Predicting alcohol relapse post-detoxification: The role of cognitive impairments in alcohol use disorder patients.

BACKGROUND: Studies on early abstinence suggest that cognitive function is significantly reduced in the first year of abstinence, which raises the question of whether it is relevant to early relapse in patients with substance use disorders. This study investigates the extent to which impairments in executive function and memory predict alcohol relapse in patients with alcohol use disorder (AUD). Understanding these relationships is crucial for improving therapeutic approaches to prevent relapse in patients with AUD. METHODS: We selected 116 adult patients (79 male and 37 female) diagnosed with AUD based on DSM-5 criteria, all of whom were undergoing alcohol detoxification treatment. A comprehensive array of neuropsychological tests was administered to assess global cognition, memory, and executive functions. Patients' alcohol use was monitored monthly during a 6-month follow-up period. Logistic regression and Cox regression were used to explore the relationship between cognitive function and the likelihood of alcohol relapse. RESULTS: Impairments in global cognition, semantic and phonemic fluency, cognitive flexibility, and learning ability during detoxification were significant predictors of relapse in AUD patients, showing similar predictive values at both 3 and 6 months post-treatment. An abnormal Montreal Cognitive Assessment (MoCA) score increased the risk of relapse by 123% (HR: 2.227), and impairments in both semantic and phonemic fluency each increased the risk by 142% (HR: 2.423). Additionally, abnormal performance on the MoCA, Trail Making Test Part B (TMT-B), and California Verbal Learning Test (CVLT) was associated with a higher number of drinking days at 3 months (IRR: 3.764; IRR: 2.237; IRR: 2.738, respectively) and abnormal MoCA and TMT-B scores at 6 months (IRR: 2.451; IRR: 1.859, respectively). CONCLUSIONS: The MoCA test is a valuable tool for predicting relapse risk in AUD patients undergoing detoxification treatment, with similar predictive value for relapse at 3 or 6 months. Learning ability needs to be assessed and their impairments considered in the treatment of AUD patients. Future research should explore strategies for managing patients with impairments in memory and learning ability to enhance treatment effectiveness and prevent relapse.

Efficacy, Effect on Mood Symptoms, and Safety of Deep Brain Stimulation in Refractory Obsessive-Compulsive Disorder: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate efficacy, effect on mood, and safety of deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) at different target sites. DATA SOURCES: Electronic records from databases MEDLINE, EMBASE, and CENTRAL up to November 2019 were searched. Search terms included OCD, depression, and DBS. STUDY SELECTION: Eight randomized controlled trials (RCTs) (n = 85) and 38 observational studies (case reports and case series) (n = 225) were included. DATA EXTRACTION: In RCTs, the differences in outcomes between sham and active stimulation for OCD and depression were evaluated and the proportion of responders was determined. In all included studies, at last follow-up, the improvement from baseline in OCD (Yale-Brown Obsessive Compulsive Scale [Y-BOCS score]) and a scale of weighted depression scores (WDS) were determined. Predictors of response (age, illness duration and severity, frequency parameters, and response in depression) were evaluated. The proportions of adverse events and dropouts were calculated. RESULTS: In RCTs, mean differences between sham and active stimulation in Y-BOCS and Hamilton Depression Rating Scale (HDRS) scores were -7.8 (95% CI = -11.2 to -4.3, I² = 40%, P = .0001) and -7.3 (95% CI = -11.5 to -3.0, I² = 0%, P = .0009), respectively. No differences between limbic and non-limbic targets were identified (χ² = 0.21, I² = 0%, P = .0006). At last follow-up, improvements in Y-BOCS and WDS were -15.0 (95% CI = -18.3 to -11.7, I² = 90%, P < .001) and -13.7 (95% CI = -20.1 to -7.3, I² = 76%, P < .001), respectively. No consistent predictors of response were found. There were 0.68 adverse events (95% CI = 0.59 to 0.78, I² = 88%), 0.32 serious adverse events (95% CI = 0.12 to 0.62, I² = 96%), and 0.13 dropouts (95% CI = 0.07 to 0.16, I² = 16%) per treated patient. CONCLUSIONS: DBS can significantly decrease Y-BOCS score and depressive symptoms in refractory OCD.

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients.

Alzheimer's disease (AD) is a neurodegenerative disorder of still unknown etiology and the leading cause of dementia worldwide. Besides its main neuropathological hallmarks, a dysfunctional homeostasis of transition metals has been reported to play a pivotal role in the pathogenesis of this disease. Dysregulation of iron (Fe) metabolism in AD has been suggested, particularly at the level of cellular iron efflux. Herein, we intended to further clarify the molecular mechanisms underlying Fe homeostasis in AD. In order to achieve this goal, the expression of specific Fe metabolism-related genes directly involved in Fe regulation and export was assessed in peripheral blood mononuclear cells (PBMCs) from 73AD patients and 74 controls by quantitative PCR. The results obtained showed a significant decrease in the expression of aconitase 1 (ACO1; P=0.007); ceruloplasmin (CP; P<0.001) and amyloid-beta precursor protein (APP; P=0.006) genes in AD patients compared with healthy volunteers. These observations point out to a significant downregulation in the expression of genes associated with ferroportin-mediated cellular Fe export in PBMCs from AD patients, when compared to controls. Taken together, these findings support previous studies suggesting impairment of Fe homeostasis in AD, which may lead to cellular Fe retention and oxidative stress, a typical feature of this disease.

Overexpression of Adenosine A2A Receptors in Rats: Effects on Depression, Locomotion, and Anxiety.

Adenosine A2A receptors (A2AR) are a sub-type of receptors enriched in basal ganglia, activated by the neuromodulator adenosine, which interact with dopamine D2 receptors. Although this reciprocal antagonistic interaction is well-established in motor function, the outcome in dopamine-related behaviors remains uncertain, in particular in depression and anxiety. We have demonstrated an upsurge of A2AR associated to aging and chronic stress. Furthermore, Alzheimer's disease patients present A2AR accumulation in cortical areas together with depressive signs. We now tested the impact of overexpressing A2AR in forebrain neurons on dopamine-related behavior, namely depression. Adult male rats overexpressing human A2AR under the control of CaMKII promoter [Tg(CaMKII-hA2AR)] and aged-matched wild-types (WT) of the same strain (Sprague-Dawley) were studied. The forced swimming test (FST), sucrose preference test (SPT), and the open-field test (OFT) were performed to evaluate behavioral despair, anhedonia, locomotion, and anxiety. Tg(CaMKII-hA2AR) animals spent more time floating and less time swimming in the FST and presented a decreased sucrose preference at 48 h in the SPT. They also covered higher distances in the OFT and spent more time in the central zone than the WT. The results indicate that Tg(CaMKII-hA2AR) rats exhibit depressive-like behavior, hyperlocomotion, and altered exploratory behavior. This A2AR overexpression may explain the depressive signs found in aging, chronic stress, and Alzheimer's disease.

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.

Genetic and biochemical markers in patients with Alzheimer's disease support a concerted systemic iron homeostasis dysregulation.

Alzheimer's disease (AD) is the most common form of dementia in the elderly individuals, resulting from a complex interaction between environmental and genetic factors. Impaired brain iron homeostasis has been recognized as an important mechanism underlying the pathogenesis of this disease. Nevertheless, the knowledge gathered so far at the systemic level is clearly insufficient. Herein, we used an integrative approach to study iron metabolism in the periphery, at both genotypic and phenotypic levels, in a sample of 116 patients with AD and 89 healthy control subjects. To assess the potential impact of iron metabolism on the risk of developing AD, genetic analyses were performed along with the evaluation of the iron status profile in peripheral blood by biochemical and gene expression studies. The results obtained showed a significant decrease of serum iron, ferritin, and transferrin concentrations in patients compared with the control subjects. Also, a significant decrease of ferroportin (SLC40A1) and both transferrin receptors TFRC and TFR2 transcripts was found in peripheral blood mononuclear cells from patients. At the genetic level, significant associations with AD were found for single nucleotide polymorphisms in TF, TFR2, ACO1, and SLC40A1 genes. Apolipoprotein E gene, a well-known risk factor for AD, was also found significantly associated with the disease in this study. Taken together, we hypothesize that the alterations on systemic iron status observed in patients could reflect an iron homeostasis dysregulation, particularly in cellular iron efflux. The intracellular iron accumulation would lead to a rise in oxidative damage, contributing to AD pathophysiology.

Escitalopram improves memory deficits induced by maternal separation in the rat.

Maternal separation (MS) induces depressive-like behavior and long-term changes in cognition in rats. Escitalopram is an antidepressant drug shown to reverse the depressive-like features caused by this stress model. However, it is not known if it can ameliorate the affected cognition. We now characterized the effect of escitalopram on hippocampal-dependent memory in rats submitted to the MS protocol. Male Wistar rats were assigned either to control (CTR) or maternal separated (MS) group. MS were separated from their dams between 2-14 postnatal days (PND) for 180min daily. Escitalopram was given in food pellets (0.34g/kg/day first 2 weeks and 0.41g/kg/day the subsequent period, average dose 25mg/kg) from PND 43 onwards, during 1 month. Depressive behavior was assessed in the forced swimming test (FST), and memory performance in the Morris water maze (MWM). Escitalopram significantly improved the FST's latency to despair in the MS group (n=6), but did not change the immobility time. All groups showed a significant learning effect in the MWM over time, but no differences have been found upon treatment (n=6). However, escitalopram treatment significantly increased the time spent on the platform quadrant in the probe trial in the MS group. We report here that chronic treatment with escitalopram is able to improve hippocampal dependent memory in a chronic stress model, while not changing the learning ability. Moreover, this is accompanied by an amelioration of the depressive like behavior. These results support the use of escitalopram to tackle underlying cognitive deficits caused by stress in early-life.

Cognitive deficits in middle-aged and older adults with bipolar disorder and cognitive complaints: comparison with mild cognitive impairment.

OBJECTIVE: Cognitive impairment has been reported in elderly bipolar disorder (BD) patients, however, few studies have evaluated middle-aged and older BD patients using standardized cognitive assessments and none (to our knowledge) analysed middle-aged and older BD patients with recent cognitive complaints. The main objective of this study is to characterize the cognitive deficits of middle-aged and older patients with BD and compare them with the common age-related cognitive deficits observed in Mild Cognitive Impairment (MCI). METHODS: For this retrospective study, a systematic search for all cases of BD patients submitted to a neuropsychological assessment from 1999-2007, at participant institutions, was performed, and cases were matched (1:2) by gender and age to a sample of MCI subjects. RESULTS: A total sample of 135 patients, 45 patients with the diagnosis of BD, clinically stable, mean age of 63.8 +/- 8.8 years, and 90 patients with the diagnosis of MCI, mean age of 64.2 +/- 8.4 years, was studied. Patients with MCI were more impaired in verbal memory, whereas BD patients showed more deficits in attention, motor initiative, calculation and verbal abstraction. Interestingly, discriminant analysis classified about half of the BD group as belonging to the MCI group. This BD subgroup showed deficits in episodic memory similar to MCI patients. CONCLUSIONS: Patients with BD and patients with MCI have distinct profiles of cognitive impairment. A subgroup of BD patients with recent cognitive complaints may actually suffer from concomitant incipient MCI, and this finding may have diagnostic and therapeutical implications.