the same doses of these drugs in the transition zone between the shell and the core did not significantly affect the dopamine levels in dialysates. These results suggest that the opioid circuits modulating dopaminergic activity in the shell could differ from those in the core of the nucleus accumbens.

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.

Can suitable candidates for levodopa/carbidopa intestinal gel therapy be identified using current evidence?

Advanced Parkinson's disease (APD) is characterized by increased functional disability, caused by motor complications, the presence of axial symptoms, and emergent disease- and drug-related non-motor symptoms. One of the advanced therapies available is intrajejunal infusion of levodopa/carbidopa intestinal gel (LCIG); however, patient selection for this treatment is sometimes difficult, particularly because of overlapping indications with other alternatives. In recent years, strong evidence has supported the use of LCIG in treating motor fluctuations associated with APD, and several clinical studies provide emerging evidence for additional benefits of LCIG treatment in certain patients. This article provides an overview of the published literature on the benefits, limitations, and drawbacks of LCIG in relation to PD symptoms, the psychosocial impact of the disease, and the quality of life of patients, with the aim of determining candidates for whom treatment with LCIG would be beneficial. According to current evidence, patients with APD (defined as inability to achieve optimal control of the disease with conventional oral treatment), a relatively well-preserved cognitive-behavioral status, and good family/caregiver would count as suitable candidates for LCIG treatment. Contraindications in the opinion of the authors are severe dementia and active psychosis.