Rifaximin Reduces Risk of All-Cause Hospitalization in Cirrhotic Liver Transplant Candidates with Hepatic Encephalopathy.

In cirrhotic patients listed for liver transplantation (LT) with a history of hepatic encephalopathy (HE), rifaximin reduces the number of hospitalizations, but whether it influences the time to first hospitalization is unknown. AIMS: to evaluate the time-dependent impact of rifaximin on the risk of all-cause hospitalization and dropout in patients on the LT waiting list. METHODS: Consecutive patients listed for LT were retrospectively enrolled. After balancing populations with and without rifaximin treatment using the inverse probability therapy weighting analysis, Fine-Gray multivariable competing risk analyses were run to explore risk factors for the first episode of hospitalization and dropout. RESULTS: When comparing 92 patients taking rifaximin to the untreated group of 152, rifaximin treatment was not associated with any of the study outcomes. In the subset of patients with a history of HE at waitlist entry (N = 81 rifaximin-treated and N = 39 untreated), rifaximin intake was independently associated with a lower risk of hospitalization for all causes (SHR 0.638; 95.0% CI 0.418-0.973; p = 0.037) and for HE (SHR 0.379; 95.0% CI 0.207-0.693; p = 0.002). CONCLUSIONS: cirrhotic LT candidates with a prior history of HE rifaximin treatment are associated with a lower risk of time-dependent all-cause hospitalization, likely due to its unique effect on gut microbiome composition/function.

Identifying the Basic Dimensions of Medication-Triggered Impulsive Compulsive Behaviours in Parkinson's Disease.

BACKGROUND: This review article integrates findings from published behavioural and neuroimaging studies of impulsive-compulsive behaviours (ICBs) in Parkinson's disease, with the aim of identifying the basic correlates of these problematic and distressing behaviours. The underlying premise is that for any feature to be a reliable marker of ICBs, it should be evident across multiple levels of analyses. When changes are evident only at one level, but not in the others, their reliability as indicators of ICBs should be questioned. SUMMARY: To this end, we draw on the conclusions from three published systematic reviews of dopamine metabolic processes in the striatum, functional magnetic resonance imaging and cognitive, affective, and motivational assessments of medicated Parkinson's patients with and without ICBs (ICB+ and ICB-, respectively). The key findings are as follows: ICB+ showed abnormal dopaminergic of the striatum, including the brain network supporting reward processing. Fronto-striatal connectivity was also reduced. These findings are consistent with the broader evidence of psychological dysfunction, evident on assessments of cognitive control (goal-driven behaviour, impulsivity), reward-driven decision-making (temporal discounting, gambling), and elevated rates of self-report negative affect (anxiety, depression, anhedonia). The implications of these findings are discussed with reference to the research domain criteria and, relatedly, directions for future research. KEY MESSAGES: The identification of markers of ICB that allow early diagnosis, monitoring, and optimisation of therapy is an ambitious goal. And whilst we have pulled together a number of convergent findings identified using different paradigms, we are still some distance off understanding the mechanism(s) that increase vulnerability to ICB. It is our hope that this review spurs future studies to further investigate the interaction between motivation and cognition with the twin aims of identifying markers of ICB that have both clinical utility and function as outcome measures in therapeutic clinical trials.

Brain Structural and Functional Alterations in Multiple Sclerosis-Related Fatigue: A Systematic Review.

Fatigue is one of the most disabling symptoms of multiple sclerosis (MS); it influences patients' quality of life. The etiology of fatigue is complex, and its pathogenesis is still unclear and debated. The objective of this review was to describe potential brain structural and functional dysfunctions underlying fatigue symptoms in patients with MS. To reach this purpose, a systematic review was conducted of published studies comparing functional brain activation and structural brain in MS patients with and without fatigue. Electronic databases were searched until 24 February 2021. The structural and functional outcomes were extracted from eligible studies and tabulated. Fifty studies were included: 32 reported structural brain differences between patients with and without fatigue; 14 studies described functional alterations in patients with fatigue compared to patients without it; and four studies showed structural and functional brain alterations in patients. The results revealed structural and functional abnormalities that could correlate to the symptom of fatigue in patients with MS. Several studies reported the differences between patients with fatigue and patients without fatigue in terms of conventional magnetic resonance imaging (MRI) outcomes and brain atrophy, specifically in the thalamus. Functional studies showed abnormal activation in the thalamus and in some regions of the sensorimotor network in patients with fatigue compared to patients without it. Patients with fatigue present more structural and functional alterations compared to patients without fatigue. Specifically, abnormal activation and atrophy of the thalamus and some regions of the sensorimotor network seem linked to fatigue.

Socially responsible investing: from the ethical origins to the sustainable development framework of the European Union.

In this work, we present an overview of the historical development of socially responsible investing (SRI). We will argue that such a financial activity has been boosting in recent decades from a niche, mainly as a religious-led exclusionary practice, towards a mainstream strategy of risk analysis for institutional and retail investors. We also discuss the advances and possible drawbacks that regulatory activity and harmonization process on such industry have achieved at international level in recent years, with a special focus on the European Union. The study shows that the lack of a globally accepted taxonomy on what constitutes sustainable activities, of regulatory clarity and of high-quality data allowing for comparisons across industries and regions, together with practical and behavioural complexities are major critical issues that discourage SRI industry at the global level.

Comment on "The association between pain and impulse control behaviours in Parkinson's disease".

The recent paper by Kobylecki et al. explored the association between impulse control behaviours and pain in Parkinson's disease, under the hypothesis of shared mesolimbic dysfunction. We discuss cognitive and motivational disturbances as potential covariates and suggest the dorsolateral prefrontal cortex as a therapeutic target for this "pain-predominant" symptom subtype.

Incentive-driven decision-making networks in de novo and drug-treated Parkinson's disease patients with impulsive-compulsive behaviors: A systematic review of neuroimaging studies.

BACKGROUND: In Parkinson's disease (PD), impulsive-compulsive behaviors (ICBs) may develop as side-effect of dopaminergic medications. Abnormal incentive-driven decision-making, which is supported by the cognitive control and motivation interaction, may represent an ICBs signature. This systematic review explored whether structural and/or functional brain differences between PD patients with vs without ICBs encompass incentive-driven decision-making networks. METHODS: Structural and functional neuroimaging studies comparing PD patients with and without ICBs, either de novo or medicated, were included. RESULTS: Thirty articles were identified. No consistent evidence of structural alteration both in de novo and medicated PD patients were found. Differences in connectivity within the default mode, the salience and the central executive networks predate ICBs development and remain stable once ICBs are fully developed. Medicated PD patients with ICBs show increased metabolism and cerebral blood flow in orbitofrontal and cingulate cortices, ventral striatum, amygdala, insula, temporal and supramarginal gyri. Abnormal ventral striatum connectivity with anterior cingulate cortex and limbic structures was reported in PD patients with ICBs. DISCUSSION: Functional brain signatures of ICBs in PD encompass areas involved in cognitive control and motivational encoding networks of the incentive-driven decision-making. Functional alterations predating ICBs may be related to abnormal synaptic plasticity in these networks.

Detoxification Improves Multidomain Cognitive Dysfunction in High-Dose Benzodiazepine Abusers.

PURPOSE: High-dose benzodiazepines (BZDs) abuse has been documented to cause multidomain cognitive dysfunction. We explored whether cognitive abnormalities to high-dose BZD abuse might be reversed by detoxification with slow subcutaneous infusion of flumazenil. METHODS: We recruited 96 patients consecutively admitted to the Department of Internal Medicine, Addiction Medicine Unit, Verona University Hospital, Italy for detoxification from high-dose BZD dependence. After selection for inclusion and exclusion criteria, 50 patients (23 men, 27 women; age 42.7 ± 10.3 years) were included. They underwent a comprehensive neuropsychological battery to explore verbal memory, visuospatial memory, working memory, attention, and executive functions 28-30 days prior to admission for detoxification (T0) and at the end of detoxification, i.e., 7 days after admission (T1). A group of 50 healthy adults (24 men, 26 women; mean age 44.5 ± 12.8 years) matched for age, sex, and education served as controls. RESULTS: At T0, patients scored significantly worse than healthy controls in all the neuropsychological tests. Depression and anxiety scores were associated with impaired verbal memory at T0 in patients. T1-T0 comparison showed improved performances in all neuropsychological tests after the end of detoxification in patients. CONCLUSION: We confirmed that all neuropsychological domains were significantly and profoundly impaired by high-dose BZD abuse and documented that cognitive abnormalities improved after detoxification with slow subcutaneous infusion of flumazenil.

Differences in cognitive profiles between Lewy body and Parkinson's disease dementia.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) not only differ for the time of onset of cognitive deficits but also present variability in affected functions which are relevant in understanding underlying pathology. Cognitive performance of two global cognitive screening scales, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), as well as of a neuropsychological test battery, was evaluated in 18 DLB and 21 PDD patients. Feasibility for each cognitive test was investigated. Both MMSE and MoCA are feasible assessments in PDD and DLB patients. MoCA was more sensitive in discriminating groups as higher number of DLB patients showed pathological performances on the Digit Span Forward subitem (p = 0.049). The Stroop test in PDD and the Trail Making Tests-A and B, and the Benton's judgment of line orientation tests in both groups were considered not feasible. Among feasible cognitive tests in at least one group, Rey-Osterrieth complex figure test copy (p = 0.013) and semantic fluency (p = 0.038) are sensitive in discriminating DLB from PDD cognitive profile. Trail Making Tests-A and B, the Benton's judgment of line orientation and the Stroop tests are not feasible for assessing patients with frank dementia. Longitudinal studies should not include those tasks to reduce the risk of missing data once disease progresses and dementia develops. DLB patients present more severe and widespread cognitive dysfunction than PDD, particularly in attentive, visuospatial, and language domains.

QTc Prolongation in Patients with Dementia and Mild Cognitive Impairment: Neuropsychological and Brain Imaging Correlations.

The QTc interval is the electrocardiographic manifestation of ventricular depolarization and repolarization. This marker is often prolonged in acute and chronic neurological conditions. The cause of the cerebrogenic QT prolongation remains unclear. The aim of the study was to analyze the relation between QTc interval and the degree of cognitive impairment and structural brain imaging changes in patients with dementia and mild cognitive impairment (MCI). To this aim, 269 patients were screened, of whom 61 met one or more exclusion criteria. The remaining 208 patients (56 control subjects, 44 patients with MCI, and 108 with dementia) were recruited. Eighty-five patients using drugs causing prolongation of QT interval were further excluded. The QT interval was measured manually in all 12 leads by a single blinded observer, assuming the longest QT value adjusted for heart rate by using the Bazett's formula. All patients underwent a structural brain imaging and the following measures were obtained: the bicaudate ratio and the periventricular hyperintensity and deep white matter hyperintensity using the modified Fazekas scale. Prolonged QTc interval was prevalent in 1) patients with dementia, especially in those with moderate-severe degree; 2) subjects with impairment of praxis and attention, low functional status, and behavioral symptoms; 3) patients with global and temporal atrophy and with higher scores on the Fazekas or leukoaraiosis scales. Degenerative and vascular processes might play a main role in QTc interval prolongation because of the damage to brain areas involved in the control of the autonomic cardiac nervous system.

Impact of Cognitive Profile on Impulse Control Disorders Presence and Severity in Parkinson's Disease.

Background: Impulse control disorders (ICDs) and related behaviors are frequent in Parkinson's disease (PD). Mild cognitive impairment (PD-MCI) and dementia (PDD), both characterized by heterogeneous cognitive phenotypes, are also commonly reported in PD. However, the frequency and severity of ICD within PD cognitive states is unknown. Methods: Three hundred and twenty-six PD patients completed a comprehensive neuropsychological assessment and were classified as PD-MCI, PDD, or without cognitive alterations (PD-NC). The Minnesota impulsive disorders interview was used to ascertain the presence (ICD+) or absence (ICD-) of ICD. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale was used to assess ICD severity. A subsample of 286 patients evaluated with the same cognitive tasks was selected in order to investigate the characteristics of ICD in PD cognitive phenotypes. Results: ICDs were present in 55% of PD-NC, in 50% of PD-MCI, and in 42% of PDD patients. Frequencies of ICD+ with attentive (ICD+: 20% vs. ICD-: 4%; p = 0.031) and executive impairments (ICD+: 44% vs. ICD-: 30%; p = 0.027) were higher in the PD-MCI and PDD subgroups, respectively. As expected, no differences were observed in the PD-NC. PD-MCI with attentive impairments presented higher percentage of ICD+ with deficits in the Trail Making Test B-A but not in the Digit Span Sequencing task. In PDD, executive failures concerned Similarities task (ICD+: 67%; ICD-: 29%; p = 0.035), with no differences between ICD+ and ICD- in the Stroop task. Conclusions: Prevalence and severity of ICDs and related behaviors do not differ in PD with different cognitive states. However, ICD+ are more likely to show deficits, respectively in attentive and in executive domains, specifically in the Trail Making Test B-A task for the attention and working memory domain in PD-MCI and in the Similarities task for the executive function domain in PDD. Prospective studies should evaluate if these tests can be used as screening tool for ICDs in PD.

Dopaminergic Neurotransmission in Patients With Parkinson's Disease and Impulse Control Disorders: A Systematic Review and Meta-Analysis of PET and SPECT Studies.

Background: Around 30% Parkinson's disease (PD) patients develop impulse control disorders (ICDs) to D2/3 dopamine agonists and, to a lesser extent, levodopa. We aim to investigate striatal dopaminergic function in PD patients with and without ICD. Methods: PubMed, Science Direct, EBSCO, and ISI Web of Science databases were searched (from inception to March 7, 2018) to identify PET or SPECT studies reporting striatal dopaminergic function in PD patients with ICD (ICD+) compared to those without ICD (ICD-). Studies which included drug naïve patients, explored non-pharmacological procedures (e.g., deep brain stimulation), and those using brain blood perfusion or non-dopaminergic markers were excluded. Standardized mean difference (SDM) was used and random-effect models were applied. Separate meta-analyses were performed for dopamine transporter level, dopamine release, and dopamine receptors availability in the putamen, caudate, dorsal, and ventral striatum. Results: A total of 238 studies were title and abstract screened, of which 19 full-texts were assessed. Nine studies (ICD+: N = 117; ICD-: N = 175 patients) were included in the analysis. ICD+ showed a significant reduction of dopamine transporter binding in the putamen (SDM = -0.46; 95% CI: -0.80, -0.11; Z = 2.61; p = 0.009), caudate (SDM = -0.38; 95% CI: -0.73, -0.04; Z = 2.18; p = 0.03) and dorsal striatum (SDM = -0.45; 95% CI: -0.77, -0.13; Z = 2.76; p = 0.006), and increased dopamine release to reward-related stimuli/gambling tasks in the ventral striatum (SDM = -1.04; 95% CI: -1.73, -0.35; Z = 2.95; p = 0.003). Dopamine receptors availability did not differ between groups. Heterogeneity was low for dopamine transporter in the dorsal striatum (I 2 = 0%), putamen (I 2 = 0%) and caudate (I 2 = 0%), and pre-synaptic dopamine release in the dorsal (I 2 = 0%) and ventral striatum (I 2 = 0%); heterogeneity was high for dopamine transporter levels in the ventral striatum (I 2 = 80%), and for dopamine receptors availability in the ventral (I 2 = 89%) and dorsal (I 2 = 86%) striatum, putamen (I 2 = 93%), and caudate (I 2 = 71%). Conclusions: ICD+ patients show lower dopaminergic transporter levels in the dorsal striatum and increased dopamine release in the ventral striatum when engaged in reward-related stimuli/gambling tasks. This dopaminergic imbalance might represent a biological substrate for ICD in PD. Adequately powered longitudinal studies with drug naïve patients are needed to understand whether these changes may represent biomarkers of premorbid vulnerability to ICD.

Impulse Control Disorder in Parkinson's Disease: A Meta-Analysis of Cognitive, Affective, and Motivational Correlates.

Background: In Parkinson's disease (PD), impulse control disorders (ICDs) develop as side-effect of dopaminergic replacement therapy (DRT). Cognitive, affective, and motivational correlates of ICD in medicated PD patients are debated. Here, we systematically reviewed and meta-analyzed the evidence for an association between ICD in PD and cognitive, affective, and motivational abnormalities. Methods: A systematic review and meta-analysis was performed on PubMed, Science Direct, ISI Web of Science, Cochrane, EBSCO for studies published between 1-1-2000 and 8-3-2017 comparing cognitive, affective, and motivational measures in PD patients with ICD (ICD+) vs. those without ICD (ICD-). Exclusion criteria were conditions other than PD, substance and/or alcohol abuse, dementia, drug naïve patients, cognition assessed by self-report tools. Standardized mean difference (SMD) was used, and random-effect model applied. Results: 10,200 studies were screened (title, abstract), 79 full-texts were assessed, and 25 were included (ICD+: 625 patients; ICD-: 938). Compared to ICD-, ICD+ showed worse performance reward-related decision-making (0.42 [0.02, 0.82], p = 0.04) and set-shifting tasks (SMD = -0.49 [95% CI -0.78, -0.21], p = 0.0008). ICD in PD was also related to higher self-reported rate of depression (0.35 [0.16, 0.54], p = 0.0004), anxiety (0.43 [0.18, 0.68], p = 0.0007), anhedonia (0.26 [0.01, 0.50], p = 0.04), and impulsivity (0.79 [0.50, 1.09], p < 0.00001). Heterogeneity was low to moderate, except for depression (I2 = 61%) and anxiety (I2 = 58%). Conclusions: ICD in PD is associated with worse set-shifting and reward-related decision-making, and increased depression, anxiety, anhedonia, and impulsivity. This is an important area for further studies as ICDs have negative impact on the quality of life of patients and their caregivers.

Neuropsychological testing.

Neuropsychological testing is a key diagnostic tool for assessing people with dementia and mild cognitive impairment, but can also help in other neurological conditions such as Parkinson's disease, stroke, multiple sclerosis, traumatic brain injury and epilepsy. While cognitive screening tests offer gross information, detailed neuropsychological evaluation can provide data on different cognitive domains (visuospatial function, memory, attention, executive function, language and praxis) as well as neuropsychiatric and behavioural features. We should regard neuropsychological testing as an extension of the neurological examination applied to higher order cortical function, since each cognitive domain has an anatomical substrate. Ideally, neurologists should discuss the indications and results of neuropsychological assessment with a clinical neuropsychologist. This paper summarises the rationale, indications, main features, most common tests and pitfalls in neuropsychological evaluation.

Risky decision-making and affective features of impulse control disorders in Parkinson's disease.

Impulse control disorders (ICDs) in Parkinson's disease (PD) are considered dopaminergic treatment side effects. Cognitive and affective factors may increase the risk of ICD in PD. The aim is to investigate risky decision-making and associated cognitive processes in PD patients with ICDs within a four-stage conceptual framework. Relationship between ICDs and affective factors was explored. Thirteen PD patients with ICD (ICD+), 12 PD patients without ICD (ICD-), and 17 healthy controls were recruited. Overall risky decision-making and negative feedback effect were examined with the Balloon Analogue Risk Task (BART). A cognitive battery dissected decision-making processes according to the four-stage conceptual framework. Affective and motivational factors were measured. ANOVA showed no effect of group on overall risky decision-making. However, there was a group × feedback interaction [F (2, 39) = 3.31, p = 0.047]. ICD+, unlike ICD- and healthy controls, failed to reduce risky behaviour following negative feedback. A main effect of group was found for anxiety and depression [F(2, 38) = 8.31, p = 0.001], with higher symptoms in ICD+ vs. healthy controls. Groups did not differ in cognitive outcomes or affective and motivational metrics. ICD+ may show relatively preserved cognitive function, but reduced sensitivity to negative feedback during risky decision-making and higher symptoms of depression and anxiety.

Cognitive function in survivors of out-of-hospital cardiac arrest after target temperature management at 33°C versus 36°C.

BACKGROUND: Target temperature management is recommended as a neuroprotective strategy after out-of-hospital cardiac arrest. Potential effects of different target temperatures on cognitive impairment commonly described in survivors have not been investigated sufficiently. The primary aim of this study was to evaluate whether a target temperature of 33°C compared with 36°C was favorable for cognitive function; the secondary aim was to describe cognitive impairment in cardiac arrest survivors in general. METHODS AND RESULTS: Study sites included 652 cardiac arrest survivors originally randomized and stratified for site to temperature control at 33°C or 36°C within the Target Temperature Management trial. Survival until 180 days after the arrest was 52% (33°C, n=178/328; 36°C, n=164/324). Survivors were invited to a face-to-face follow-up, and 287 cardiac arrest survivors (33°C, n=148/36°C, n=139) were assessed with tests for memory (Rivermead Behavioural Memory Test), executive functions (Frontal Assessment Battery), and attention/mental speed (Symbol Digit Modalities Test). A control group of 119 matched patients hospitalized for acute ST-segment-elevation myocardial infarction without cardiac arrest performed the same assessments. Half of the cardiac arrest survivors had cognitive impairment, which was mostly mild. Cognitive outcome did not differ (P>0.30) between the 2 temperature groups (33°C/36°C). Compared with control subjects with ST-segment-elevation myocardial infarction, attention/mental speed was more affected among cardiac arrest patients, but results for memory and executive functioning were similar. CONCLUSIONS: Cognitive function was comparable in survivors of out-of-hospital cardiac arrest when a temperature of 33°C and 36°C was targeted. Cognitive impairment detected in cardiac arrest survivors was also common in matched control subjects with ST-segment-elevation myocardial infarction not having had a cardiac arrest. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01946932.