Cognitive Outcomes In Patients Research Articles

Long-term cognitive performance and its relation to anti-inflammatory therapy in a cohort of survivors of severe COVID-19

Background and objectivesLong-term cognitive performance data in former critically ill COVID-19 patients are sparse. Current evidence suggests that cognitive decline is related to neuroinflammation, which might be attenuated by COVID-19 related anti-inflammatory therapies. The objective of this prospective cohort study was to study long term cognitive outcomes following severe COVID-19 and the relation to anti-inflammatory therapies. MethodsProspective observational cohort of patients that survived an intensive care unit (ICU) admission due to severe COVID-19. Six months after hospital discharge, we extensively assessed both objective cognitive functioning and subjective cognitive complaints. Furthermore, patients were stratified in cohorts according to their anti-inflammatory treatment (i.e. no immunomodulatory therapy, dexamethasone, or both dexamethasone and interleukin-6 receptor antagonist tocilizumab). Results96 patients were included (March 2020–June 2021, median [IQR] age 61 [55–69] years). 91% received invasive mechanical ventilation, and mean ± SD severity-of-disease APACHE–II–score at admission was 15.8 ± 4.1. After 6.5 ± 1.3 months, 27% of patients scored cognitively impaired. Patients that did or did not develop cognitive impairments were similar in ICU-admission parameters, clinical course and delirium incidence. Patients with subjective cognitive complaints (20%) were more likely women (61% vs 26%), and had a shorter ICU stay (median [IQR] 8 [5–15] vs 18 [9–31], p = 0.002). Objective cognitive dysfunction did not correlate with subjective cognitive dysfunction. 27% of the participants received dexamethasone during intensive care admission, 44% received additional tocilizumab and 29% received neither. Overall occurrence and severity of cognitive dysfunction were not affected by anti-inflammatory therapy, although patients treated with both dexamethasone and tocilizumab had worse executive functioning scores (Trail Making Test interference) than patients without anti-inflammatory treatment (T-score 40.3 ± 13.5 vs 49.1 ± 9.3, p = 0.007). DiscussionA relevant proportion of critically ill COVID-19 patients shows deficits in long-term cognitive functioning. Apart from more pronounced executive dysfunction, overall, anti-inflammatory therapy appeared not to affect long-term cognitive performance. Our findings provide insight in long-term cognitive outcomes in patients who survived COVID-19, that may facilitate health-care providers counseling patients and their caregivers.

Predictors and occurrence of postoperative cognitive dysfunction in children undergoing noncardiac surgery: A prospective cohort study.

In children after cardiac surgery, alterations in cognitive ability and behavior are increasingly common, but whether postoperative cognitive dysfunction (POCD) occurs in children undergoing noncardiac surgery is not known. The present study was performed to investigate the incidence rate and potential risk factors of early neurocognitive dysfunction in children after noncardiac surgery. Two hundredpatients aged between 4 and 14 years old underwent elective noncardiac surgery and 100 healthy age-matched controls were enrolled in this prospective observational study. Wechsler Preschool and Primary Scale of Intelligence or Wechsler Intelligence Scale for Children-Revised were conducted 1 daybefore and 3 days after surgery. POCD was calculated and diagnosed as a combined Z score. Any factors that differed between POCD and non-POCD group (p < 0.10) were tested together by multivariate logistic regression analysis against the cognitive outcome of patients, to find out the independent risk factors of POCD. The general incidence of POCD was 15.6%. The univariate analysis revealed that POCD was associated with general anesthesia, surgical and anesthesia duration, early postoperative fever (EPF), and surgical history. However, only the history of surgery (p = 0.029), anesthesia duration (p = 0.010), and EPF (p < 0.001) were demonstrated to be independent risk factors for POCD. The occurrence rate of early POCD after noncardiac surgery in children is 15.6%. Children who had surgical history, longer anesthesia duration, or EPF are more prone to develop POCD.

Regional rather than global brain age mediates cognitive function in cerebral small vessel disease.

The factors and mechanisms underlying the heterogeneous cognitive outcomes of cerebral small vessel disease are largely unknown. Brain biological age can be estimated by machine learning algorithms that use large brain MRI data sets to integrate and compute neuroimaging-derived age-related features. Predicted and chronological ages difference (brain-age gap) reflects advanced or delayed brain aging in an individual. The present study firstly reports the brain aging status of cerebral small vessel disease. In addition, we investigated whether global or certain regional brain age could mediate the cognitive functions in cerebral small vessel disease. Global and regional (400 cortical, 14 subcortical and 28 cerebellum regions of interest) brain-age prediction models were constructed using grey matter features from MRI of 1482 healthy individuals (age: 18–92 years). Predicted and chronological ages differences were obtained and then applied to non-stroke, non-demented individuals, aged ≥50 years, from another community-dwelling population (I-Lan Longitudinal Aging Study cohort). Among the 734 participants from the I-Lan Longitudinal Aging Study cohort, 124 were classified into the cerebral small vessel disease group. The cerebral small vessel disease group demonstrated significantly poorer performances in global cognitive, verbal memory and executive functions than that of non-cerebral small vessel disease group. Global brain-age gap was significantly higher in the cerebral small vessel disease (3.71 ± 7.60 years) than that in non-cerebral small vessel disease (−0.43 ± 9.47 years) group (P = 0.003, η2 = 0.012). There were 82 cerebral cortical, 3 subcortical and 4 cerebellar regions showing significantly different brain-age gap between the cerebral small vessel disease and non-cerebral small vessel disease groups. Global brain-age gap failed to mediate the relationship between cerebral small vessel disease and any of the cognitive domains. In 89 regions with increased brain-age gap in the cerebral small vessel disease group, seven regional brain-age gaps were able to show significant mediation effects in cerebral small vessel disease-related cognitive impairment (we set the statistical significance P < 0.05 uncorrected in 89 mediation models). Of these, the left thalamus and left hippocampus brain-age gap explained poorer global cognitive performance in cerebral small vessel disease. We demonstrated the interconnections between cerebral small vessel disease and brain age. Strategic brain aging, i.e. advanced brain aging in critical regions, may be involved in the pathophysiology of cerebral small vessel disease-related cognitive impairment. Regional rather than global brain-age gap could potentially serve as a biomarker for predicting heterogeneous cognitive outcomes in patients with cerebral small vessel disease.

Association Between Lysine Reduction Therapies and Cognitive Outcomes in Patients With Pyridoxine-Dependent Epilepsy.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy characterized by seizure improvement after pyridoxine supplementation. Adjunct lysine reduction therapies (LRTs) reduce the accumulation of putative neurotoxic metabolites with the goal to improve developmental outcomes. Our objective was to examine the association between treatment with LRTs and cognitive outcomes. Participants were recruited from within the International Registry for Patients with Pyridoxine-Dependent Epilepsy from August 2014 through March 2021. The primary outcome was standardized developmental test scores associated with overall cognitive ability. The relationship between test scores and treatment was analyzed with multivariable linear regression using a mixed-effects model. A priori, we hypothesized that treatment in early infancy with pyridoxine and LRTs would result in a normal developmental outcome. A subanalysis was performed to evaluate the association between cognitive outcome and LRTs initiated in the first 6 months of life. A total of 112 test scores from 60 participants were available. On average, treatment with pyridoxine and LRTs was associated with a nonsignificant increase of 6.9 points (95% CI -2.7 to 16.5) on developmental testing compared with treatment with pyridoxine alone. For the subanalysis, a total of 14 developmental testing scores were available from 8 participants. On average, treatment with pyridoxine and LRTs in the first 6 months of life was associated with a significant increase of 21.9 points (95% CI 1.7-42.0) on developmental testing. Pyridoxine and LRTs at any age was associated with mild improvement in developmental testing, and treatment in early infancy was associated with a clinically significant increase in developmental test scores. These results provide insight into the mechanism of intellectual and developmental disability in PDE-ALDH7A1 and emphasize the importance of treatment in early infancy with both pyridoxine and LRTs. This study provides Class IV evidence that in PDE-ALDH7A1, pyridoxine and LRTs compared with pyridoxine alone is not significantly associated with overall higher developmental testing scores, but treatment in the first 6 months of life is associated with significantly higher developmental testing scores.

Mechanistic insights from animal models of neurofibromatosis type 1 cognitive impairment.

ABSTRACTNeurofibromatosis type 1 (NF1) is an autosomal-dominant neurogenetic disorder caused by mutations in the gene neurofibromin 1 (NF1). NF1 predisposes individuals to a variety of symptoms, including peripheral nerve tumors, brain tumors and cognitive dysfunction. Cognitive deficits can negatively impact patient quality of life, especially the social and academic development of children. The neurofibromin protein influences neural circuits via diverse cellular signaling pathways, including through RAS, cAMP and dopamine signaling. Although animal models have been useful in identifying cellular and molecular mechanisms that regulate NF1-dependent behaviors, translating these discoveries into effective treatments has proven difficult. Clinical trials measuring cognitive outcomes in patients with NF1 have mainly targeted RAS signaling but, unfortunately, resulted in limited success. In this Review, we provide an overview of the structure and function of neurofibromin, and evaluate several cellular and molecular mechanisms underlying neurofibromin-dependent cognitive function, which have recently been delineated in animal models. A better understanding of neurofibromin roles in the development and function of the nervous system will be crucial for identifying new therapeutic targets for the various cognitive domains affected by NF1.

Epigenetic GrimAge acceleration and cognitive impairment in bipolar disorder

Bipolar disorder (BD) has been previously associated with clinical signs of premature aging, including accelerated epigenetic aging in blood and brain, and a steeper age-related decline in cognitive function. However, the clinical drivers and cognitive correlates of epigenetic aging in BD are still unknown. We aimed to investigate the relationship between multiple measures of epigenetic aging acceleration with clinical, functioning, and cognitive outcomes in patients with BD and controls. Blood genome-wide DNA methylation levels were measured in BD patients (n = 153) and matched healthy controls (n = 50) with the Infinium MethylationEPIC BeadChip (Illumina). Epigenetic age estimates were calculated using an online tool, including the recently developed lifespan predictor GrimAge, and analyzed with generalized linear models controlling for demographic variables and blood cell proportions. BD was significantly associated with greater GrimAge acceleration (AgeAccelGrim, β=0.197, p = 0.009), and significant group-dependent interactions were found between AgeAccelGrim and blood cell proportions (CD4+ T-lymphocytes, monocytes, granulocytes, and B-cells). Within patients, higher AgeAccelGrim was associated with worse cognitive function in multiple domains (short-term affective memory (β=-0.078, p = 0.030), short-term non-affective memory (β=-0.088, p = 0.018), inhibition (β=0.064, p = 0.046), and problem solving (β=-0.067, p = 0.034)), age of first diagnosis with any mood disorder (β=-0.076, p = 0.039) or BD (β=-0.102, p = 0.016), as well as with current non-smoking status (β=-0.392, p < 0.001). Overall, our findings support the contribution of epigenetic factors to the aging-related cognitive decline and premature mortality reported in BD patients, with an important driving effect of smoking in this population.

LINC-11. Intrathecal methotrexate in a young child with medulloblastoma with extensive nodularity. An alternative to intra-ventricular route in Low and Middle Income Countries?

BACKGROUND: In places where determination of molecular subgrouping of Medulloblastoma is not available, histology remains standard for risk stratification and treatment. Young children with medulloblastoma treated with craniospinal irradiation show a negative impact in neurocognitive functions, thus avoiding radiation in this specific population is encouraged. High dose chemotherapy and stem cell rescue have been internationally used as a strategy to spare radiation in infants and young children with Medulloblastoma. German HIT protocol (SKK) reported a PFS 85±8 % and good cognitive outcome in patients with Desmoplastic Medulloblastoma treated with intra-ventricular (i.vtr.) methotrexate (MTX). SKK protocol includes 36 i.vtr. administrations of MTX through a subcutaneous reservoir. Complications related to the use of this kind of reservoir could be due to the lack of experienced staff. METHODS: We report a patient with localized Medulloblastoma with extensive nodullarity (MBEN) treated as per SKK using intrathecal route instead of i.vtr MTX. A 2.5 year old boy was diagnosed with MBEN, surgery was complete and no shunt was required. Spinal MRI and CSF cytology were negative. Patient received 3 cycles of SKK protocol and 2 cycles of modified SKK. During the first 3 cycles he received one dose of intrathecal MTX 8mg on weeks 1, 3, 5 and 7 (12 doses in all). Patient remains free of disease 2 years after chemotherapy completion and without signs of leukoencephalopathy on T2 weighted cranial MRI. DISCUSSION: Intrathecal administration of MTX is commonly used for the treatment of Acute Lymphoblastic Leukemia, the most common childhood cancer. Staff in Low and Middle Income Countries (LMIC) may be better trained for such procedure than using a ventricular access device. This strategy could be considered when using SKK protocol in selected young children with Demoplastic Medulloblastoma and MBEN in LMIC where centers with enough experience with ventricular access device placement and handling are scarce.

Effects of intensive blood pressure control on cardiovascular and cognitive outcomes in patients with atrial fibrillation: insights from the SPRINT trial.

Patients with atrial fibrillation (AF) have an increased risk of cardiovascular events and dementia, even if anticoagulated. Hypertension is highly prevalent in AF population; however, the optimal blood pressure (BP) target for AF patients remains unknown. We conducted subgroup analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) to examine whether AF modified the treatment effects of intensive BP control on cardiovascular and cognitive outcomes using Cox proportional hazards regression and likelihood ratio tests. Among 9361 randomized participants, 778 (8.3%) had baseline AF, and 695 (89.3%) completed at least one follow-up cognitive assessment. Intensive BP control reduced the similar relative risk of cardiovascular events irrespective of the presence of AF, with all interaction P-values > 0.05. Patients with AF experienced a greater absolute risk reduction in the composite primary cardiovascular outcome (12.3 vs. 5.6 events per 1000 person-years) with intensive treatment, compared with those without AF. However, intensive BP control increased the risk of probable dementia in patients with AF [hazard ratio (HR), 2.22; 95% confidence interval (CI), 1.03-4.80], while reducing the dementia risk in patients without AF (HR, 0.75; 95% CI, 0.60-0.95; P = 0.009 for interaction). There were no significant interactions between the presence of AF and intensive BP treatment for mild cognitive impairment. Patients with AF experienced greater absolute cardiovascular benefits with intensive BP treatment, but may need to be cautious of an increased risk of dementia. This post hoc analysis should be considered as hypothesis generating and merit further study. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.

Transcranial Direct Current Stimulation as an Approach to Mitigate Neurodevelopmental Disorders Affecting Excitation/Inhibition Balance: Focus on Autism Spectrum Disorder, Schizophrenia, and Attention Deficit/Hyperactivity Disorder.

Transcranial direct current stimulation (tDCS) has been proposed as a promising therapy for rehabilitation of neurodevelopmental disorders. In this review, we discuss studies on the impact of tDCS as a therapy for autism, schizophrenia, and attention deficit/hyperactivity disorder, as well as the tDCS’ mechanism of action, and propose future paths of research to optimize tDCS treatment protocols. The mechanism underlying tDCS effects is the modulation of excitatory and/or inhibitory activity, making it a valuable tool for restoring the excitation/inhibition (E/I) balance which is disrupted in many neurodevelopmental disorders. Clinical studies have shown that tDCS therapy is well-tolerated by patients and seems to ameliorate behavior and cognitive functions. Alterations in early development of neuronal circuits lead to disruptions in brain activity in neurodevelopmental disorders. An increasing amount of research into the effects of tDCS on neuronal activity has provided a foundation for its use as a therapy for behavior and cognitive characteristics of neurodevelopmental disorders. Clinical studies show that tDCS appears to ameliorate behavioral and cognitive outcomes of patients with autism, schizophrenia, and attention deficit/hyperactivity disorder. More research is needed to understand the mechanisms of action of tDCS and to optimize treatment protocols.

Clinical evaluation and resting state fMRI analysis of virtual reality based training in Parkinson’s disease through a randomized controlled trial

There are few studies investigating the short-term effects of Virtual Reality based Exergaming (EG) on motor and cognition simultaneously and pursue the brain functional activity changes after these interventions in patients with Parkinson’s Disease (PD). The purpose of this study was to investigate the synergistic therapeutic effects of Virtual Reality based EG on motor and cognitive symptoms in PD and its possible effects on neuroplasticity. Eligible patients with the diagnosis of PD were randomly assigned to one of the two study groups: (1) an experimental EG group, (2) an active control Exercise Therapy (ET) group. All patients participated in a 4-week exercise program consisting of 12 treatment sessions. Every session lasted 60 min. Participants underwent a motor evaluation, extensive neuropsychological assessment battery and rs-fMRI before and after the interventions. Thirty patients fulfilled the inclusion criteria and were randomly assigned to the EG and ET groups. After the dropouts, 23 patients completed the assessments and interventions (11 in EG, 13 in ET). Within group analysis showed significant improvements in both groups. Between group comparisons considering the interaction of group × time effect, showed superiority of EG in terms of general cognition, delayed visual recall memory and Boston Naming Test. These results were consistent in the within-group and between-group analysis. Finally, rs-fMRI analysis showed increased activity in the precuneus region in the time × group interaction in the favor of EG group. EG can be an effective alternative in terms of motor and cognitive outcomes in patients with PD. Compared to ET, EG may affect brain functional connectivity and can have beneficial effects on patients’ cognitive functions and motor symptoms. Whenever possible, using EG and ET in combination, may have the better effects on patients daily living and patients can benefit from the advantages of both interventions.

Seizure Control and Cognitive Outcomes in Patients with Encephalitis - A Retrospective Review (P1-1.005)

Seizure Control and Cognitive Outcomes in Patients with Encephalitis - A Retrospective Review (P1-1.005)

Neuropsychiatric and Cognitive Outcomes in Patients 6 Months After COVID-19 Requiring Hospitalization Compared With Matched Control Patients Hospitalized for Non–COVID-19 Illness

Prolonged neuropsychiatric and cognitive symptoms are increasingly reported in patients after COVID-19, but studies with well-matched controls are lacking. To investigate cognitive impairment, neuropsychiatric diagnoses, and symptoms in survivors of COVID-19 compared with patients hospitalized for non-COVID-19 illness. This prospective case-control study from a tertiary referral hospital in Copenhagen, Denmark, conducted between July 2020 and July 2021, followed up hospitalized COVID-19 survivors and control patients hospitalized for non-COVID-19 illness, matched for age, sex, and intensive care unit (ICU) status 6 months after symptom onset. Hospitalization for COVID-19. Participants were investigated with the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semi-structured interview for subjective symptoms. Primary outcomes were total MoCA score and new onset of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses, subjective symptoms, and neurologic examination results. All outcomes were adjusted for age, sex, ICU admission, admission length, and days of follow-up. Secondary outcomes were adjusted for multiple testing. A total of 85 COVID-19 survivors (36 [42%] women; mean [SD] age 56.8 [14] years) after hospitalization and 61 matched control patients with non-COVID-19 illness (27 [44%] women, mean age 59.4 years [SD, 13]) were enrolled. Cognitive status measured by total geometric mean MoCA scores at 6-month follow-up was lower (P = .01) among COVID-19 survivors (26.7; 95% CI, 26.2-27.1) than control patients (27.5; 95% CI, 27.0-27.9). The cognitive status improved substantially (P = .004), from 19.2 (95% CI, 15.2-23.2) at discharge to 26.1 (95% CI, 23.1-29.1) for 15 patients with COVID-19 with MoCA evaluations from hospital discharge. A total of 16 of 85 patients with COVID-19 (19%) and 12 of 61 control patients (20%) had a new-onset psychiatric diagnosis at 6-month follow-up, which was not significantly different (odds ratio, 0.93; 95% CI, 0.39-2.27; P = .87). In fully adjusted models, secondary outcomes were not significantly different, except anosmia, which was more common after COVID-19 (odds ratio, 4.56; 95% CI, 1.52-17.42; P = .006); but no longer when adjusting for multiple testing. In this prospective case-control study, cognitive status at 6 months was worse among survivors of COVID-19, but the overall burden of neuropsychiatric and neurologic signs and symptoms among survivors of COVID-19 requiring hospitalization was comparable with the burden observed among matched survivors hospitalized for non-COVID-19 causes.

Association of Haptoglobin Phenotype With Neurological and Cognitive Outcomes in Patients With Subarachnoid Hemorrhage.

BackgroundTo assess the association of haptoglobin (Hp) phenotype with neurological and cognitive outcomes in a large cohort of patients with subarachnoid hemorrhage (SAH).MethodsThis prospective multicenter study enrolled patients with aneurysmal SAH between May 2015 and September 2020. The Hp phenotype was confirmed via Western blots. The relative intensities of α1 in individuals carrying Hp2-1 were compared with those of albumin. Multivariable logistic and Cox proportional-hazard regression analyses were used to identify the risk factors for 6-month and long-term outcomes, respectively.ResultsA total of 336 patients including the phenotypes Hp1-1 (n = 31, 9.2%), Hp2-1 (n = 126, 37.5%), and Hp2-2 (n = 179, 53.3%) were analyzed. The Hp phenotype was closely associated with 6-month outcome (p = 0.001) and cognitive function (p = 0.013), and long-term outcome (p = 0.002) and cognitive function (p < 0.001). Compared with Hp1-1 as the reference value, Hp2-2 significantly increased the risk of 6-month poor outcome (OR: 7.868, 95% CI: 1.764–35.093) and cognitive impairment (OR: 8.056, 95% CI: 1.020–63.616), and long-term poor outcome (HR: 5.802, 95% CI: 1.795–18.754) and cognitive impairment (HR: 7.434, 95% CI: 2.264–24.409). Long-term cognitive impairment based on the Hp phenotype was significantly higher in patients under 65 years of age (p < 0.001) and female gender (p < 0.001). A lower relative α1/albumin intensity (OR: 0.010, 95% CI: 0.000–0.522) was associated with poor outcome at 6 months but not cognitive impairment in patients with SAH expressing Hp2-1.ConclusionHp2-2 increased the risk of poor neurological outcomes and cognitive impairment compared with Hp1-1. For Hp2-1, higher relative α1 intensities were related to 6-month favorable outcomes.

Evaluating cognitive outcomes in adult patients with acute encephalitis syndrome: a prospective study from a tertiary care center in Nepal.

Although cognitive impairment is a known complication of acute encephalitis syndrome (AES), few studies have evaluated cognitive outcomes in patients with encephalitis. The primary objective of this study was to assess the cognitive profiles of patients diagnosed with AES, which is pivotal for improving rehabilitation strategies and prognostic measures. This study was conducted at the Tribhuvan University Teaching Hospital. Adult patients with AES who met inclusion criteria were enrolled. The Montreal Cognitive Assessment (MoCA) tool was used to assess cognitive function at admission, discharge, and 3-month follow-up. Thirty-six patients were enrolled in our study. The mean age of the participants was 43 ± 18 years. Fourteen patients (38.9%) were female, and 22 (61.1%) were male. Tuberculous (TB) meningoencephalitis was present in 14 cases (38.9%), with herpes simplex virus (HSV) encephalitis in 14 (38.9%), bacterial meningoencephalitis in 4 (11.1%), autoimmune encephalitis in 2 (5.6%), and Japanese encephalitis in 2 (5.6%). Patients with bacterial meningoencephalitis had the highest MoCA scores at admission, whereas those with HSV encephalitis had the highest scores at discharge and follow-up. Compared with the scores at admission, the scores at discharge and follow-up increased significantly in patients with TB meningoencephalitis and HSV encephalitis. The MoCA score at discharge was established as a significant predictor of cognitive function at follow-up. We found that active treatment can improve the outcomes of AES patients with cognitive impairment. Although infectious etiologies are most common in low-income countries such as Nepal, autoimmune etiologies should not be overlooked.

Heterogeneity of White Matter Hyperintensities in Cognitively Impaired Patients With Cerebral Small Vessel Disease.

ObjectiveSimilar white matter hyperintensities (WMH) might have different impact on the cognitive outcomes in patients with cerebral small vessel disease (CSVD). This study is to assess the possible factors related to the heterogeneity of WMH in cognitively impaired patients with CVSD.MethodsWe analyzed data from a cohort of patients with CVSD who were recruited consecutively from the Beijing Tiantan Hospital from 2015 to 2020. WMH, lacunes, enlarged perivascular space (ePVS), microbleeds and lacunar infarcts were rated on brain MRI. A score of <26 on the Montreal Cognitive Assessment (MoCA) indicated cognitive impairment. A mismatch was defined as the severity of WMH not matching the severity of cognitive dysfunction. Type-1 mismatch was defined as a mild WMH (Fazekas score = 0-1) associated with cognitive impairment, and type-2 mismatch was defined as a severe WMH (Fazekas score = 5-6) associated with normal cognitive function. Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced SWI on 3-Tesla MRI was used to image the penetrating arteries in basal ganglia to explore the underlying mechanism of this mismatch. Multivariable logistic regression was used to analyze the association between the imaging features and cognitive impairment.ResultsIn 156 patients, 118 (75.6%) had cognitive impairment and 37 (23.7%) showed mismatch. Twenty five (16.0%) had type-1 mismatch and 12 (7.7%) had type-2 mismatch. Regression analysis found that WMH, lacunes, microbleeds and total CSVD scores were associated with cognitive impairment and were independent of vascular risk factors. However, lacunes, microbleeds and total CSVD scores were related to the mismatch between WMH and cognitive impairment (p=0.006, 0.005 and 0.0001, respectively). Specially, age and ePVS in basal ganglia were related to type-1 mismatch (p=0.04 and 0.02, respectively); microbleeds and total CSVD scores were related to type-2 mismatch (p=0.01 and 0.03, respectively). Although the severity of WMH was similar, the injury scores of penetrating arteries were significantly different between those with and without cognitive impairment (p=0.04).ConclusionsHeterogeneity of WMH was present in cognitively impaired patients with CSVD. Conventional imaging features and injury of penetrating arteries may account for such heterogeneity, which can be a hallmark for early identification and prevention of cognitive impairment.

Cognitive outcomes of anti‐amyloid‐β monoclonal antibodies in patients with Alzheimer's disease: A systematic review and meta‐analysis of randomized controlled trials

AbstractBackgroundFor the last 20 years, the amyloid‐beta (Aβ) cascade hypothesis has been dominant in the research of disease‐modifying therapeutics, with spent of financial and clinical resources in potential drugs targeting Aβ peptide production or clearance. (1) In this context, monoclonal antibodies targeting beta‐amyloid (Aβ‐mAbs) are being tested to reduce the amyloid burden in patients with Alzheimer’s Disease (AD). (2) However, the cognitive impact of Aβ‐mAbs remains controversial. (3) We aim to evaluate the conflicting results of previous studies using a meta‐analysis.MethodWe searched PubMed, Embase, and Cochrane databases, following until April 2021, using the search terms: ''Alzheimer's disease'' OR ''dementia'' cross‐referenced with ''monoclonal antibodies'', considering the synonyms. Eligible articles were randomized clinical trials with Aβ‐mAbs that reported cognitive outcomes. The cognitive function was assessed by Alzheimer’s Disease Assessment Scale (ADAS‐cog) and Mini‐Mental State‐Exam (MMSE). We performed a meta‐analysis comparing mAbs and placebo, considering a minimal significant clinical change of 3 points in ADAS‐Cog and 2 points in MMSE.ResultWe found 12 eligible studies in 443 identified records, involving 6736 patients, mean age 71.4 ± 2. We found a small benefit in cognitive outcomes in patients treated with Aβ‐mAbs: ADAS‐Cog: mean difference (MD) = ‐ 0.65; 95% CI (‐1.05 to ‐ 0.26); I² = 12%; (p = 0.001) and MMSE: MD = 0.40; 95% CI (0.18 to 0.63); I² = 10%; (p = 0.0004). The Funnel plot and Egger’s test did not show publication bias. MD was below the minimal clinically relevant change in both scales.ConclusionAβ‐mAbs may have a positive cognitive benefit in AD patients. However, the impact magnitude is small, not reaching minimal clinically relevant change for these scales.

Cerebral blood flow and cognitive outcome after pediatric stroke in the middle cerebral artery

Adaptive recovery of cerebral perfusion after pediatric arterial ischemic stroke (AIS) is sought to be crucial for sustainable rehabilitation of cognitive functions. We therefore examined cerebral blood flow (CBF) in the chronic stage after stroke and its association with cognitive outcome in patients after pediatric AIS. This cross-sectional study investigated CBF and cognitive functions in 14 patients (age 13.5 ± 4.4 years) after pediatric AIS in the middle cerebral artery (time since AIS was at least 2 years prior to assessment) when compared with 36 healthy controls (aged 13.8 ± 4.3 years). Cognitive functions were assessed with neuropsychological tests, CBF was measured with arterial spin labeled imaging in the anterior, middle, and posterior cerebral artery (ACA, MCA, PCA). Patients had significantly lower IQ scores and poorer cognitive functions compared to healthy controls (p < 0.026) but mean performance was within the normal range in all cognitive domains. Arterial spin labeled imaging revealed significantly lower CBF in the ipsilesional MCA and PCA in patients compared to healthy controls. Further, we found significantly higher interhemispheric perfusion imbalance in the MCA in patients compared to controls. Higher interhemispheric perfusion imbalance in the MCA was significantly associated with lower working memory performance. Our findings revealed that even years after a pediatric stroke in the MCA, reduced ipsilesional cerebral blood flow occurs in the MCA and PCA and that interhemispheric imbalance is associated with cognitive performance. Thus, our data suggest that cerebral hypoperfusion might underlie some of the variability observed in long-term outcome after pediatric stroke.

Prediction of residual cognitive disturbances by early response of depressive symptoms to antidepressant treatments in patients with major depressive disorder

BackgroundPatients with major depressive disorder (MDD) frequently retain cognitive disturbances after recovery from mood symptoms. We investigated the relationship between early response of mood symptoms and/or remission, and residual cognitive disturbances after 6 months of antidepressant treatment. Methods518 patients with MDD were followed up for 6 months after antidepressant treatment initiation (first-line or switch from a previous drug). Subjective and objective cognitive disturbances were assessed by the Perceived Deficits Questionnaire – Depression (PDQ-D) and digit symbol substitution test (DSST), respectively. Depressive symptoms, as well as remission and early response to treatment, were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). Multivariable linear and logistic regression models were used to adjust for confounders. ResultsEarly response of depressive mood (≥50% reduction in MADRS score at month 1) was related with fewer residual subjective cognitive symptoms, as evaluated by the PDQ-D at month 6 (p<0.001). Likewise, early remission status at month 2 was inversely associated with PDQ-D scores at month 6 (p<0.001). Among patients with baseline DSST scores of ≥1 standard deviation below the norm, early response/remission was associated with better performance on the DSST at month 6 (p<0.05). LimitationsThe cohort may not be representative of the general MDD patient population, and the possible influence of concomitant medications was not evaluated. ConclusionsThese findings suggest that early improvements in depressive symptoms predict better cognitive outcomes in patients with MDD. Grouping of patients by mood and cognition status in early stages of antidepressant treatments may facilitate efforts to improve long-term functional outcomes.

Cognitive outcome in patients one month after mild to moderate aneurysmal subarachnoid hemorrhage: Focus on the location of the aneurysm

ObjectivePatients with good recovery after aneurysmal subarachnoid hemorrhage (SAH) are commonly discharged about one month after the event. However, these patients often still show cognitive symptoms, such as fatigue, difficulty concentrating, and irritability. Understanding the early cognitive outcome of patients with SAH with good recovery is thought to be crucial for neurosurgical nursing staff. We analyzed patient data to clarify whether cognitive outcome depends on the location of the ruptured aneurysm 1 month after SAH. MethodsFor 186 patients (72 men and 114 women; median age, 57 years; age range, 21–83 years) who had experienced SAH (Hunt & Kosnik grade I to III), we retrospectively analyzed data on the location of the ruptured aneurysm, Fisher grade at admission, treatment modality (coil embolization, clipping, or no surgical treatment), neuropsychological assessments 1 month after SAH, and modified Rankin Scale 6 months after SAH. ResultsCrystallized intelligence (i.e., IQ, assessed using the Mini-Mental State Examination and Kohs Block Design Test) improved to almost normal levels in all patients, irrespective of the location of the ruptured aneurysm. In contrast, fluid intelligence (e.g., executive function and attention, assessed using the Frontal Assessment Battery; Trail Making Test, Part A; and the Japanese Kana-hiroi test) did not improve as much, specifically in patients with a ruptured aneurysm in the basilar artery. ConclusionsThese results may help nursing staff to identify mild- to moderate-grade patients at greater risk of problems and to arrange appropriate support strategies for patients after discharge.

Reduced default mode network connectivity relative to white matter integrity is associated with poor cognitive outcomes in patients with idiopathic normal pressure hydrocephalus

BackgroundThe aim of this study was to investigate whether default mode network (DMN) connectivity and brain white matter integrity at baseline were associated with severe cognitive impairments at baseline and poor cognitive outcomes after shunt placement in patients with idiopathic normal pressure hydrocephalus (iNPH).MethodsTwenty consecutive patients with iNPH whose symptoms were followed for 6 months after shunt placement and 10 healthy controls (HCs) were enrolled. DMN connectivity and brain white matter integrity at baseline in the patients with iNPH and HCs were detected by using resting-state functional magnetic resonance imaging (MRI) with independent component analysis and diffusion tensor imaging, respectively, and these MRI indexes were compared between the patients with iNPH and HCs. Performance on neuropsychological tests for memory and executive function and on the gait test was assessed in the patients with iNPH at baseline and 6 months after shunt placement. We divided the patients with iNPH into the relatively preserved and reduced DMN connectivity groups using the MRI indexes for DMN connectivity and brain white matter integrity, and the clinical measures were compared between the relatively preserved and reduced DMN connectivity groups.ResultsMean DMN connectivity in the iNPH group was significantly lower than that in the HC group and was significantly positively correlated with Rey auditory verbal learning test (RAVLT) immediate recall scores and frontal assessment battery (FAB) scores. Mean fractional anisotropy of the whole-brain white matter skeleton in the iNPH group was significantly lower than that in the HC group. The reduced DMN connectivity group showed significantly worse performance on the RAVLT at baseline and significantly worse improvement in the RAVLT immediate recall and recognition scores and the FAB scores than the preserved DMN connectivity group. Moreover, the RAVLT recognition score highly discriminated patients with relatively preserved DMN connectivity from those with relatively reduced DMN connectivity.ConclusionsOur findings indicated that iNPH patients with reduced DMN connectivity relative to the severity of brain white matter disruption have severe memory deficits at baseline and poorer cognitive outcomes after shunt placement. However, further larger-scale studies are needed to confirm these findings.