Substantial Cognitive Impairment Research Articles

The extent of intrauterine growth restriction determines the severity of cerebral injury and neurobehavioural deficits in rodents.

BackgroundCerebral Palsy (CP) is the most common physical pediatric neurodevelopmental disorder and spastic diplegic injury is its most frequent subtype. CP results in substantial neuromotor and cognitive impairments that have significant socioeconomic impact. Despite this, its underlying pathophysiological mechanisms and etiology remain incompletely understood. Furthermore, there is a need for clinically relevant injury models, which a) reflect the heterogeneity of the condition and b) can be used to evaluate new translational therapies. To address these key knowledge gaps, we characterized a chronic placental insufficiency (PI) model, using bilateral uterine artery ligation (BUAL) of dams. This injury model results in intrauterine growth restriction (IUGR) in pups, and animals recapitulate the human phenotype both in terms of neurobehavioural and anatomical deficits.MethodsEffects of BUAL were studied using luxol fast blue (LFB)/hematoxylin & eosin (H&E) staining, immunohistochemistry, quantitative Magnetic Resonance Imaging (MRI), and Catwalk neurobehavioural tests.ResultsNeuroanatomical analysis revealed regional ventricular enlargement and corpus callosum thinning in IUGR animals, which was correlated with the extent of growth restriction. Olig2 staining revealed reductions in oligodendrocyte density in white and grey matter structures, including the corpus callosum, optic chiasm, and nucleus accumbens. The caudate nucleus, along with other brain structures such as the optic chiasm, internal capsule, septofimbrial and lateral septal nuclei, exhibited reduced size in animals with IUGR. The size of the pretectal nucleus was reduced only in moderately injured animals. MAG/NF200 staining demonstrated reduced myelination and axonal counts in the corpus callosum of IUGR animals. NeuN staining revealed changes in neuronal density in the hippocampus and in the thickness of hippocampal CA2 and CA3 regions. Diffusion weighted imaging (DWI) revealed regional white and grey matter changes at 3 weeks of age. Furthermore, neurobehavioural testing demonstrated neuromotor impairments in animals with IUGR in paw intensities, swing speed, relative print positions, and phase dispersions.ConclusionsWe have characterized a rodent model of IUGR and have demonstrated that the neuroanatomical and neurobehavioural deficits mirror the severity of the IUGR injury. This model has the potential to be applied to examine the pathobiology of and potential therapeutic strategies for IUGR-related brain injury. Thus, this work has potential translational relevance for the study of CP.

Cognitive development prior to onset of psychosis.

Schizophrenia patients commonly exhibit substantial and diffuse cognitive impairment. Evidence suggests that subtle cognitive deficits are already apparent in childhood and adolescence, many years prior to onset of psychosis. While there is almost unequivocal evidence of some degree of cognitive impairment in individuals who later develop schizophrenia, the literature remains inconclusive regarding the exact nature of this impairment and warrants careful review and interpretation. Meta-analytic findings suggest that individuals who later develop schizophrenia, but not related disorders, such as bipolar disorder, exhibit a premorbid IQ deficit of around 8 points. Several studies have also found evidence for premorbid deficits across most cognitive domains, such as language, processing speed and executive functions. Longitudinal studies, although rare, suggest that individuals who go on to develop schizophrenia may show a course of increasing cognitive impairment prior to onset of psychosis. While evidence regarding the etiology of premorbid deficits is scarce, common and rare genetic variants, as well as environmental factors such as obstetric complications and cannabis use may play an important role and warrant further examination. In this selected review, we give an overview of population-based studies on premorbid cognitive deficits in schizophrenia, with a special focus on evidence regarding the specificity, profile and course of these deficits.

Abstract WMP48: Cerebral Endothelial Derived Exosomes Abolish Cognitive Impairment Induced by Ablation of Dicer in Adult Neural Progenitor Cells

Introduction: Dicer processes precursor miRNAs into mature miRNAs. We have demonstrated that conditional knockout of Dicer (Dicer/Cko) in adult neural progenitor cells (NPCs) impairs neurogenesis and cognitive function. The present study tested the hypothesis that cerebral endothelial-derived exosomes carrying mature miRNAs promote neurogenesis and improve cognitive function by communication with NPCs in Dicer/Cko mice. Methods and Results: Exosomes harvested from cultured cerebral endothelial cells (CEC-Ex, 1x10 9 exosomes) were intranasally administered twice a week for two consecutive weeks into mice (n=10) with conditional ablation of Dicer (Dicer/Cko) in NPCs ( Ascl1- CreER :Dicer flox/flox ). Dicer/Cko mice treated with saline (n=12) were used as control. Cognitive tests were performed, including Morris Water Maze (MWM) for hippocampal related learning and memory, odor-based novelty recognition for olfactory memory, and social interaction for memory of interactions with novel conspecifics. Compared to wild-type mice, Dicer/Cko mice treated with saline exhibited substantial cognitive impairment. The CEC-Ex treatment diminished cognitive deficits and these mice exhibited an increase of 40% more time spent in the correct quadrant (p<0.05) of the MWM, and increased time exploring new odor objects (71±9% vs 41 ±10% saline, p<0.05) and increased time in contact with a strange mouse during the sociability test. Using a Cre/flox reporter approach, we found that the exosomes carrying Cre mRNA entered NPCs in the subventricular zone (SVZ) and dentate gyrus (DG). The CEC-Ex treatment significantly (p<0.05) increased BrdU + NPCs (20 ± 1% vs 14 ± 2%, SVZ, 16±1% vs 12±3%, DG ) and DCX+ neuroblasts (27 ± 2% vs 22 ± 3%, SVZ, 33 ± 2% vs 25 ± 3%, DG), and reduced apoptotic cells by more than 50% in these two areas. RT-PCR analysis showed that Dicer/Cko mice exhibited substantial reduction of mature miRNAs that regulate neurogenesis including miR-124, -146a and -17-92 cluster in NPCs, whereas the CEC-Ex treatment increased these mature miRNAs in Dicer/Cko NPCs. Conclusion: The CEC-Ex can reverse impaired neurogenesis and cognitive function induced by ablation of Dicer, which is likely attributed to the delivery of mature miRNAs into NPCs by CEC-Ex.

Association of β-Blockers With Functional Outcomes, Death, and Rehospitalization in Older Nursing Home Residents After Acute Myocardial Infarction

Although β-blockers are a mainstay of treatment after acute myocardial infarction (AMI), these medications are commonly not prescribed for older nursing home residents after AMI, in part owing to concerns about potential functional harms and uncertainty of benefit. To study the association of β-blockers after AMI with functional decline, mortality, and rehospitalization among long-stay nursing home residents 65 years or older. This cohort study of nursing home residents with AMI from May 1, 2007, to March 31, 2010, used national data from the Minimum Data Set, version 2.0, and Medicare Parts A and D. Individuals with β-blocker use before AMI were excluded. Propensity score-based methods were used to compare outcomes in people who did vs did not initiate β-blocker therapy after AMI hospitalization. Functional decline, death, and rehospitalization in the first 90 days after AMI. Functional status was measured using the Morris scale of independence in activities of daily living. The initial cohort of 15 720 patients (11 140 women [70.9%] and 4580 men [29.1%]; mean [SD] age, 83 [8] years) included 8953 new β-blocker users and 6767 nonusers. The propensity-matched cohort included 5496 new users of β-blockers and an equal number of nonusers for a total cohort of 10 992 participants (7788 women [70.9%]; 3204 men [29.1%]; mean [SD] age, 84 [8] years). Users of β-blockers were more likely than nonusers to experience functional decline (odds ratio [OR], 1.14; 95% CI, 1.02-1.28), with a number needed to harm of 52 (95% CI, 32-141). Conversely, β-blocker users were less likely than nonusers to die (hazard ratio [HR], 0.74; 95% CI, 0.67-0.83) and had similar rates of rehospitalization (HR, 1.06; 95% CI, 0.98-1.14). Nursing home residents with moderate or severe cognitive impairment or severe functional dependency were particularly likely to experience functional decline from β-blockers (OR, 1.34; 95% CI, 1.11-1.61 and OR, 1.32; 95% CI, 1.10-1.59, respectively). In contrast, little evidence of functional decline due to β-blockers was found in participants with intact cognition or mild dementia (OR, 1.03; 95% CI, 0.89-1.20; P = .03 for effect modification) or in those in the best (OR, 0.99; 95% CI, 0.77-1.26) and intermediate (OR, 1.05; 95% CI, 0.86-1.27) tertiles of functional independence (P = .06 for effect modification). Mortality benefits of β-blockers were similar across all subgroups. Use of β-blockers after AMI is associated with functional decline in older nursing home residents with substantial cognitive or functional impairment, but not in those with relatively preserved mental and functional abilities. Use of β-blockers yielded a considerable mortality benefit in all groups.

Close Contact Casting vs Surgery for Initial Treatment of Unstable Ankle Fractures in Older Adults: A Randomized Clinical Trial.

Ankle fractures cause substantial morbidity in older persons. Surgical fixation is the contemporary intervention but is associated with infection and other healing complications. To determine whether initial fracture treatment with close contact casting, a molded below-knee cast with minimal padding, offers outcome equivalent to that with immediate surgery, with fewer complications and less health resource use. This was a pragmatic, equivalence, randomized clinical trial with blinded outcome assessors. A pilot study commenced in May 2004, followed by multicenter recruitment from July 2010 to November 2013; follow-up was completed May 2014. Recruitment was from 24 UK major trauma centers and general hospitals. Participants were 620 adults older than 60 years with acute, overtly unstable ankle fracture. Exclusions were serious limb or concomitant disease or substantial cognitive impairment. Participants were randomly assigned to surgery (n = 309) or casting (n = 311). Casts were applied in the operating room under general or spinal anesthesia by a trained surgeon. The primary 6-month, per-protocol outcome was the Olerud-Molander Ankle Score at 6 months (OMAS; range, 0-100; higher scores indicate better outcomes and fewer symptoms), equivalence prespecified as ±6 points. Secondary outcomes were quality of life, pain, ankle motion, mobility, complications, health resource use, and patient satisfaction. Among 620 adults (mean age, 71 years; 460 [74%] women) who were randomized, 593 (96%) completed the study. Nearly all participants (579/620; 93%) received allocated treatment; 52 of 275 (19%) who initially received casting later converted to surgery, which was allowable in the casting treatment pathway to manage early loss of fracture reduction. At 6 months, casting resulted in ankle function equivalent to that with surgery (OMAS score, 66.0 [95% CI, 63.6-68.5] for surgery vs 64.5 [95% CI, 61.8-67.2] for casting; mean difference, -0.6 [95% CI, -3.9 to 2.6]; P for equivalence = .001). Infection and wound breakdown were more common with surgery (29/298 [10%] vs 4/275 [1%]; odds ratio [OR], 7.3 [95% CI, 2.6-20.2]), as were additional operating room procedures (18/298 [6%] for surgery and 3/275 [1%] for casting; OR, 5.8 [95% CI, 1.8-18.7]). Radiologic malunion was more common in the casting group (38/249 [15%] vs 8/274 [3%] for surgery; OR, 6.0 [95% CI, 2.8-12.9]). Casting required less operating room time compared with surgery (mean difference [minutes/participant], -54 [95% CI, -58 to -50]). There were no significant differences in other secondary outcomes: quality of life, pain, ankle motion, mobility, and patient satisfaction. Among older adults with unstable ankle fracture, the use of close contact casting compared with surgery resulted in similar functional outcomes at 6 months. Close contact casting may be an appropriate treatment for such patients. isrctn.com Identifier: ISRCTN04180738.

The Ankle Injury Management (AIM) trial: a pragmatic, multicentre, equivalence randomised controlled trial and economic evaluation comparing close contact casting with open surgical reduction and internal fixation in the treatment of unstable ankle fractures in patients aged over 60 years

Close contact casting (CCC) may offer an alternative to open reduction and internal fixation (ORIF) surgery for unstable ankle fractures in older adults. We aimed to (1) determine if CCC for unstable ankle fractures in adults aged over 60 years resulted in equivalent clinical outcome compared with ORIF, (2) estimate cost-effectiveness to the NHS and society and (3) explore participant experiences. A pragmatic, multicentre, equivalence randomised controlled trial incorporating health economic evaluation and qualitative study. Trauma and orthopaedic departments of 24 NHS hospitals. Adults aged over 60 years with unstable ankle fracture. Those with serious limb or concomitant disease or substantial cognitive impairment were excluded. CCC was conducted under anaesthetic in theatre by surgeons who attended training. ORIF was as per local practice. Participants were randomised in 1 : 1 allocation via remote telephone randomisation. Sequence generation was by random block size, with stratification by centre and fracture pattern. Follow-up was conducted at 6 weeks and, by blinded outcome assessors, at 6 months after randomisation. The primary outcome was the Olerud-Molander Ankle Score (OMAS), a patient-reported assessment of ankle function, at 6 months. Secondary outcomes were quality of life (as measured by the European Quality of Life 5-Dimensions, Short Form questionnaire-12 items), pain, ankle range of motion and mobility (as measured by the timed up and go test), patient satisfaction and radiological measures. In accordance with equivalence trial US Food and Drug Administration guidance, primary analysis was per protocol. We recruited 620 participants, 95 from the pilot and 525 from the multicentre phase, between June 2010 and November 2013. The majority of participants, 579 out of 620 (93%), received the allocated treatment; 52 out of 275 (19%) who received CCC later converted to ORIF because of loss of fracture reduction. CCC resulted in equivalent ankle function compared with ORIF at 6 months {OMAS 64.5 points [standard deviation (SD) 22.4 points] vs. OMAS 66.0 points (SD 21.1 points); mean difference -0.65 points, 95% confidence interval (CI) -3.98 to 2.68 points; standardised effect size -0.04, 95% CI -0.23 to 0.15}. There were no differences in quality of life, ankle motion, pain, mobility and patient satisfaction. Infection and/or wound problems were more common with ORIF [29/298 (10%) vs. 4/275 (1%)], as were additional operating theatre procedures [17/298 (6%) vs. 3/275 (1%)]. Malunion was more common with CCC [38/249 (15%) vs. 8/274 (3%); p < 0.001]. Malleolar non-union was lower in the ORIF group [lateral: 0/274 (0%) vs. 8/248 (3%); p = 0.002; medial: 3/274 (1%) vs. 18/248 (7%); p < 0.001]. During the trial, CCC showed modest mean cost savings [NHS mean difference -£644 (95% CI -£1390 to £76); society mean difference -£683 (95% CI -£1851 to £536)]. Estimates showed some imprecision. Incremental quality-adjusted life-years following CCC were no different from ORIF. Over common willingness-to-pay thresholds, the probability that CCC was cost-effective was very high (> 95% from NHS perspective and 85% from societal perspective). Experiences of treatments were similar; both groups endured the impact of fracture, uncertainty regarding future function and the need for further interventions. Assessors at 6 weeks were necessarily not blinded. The learning-effect analysis was inconclusive because of limited CCC applications per surgeon. CCC provides a clinically equivalent outcome to ORIF at reduced cost to the NHS and to society at 6 months. Longer-term follow-up of trial participants is under way to address concerns over potential later complications or additional procedures and their potential to impact on ankle function. Further study of the patient factors, radiological fracture patterns and outcomes, treatment responses and prognosis would also contribute to understanding the treatment pathway. Current Controlled Trials ISRCTN04180738. The National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 75. See the NIHR Journals Library website for further project information. This report was developed in association with the National Institute for Health Research Oxford Biomedical Research Unit funding scheme. The pilot phase was funded by the AO Research Foundation.

Behavioral and emerging pharmacologic treatment options for cognitive impairment in schizophrenia.

In recent years, the goal of treatment for individuals with schizophrenia has shifted from symptom control to functional recovery. For recovery to occur, the substantial cognitive impairments associated with this disorder must be addressed. Advances in neuroscience have paved the way for the development of more effective behavioral and pharmacologic treatments. Behavioral interventions such as cognitive training are tapping into the innate plasticity and adaptive qualities of the brain. Emerging pharmacologic treatments are targeting new neurotransmitters and systems, such as the glutamatergic system and the nicotinic-cholinergic system, which are involved in the cognitive and sensory deficits that lead to impairment. The best chances for recovery will most likely occur by combining behavioral and pharmacologic interventions.

Behavioral and Neurochemical Characteristics of Two Months Old WAG/Rij Rats with Genetic Absence Epilepsy

WAG/Rij rats are genetic animal model of absence epilepsy with comorbidity of depression. The first spike-wave discharges (SWDs) in WAG/Rij rats begin to appear at the age of 2-3 months and are fully manifested by 5-6 months. Occurrence of SWDs in the EEG is the main index of absence epilepsy. Previously it has been shown that the extensive absence epilepsy in 5-6 months old WAG/Rij rats is accompanied by decrease of dopamine and its metabolites concentrations in the meso-cortico-limbic and nigro-striatal dopaminergic brain systems, resulting in the expression of depression-like behavioral symptoms, and impairments of the learning and memory processes. In 36 days old WAG/Rij rats, SWDs are not manifested, deficiency of the mesolimbic dopamine is not revealed, and symptoms of depression-like behavior are not expressed. In this study, behavior in the open field, light-dark choice, forced swimming tests, monoamines and their metabolites concentrations in 5 brain structures (prefrontal cortex, nucleus accumbens, hypothalamus, striatum, hippocampus) were investigated in two months old WAG/Rij rats in comparison with age-matched Wistar rats. Reduced concentration of the dopamine and its metabolites, and increased concentration of the serotonin was found in WAG/Rij rats compared with Wistar rats only in the prefrontal cortex, indicating that the prefrontal cortex is the brain structure where neurochemical abnormalities appear first. No substantial changes in the monoamine and their metabolites concentrations have been revealed in other brain structures. Two months old WAG/Rij rats didn’t exhibit depression-like behavior in the forced swimming test, and learning/memory deficits in the passive avoidance test, but they showed behavioral changes, indicating increase anxiety/stress-reactivity, and alterations in learning/memory in the active avoidance test. Results suggest that two month-old WAG/Rij rats are at the stage of so called “pre-pathology” (increased anxiety and stress reactivity) preceding the development of depression-like behavior and substantial cognitive impairments which are co-morbid to fully expressed absence epilepsy in 5-6 months old rats of this strain.

Intermediate- and Long-Term Cognitive Outcomes After Cardiovascular Procedures in Older Adults: A Systematic Review.

Risks for intermediate- and long-term cognitive impairment after cardiovascular procedures in older adults are poorly understood. To summarize evidence about cognitive outcomes in adults aged 65 years or older at least 3 months after coronary or carotid revascularization, cardiac valve procedures, or ablation for atrial fibrillation. MEDLINE, Cochrane, and Scopus databases from 1990 to January 2015; ClinicalTrials.gov; and bibliographies of reviews and eligible studies. English-language trials and prospective cohort studies. One reviewer extracted data, a second checked accuracy, and 2 independently rated quality and strength of evidence (SOE). 17 trials and 4 cohort studies were included; 80% of patients were men, and mean age was 68 years. Cognitive function did not differ after the procedure between on- and off-pump coronary artery bypass grafting (CABG) (n=6; low SOE), hypothermic and normothermic CABG (n=3; moderate to low SOE), or CABG and medical management (n=1; insufficient SOE). One trial reported lower risk for incident cognitive impairment with minimal versus conventional extracorporeal CABG (risk ratio, 0.34 [95% CI, 0.16 to 0.73]; low SOE). Two trials found no difference between surgical carotid revascularization and carotid stenting or angioplasty (low and insufficient SOE, respectively). One cohort study reported increased cognitive decline after transcatheter versus surgical aortic valve replacement but had large selection and outcome measurement biases (insufficient SOE). Mostly low to insufficient SOE; no pertinent data for ablation; limited generalizability to the most elderly patients, women, and persons with substantial baseline cognitive impairment; and possible selective reporting and publication bias. Intermediate- and long-term cognitive impairment in older adults attributable to the studied cardiovascular procedures may be uncommon. Nevertheless, clinicians counseling patients before these procedures should discuss the uncertainty in their risk for adverse cognitive outcomes. Agency for Healthcare Research and Quality.

A systematic review of outcomes following emergency transfer to hospital for residents of aged care facilities.

residential aged care facility (RACF) resident numbers are increasing. Residents are frequently frail with substantial co-morbidity, functional and cognitive impairment with high susceptibility to acute illness. Despite living in facilities staffed by health professionals, a considerable proportion of residents are transferred to hospital for management of acute deteriorations in health. This model of emergency care may have unintended consequences for patients and the healthcare system. This review describes available evidence about the consequences of transfers from RACF to hospital. a comprehensive search of the peer-reviewed literature using four electronic databases. Inclusion criteria were participants lived in nursing homes, care homes or long-term care, aged at least 65 years, and studies reported outcomes of acute ED transfer or hospital admission. Findings were synthesized and key factors identified. residents of RACF frequently presented severely unwell with multi-system disease. In-hospital complications included pressure ulcers and delirium, in 19 and 38% of residents, respectively; and up to 80% experienced potentially invasive interventions. Despite specialist emergency care, mortality was high with up to 34% dying in hospital. Furthermore, there was extensive use of healthcare resources with large proportions of residents undergoing emergency ambulance transport (up to 95%), and inpatient admission (up to 81%). acute emergency department (ED) transfer is a considerable burden for residents of RACF. From available evidence, it is not clear if benefits of in-hospital emergency care outweigh potential adverse complications of transfer. Future research is needed to better understand patient-centred outcomes of transfer and to explore alternative models of emergency healthcare.

Domain-Specific Intolerance of Uncertainty in Socially Anxious and Contamination-Focused Obsessive–Compulsive Individuals

Intolerance of uncertainty (IU) has been increasingly recognized as a transdiagnostic factor across anxiety disorders and depression and is associated with substantial cognitive, behavioral, and emotional impairment. IU is typically construed as a dispositional tendency to view ambiguous stimuli and unknown outcomes as unacceptably threatening regardless of context, but recent findings suggest that the domain in which uncertainty is encountered may be relevant. Taking that research to the next step, the aim of the present study was to determine whether IU is more salient in concern-congruent versus incongruent domains and whether domain-specific IU is a better predictor of anxiety symptoms than trait IU. A total of 102 undergraduates were recruited into analog socially anxious (SA), obsessive–compulsive contamination (OCC), and nonanxious control (NAC) groups based on responses to measures of SA and OCC symptoms. Both groups reported more domain-congruent IU than trait IU or domain-incongruent IU. The SA group reported more social interaction IU than the OCC and NAC groups; the OCC group reported more cleanliness IU than the SA and NAC groups. Domain-specific IU predicted social anxiety and OCC fears above and beyond trait IU. Results suggest that IU has a substantial context-specific component and should be examined both transdiagnostically and transsituationally.

Current advances in neurotrauma research: diagnosis, neuroprotection, and neurorepair.

Current advances in neurotrauma research: diagnosis, neuroprotection, and neurorepair.

Biological Basis for Cerebral Dysfunction in Schizophrenia in Contrast with Alzheimer’s Disease

Schizophrenia and Alzheimer’s disease are two disorders that, while conceptualized as pathophysiologically and clinically distinct, cause substantial cognitive and behavioral impairment worldwide, and target apparently similar – or nearby – circuitry in regions such as the temporal and frontal lobes. We review the salient differences and similarities from selected historical, nosological, and putative mechanistic viewpoints, as a means to help both clinicians and researchers gain a better insight into these intriguing disorders, for which over a century of research and decades of translational development was needed to begin yielding treatments that are objectively effective, but still very far from entirely satisfactory. Ongoing comparison and “cross-pollination” among these approaches to disorders that produce similar deficits is likely to continue improving both our insight into the mechanisms at play, and the development of biotechnological approaches to tackle both conditions – and related disorders – more rapidly and efficaciously.

Relationship of changes in cognitive and depressive symptoms during antidepressant treatment of individuals with geriatric depression and their relationship to the APOE epsilon 4 allele.

BackgroundCo-occurring cognitive impairment in geriatric depression may not improve with antidepressant treatment and it may progress to dementia.AimAssess the relationship between changes in cognitive and depressive symptoms among patients with geriatric depression and their association with the APOE epsilon 4 allele before and after antidepressant treatment.MethodsThe presence of the APOE epsilon 4 allele was assessed in 64 incident cases of geriatric depression and 31 elderly individuals without depression and the Geriatric Depression Scale (GDS), Mini-Mental State Examination (MMSE), digit span test, and Trail Making Tests A and B (TMT-A, TMT-B) were administered to these subjects at baseline and 12 months after baseline, during which time the depressed group received standardized treatment with selective serotonin reuptake inhibitors (SSRIs).ResultsPrior to treatment patients with geriatric depression had significantly worse cognitive functioning than control subjects and 31 (48%) met criteria for mild cognitive impairment (MCI). After treatment depressed patients with and without comorbid MCI both had significant improvements in their depressive and cognitive symptoms, but those with MCI had more residual symptoms. The severity of cognitive symptoms was not associated with the severity of depressive symptoms at baseline, but they were positively correlated at the 12-month follow-up. The APOE epsilon 4 allele was identified in 14% (9/64) of the patients and in 3% (1/31) of the controls (Fisher's Exact Test, p=0.158). Compared to depressed patients without the allele, depressed patients with the allele had more severe cognitive deficits both before and after treatment, though only some of these differences were statistically significant.ConclusionsThere is substantial cognitive impairment in elderly individuals with geriatric depression. Both the depressive and cognitive symptoms improve with standard SSRI treatment, but individuals with comorbid MCI have more residual depressive and cognitive symptoms after treatment. The APOE epsilon 4 allele is associated with greater cognitive impairment in geriatric depressed patients and may be associated with less responsiveness of cognitive symptoms to antidepressant treatment.

One year outcomes in patients with acute lung injury randomised to initial trophic or full enteral feeding: prospective follow-up of EDEN randomised trial

Objective To evaluate the effect of initial low energy permissive underfeeding (“trophic feeding”) versus full energy enteral feeding (“full feeding”) on physical function and secondary outcomes in patients with acute...

The influence of motor and cognitive impairment upon visually-guided saccades in Parkinson's disease

Studies of saccades in Parkinson's disease (PD) have seldom examined the influence of cognitive status, ranging from normal cognition, through mild cognitive impairment, to dementia. In a large and heterogeneous sample, we examined how motor and cognitive impairment was reflected in the performance of reflexive, visually-guided saccades. We examined 163 people with PD and 47 similar-aged controls. Ninety three of the PD group had normal cognition (PDN), 48 had mild cognitive impairment (PD-MCI), and 22 had dementia (PDD). Pseudo-random targets (amplitudes of 5, 10, 15 and 20deg and inter-stimulus-intervals ranging from 550 to 1800ms) were shown in 108 mixed randomised trials, incorporating gap, step, and overlap onset conditions. Analyses were conducted using multi-level regression modeling. Participants were first assessed by continuous measures (Unified PD Rating Scale motor score and the Montreal Cognitive Assessment). Prolonged latency was significantly related to both motor and cognitive impairment, with the cognitive effect being compounded by increasing age. Decreased saccade amplitude, meanwhile, was primarily related to motor impairment. When assessed by discrete cognitive categories, all of the PD groups showed reduced saccadic amplitude relative to controls. Saccadic latencies, meanwhile, were abnormally prolonged only in the PD-MCI and PDD groups (the control and PDN groups were similar to each other). Latency in the overlap task was particularly sensitive to increasing motor and cognitive impairment. We conclude that reflexive saccades in PD are subtly decreased in amplitude even early in the disease process. Prolonged saccade latency, meanwhile, tends to occur later in the disease process, in the presence of more substantial motor and cognitive impairment, and greater age. The progressive impairment of reflexive saccades, and the differential onset of amplitude and latency impairments, may make them a useful objective tool for assessing disease status.

Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta‐analysis

Bipolar disorder (BD) is a common and highly disabling disease characterized by substantial cognitive and functional impairment. The exact neurobiological mechanisms underlying the expression of symptoms in this condition remain unknown but there is growing evidence that glutamate might play an important role. Using proton magnetic resonance spectroscopy (¹H-MRS), a number of studies have examined brain glutamate/glutamine levels in patients with bipolar disorder, but they have produced conflicting results. The objective of this paper was to conduct a systematic review and meta-analysis of the literature on brain glutamate/glutamine in BD as measured by ¹H-MRS. A Medline search for the period January 1980-April 2010 was conducted to identify published studies that used ¹H-MRS to measure glutamate + glutamine (Glx), the Glx/creatine (Cr) ratio, glutamate (Glu), or the Glu/Cr ratio in any brain region in adult or child/adolescent patients with BD and healthy subjects. A meta-analysis of the pooled data was conducted. BD patients were found to have increased Glx compared to healthy subjects when all brain areas were combined. This finding remained true in medicated and non-medicated patients, and in frontal brain areas in adults. There was a non-significant trend (p = 0.09) for an increase in whole-brain Glx/Cr and Glu in patients compared with healthy subjects. No significant difference was found in Glu/Cr. The results of this meta-analysis suggest that brain Glx levels are elevated in BD patients and support the idea that glutamate might play an important role in the pathophysiology of BD.

The Effect of Duloxetine Treatment on Cognition in Patients With Fibromyalgia

To determine the effect of duloxetine treatment on cognition in patients with fibromyalgia. Cognitive testing was conducted in a subset of adult patients in a randomized, double-blind, placebo-controlled trial of duloxetine. Patients met the American College of Rheumatology criteria for fibromyalgia and had a score of 4 or higher on the Brief Pain Inventory 24-hour average pain severity item. Patients who consented to cognitive testing were randomized to duloxetine (n = 80) or placebo (n = 76). The primary end point was at Week 12. Speed of processing on tasks requiring visual attention, working memory, and executive function was assessed with a Symbol Digit Substitution Test and Trail-Making Test A and B. Episodic memory was tested using the Verbal Learning and Recall Test. The change from baseline to end point (last-observation-carried-forward analysis) was analyzed by an analysis of covariance model, which included baseline, treatment, investigator, and treatment-by-investigator interaction. Most of the patients were white (89%) women (92%), ranging in age from 21 to 88 years. Mean scores on the cognitive tests were within 2 SD of published scores for similar-aged participants in the general population, indicating no substantial impairment. Baseline-to-end point changes in cognitive scores did not differ significantly between duloxetine and placebo treatment groups. Although scores differed somewhat from norms for age, substantial cognitive impairment was not evident in patients with fibromyalgia as assessed by the Symbol Digit Substitution Test, Trail-Making Test, and Verbal Learning and Recall Test. Overall, duloxetine treatment had neither positive nor negative effects on cognition. Clintrials.gov NCT00673452.

Cognitive impairment in fibromyalgia syndrome: The impact of cardiovascular regulation, pain, emotional disorders and medication

This study investigated cognitive performance in fibromyalgia syndrome (FMS) and its association with cardiovascular and clinical parameters. Thirty-five patients with FMS and 29 matched healthy controls completed a neuropsychological test measuring attention and arithmetic processing. As possible factors underlying the expected cognitive impairment, clinical pain intensity, co-morbid depression and anxiety disorders, sleep complaints, medication use, as well as blood pressure parameters were investigated. The patients' test performance was substantially reduced, particularly in terms of lower speed of cognitive processing and restricted improvement of performance in the course of the task. While the extent of depression, anxiety, fatigue and sleep complaints was unrelated to test performance, better performance was observed in patients showing lower pain ratings and those using opiate medication. The data corroborate the presence of substantial cognitive impairment in FMS. While the experience of chronic pain is crucial in mediating the deficits, co-morbid depression, anxiety, fatigue and sleep complaints play only a subordinate role. In the control group, but not in the patients, blood pressure was inversely associated with mental performance. This finding is in line with the well known cognitive impairment in hypertension. The lack of this association in FMS confirms previous research showing aberrances in the interaction between blood pressure and central nervous function in the affected patients.

The Role of Cognitive Impairment in the Use of the Diskus Inhaler

Drugs delivered by metered-dose inhalers and dry powder inhalers (DPIs) are a mainstay in the treatment of chronic lung disease; however, previous studies suggest cognitive impairment hinders proper use of inhalers. The purpose of this study was to determine the relationship between the score on the Mini-Mental State Exam (MMSE) and the ability of nursing facility residents to complete the steps required for proper use of a multiunit-dose DPI (Diskus). Nursing facility residents who had never used a multiunit-dose DPI (Diskus), who scored between 10 and 24 inclusive on the MMSE, and who were able to hold a breath for 10 seconds were recruited for an observational study to test their ability to use a placebo-loaded Diskus when supervised and assisted by personnel trained in the proper use the Diskus. Ability to use the DPI was assessed by the Diskus Evaluation Rating Scale (DERS), an instrument developed specifically for this study. Possible scores on the DERS ranged from 0 to 19, with a score of 0 indicating no limitations in any of the steps involved in using the Diskus and 19 indicating inability to do any of the steps after 3 supervised attempts. Forty Diskus-naïve nursing facility residents (86 ± 9 years of age; 32 women) with MMSE scores between 10 and 24 inclusive and the ability to hold a breath for 10 seconds were enrolled in the study. Mean MMSE scores were 17.4 ± 4.2, whereas the mean score on the DERS was 5.1 ± 3.2 (range 1-16). After controlling for age, gender, and education, a significant inverse relationship was noted between scores on the MMSE and the DERS such that for every 1-point increase on the MMSE, the subject's DERS score decreased by 0.345 points (P = .003). Overall, 38 of the 40 subjects with MMSE scores between 10 and 24 inclusive were able to use the Diskus successfully. For MMSE scores, the better the performance on the MMSE, the better the performance on the DERS. More important, 95% of the subjects in this study could use the Diskus successfully when properly supervised. In contrast to earlier studies, these findings suggest that a multiunit-dose DPI can be prescribed as one component of the regimen for chronic lung disease in patients with substantial cognitive impairment.