Long-term follow-up in osteogenesis imperfecta type VI.

This retrospective study on long-term outcomes in osteogenesis imperfecta type VI found that patients who received intravenous bisphosphonate treatment had an increase in lumbar spine areal bone mineral density, a higher final height z-score, and some reshaping of vertebral bodies. INTRODUCTION: Osteogenesis imperfecta (OI) type VI is an ultra-rare bone fragility disorder caused by recessive mutations in SERPINF1. Here, we describe long-term outcomes in OI type VI and compare the clinical phenotypes caused by different types of SERPINF1 mutations. METHODS: This study includes a retrospective chart review of 13 individuals with OI type VI. RESULTS: In the absence of therapy, lumbar spine areal bone mineral density (BMD) did not increase during childhood and longitudinal growth seemed to stall after the age of 6 to 8 years. The phenotype was similar between individuals with different types of SERPINF1 mutations. Intravenous bisphosphonate treatment was associated with an increase in lumbar spine areal BMD and some reshaping of compressed vertebral bodies. Patients who had started bisphosphonate treatment early (before the age of 6 years) were taller than patients who had received bisphosphonate treatment later during their growing years. Lower extremity fractures were frequent despite bisphosphonate treatment and scoliosis was present in all patients who had reached the final height. Most patients had restricted mobility. In four patients, intravenous bisphosphonate treatment was eventually substituted by subcutaneous injections of denosumab, without clear changes in the clinical picture. CONCLUSIONS: Patients with OI type VI who received intravenous bisphosphonate treatment during growth had an increase in lumbar spine areal BMD, a higher final height z-score, and presented some reshaping of vertebral bodies. More effective treatment modalities are clearly required in OI type VI.

Conversion to dementia in mild cognitive impairment diagnosed with DSM-5 criteria and with Petersen's criteria.

OBJECTIVE: In a background of revision of criteria for states of increased risk for progression to dementia, we compare the conversion rate to dementia and Alzheimer's disease (AD) of mild cognitive impairment (MCI) as diagnosed using DSM-5 (DSM-5-MCI) and Petersen's (P-MCI) criteria. METHOD: A population representative cohort of 4057 dementia-free individuals 55+ years of age was followed up at 2.5 and 4.5 years in Zaragoza, Spain (ZARADEMP). Using the Geriatric Mental State- AGECAT for assessment, research psychiatrists diagnosed DSM-5-MCI and P-MCI following operationalized criteria. 'Conversion rate' (CR), 'annual conversion rate' (ACR), and incidence rate (IR) were calculated along with incidence rate ratio (IRR) to compare the performance of the intermediate cognitive definitions. RESULTS: At 4.5-year follow-up, in individuals aged 65+ years, ACRs for non-cases, P-MCI, and DSM-5-MCI were 0.8, 1.9 and 3.4, respectively, for global dementia. The IRRs were 2.9 and 5.3 for P-MCI and DSM5-MCI, respectively, being the non-cases the reference category. The corresponding values were slightly lower for AD. CONCLUSION: Conversion rate to dementia and AD was higher using DSM-5-MCI criteria than using Petersen's criteria. However, prediction of the construct still has some way to go, as most MCI individuals did not convert at 4.5-year follow-up.

Differential relationships between set-shifting abilities and dimensions of insight in schizophrenia.

BACKGROUND: To assess insight in a large sample of patients with schizophrenia and to study its relationship with set shifting as an executive function. METHODS: The insight of a sample of 161 clinically stable, community-dwelling patients with schizophrenia was evaluated by means of the Scale to Assess Unawareness of Mental Disorder (SUMD). Set shifting was measured using the Trail-Making Test time required to complete part B minus the time required to complete part A (TMT B-A). Linear regression analyses were performed to investigate the relationships of TMT B-A with different dimensions of general insight. RESULTS: Regression analyses revealed a significant association between TMT B-A and two of the SUMD general components: 'awareness of mental disorder' and 'awareness of the efficacy of treatment'. The 'awareness of social consequences' component was not significantly associated with set shifting. CONCLUSIONS: Our results show a significant relation between set shifting and insight, but not in the same manner for the different components of the SUMD general score.

Incidence and lifetime risk of dementia and Alzheimer's disease in a Southern European population.

OBJECTIVE: To calculate both the incidence rates and the lifetime risk (LTR) of dementia and Alzheimer's disease (AD). METHODS: A two-phase case-finding procedure was implemented in a cohort of 4057 cognitively intact individuals 55+ years of age living in Zaragoza, Spain, and followed-up at 2.5 and 4.5 years. Age- and sex-specific incidence rates were calculated. A mortality-adjusted, multivariate model was used to document LTRs. RESULTS: The incidence rate of dementia continued to rise after the age of 90 years, but was slightly lower than in North and West European studies. Only a tendency for an increased LTR with age was observed. Thus, LTR was 19.7% for a 65-year-old woman and 20.4% at the age of 85 years, the corresponding figures for AD being 16.7% and 17.6%. The LTR of AD was higher in women and was about twice as high among illiterate individuals when compared with individuals with higher educational levels. CONCLUSIONS: The incidence rate of dementia in this Southern European city was slightly lower than in previous studies in North-West Europe. LTR of dementia and AD seems to be slightly increased with age. The association of illiteracy with higher LTR of AD is intriguing.

Parcel-guided rTMS for depression.

Transcranial magnetic stimulation (TMS) is an approved intervention for treatment-resistant depression (TRD), but current targeting approaches are only partially successful. Our objectives were (1) to examine the feasibility of MRI-guided TMS in the clinical setting using a recently published surface-based, multimodal parcellation in patients with TRD who failed standard TMS (sdTMS); (2) to examine the neurobiological mechanisms and clinical outcomes underlying MRI-guided TMS compared to that of sdTMS. We used parcel-guided TMS (pgTMS) to target the left dorsolateral prefrontal cortex parcel 46. Resting-state functional connectivity (rsfc) was assessed between parcel 46 and predefined nodes within the default mode and visual networks, following both pgTMS and sdTMS. All patients (n = 10) who had previously failed sdTMS responded to pgTMS. Alterations in rsfc between frontal, default mode, and visual networks differed significantly over time between groups. Improvements in symptoms correlated with alterations in rsfc within each treatment group. The outcome of our study supports the feasibility of pgTMS within the clinical setting. Future prospective, double-blind studies of pgTMS vs. sdTMS appear warranted.

Resting state functional connectivity predictors of treatment response to electroconvulsive therapy in depression.

There is increasing focus on use of resting-state functional connectivity (RSFC) analyses to subtype depression and to predict treatment response. To date, identification of RSFC patterns associated with response to electroconvulsive therapy (ECT) remain limited, and focused on interactions between dorsal prefrontal and regions of the limbic or default-mode networks. Deficits in visual processing are reported in depression, however, RSFC with or within the visual network have not been explored in recent models of depression. Here, we support prior studies showing in a sample of 18 patients with depression that connectivity between dorsal prefrontal and regions of the limbic and default-mode networks serves as a significant predictor. In addition, however, we demonstrate that including visual connectivity measures greatly increases predictive power of the RSFC algorithm (>80% accuracy of remission). These exploratory results encourage further investigation into visual dysfunction in depression, and use of RSFC algorithms incorporating the visual network in prediction of response to both ECT and transcranial magnetic stimulation (TMS), offering a new framework for the development of RSFC-guided TMS interventions in depression.

MCCB cognitive profile in Spanish first episode schizophrenia patients.

The objective of the study was to examine the cognitive profile of Spanish patients with a first episode of schizophrenia (FESz) and to compare that to the profile of patients with a chronic schizophrenia (CSz) and non-psychiatric (NP) control subjects. The study included 106 FESz, 293 CSz, and 210 NP, assessed with the Spanish version of the MATRICS Consensus Cognitive Battery (MCCB). The MCCB cognitive profile in a Spanish sample of FESz was similar to the cognitive profile of CSz with some discrepancies in select domains. The scores of both patient samples were about 1-2 SD below the scores of non-psychiatric control subjects.

Differential clinical, structural and P300 parameters in schizophrenia patients resistant to conventional neuroleptics.

Schizophrenia is a heterogeneous clinical condition that may reflect a variety of biological processes. In particular, treatment-resistant (TR) schizophrenia may have a distinct neurobiological substrate. Within the context of clinical data, a simultaneous study with different imaging techniques could help to elucidate differences in cerebral substrates among schizophrenia patients with different responses to treatment. In the present work we used a set of biological data (basal and longitudinal volumetry, and P300 event-related potential measurements) to compare TR and treatment-responsive chronic schizophrenia patients with healthy controls. The TR patients showed higher baseline clinical scores, a more severe basal profile of brain alterations, as well as a different outcome as regards to volume deficits. These data support the notion that biological substrates vary among groups of different psychotic patients, even when they have the same diagnosis, and that those substrates may be related to the response to treatment.

Focusing on symptoms rather than diagnoses in brain dysfunction: conscious and nonconscious expression in impulsiveness and decision-making.

Symptoms and syndromes in neuropathology, whether expressed in conscious or nonconscious behaviour, remain imbedded in often complex diagnostic categories. Symptom-based strategies for studying brain disease states are driven by assessments of presenting symptoms, signs, assay results, neuroimages and biomarkers. In the present account, symptom-based strategies are contrasted with existing diagnostic classifications. Topics include brain areas and regional circuitry underlying decision-making and impulsiveness, and motor and learned expressions of explicit and implicit processes. In three self-report studies on young adult and adolescent healthy individuals, it was observed that linear regression analyses between positive and negative affect, self-esteem, four different types of situational motivation: intrinsic, identified regulation, extrinsic regulation and amotivation, and impulsiveness predicted significant associations between impulsiveness with negative affect and lack of motivation (i.e., amotivation) and internal locus of control, on the one hand, and non-impulsiveness with positive affect, self-esteem, and high motivation (i.e., intrinsic motivation and identified regulation), on the other. Although presymptomatic, these cognitive-affective characterizations illustrate individuals' choice behaviour in appraisals of situations, events and proclivities essentially of distal perspective. Neuropathological expressions provide the proximal realities of symptoms and syndromes with underlying dysfunctionality of brain regions, circuits and molecular mechanisms.

Psychopathology and Wisconsin Card Sorting Test performance in male schizophrenic patients: influence of dual diagnosis.

BACKGROUND: Different neuropsychological studies have shown schizophrenic patients to have executive function deficits, as illustrated by their performance in neuropsychological tasks such as the Wisconsin Card Sorting Test (WCST); certain studies have described a relationship between these deficits and negative symptoms. Schizophrenic patients also exhibit a high lifetime prevalence (40-50%) of comorbid substance use disorders (SUDs). However, little attention has been paid to this comorbidity (dual diagnosis) in studies associating executive functions and negative symptoms. SAMPLING AND METHODS: Our objective is to investigate the relationship between performance in the WCST and psychopathology as measured by the Positive and Negative Syndrome Scale (PANSS) in a sample of 65 male schizophrenic patients with a history of SUDs (Sch SUD+) and in a sample of 48 male schizophrenic patients without such history (Sch SUD-). RESULTS: In the Sch SUD- group, patients who completed 4 or more categories in the WCST ('good performers') obtained a mean score of 21.2 +/- 8.8 on the negative subscale of the PANSS, compared with a mean score of 27.8 +/- 8.6 in those who completed 3 or less ('poor performers'); these differences were statistically significant (p = 0.015). In the Sch SUD+ group, however, no association was found between WCST performance and the PANSS negative subscale score. CONCLUSIONS: The presence of a history of comorbid SUDs should be taken into consideration in studies investigating executive functions and negative symptoms in schizophrenia.

Dorsolateral prefrontal N-acetyl-aspartate concentration in male patients with chronic schizophrenia and with chronic bipolar disorder.

OBJECTIVES: A study of N-acetyl-aspartate (NAA) can provide data of interest about cortical alterations in psychotic illnesses. Although a decreased NAA level in the cerebral cortex is a replicated finding in chronic schizophrenia, the data are less consistent for bipolar disease. On the other hand, it is likely that NAA values in schizophrenia may differ in men and women. METHODS: We used proton magnetic resonance spectroscopy ((1)H MRS) to examine NAA levels in the prefrontal cortex in two groups of male patients, one with schizophrenia (n=11) and the other with bipolar disorder (n=13) of similar duration, and compared them to a sample of healthy control males (n=10). Additionally, we compared the degree of structural deviations from normal volumes of gray matter (GM) and cerebrospinal fluid (CSF) in the dorsolateral prefrontal cortex. RESULTS: Compared to controls, schizophrenia and bipolar patients presented decreased NAA to creatine ratios, while only the schizophrenia group showed an increase in CSF in the dorsolateral prefrontal region. There were no differences in choline to creatine ratios among the groups. CONCLUSIONS: These data suggest that the decrease in NAA in the prefrontal region may be similar in schizophrenia and bipolar disorder, at least in the chronic state. However, cortical CSF may be markedly increased in schizophrenia patients.

The TaqIA polymorphism linked to the DRD2 gene is related to lower attention and less inhibitory control in alcoholic patients.

The TaqIA polymorphism linked to the DRD2 gene has been associated with alcoholism. The aim of this work is to study attention and inhibitory control as per the continuous performance test and the stop task in a sample of 50 Spanish male alcoholic patients split into two groups according to the presence of the TaqIA1 allele in their genotype. Our results show that alcoholics carrying the TaqIA1 allele present lower sustained attention and less inhibitory control than those patients without such allele.

Impulsivity and sustained attention in pathological gamblers: influence of childhood ADHD history.

Pathological gambling (PG) has been associated to both impulsiveness and attention deficit/hyperactivity disorder (ADHD) in different studies. Our objective was to compare different impulsivity and sustained attention variables, using both behavioural tasks and self-administered questionnaires, in a group of pathological gamblers with a history of childhood ADHD (PG-ADHD; n = 16), a group of pathological gamblers without this history (PG-non-ADHD; n = 39), and a control group (n = 40). As instruments of measure, we used the stop signal task (to evaluate inhibitory control/impulsivity), the differential reinforcement of Low Rate Responding Task (delay of gratification/impulsivity) and the Continuous Performance Test (sustained attention). The Barratt Impulsivity Scale (BIS-11) was used as a self-administered questionnaire to measure impulsiveness. Our results show that patients in the PG-ADHD group exhibit a significantly lower capacity to delay gratification than those in the PG-non-ADHD and control groups, and less inhibitory control than patients in the PG-non-ADHD group. On self-administered questionnaires such as the BIS-11 the PG-ADHD group obtained higher scores than the PG-non-ADHD and control groups. However, no differences were found with respect to sustained attention using the CPT. Our results suggest a possible selective implication of the prefrontal cortex in PG, which would be especially evident in those with a childhood history of ADHD.

[Executive dysfunctions in adults with attention deficit hyperactivity disorder]. / Disfunciones ejecutivas en adultos con trastorno por déficit de atención e hiperactividad.

INTRODUCTION: Several different follow-up studies have shown that attention deficit hyperactivity disorder (ADHD) can persist into adulthood. AIM: To review the findings in adults with ADHD related to alterations in the executive functions. DEVELOPMENT: Research conducted among children with ADHD has revealed the existence of alterations in different tasks that evaluate the executive functions, such as the planning test, sustained attention tasks, cognitive flexibility, verbal fluency and working memory tasks, as well as several inhibition response tasks. In adults with ADHD, despite the lower number of reports in the literature and the methodological shortcomings that exist in some studies, analogous results have also been described with respect to executive functioning, namely, disorders affecting inhibition response, the capacity for planning, difficulties in cognitive flexibility and verbal fluency, and problems with working memory, which include aspects of spatial working memory, logical or visual memory. CONCLUSIONS: The findings we have available at present enable us to confirm the persistence of executive dysfunctions in adult patients with ADHD that are similar to those observed in children with ADHD.

Staging cognitive impairment and incidence of dementia.

AIMS: In a background of interest in staging models in psychiatry, we tested the validity of a simple staging model of cognitive impairment to predict incident dementia. METHOD: A large community sample of adults aged ≥55 years (N = 4803) was assessed in the baseline of a longitudinal, four-wave epidemiological enquiry. A two-phase assessment was implemented in each wave, and the instruments used included the Mini-Mental Status Examination (MMSE); the History and Aetiology Schedule and the Geriatric Mental State-AGECAT. For the standardised degree of cognitive impairment Perneczky et al's MMSE criteria were applied. A panel of psychiatrists diagnosed cases of dementia according to DSM-IV criteria, and cases and sub-cases of dementia were excluded for the follow-up waves. Competing risk regression models, adjusted by potential confounders, were used to test the hypothesised association between MMSE levels and dementia risk. RESULTS: Out of the 4057 participants followed up, 607 (14.9%) were classified as 'normal' (no cognitive impairment), 2672 (65.8%) as 'questionable' cognitive impairment, 732 (18.0%) had 'mild' cognitive impairment, 38 (0.9%) had 'moderate' cognitive impairment and eight (0.2%) had 'severe' impairment. Cognitive impairment was associated with risk of dementia, the risk increasing in parallel with the level of impairment (hazard ratio: 2.72, 4.78 and 8.38 in the 'questionable', 'mild' and 'moderate' level of cognitive impairment, respectively). CONCLUSIONS: The documented gradient of increased risk of dementia associated with the severity level of cognitive impairment supports the validity of the simple staging model based on the MMSE assessment.

[Oxcarbazepine in the prevention of epileptic syndromes in alcohol detoxification]. / Oxcarbacepina para la prevención de patología epiléptica en la desintoxicación alcohólica.

INTRODUCTION: Alcohol withdrawal syndrome may be accompanied by severe complications, such as epileptic syndromes or delirium tremens. A number of pharmacological strategies, especially benzodiazepines (BZD), have been used in their treatment and prevention, although problems can arise from the use of these drugs due to their addictive properties. The classical anticonvulsive drugs are rarely employed as an alternative because of their side effects, but the latest generation of substances could be especially useful. AIMS. The aim of this study was to examine the safety of oxcarbazepine (OXC) in the prevention of epileptic seizures and complications deriving from the withdrawal syndrome in alcohol detoxification treatment. PATIENTS AND METHODS: The study involved a comparison of two groups of patients with a syndrome of physical dependence on alcohol, 42 of whom were treated with OXC and the remaining 42 received BZD as part of a programmed detoxification therapy. RESULTS: Both OXC and BZD were equally efficient in preventing the appearance of epileptic complications and in reducing withdrawal symptoms. Overall, OXC produced fewer adverse events (p < 0.001) and offered fewer problems when it came to ending administration (p < 0.001). CONCLUSIONS: OXC can be a valuable alternative to BZD and other pharmacological treatments in the prevention of complications in detoxification therapy, especially because of the absence of addictive properties and its having a better safety profile than classical anticonvulsant drugs.

The MCCB impairment profile in a Spanish sample of patients with schizophrenia: Effects of diagnosis, age, and gender on cognitive functioning.

The MATRICS Consensus Cognitive Battery (MCCB) was administered to 293 schizophrenia outpatients and 210 community residents in Spain. Our first objective was to identify the age- and gender-corrected MCCB cognitive profile of patients with schizophrenia. The profile of schizophrenia patients showed deficits when compared to controls across the seven MCCB domains. Reasoning and Problem Solving and Social Cognition were the least impaired, while Visual Learning and Verbal Learning showed the greatest deficits. Our second objective was to study the effects on cognitive functioning of age and gender, in addition to diagnosis. Diagnosis was found to have the greatest effect on cognition (Cohen's d>0.8 for all MCCB domains); age and gender also had effects on cognitive functioning, although to a lesser degree (with age usually having slightly larger effects than gender). The effects of age were apparent in all domains (with better performance in younger subjects), except for Social Cognition. Gender had effects on Attention/Vigilance, Working Memory, Reasoning and Problem Solving (better performance in males), and Social Cognition (better performance in females). No interaction effects were found between diagnosis and age, or between diagnosis and gender. This lack of interactions suggests that age and gender effects are not different in patients and controls.

Extinction of cocaine self-administration produces a differential time-related regulation of proenkephalin gene expression in rat brain.

The purpose of this study was to examine the time course effects of extinction of cocaine self-administration behavior on proenkephalin (PENK) gene expression in caudate-putamen nucleus (ST), nucleus accumbens (Acc), olfactory tubercle (Tu), piriform cortex (Pir), ventromedial hypothalamic nucleus (VMN), and central amygdala (Ce) as measured by in situ hybridization histochemistry. Seventy-two littermate male Lewis rats were randomly assigned in triads to one of three conditions: (1) contingent intravenous self-administration of 1 mg/kg/injection of cocaine (CONT); (2) noncontingent injections of either 1 mg/kg/injection of cocaine (NONCONT); or (3) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to self-administer cocaine under a FR5 schedule of reinforcement for a minimum of 3 weeks. After stable baseline levels of drug intake had been reached, saline was substituted for drug. Following this first extinction period, cocaine self-administration was reinstated for an additional period of 2 weeks. Immediately after cessation of the last session of cocaine self-administration (day 0) and 1-, 5-, and 10-day after the second extinction period, animal brains in each triad were removed to be processed for in situ hybridization. PENK mRNA levels were significantly higher in the cocaine groups when compared with SALINE group in the ST, Acc, Pir, and Tu regions on days 0, 1, 5, and 10 of the extinction and lower in the Ce region of CONT group when compared to NONCONT and SALINE groups on days 1, 5, and 10 of the extinction period. In the VMN nucleus, PENK mRNA content in CONT group versus NONCONT and SALINE groups was also lower, but there were statistically significant differences only on day 5. These results suggest that changes in PENK gene expression after contingent cocaine administration might be involved in cocaine withdrawal states.

Cerebral metabolism and risperidone treatment in schizophrenia.

This paper compares the metabolic changes associated with risperidone treatment in schizophrenia to those induced by haloperidol, as a representative typical neuroleptic. A group of 11 schizophrenic patients of recent onset underwent two [18F] fluoro-desoxi-glucose (FDG)-positron emission tomography (PET) scans at rest: the first one at the moment of the diagnosis, after a minimal treatment with haloperidol followed by wash-out, and the second one after 6 months on risperidone. The study also included 34 patients on chronic haloperidol for comparison. PET images were analyzed using Statistical Parametric Mapping (SPM'99) methods. The only change after treatment with risperidone with respect to the baseline was a slight increase in activity in the primary visual area and the right insula. Patients on chronic haloperidol showed increased activity in the motor cortex and cerebellum, as compared to both minimally treated and risperidone-treated patients. The pattern of metabolic changes induced by risperidone appears to be different from that produced by typical antipsychotics.

P300 amplitude as a possible correlate of frontal degeneration in schizophrenia.

The existence of neurodegeneration is a debated issue in schizophrenia research. The P300 component of event-related electrical potentials (ERP) has been related to the different degree of damage to gray and white matter. This study explores the possible relationship between P300 amplitude and/or latency and the existence of degenerative processes in schizophrenia, by assessing its correlation with volume of sulcal CSF and duration of illness, as transversal indicators of neurodegeneration. Nineteen patients (14 males, 5 females) and 13 controls (6 males, 7 females) were studied with MRI and electrophysiological records (P300). The possible influence of sex and age at the time of the exploration was statistically controlled in both groups. The results show a significant negative correlation between P300 amplitude and prefrontal CSF volume in the patient group. A lower though still significant correlation was also found between P300 amplitude and duration of illness, whereas no correlation was found in the control group. These results support the hypothesis that P300 amplitude may be interpreted as a marker of neurodegeneration in schizophrenia.