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Purpose of Review: The risk of cognitive impairment is higher in people with CKD than in the general population. The complex relationship between CKD and cognitive dysfunction has not been extensively characterized. Here, we review epidemiological associations, specific patterns of CKD-related cognitive impairment, the underlying mechanisms, and recently published data on relevant biomarkers., Recent Findings: Despite some discrepancies, recent published studies have confirmed that CKD is associated with cognitive function (e.g. incident cognitive events). Although patients with CKD often exhibit impairments in executive functions and attention, it is noteworthy that other cognitive functions (e.g. memory) can be preserved. The key mechanisms described recently include vascular damage, genetic factors, the accumulation of uremic toxins, disruption of the blood-brain barrier, glymphatic system dysfunction, and changes in the gut-brain axis. Kidney function is increasingly seen as a game changer in the interpretation of biomarkers of cognitive impairment and, especially, hallmarks of Alzheimer disease., Summary: The data reviewed here highlight the need for interdisciplinary collaboration between nephrologists and neurologists in the care of patients with CKD at risk of cognitive impairment. In order to further improving diagnosis and therapy, future research must elucidate the mechanisms underlying the CKD-cognitive impairment association and confirm the value of biomarkers., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Electroconvulsive therapy (ECT) is an effective somatic treatment, but it may be limited by cognitive adverse effects. The existing cognitive screening instruments often lack specificity to ECT-associated cognitive deficits. The ElectroConvulsive Therapy Cognitive Assessment was developed and validated in a clinical setting, but the reliability and validity of the Chinese version of ElectroConvulsive Therapy Cognitive Assessment (ECCA-C) have not been studied in a large clinical sample., Methods: The ECCA-C and the Montreal Cognitive Assessment (MoCA) were administered to patients with major depressive disorder (MDD) undergoing ECT at 3 time points: pretreatment (baseline), before the fifth treatment, and 1 week posttreatment. The instruments were also administered to a sample of healthy subjects., Results: Sixty-five patients with MDD and 50 age- and sex-matched healthy controls were recruited in this study. Overall, the patient group had statistically significantly lower MoCA and ECCA-C scores than the control group (both P values <0.001). The Cronbach α of the ECCA-C was 0.88 at baseline. Statistically significant decreases over time were observed in ECCA-C: pre-ECT (23.9 ± 4.0) > mid-ECT (21.3 ± 3.4) > post-ECT (18.7 ± 4.8) (all P values <0.001), whereas no statistically significant changes in MoCA scores were found at these 3 time points ( F = 1.86, P = 0.165). A cutoff score of 26.5 on the ECCA-C was found to best differentiate between MDD patients and healthy controls., Conclusions: The ECCA-C showed satisfactory psychometric properties and may be a more sensitive instrument than the MoCA to assess cognitive impairment associated with ECT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study was supported by the Beijing Anding Hospital, Capital Medical University (YJ2021-05)., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cerebral small vessel disease is a common cause of vascular cognitive impairment and dementia. There is an urgent need for preventative treatments for vascular cognitive impairment and dementia, and reducing vascular dysfunction may provide a therapeutic route. Here, we investigate whether the chronic administration of nimodipine, a central nervous system-selective dihydropyridine calcium channel blocking agent, protects vascular, metabolic, and cognitive function in an animal model of cerebral small vessel disease, the spontaneously hypertensive stroke-prone rat., Methods: Male spontaneously hypertensive stroke-prone rats were randomly allocated to receive either a placebo (n=24) or nimodipine (n=24) diet between 3 and 6 months of age. Animals were examined daily for any neurological deficits, and vascular function was assessed in terms of neurovascular and neurometabolic coupling at 3 and 6 months of age, and cerebrovascular reactivity at 6 months of age. Cognitive function was evaluated using the novel object recognition test at 6 months of age., Results: Six untreated control animals were terminated prematurely due to strokes, including one due to seizure, but no treated animals experienced strokes and so had a higher survival ( P =0.0088). Vascular function was significantly impaired with disease progression, but nimodipine treatment partially preserved neurovascular coupling and neurometabolic coupling, indicated by larger ( P <0.001) and more prompt responses ( P <0.01), and less habituation upon repeated stimulation ( P <0.01). Also, animals treated with nimodipine showed greater cerebrovascular reactivity, indicated by larger dilation of arterioles ( P =0.015) and an increase in blood flow velocity ( P =0.001). This protection of vascular and metabolic function achieved by nimodipine treatment was associated with better cognitive function ( P <0.001) in the treated animals., Conclusions: Chronic treatment with nimodipine protects from strokes, and vascular and cognitive deficits in spontaneously hypertensive stroke-prone rat. Nimodipine may provide an effective preventive treatment for stroke and cognitive decline in cerebral small vessel disease., Competing Interests: Disclosures Dr Werring has received speaking honoraria from Bayer; speaking and chairing honoraria from Alexion Pharmaceuticals Inc and Novo Nordisk; and consultancy fees from Alnylam Pharmaceuticals, Bayer, and Novo Nordisk. Dr Tachtsidis is the CEO and founder of Metabolight Ltd.

Background: Recent studies, using diffusion tensor image analysis along the perivascular space (DTI-ALPS), suggest impaired perivascular space (PVS) function in cerebral small vessel disease, but they were cross-sectional, making inferences on causality difficult. We determined associations between impaired PVS, measured using DTI-ALPS and PVS volume, and cognition and incident dementia., Methods: In patients with lacunar stroke and confluent white matter hyperintensities, without dementia at baseline, recruited prospectively in a single center, magnetic resonance imaging was performed annually for 3 years, and cognitive assessments, including global, memory, executive function, and processing speed, were performed annually for 5 years. We determined associations between DTI-ALPS and PVS volume with cerebral small vessel disease imaging markers (white matter hyperintensity volume, lacunes, and microbleeds) at baseline and with changes in imaging markers. We determined whether DTI-ALPS and PVS volume at baseline and change over 3 years predicted incident dementia. Analyses were controlled for conventional diffusion tensor image metrics using 2 markers (median mean diffusivity [MD] and peak width of skeletonized MD) and adjusted for age, sex, and vascular risk factors., Results: A total of 120 patients, mean age 70.0 years and 65.0% male, were included. DTI-ALPS declined over 3 years, while no change in PVS volume was found. Neither DTI-ALPS nor PVS volume was associated with cerebral small vessel disease imaging marker progression. Baseline DTI-ALPS was associated with changes in global cognition (β=0.142, P =0.032), executive function (β=0.287, P =0.027), and long-term memory (β=0.228, P =0.027). Higher DTI-ALPS at baseline predicted a lower risk of dementia (hazard ratio, 0.328 [0.183-0.588]; P <0.001), and this remained significant after including median MD as a covariate (hazard ratio, 0.290 [0.139-0.602]; P <0.001). Change in DTI-ALPS predicted dementia conversion (hazard ratio, 0.630 [0.428-0.964]; P =0.048), but when peak width of skeletonized MD and median MD were entered as covariates, the association was not significant. There was no association between baseline PVS volume, or PVS change over 3 years, and conversion to dementia., Conclusions: DTI-ALPS predicts future dementia risk in patients with lacunar strokes and confluent white matter hyperintensities. However, the weakening of the association between change in DTI-ALPS and incident dementia after controlling for peak width of skeletonized MD and median MD suggests part of the signal may represent conventional diffusion tensor image metrics. PVS volume is not a predictor of future dementia risk., Competing Interests: Disclosures Dr Tozer was funded by the Medical Research Council. H.S. Markus discloses grant support from the British Heart Foundation. The other author reports no conflict.

Memory impairment occurs in over a third of patients after symptomatic stroke. Memory deficits rarely occur in isolation but are an important component of the poststroke cognitive syndrome because of the strong relationship with the risk of poststroke dementia. In this review, we summarize available data on impairment of episodic memory, with a particular emphasis on the natural history of memory impairment after stroke and the factors influencing trajectory informed by an updated systematic review. We next discuss the pathophysiology of memory impairment and mechanisms of both decline and recovery of function. We then turn to the practical issue of measurement of memory deficits after stroke, emerging biomarkers, and therapeutic approaches. Our review identifies critical gaps, particularly in studies of the natural history that properly map the long-term trajectory of memory and the associations with factors that modulate prognosis. Few studies have used advanced neuroimaging and this, in conjunction with other biomarker approaches, has the potential to provide a much richer understanding of the mechanisms at play and promising therapeutic avenues.

Background: Transcranial direct current stimulation (tDCS) is a promising tool for improving poststroke cognitive function. Home-based rehabilitation is increasingly required for patients with stroke, and additional benefits are expected if supplemented with remotely supervised tDCS (RS-tDCS). We evaluated the cognitive improvement effect and feasibility of RS-tDCS in patients with chronic stroke., Methods: Twenty-six patients with chronic stroke and cognitive impairment (Korean version of the Montreal Cognitive Assessment [K-MoCA] score <26) were randomized into real and sham RS-tDCS groups and underwent concurrent computerized cognitive training and RS-tDCS. Patients and caregivers underwent training to ensure correct tDCS self-application, were monitored, and treated 5 d/wk for 4 weeks. We investigated several cognition tests including K-MoCA, Korean version of the Dementia Rating Scale-2, Korean-Boston Naming Test, Trail Making Test, Go/No Go, and Controlled Oral Word Association Test at the end of the training sessions and one month later. Repeated-measures ANOVA was used for comparison between the groups and within each group. The adherence rate of the appropriate RS-tDCS session was also investigated., Results: In within-group comparison, unlike the sham group, the real group showed significant improvement in K-MoCA ( P real =0.004 versus P sham =0.132), particularly in patients with lower baseline K-MoCA (K-MoCA 10-17 ; P real =0.001 versus P sham =0.835, K-MoCA 18-25 ; P real =0.060 versus P sham =0.064) or with left hemispheric lesions (left; P real =0.010 versus P sham =0.454, right; P real =0.106 versus P sham =0.128). In between-group comparison, a significant difference was observed in K-MoCA in the lower baseline K-MoCA subgroup (K-MoCA 10-17 ; P time×group =0.048), but no significant difference was found in other cognitive tests. The adherence rate of successful application of the RS-tDCS was 98.4%, and no serious adverse effects were detected., Conclusions: RS-tDCS is a safe and feasible rehabilitation modality for poststroke cognitive dysfunction. Specifically, RS-tDCS is effective in patients with moderate cognitive decline. Additionally, these data demonstrate the potential to enhance home-based cognitive training, although significant differences were not consistently found in between-group comparisons; therefore, further larger studies are needed., Registration: URL: https://cris.nih.go.kr; Unique identifier: KCT0003427.

We present the case of a man exhibiting a clinical phenotype of behavioral variant of frontotemporal dementia (bvFTD). The man had developed psychiatric disturbances with verbal aggressiveness over a few months, followed by cognitive and frontal behavioral disorders, fulfilling the clinical criteria for bvFTD. Atrophy and hypometabolism in frontotemporal regions were consistent with the diagnosis. However, serum-screening exams for syphilis infection were positive, and CSF analysis, despite a negative Venereal Disease Research Laboratory Test, suggested the diagnosis of neurosyphilis. After specific antibiotic therapy, the man's behavioral abnormalities and cognitive deficits notably improved, confirming neurosyphilis as the cause of the clinical phenotype. The cognitive deficits completely recovered 1 year post therapy and remained stable for 2 years. After ∼2½ years from the first treatment, the man's behavioral disorders mildly worsened, at which time we re-evaluated him. His cognition was stable, and a positive Venereal Disease Research Laboratory Test confirmed the diagnosis of neurosyphilis. With this case, we demonstrated that in some instances, neurosyphilis can mimic frontotemporal dementia. As a cause of treatable dementia, it should be considered in the differential diagnosis of bvFTD, particularly when psychiatric symptoms and a rapid cognitive decline are noted, even in the presence of brain atrophy and/or hypometabolism., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Rationable: The aim of this study is to investigate the effects of an advanced neuroRehabilitation protocol using virtual reality in the treatment of a patient with fronto- temporal dementia due to TREM2 mutation., Patients Concern: A 41-year-old caucasian male, affected by Nasu-Hakola Disease (NHD), presented a 1-year history of change in behavioral and cognitive functioning, before our observation. The onset of the disease was characterized by severe pain in the lower limbs and knees with limitations in the performance of daily life activities., Diagnosis: Motor and cognitive deficits in NHD., Interventions: As the patient was in a chronic phase, to manage his cognitive and motor status, we decided to treat him by using a specific rehabilitation protocol, including 2 different types of training: conventional cognitive and motor treatment and a combined advanced approach using the virtual reality rehabilitation system (VRRS). The two protocols were separated by 4 weeks of rest, to avoid/reduce a cumulative effect. The patient's cognitive and motor profile was assessed three times: that is before (at T0) and after (at T1) the conventional training as well as at the beginning (T2) and at the end of the combined experimental approach (T3)., Outcomes: After the combined therapeutic approach with the virtual reality rehabilitation system, we observed a significant reduction in anxiety, apathy, indifference and depressive symptoms with a more evident motor improvement involving the head and the trunk control., Lessons: Virtual reality can be considered a promising tool for the motor and cognitive rehabilitation of rare neurodegenerative disorders, including patients with NHD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

High blood pressure (BP) is detrimental to brain health. High BP contributes to cognitive impairment and dementia through pathways independent of clinical stroke. Emerging evidence shows that the deleterious effect of high BP on cognition occurs across the life span, increasing the risk for early-onset and late-life dementia. The term vascular cognitive impairment includes cognitive disorders associated with cerebrovascular disease, regardless of the pathogenesis. This focused report is a narrative review that aims to summarize the epidemiology of BP and vascular cognitive impairment, including differences by sex, race, and ethnicity, as well as the management and reversibility of BP and vascular cognitive impairment. It also discusses knowledge gaps and future directions.

Background and Purpose: Neonatal encephalopathy caused by hypoxia-ischemia (HI) is a major cause of death and disability in newborns. Clinical and experimental studies suggest a sexual dimorphism in HI-induced brain injury and therapy responses. A major hallmark of HI pathophysiology is the infiltration of peripheral immune cells into the injured brain. However, the specific role of regulatory T cells (Tregs) in neonatal HI is still unknown., Methods: Nine-day-old mice were exposed to HI by ligation of the right common carotid artery followed by 1 hour hypoxia (10% oxygen). Using immunohistochemistry, flow cytometry, and microarray analyses, Tregs were investigated in the brain, spleen, and blood 24 hours post HI. The functional role of Tregs was evaluated by acute Treg depletion in depletion of regulatory T cells transgenic mice. Brain injury, neuroinflammatory responses, and vascular injury were analyzed via immunohistochemistry and Western blot 48 hours and 7 days after HI. Functional outcome was assessed 3 days and 5 weeks after HI., Results: Female mice revealed an increased cerebral Treg infiltration, coinciding with elevated chemokine receptor expression. Treg depletion in females aggravated HI-induced brain tissue injury, short-term motor deficits, and long-term deficits in exploratory activity, paralleled by an increased microglia and endothelial activation and leukocyte infiltration. Treg depletion in male mice reduced HI-induced brain injury, short-term motor, and long-term cognitive deficits, associated with reduced vascular injury. Ex vivo isolated female Tregs displayed an increased immunosuppressive activity on effector T cell proliferation and an increased gene enrichment in pathways related to enhanced Treg activity., Conclusions: Tregs from neonatal female mice provide endogenous neuroprotection, whereas Tregs from male mice increase secondary neurodegeneration. As potential mechanisms, we identified intrinsic transcriptional differences associated with enhanced anti-inflammatory activity of female Tregs. Our study emphasizes the urgent need for sex-stratified clinical and preclinical analyses.

Background: Intraoperative electroencephalography (EEG) signatures related to the development of postoperative delirium (POD) in older patients are frequently studied. However, a broad analysis of the EEG dynamics including preoperative, postinduction, intraoperative and postoperative scenarios and its correlation to POD development is still lacking. We explored the relationship between perioperative EEG spectra-derived parameters and POD development, aiming to ascertain the diagnostic utility of these parameters to detect patients developing POD., Methods: Patients aged ≥65 years undergoing elective surgeries that were expected to last more than 60 minutes were included in this prospective, observational single center study (Biomarker Development for Postoperative Cognitive Impairment [BioCog] study). Frontal EEGs were recorded, starting before induction of anesthesia and lasting until recovery of consciousness. EEG data were analyzed based on raw EEG files and downloaded excel data files. We performed multitaper spectral analyses of relevant EEG epochs and further used multitaper spectral estimate to calculate a corresponding spectral parameter. POD assessments were performed twice daily up to the seventh postoperative day. Our primary aim was to analyze the relation between the perioperative spectral edge frequency (SEF) and the development of POD., Results: Of the 237 included patients, 41 (17%) patients developed POD. The preoperative EEG in POD patients was associated with lower values in both SEF (POD 13.1 ± 4.6 Hz versus no postoperative delirium [NoPOD] 17.4 ± 6.9 Hz; P = .002) and corresponding γ-band power (POD -24.33 ± 2.8 dB versus NoPOD -17.9 ± 4.81 dB), as well as reduced postinduction absolute α-band power (POD -7.37 ± 4.52 dB versus NoPOD -5 ± 5.03 dB). The ratio of SEF from the preoperative to postinduction state (SEF ratio) was ~1 in POD patients, whereas NoPOD patients showed a SEF ratio >1, thus indicating a slowing of EEG with loss of unconscious. Preoperative SEF, preoperative γ-band power, and SEF ratio were independently associated with POD (P = .025; odds ratio [OR] = 0.892, 95% confidence interval [CI], 0.808-0.986; P = .029; OR = 0.568, 95% CI, 0.342-0.944; and P = .009; OR = 0.108, 95% CI, 0.021-0.568, respectively)., Conclusions: Lower preoperative SEF, absence of slowing in EEG while transitioning from preoperative state to unconscious state, and lower EEG power in relevant frequency bands in both these states are related to POD development. These findings may suggest an underlying pathophysiology and might be used as EEG-based marker for early identification of patients at risk to develop POD., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2021 International Anesthesia Research Society.)

Background and Purpose: Aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits. Neutrophil infiltration into the central nervous system is linked to the development of these deficits after SAH. It is however unclear how neutrophil activity influences central nervous system function in SAH. The present project aims to elucidate which neutrophil factors mediate central nervous system injury and cognitive deficits after SAH., Methods: Using a murine model of SAH and mice deficient in neutrophil effector functions, we determined which neutrophil effector function is critical to the development of deficits after SAH. In vivo and in vitro techniques were used to investigate possible pathways of neutrophils effect after SAH., Results: Our results show that mice lacking functional MPO (myeloperoxidase), a neutrophil enzyme, lack both the meningeal neutrophil infiltration (wild type, sham 872 cells/meninges versus SAH 3047, P=0.023; myeloperoxidase knockout [MPOKO], sham 1677 versus SAH 1636, P=NS) and erase the cognitive deficits on Barnes maze associated with SAH (MPOKO sham versus SAH, P=NS). The reintroduction of biologically active MPO, and its substrate hydrogen peroxide (H2O2), to the cerebrospinal fluid of MPOKO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH (time to goal box MPOKO sham versus MPOKO+MPO/H2O2, P=0.001). We find evidence of changes in neurons, astrocytes, and microglia with MPO/H2O2 suggesting the effect of MPO may have complex interactions with many cell types. Neurons exposed to MPO/H2O2 show decreased calcium activity at baseline and after stimulation with potassium chloride. Although astrocytes and microglia are affected, changes seen in astrocytes are most consistent with inflammatory changes that likely affect neurons., Conclusions: These results implicate MPO as a mediator of neuronal dysfunction in SAH through its effect on both neurons and glia. These results show that, in SAH, the activity of innate immune cells in the meninges modulates the activity and function of the underlying brain tissue.

Background and Purpose: Prediction of long-term recovery of a poststroke cognitive disorder (PSCD) is currently inaccurate. We assessed whether diffusion-weighted imaging (DWI)-based measures of brain connectivity predict cognitive recovery 1 year after stroke in patients with PSCD in addition to conventional clinical, neuropsychological, and imaging variables., Methods: This prospective monocenter cohort study included 217 consecutive patients with a clinical diagnosis of ischemic stroke, aged ≥50 years, and Montreal Cognitive Assessment score below 26 during hospitalization. Five weeks after stroke, patients underwent DWI magnetic resonance imaging. Neuropsychological assessment was performed 5 weeks and 1 year after stroke and was used to classify PSCD as absent, modest, or marked. Cognitive recovery was operationalized as a shift to a better PSCD category over time. We evaluated 4 DWI-based measures of brain connectivity: global network efficiency and mean connectivity strength, both weighted for mean diffusivity and fractional anisotropy. Conventional predictors were age, sex, level of education, clinical stroke characteristics, neuropsychological variables, and magnetic resonance imaging findings (eg, infarct size). DWI-based measures of brain connectivity were added to a multivariable model to assess additive predictive value., Results: Of 135 patients (mean age, 71 years; 95 men [70%]) with PSCD 5 weeks after ischemic stroke, 41 (30%) showed cognitive recovery. Three of 4 brain connectivity measures met the predefined threshold of P <0.1 in univariable regression analysis. There was no added value of these measures to a multivariable model that included level of education and infarct size as significant predictors of cognitive recovery., Conclusions: Current DWI-based measures of brain connectivity appear to predict recovery of PSCD but at present have no added value over conventional predictors.

Background: Electroconvulsive therapy (ECT), though reliable and effective, is controversial due to its media portrayal as a treatment with severe side effects. Electroconvulsive therapy is mainly given to patients suffering from affective disorders and treatment-resistant schizophrenia. Although past research assessed the amount and duration of memory loss due to ECT, little is known about its influence on cognition for patients suffering from schizophrenia, whose cognitive decline is an inherent part of their illness. We aimed to test whether maintenance ECT causes cognitive decline among elderly schizophrenia patients., Methods: Twenty elderly (age >65 years) patients suffering from schizophrenia and schizoaffective disorder who received maintenance ECT were matched with 20 controls suffering from the same illnesses that have never been treated with ECT. The match was based on age, sex, and illness duration. The participants were evaluated using the Montreal Cognitive Assessment for cognitive decline and a Positive and Negative Syndrome Scale (PANSS) for illness severity., Results: A lower score in the abstraction subscale was found in the maintenance ECT population (P = 0.002), without significant differences in the total Montreal Cognitive Assessment and the delayed-recall subscale scores. In the treatment group, a correlation was found between an impairment in naming and positive symptoms in the PANSS score (r = -0.45) and between abstraction impairment and negative symptoms (r = -0.56) and total PANSS score (r = -0.497)., Conclusions: Maintenance ECT does not worsen existing global cognitive deficits or delayed recall in elderly schizophrenia patients. The abstraction impairment was possibly due to the higher disease burden of the patients referred to ECT., Competing Interests: The authors have no conflicts of interest or financial disclosures to report., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Electroconvulsive therapy (ECT) has been used for decades for the treatment of mental illness. Despite its proven efficacy, ECT is rarely offered to individuals with psychiatric disorders who are incarcerated in jails and prisons. There are currently 2.2 million people confined in US correctional facilities. Research has demonstrated that the prevalence of serious mental illness among the US incarcerated population is 4 to 5 times what is observed in the community, and there can be no doubt that individuals currently exist within jails and prisons who would benefit from this treatment modality. One issue identified as a barrier to ECT being offered to this patient population is a lack of professional guidance on the administration of ECT to individuals who are incarcerated in correctional facilities. Indeed, very little information has been published on this subject in the medical literature. We offer this article as a resource document for the utilization of ECT within adult corrections. This resource document includes a protocol to assist correctional providers and administrators in navigating the ECT referral process, a review of options for delivery of ECT to adult inmate patients, and a discussion of topics related to correctional ECT that warrant special attention, such as informed consent, the perception of ECT use within corrections, ECT-associated cognitive impairment, involuntary ECT, and ECT for competence restoration. It is vital that this important therapy be made accessible to individuals in correctional settings who are experiencing mental illness., Competing Interests: The authors have no conflicts of interest or financial disclosures to report., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Testing for time to reorientation (TRO) after electroconvulsive therapy (ECT) has been one of the most predictive measures for cognitive adverse effects of ECT. However, measuring TRO varies between clinical trials, and there is no standardized approach on its measurement between studies. The objective of this report is to systematically review the literature on the different ways of measuring TRO. This would be a first step to establish a consensus on a standard method for TRO. We performed a systematic literature review from 1968 to October 2019 for clinical trials with a sample size of more than 50 and published in English that describe measures of TRO. We searched both PubMed and Web of Science databases. The literature search generated 12 clinical trials, which met the inclusion criteria. Studies measured TRO using 3-, 5-, or 10-item questionnaires. Most studies measured full orientation as answering 4/5 questions. Other studies smaller than 50 required 14/14 items to be answered correctly. There was wide variation between studies on how often and when orientation questions were initiated. These factors have obvious implications to the results and interpretation of the ECT literature.There was no clear consensus on measuring TRO in a uniform fashion. Research and clinical care would benefit from a standardized approach to measuring TRO. Measuring TRO using a 4/5 method seems the most common and quickest way, whereas using a 14/14 method seems to be the most rigorous and sensitive to change in trials., Competing Interests: N.A.Y. received research support (but not salary support) from Merck & Co, VistaGen Therapeutics, Inc, MECTA Corporation, the US Department of Veterans Affairs, and August Biomedical Research Corporation. The other authors have no conflicts of interest or financial disclosures to report., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Urinary incontinence (UI) is a common problem after stroke. Risk factors for UI seem to be multifactorial. There is still controversy in which risk factors contribute to UI. The aim of this study was to investigate risk factors for UI in stroke patients during rehabilitation. Study investigated 150 participants after the first stroke consecutively admitted to a post-acute inpatient rehabilitation program. They were divided into continence and incontinence group according to continence status on rehabilitation admission. Data about sociodemographic factors, functional status, comorbidities, current medications, type and localisation of stroke were collected. Compared with the continence group, incontinent participants had significantly worse cognitive status and upper limb function (P ≤ 0.005), more common global aphasia, neglect, visual field defect, agitation/confusion and deficits in somatic sensation (P ≤ 0.014). There were no differences between the groups regarding comorbidities, but incontinent participants received a larger number of current medications (P = 0.020). Incontinent participants had stroke located more common in the right hemisphere, corticosubcortical region and in the total anterior circulation region (P ≤ 0.051). In the multivariate analysis, Brunnstrom recovery stages of the affected upper limb [odds ratio (95% confidence interval: 1.61 (1.27-2.03)], agitation/confusion [5.36 (1.74-16.54)], global aphasia [5.06 (1.40-18.26)] and faecal impaction [3.41 (1.15-10.09)] were independent risk factors for UI. Findings suggest that communicative and cognitive problems, affected upper limb function and faecal impaction are the most important clinical risk factors for UI after stroke. Knowledge of these risk factors may help in the management of UI during rehabilitation of stroke patients.

Background: Frailty is a reduced capacity to recover from a physiologically stressful event. It is well established that preoperative frailty is associated with poor postoperative outcomes, but it is unclear if this includes cognitive decline following anesthesia and surgery. This retrospective observational study was a secondary analysis of data from a previous study (the Anaesthesia, Cognition, Evaluation [ACE] study). We aimed to identify if preoperative frailty or prefrailty is associated with preoperative and postoperative neurocognitive disorders or postoperative cognitive dysfunction., Methods: The ACE study enrolled 300 participants aged ≥60 scheduled for elective total hip joint replacement and who underwent a full neuropsychological assessment at baseline and 3 and 12 months postoperatively. We applied patient data to 2 frailty models; both were based on an accumulation of deficits score: the reported Edmonton frail scale (REFS) and the comprehensive geriatric assessment-frailty index (CGA-FI) based on the comprehensive geriatric assessment. We calculated these 2 scores using baseline data collected from the medical history, demographic and clinical data as well as self-reported questionnaires. Some items on the REFS (3 of 18 or 17%) and the CGA-FI (37 of 51 or 27%) did not have an equivalent item in the ACE data., Results: The mean age (standard deviation [SD]) was 70.1 years (6.6) with more women (197 [66%]). Using the REFS model, 40 of 300 (13.3%) patients were classified as vulnerable, mild, or moderately frail. Using the CGA-FI model, 69 of 300 (23%) were classified as intermediate or high frailty. The REFS and the CGA-FI were strongly correlated (r = 0.75; P < .01) with 34 of 300 (11%) meeting criteria for frailty by both the REFS and the CGA-FI.Frailty or prefrailty was associated with cognitive decline at 3 and 12 months using the REFS (odds ratio [OR], 1.51, 95% confidence interval [CI], 1.02-2.23 and OR, 2.00, 95% CI, 1.26-3.17, respectively) after adjusting for baseline mini-mental state examination (MMSE), smoking, hypertension, diabetes, history of acute myocardial infarction (AMI), and estimated intelligence quotient (IQ). Age did not modify this association. After adjusting for multiple comparisons, 3-month cognitive decline was no longer significantly associated with baseline frailty., Conclusions: This retrospective analysis demonstrates an association between baseline frailty and postoperative neurocognitive disorders, particularly using the more extensive REFS scoring method. This supports preoperative screening for frailty to risk-stratify patients, and identify and implement preventive strategies and to improve postoperative outcomes for older individuals.

Background: Breast cancer survivors (BCSs) experience long-term symptoms of cancer and treatment, which may exacerbate cognitive function and ability to adhere to interventions aimed at improving cognition., Objective: The intent of this study was to explore the relationship between selected cancer-related symptoms and adherence to the Speed of Processing in Middle Aged and Older BreAst Cancer SuRvivors (SOAR) cognitive training (CT) intervention among BCSs residing in Alabama., Methods: A sequential quantitative to qualitative (Quan→Qual) mixed-methods design was used. First, the relationship between selected cancer-related symptoms and adherence to SOAR among BCSs (n = 30) was examined using self-reported questionnaire data. Follow-up semistructured interviews with 15 purposefully selected participants (adherent and nonadherent) were conducted to explore how symptoms contributed to/explained differences in adherence to SOAR. Data were analyzed using RStudio and NVivo software., Results: Spearman's ρ correlation suggested relationships between adherence and perceived cognitive impairment, depressive symptoms, and sleep quality. Inductive thematic analysis yielded 4 themes: (1) experiences of cancer-related symptoms, (2) influences of CT, (3) adherence to CT, and (4) environment for CT. Integration of quantitative and qualitative results revealed that experiences of and responses to CT and cancer-related symptoms differently shape adherence to CT among BCSs., Conclusions: To aid in cognitive intervention adherence among BCSs, future studies may consider applying a comprehensive approach aimed at addressing concurrent cancer-related symptoms., Implications for Practice: Clinicians can routinely assess cognition and provide education and resources for management of cancer-related symptoms.

The metabolic syndrome (MetS) is a cluster of risk factors for cognitive impairment. We aimed to investigate the association between MetS and risk of persistent cognitive impairment in patients with a transient ischemic attack (TIA) or mild ischemic stroke. This is a prospective and observational study in consecutive patients with first-ever TIA or mild stroke (National Institutes of Health Stroke Scale score ≤ 6). Patients underwent Montreal cognitive assessment (MoCA) at hospital admission and day 30 after discharge. We defined cognitive impairment as a MoCA score of ≤26. Persistent cognitive impairment was defined as baseline cognitive impairment and an increase of <2 point or decrease in MoCA score at 1 month after discharge. Three hundred eleven eligible patients were enrolled, aged 21-80 years, and mean age was 61.87 ± 9.643 years and 211 patients were males (70.1%). Cognitive impairments were present in 166 (53.4%) patients at admission. The cognitive impairment rate was significantly higher in MetS patients than those without MetS both at admission and day 30 after discharge (66.1% vs 33.6%, P < 0.001 and 56.6% vs 27.9%, P < 0.001). In logistic regression analysis, MetS, hyperglycemia, hypertension, dyslipidemia, and obesity had no significant interaction with persistent cognitive impairment. However, hypertension had a tendency to be a predictor of persistent cognitive impairment, although this tendency had no statistical significance (odds ratio = 2.545, 95% confidence interval 0.872, 7.430, P = 0.0874). Baseline MetS is associated with the risk of cognitive impairment, but MetS does not affect short-term cognitive recovery from cognitively impaired in patients with TIA/mild stroke.

Objective: To characterize the extent of CNS involvement in children with Pompe disease using brain MRI and developmental assessments., Methods: The study included 14 children (ages 6-18 years) with infantile Pompe disease (IPD) (n = 12) or late-onset Pompe disease (LOPD) (n = 2) receiving enzyme replacement therapy. White matter (WM) hyperintense foci seen in the brain MRIs were systematically quantified using the Fazekas scale (FS) grading system with a novel approach: the individual FS scores from 10 anatomical areas were summed to yield a total FS score (range absent [0] to severe [30]) for each child. The FS scores were compared to developmental assessments of cognition and language obtained during the same time period., Results: Mild to severe WM hyperintense foci were seen in 10/12 children with IPD (median age 10.6 years) with total FS scores ranging from 2 to 23. Periventricular, subcortical, and deep WM were involved. WM hyperintense foci were seen throughout the path of the corticospinal tracts in the brain in children with IPD. Two children with IPD had no WM hyperintense foci. Children with IPD had relative weaknesses in processing speed, fluid reasoning, visual perception, and receptive vocabulary. The 2 children with LOPD had no WM hyperintense foci, and high scores on most developmental assessments., Conclusion: This study systematically characterized WM hyperintense foci in children with IPD, which could serve as a benchmark for longitudinal follow-up of WM abnormalities in patients with Pompe disease and other known neurodegenerative disorders or leukodystrophies in children., (© 2020 American Academy of Neurology.)

Objective: To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and β-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies., Methods: A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants ( GBA -PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years)., Results: β-Glucocerebrosidase activity was low in blood of patients with GBA -PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS ( p < 0.001) and PDBP ( p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual β-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean β-glucocerebrosidase activity by 0.85 μmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in β-glucocerebrosidase activity during a median 2 years of follow-up ( p = 0.02)., Conclusions: Residual activity of the β-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. β-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically., (© 2020 American Academy of Neurology.)

Objective: To describe clinical and pathologic characteristics of corticobasal degeneration (CBD) with cognitive predominant problems during the disease course., Methods: In a series of autopsy-confirmed cases of CBD, we identified patients with cognitive rather than motor predominant features (CBD-Cog), including 5 patients thought to have Alzheimer disease (AD) and 10 patients thought to have behavioral variant frontotemporal dementia (FTD). We compared clinical and pathologic features of CBD-Cog with those from a series of 31 patients with corticobasal syndrome (CBD-CBS). For pathologic comparisons between CBD-Cog and CBD-CBS, we used semiquantitative scoring of neuronal and glial lesion types in multiple brain regions and quantitative assessments of tau burden from image analysis., Results: Five of 15 patients with CBD-Cog never had significant motor problems during their disease course. The most common cognitive abnormalities in CBD-Cog were executive and visuospatial dysfunction. The frequency of language problems did not differ between CBD-Cog and CBD-CBS. Argyrophilic grain disease, which is a medial temporal tauopathy associated with mild cognitive impairment, was more frequent in CBD-Cog. Apathy was also more frequent in CBD-Cog. Tau pathology in CBD-Cog was greater in the temporal and less in perirolandic cortices than in CBD-CBS., Conclusion: A subset of patients with CBD has a cognitive predominant syndrome than can be mistaken for AD or FTD. Our findings suggest that distribution of tau cortical pathology (greater in temporal and less in perirolandic cortices) may be the basis of this uncommon clinical variant of CBD., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To determine whether black or Hispanic patients with newly diagnosed multiple sclerosis (MS) are more likely to have cognitive impairment than white patients when compared to controls matched on age, sex, and race/ethnicity. Whether black or Hispanic patients have a more aggressive MS disease course than white patients remains unclear. No prior studies have examined differences in early cognitive impairment. The oral Symbol Digit Modalities Test (SDMT) is sensitive to early cognitive impairment in MS but normative data in nonwhite patients are limited., Methods: We studied 1,174 adults who enrolled in the MS Sunshine Study. SDMT and verbal fluency were measured in 554 incident cases of MS or clinically isolated syndrome (CIS) and 620 matched controls. Multivariable regression was used to examine correlates of abnormal SDMT in the entire cohort., Results: The strongest independent predictors of lower oral SDMT scores in rank order were having MS/CIS, lower educational attainment, and being black or Hispanic. Black and Hispanic patients and controls had lower SDMT scores than white participants even after controlling for age, sex, and education. However, no interaction between race/ethnicity and MS case status on SDMT scores was detected. Easy-to-use reference scores stratified by age and educational attainment for black and Hispanic patients are provided., Conclusion: Persons with newly diagnosed MS/CIS are more likely to have subtly impaired cognitive function than controls regardless of race/ethnicity. Lower absolute SDMT scores among black and Hispanic patients compared to white patients highlight underlying US population differences rather than differences in MS disease severity., (© 2020 American Academy of Neurology.)

Purpose of Review: To illustrate the frequency and trends of the comorbidity of epilepsy and dementia and the effects of antiepileptic drugs (AEDs) on cognitive functions., Recent Findings: Although the mortality and incidence of epilepsy are decreasing overall, they are increasing in the elderly as a result of population growth and increased life expectancy. Alzheimer's disease and other dementias are among the commonest causes of seizures and epilepsy. Epilepsy can be also complicated by cognitive impairment, suggesting a bidirectional association. Although epilepsy with onset in the elderly can be the manifestation of a CNS disease/injury, the cause of cognitive impairment is multifactorial and includes static (genetic background, age at seizure onset, developmental and acquired cerebral lesions) and dynamic factors [recurrent seizures, epileptiform discharges, type and number of AEDs and psychiatric comorbidities]. Most AEDs, with special reference to first-generation drugs, have negative effects on cognitive functions; however, none was found to increase the risk of dementia., Summary: A net increase in the burden of epilepsy, dementia and epilepsy-dementia comorbidity is expected. The growing use of second-generation AEDs might help reducing adverse cognitive effects. However, the fairly high cost of these drugs might delay their widespread use in resource-poor countries. VIDEO ABSTRACT: http://links.lww.com/CONR/A49.

Purpose of Review: Access to epilepsy surgery is rapidly growing throughout the world. While it is an established and effective treatment for seizures, epilepsy surgery has the potential to exacerbate cognitive comorbidities of the condition., Recent Findings: Not all surgical patients experience a postoperative decline in cognitive function. Postoperative cognitive function depends upon the functional integrity of the tissue to be removed and the functional reserve of the structures that remain in situ. While developments in surgical technique can reduce the cognitive morbidity of epilepsy surgery, the same procedure may result in different cognitive outcomes for different candidates, depending on their preoperative characteristics and postoperative trajectories. Multivariate models can be used to identify those most at risk of cognitive decline. There remains a significant lack of research into clinical interventions aimed at reducing the impact of surgically induced cognitive deficits on the lives of the patients who experience them., Summary: Accurate identification of the cognitive risks associated with surgery, based on an individual's personal risk profile rather than the generic risks associated with the procedure, is now recognized as a mandatory part of the preoperative evaluation and is one of the pillars of informed consent for the procedure.

Myotonic dystrophy type 1 is a neuromuscular disease, characterized by a progressive loss of strength, muscle stiffness, and difficulty in relaxation. Myotonic dystrophy type 1 patients can present several neuropsychological deficits, as well as anxiety and mood disorders. Aim of this study is to evaluate the feasibility and the effect of virtual reality in the cognitive and behavioral recovery of myotonic dystrophy type 1 patients. Eleven patients (8 female and 3 male) underwent a specific cognitive rehabilitation program including a conventional neuropsychological treatment followed by a virtual reality neurorehabilitation training using the Virtual Reality Rehabilitation System (Khymeia, Italy). Virtual reality improved many cognitive domains, including executive function, attention, verbal and visuo-spatial abilities, as well as mood and coping strategies. Due to the high prevalence of neuropsychological symptoms in patients with myotonic dystrophy type 1, cognitive rehabilitation should enter into the framework of these patients to potentially boost cognitive and behavioral function and improve quality of life.

Purpose of Review: Alterations in cognitive functions are common in the perioperative course. Although often unnoticed by physicians, these alterations might have distinct long-term consequences for the patient with regard to everyday functioning, self-dependency, and quality of life. In recent years, however, perioperative cognition has gained increased interest, both by clinicians and scientists, and knowledge of the preventive measures of postoperative cognitive decline has become mandatory for anesthetists and surgeons., Recent Findings: This review offers a brief overview of the current state of knowledge concerning perioperative changes in cognition, including its pathophysiology and prevention strategies., Summary: Postoperative neurocognitive disorders are frequent complications, especially in elderly patients, with postoperative delirium being its most pronounced and acute postoperative form, predisposing the patient for long-term cognitive impairment. The incidence of postoperative cognitive decline can be reduced by implementing preventive measures during perioperative patient care as recommended by national and international guidelines.

Objective: The impact of pediatric intestinal failure (IF) on neurodevelopment beyond infancy has not been systematically studied. Our aim was to evaluate cognitive and motor impairment and to identify risk factors for adverse outcomes among children with IF., Methods: We conducted a cross-sectional single-center study at the Helsinki University Children's Hospital. Patients with IF with >60 days of parental nutrition (PN) dependency aged between 3 and 16 years (n = 40) were invited to participate. The cognitive and motor skills were evaluated using validated tests: Wechsler Preschool and Primary Scale of Intelligence, 3rd edition, Wechsler Intelligence Scale for Children, 4th edition, and Movement Assessment Battery for Children, 2nd edition., Results: All the patients attending the study tests (n = 30, males = 24) were included. Their median age, gestational age, and birth weight was 7.5 (range 3-16) years, 35 (interquartile range [IQR] 28-38) weeks and 2238 (IQR 1040-3288) grams, respectively. Median duration of PN was 13 (IQR 5-37) months and 9 patients were currently on PN. Median intelligence quotient was 78 (IQR 65-91) and 10 (35%) patients had an intelligence quotient under 70 (-2 standard deviation). Significant motor impairment was detected in 10 patients (36%) and milder difficulties in 8 (28%). Adverse cognitive outcome was associated with neonatal short bowel syndrome, number of interventions under general anesthesia, and length of inpatient status, whereas adverse motor outcome was associated with prematurity., Conclusion: Clinically significant cognitive and motor impairments are alarmingly common among neonatal patients with IF. We recommend early neurodevelopmental follow-up for all children with IF.

Better ways to manage preoperative, intraoperative and postoperative care of surgical patients is the bailiwick of anesthesiologists. Although we care for patients of all ages, protecting the cognitive capacity of elderly patients more frequently requires procedures and practices that go beyond routine care for nonelderly adults. This narrative review will consider current understanding of the reasons that elderly patients need enhanced care, and recommendations for that care based on established and recent empirical research. In that latter regard, unless and until we are able to classify anesthetic neurotoxicity as a rare complication, the first-do-no-harm approach should: (1) add anesthesia to surgical intervention on the physiological cost side of the cost/benefit ratio when making decisions about whether and when to proceed with surgery; (2) minimize anesthetic depth and periods of electroencephalographic suppression; (3) limit the duration of continuous anesthesia whenever possible; (4) consider the possibility that regional anesthesia with deep sedation may be as neurotoxic as general anesthesia; and (5) when feasible, use regional anesthesia with light or no sedation.

Background: The role(s) of inflammation in obesity-associated cognitive decline in overweight or obese populations is not completely understood., Objective: To investigate the profile of plasma inflammatory cytokines in overweight and obese Chinese individuals and to assess the relationship between inflammation and cognitive function., Methods: We evaluated the cognitive domains of 282 Chinese adults, aged 35 to 64 years, using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The participants were classified into three groups according to their body mass index. Inflammatory cytokines were determined by immune turbidimetric analysis and enzyme-linked immunosorbent assay. Data were analyzed using covariance and partial correlation analyses after adjusting for gender, age, education level, hypertension, and hyperlipemia., Results: The total MoCA scores of the overweight and obese groups were significantly lower than that of the control group. The obese group displayed a significantly higher level of tumor necrosis factor-α than the overweight and control groups and a significantly higher level of transforming growth factor-β than the control group. The overweight group displayed a significantly higher interleukin-4 level than the control and obese groups. After adjusting for confounding factors, however, we found no significant correlation between the level of plasma inflammatory cytokines and MMSE or MoCA total score., Conclusions: Compared to normal-weight Chinese participants, overweight and obese Chinese participants revealed significant differences in their inflammatory cytokines profile; however, the inflammatory cytokine levels did not correlate with the significantly lower cognitive scores observed in the overweight and obese groups.

Objective: Many tinnitus patients report cognitive deficits such as concentration and attention difficulties. The aim of this study was to comprehensively assess cognitive functioning in tinnitus patients using a standardized test battery, the repeatable battery for the assessment of neuropsychological status adjusted for hearing impaired individuals (RBANS-H)., Study Design: Cross-sectional study., Setting: Tertiary referral center., Participants: Twenty-eight chronic tinnitus patients and 28 control participants, matched for sex, age, hearing loss, and education level., Intervention: Diagnostic., Main Outcome Measures: All participants completed the RBANS-H, which includes subtests probing immediate and delayed memory, visuospatial capabilities, language, and attention. The tinnitus patients completed the tinnitus functional index (TFI), a visual analogue scale (VAS) measuring subjective mean tinnitus loudness and the hyperacusis questionnaire (HQ)., Results: The total RBANS-H scores did not differ between tinnitus patients and controls. However, on the language subscale, mean scores of the tinnitus group (97.6 ± 11.0) were significantly lower than those of controls (104.4 ± 12.0), with correction for sex, age, hearing level, and education level (general linear model: p = 0.034). Post hoc t tests revealed a specific deficit concerning the semantic fluency subtest (tinnitus: 19.5 ± 6.2; control: 23.1 ± 5.9; p = 0.015). VAS scores for tinnitus loudness were negatively correlated to scores on the RBANS-H attention subscale (r = -0.48, p = 0.012)., Conclusions: The current study successfully employed the RBANS-H to provide a broader view on cognitive functioning in tinnitus patients. The results showed a specific negative influence of tinnitus on verbal fluency, which could be related to a deficit in executive cognitive control. Moreover, patients experiencing louder tinnitus performed worse on specific subtests concerning attention.

Background and Purpose- It is uncertain what determines the potential for cognitive recovery after ischemic stroke. The extent to which strategic areas of the brain network, so-called hubs, are affected by the infarct could be a key factor. We developed a lesion impact score, which estimates the damage to network hubs by integrating information on infarct size with healthy brain network topology. We verified whether the lesion impact score indeed reflects global network disturbances in patients and assessed if it could predict cognitive recovery. Methods- Seventy-five ischemic stroke patients without signs of a prestroke cognitive disorder were included, all with evidence of a cognitive disorder during hospitalization. A brain magnetic resonance imaging and neuropsychological assessment were performed 5 weeks (±1 week) after stroke. Neuropsychological testing was repeated after 1 year to assess cognitive recovery. Brain networks were reconstructed from diffusion-weighted data and consisted of 90 gray matter regions (ie, network nodes). A standard brain network map, indicating the hub-score of each node, was obtained from network data of 44 cognitively healthy adults. For each patient, we calculated the lesion impact score by multiplying the percentage of node volume affected by the infarct with the node's corresponding hub-score. The patients' maximum lesion impact score was used as outcome predictor. Results- A higher lesion impact score in patients, indicating an increasing infarct size in nodes with a higher hub-score, was related to lower global brain network efficiency (β=-0.528 [-0.776 to -0.277]; P <0.001), independent of age, brain volume, infarct volume, and white matter hyperintensity severity. A lower lesion impact score, however, was an independent predictor of cognitive recovery 1 year after stroke (odds ratio=0.434 [0.193-0.978]; P =0.044). Conclusions- We introduced a lesion impact score that combines information on infarct size and network topology to predict long-term recovery after stroke. This score can potentially be used in a clinical setting, also without availability of high-resolution diffusion-weighted magnetic resonance imaging.

Background: Although it is widely recognized that a high percentage of individuals with amyotrophic lateral sclerosis (ALS) have cognitive and behavioral impairment, the associated clinical and functional parameters remain unknown. ALS is typically assessed via screening tests, such as the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)., Objective: To investigate the relationship between cognitive-behavioral impairment and other clinical and functional parameters and to compare the assessment results from a set of standardized neuropsychological tests with those from the ECAS., Methods: Forty individuals with ALS participated in the study. We assessed attention, memory and learning ability, and executive function using a set of standardized neuropsychological tests and the ECAS. Sociodemographic variables, time since onset of symptoms, time since diagnosis, and functional respiratory values were recorded., Results: No relationship was found between time since onset of symptoms and time since definitive diagnosis and either attention (P=0.206, 0.314, respectively), memory and learning ability (P=0.618, 0.692), or executive function (P=0.844, 0.583). The set of standardized neuropsychological tests identified an impairment in executive function in 29% of the participants, whereas the ECAS identified it in 89%., Conclusions: We found no relationship between cognitive-behavioral impairment and time since onset of symptoms nor time since ALS diagnosis. Because the ECAS does not correctly reflect the executive function of individuals with ALS, function-specific neuropsychological tests are preferred. Test selection must take into account individuals' physical characteristics and their consequent ability to respond gesturally or orally.

Transcranial alternating current stimulation (tACS), a noninvasive brain stimulation technique that uses low-intensity alternating current, has been postulated to be a potential therapeutic option in treating the cognitive deficits in schizophrenia. Transcranial alternating current stimulation synchronizes the neural oscillations to the applied stimulation frequency in the stimulated cortical regions. In this report, we have reviewed the literature pertinent to the clinical application of tACS in psychiatric disorders; in addition, we have described the clinical use of online theta tACS in a schizophrenia patient with cognitive deficits. Online theta tACS led to improvement in working memory, attention, processing speed, and emotional processing. The beneficial effect of tACS persisted during reassessment of the patient after 50 days. Transcranial alternating current stimulation, given its noninvasiveness, safety, and ease of administration, has the potential to ameliorate cognitive deficits in neuropsychiatric disorders like schizophrenia.

This study aimed to investigate the effect of task-oriented inpatient cognitive rehabilitation on fatigue perception and independence in daily activities. Forty (22 males, 18 females) children with pediatric cancer were randomized to either study [n = 22; 10.81 (1.33) years] or control [n = 18; 10.16 (1.24) years] groups. The study group received a cognitive rehabilitation intervention in addition to a routine therapy program, and the control group received a routine therapy program for 15 sessions. Cognitive status, fatigue, and daily life activity outcomes were assessed by blinded assessors in before and after interventions in the hospital setting. The study group showed a significant decrease in fatigue (P values for fatigue before, during, and after activity: P < 0.001) and in the control group (P values for fatigue only in during and post activity: P < 0.05). A statistically significant improvement was found in functional independence for the study group in all activities of daily living areas areas (P < 0.001), whereas no differences were found in the control group. Cognitive rehabilitation appears to provide beneficial effects in decreasing fatigue, improving functional status in activities of daily living, and increasing cognitive skills at the early stages in inpatient rehabilitation of pediatric cancer.

Purpose of Review: Most survivors of out-of-hospital cardiac arrest (OHCA) suffer from cardiologic symptoms and approximately half of them experience cognitive problems because of hypoxic brain damage. Symptoms of anxiety and depression are also common. This review aims to give an overview of recent literature on rehabilitation treatment aiming at improvement of quality of life after OHCA., Recent Findings: Existing cognitive screening tools are now validated for OHCA survivors. OHCA patients with cognitive deficits may have lower exercise capacity. Cardiac rehabilitation seems to be well tolerated for OHCA survivors, with outcomes comparable to myocardial infarction patients. Many caregivers suffer from posttraumatic stress disorder and emotional stress. Interventions for them are available. Implementation of integrated programs covering both cognitive and cardiac rehabilitation is hampered by lack of knowledge and organizational barriers., Summary: OHCA survivors should be routinely screened for cognitive and emotional problems. When patients with mild cognitive deficits participate in cardiac rehabilitation, their program should be adjusted to their cognitive abilities. For patients with severe cognitive or emotional problems, individualized rehabilitation seems favorable. Integrated rehabilitation treatment between cardiac and cognitive rehabilitation departments is recommended. Attention should be paid to the burden of caregivers.

Pain disrupts attention to prioritise avoidance of harm and promote analgesic behaviour. This could in turn have negative effects on higher-level cognitions, which rely on attention. In the current article, we examined the effect of thermal pain induction on 3 measures of reasoning: the Cognitive Reflection Test, Belief Bias Syllogisms task, and Conditional Inference task. In experiment 1, the thermal pain was set at each participant's pain threshold. In experiment 2, it was set to a minimum of 44°C or 7/10 on a visual analogue scale (whichever was higher). In experiment 3, performance was compared in no pain, low-intensity pain, and high-intensity pain conditions. We predicted that the experience of pain would reduce correct responding on the reasoning tasks. However, this was not supported in any of the 3 studies. We discuss possible interpretations of our failure to reject the null hypothesis and the importance of publishing null results.

Objectives: Describe a single center experience of hemophagocytic lymphohistiocytosis in a PICU over a 10-year period, to identify clinical features that may be associated with worse outcomes, including mortality, hospital and ICU length of stay, and functional and cognitive impairments on discharge., Design: Retrospective electronic medical record review, 2007-2017., Setting: PICU located in a large urban academic quaternary care children's hospital., Patients: All children admitted with hemophagocytic lymphohistiocytosis to our PICU from 2007 to 2017., Interventions: None., Measurements and Main Results: All patients were identified utilizing International Classification of Diseases, 9th Revision and International Classification of Diseases, 10th Revision codes. Each chart was reviewed for demographic information, hemophagocytic lymphohistiocytosis diagnostic criteria, laboratory data, Pediatric Risk of Mortality Score III, clinical features and events of ICU stay, and PICU and hospital (length of stay). Mortality at 1 year and change in Functional Status Scale from admission to discharge were recorded. There were 42 admissions with 33 unique patients. Median Pediatric Risk of Mortality score at admission was 9 (interquartile range, 7-16). Median PICU length of stay was 7 days (interquartile range, 2-21 d) and hospital length of stay was 24 days (interquartile range, 14-37 d). During their ICU stay, 56% of patients received mechanical ventilation, 43% required vasoactives, 18% required continuous renal replacement therapy, and 5% received extracorporeal life support. Clinical factors related to increased PICU length of stay included Pediatric Risk of Mortality III score (p = 0.019), maximum lactate dehydrogenase (p = 0.017), maximum total bilirubin (p = 0.042), need for mechanical ventilation (p = 0.002), vasoactive use (p = 0.02), and secondary infection (p = 0.007). The most common therapies for hemophagocytic lymphohistiocytosis included steroids (93%), etoposide (55%), and anakinra (48%). Of the 26 patients who survived to hospital discharge, 19% had newly acquired morbidities. Overall 1-year mortality was 42%., Conclusions: Hemophagocytic lymphohistiocytosis diagnosed in the PICU is a disease with high mortality. Patients who survive to discharge had relatively little morbidity, however, the mortality risk in the year following discharge continued to remain high.

Background: Preexisting cognitive impairment in surgical patients is one of the leading risk factors for adverse cognitive outcomes such as postoperative delirium and postoperative cognitive dysfunction. We developed a self-administered tablet computer application intended to assess the individual risk for adverse postoperative cognitive outcomes. This cross-sectional study aimed to establish normative data for the tool., Materials and Methods: Healthy volunteers aged 65 years and above were administered the Mini-Mental State Examination, Geriatric Depression Scale, and Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery to assess cognitive health. All subjects completed the tablet computer application without assistance. Primary outcome measure was the test performance. Regression models were built for each cognitive domain score with the covariates age, sex, and education in cognitively healthy subjects. Demographically adjusted standard scores (z-scores) were computed for each subtest., Results: A total of 283 participants (155 women, 128 men) were included in the final analysis. Participants' age was 73.8±5.2 years (mean±SD) and their level of education was 13.6±2.9 years. Mini-Mental State Examination score was 29.2±0.9 points, Geriatric Depression Scale score was 0.4±0.7 points, and Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery total score was 98.7±5.7 points. Older age was associated with poorer performance in the visual recognition task and in Trail Making Test B (P<0.05 after Bonferroni-Holm adjustments)., Conclusions: This study provides normative data for a novel self-administered tablet computer application that is ultimately designed to measure the individual risk for adverse postoperative cognitive outcomes in elderly patients.

As critical illness survivorship increases, patients and health care providers are faced with management of long-term sequelae including cognitive and functional impairment. Longitudinal studies have demonstrated impairments persisting at least 1-5 years after hospitalization for critical illness. Cognitive domains impacted include memory, attention, and processing speed. Functional impairments include physical weakness, reduced endurance, and dependence on others for basic tasks of daily living such as bathing or feeding. In characterizing the trajectory of long-term recovery, multiple risk factors have been identified for subsequent impairment, including increased severity of illness and severe sepsis, prolonged mechanical ventilation, and delirium. Preadmission status including frailty, high level of preexisting comorbidities, and baseline cognitive dysfunction are also associated with impairment after critical illness. Development of cognitive and functional impairment is likely multifactorial, and multiple mechanistic theories have been proposed. Neuroinflammation, disruption of the blood-brain barrier, and structural alterations in the brain have all been observed in patients with long-term cognitive dysfunction. Systemic inflammation has also been associated with alterations in muscle integrity and function, which is associated with intensive care unit-acquired weakness and prolonged functional impairment. Efforts to ease the burden of long-term impairments include prevention strategies and rehabilitation interventions after discharge. Delirium is a well-established risk factor for long-term cognitive dysfunction, and using delirium-prevention strategies may be important for cognitive protection. Current evidence favors minimizing overall sedation exposure, careful selection of sedation agents including avoidance of benzodiazepines, and targeted sedation goals to avoid oversedation. Daily awakening and spontaneous breathing trials and early mobilization have shown benefit in both cognitive and functional outcomes. Multifactorial prevention bundles are useful tools in improving care provided to patients in the intensive care unit. Data regarding cognitive rehabilitation are limited, while studies on functional rehabilitation have conflicting results. Continued investigation and implementation of prevention strategies and rehabilitation interventions will hopefully improve the quality of life for the ever-increasing population of critical illness survivors.

The main objective of this study is to identify fibromyalgia syndrome (FMS) clusters using the Revised Fibromyalgia Impact Questionnaire (FIQR), and to examine whether the clusters differ in sociodemographic characteristics, clinical measures, direct and indirect costs, levels of inflammatory markers, and brain morphometry. A hierarchical cluster analysis was performed to classify a large, pooled Spanish sample of patients with FMS (N = 947) using the FIQR as clustering variable. A latent profile analysis was subsequently conducted to confirm the optimal number of FMS clusters. To examine external validity, a battery of clinical measures, economic costs, inflammatory markers, and gray matter volumes of relevant cortical and subcortical areas were analyzed. We also compared the discriminant validity of the clusters with the original FIQR severity categories. To promote the implementation in real-world clinical practice, we built a free online cluster calculator. Our findings indicated that a four-cluster solution more clearly captured the heterogeneity of FIQR data and provided the best fit. This cluster solution allowed for detection of differences for most clinical outcomes and economic costs. Regarding the inflammatory and brain-based biomarkers, differences were found in C-reactive protein, and tendencies were found in the right medial prefrontal cortex, the right parahippocampal gyrus, and the right middle cingulate cortex; brain regions associated with executive functions and pain processing. The original FIQR categories presented similar results, although their precision in discriminating among the nonextreme categories (ie, moderate and severe) was not sound. These findings are discussed in relation to previous research on FMS clustering.

: Purpose: This study sought to evaluate midlife hypertension and hypercholesterolemia in relation to cognitive function later in life among black women., Methods: Participants were drawn from the Nurses' Health Study and the Women's Health Study databases. In these studies, health professionals reported health information by questionnaire at baseline and at regular follow-up intervals, including diagnoses of hypertension, hypercholesterolemia, or both; and they completed telephone-based cognitive assessments later in life. Multivariable-adjusted linear regression models were used to estimate mean differences in global cognition and executive function scores, comparing women with and without a history of hypertension at midlife and women with and without a history of hypercholesterolemia at midlife., Results: Data for 363 black female health professionals were analyzed. Those with a history of hypertension or hypercholesterolemia at midlife did not have lower global cognition and executive function scores later in life compared with those without such a history, although there were trends in this direction., Conclusion: In the study sample, a history of hypertension or hypercholesterolemia at midlife was not related to worse cognitive function in later life. But there was a suggestive pattern of trends that warrants further exploration in larger studies.

Objective: To determine the time course of hazard for motor and nonmotor milestones of Parkinson disease (PD) in the long term and to investigate whether risk scales nonlinearly with time is instrumental in identifying changes in pathological processes and evaluating disease-modifying therapies in PD., Methods: Outpatients with PD at the Lyon University Movement Disorders Center were evaluated for 7 clinical milestones in this retrospective cohort study, encompassing 4 domains of PD progression: (1) motor (motor fluctuations, dyskinesias); (2) axial (postural instability and falls, freezing of gait); (3) neuropsychiatric (impulse control disorders, hallucinations); and (4) cognitive (dementia) complications. For each complication, we estimated the outcome-specific hazard using parsimonious smooth parametric Poisson regression models allowing for nonlinear scaling over disease duration, age at diagnosis, current age, and their interaction., Results: A total of 1,232 patients with PD experienced 1,527 disease-related complications in up to 12 years of follow-up. Specific to each complication, hazard rates increased dramatically starting from diagnosis and were highest for motor fluctuations and lowest for dementia up to 6 years after diagnosis in patients aged 65 years at diagnosis. Nonlinear patterns indicated dramatic changes in the course of PD after 5 years and predicted more severe axial prognosis after 70 years and for motor fluctuations, dyskinesias, and impulse control disorders before 60 years at diagnosis., Conclusion: Time course of motor and nonmotor milestones in PD is determined by disease duration and age at diagnosis in nonlinear patterns and their interaction. This indicates disease- and age-specific thresholds across the multiple neurodegenerative processes accumulating in PD at different paces., (© 2018 American Academy of Neurology.)

Objective: We characterized the epilepsy features and contribution to cognitive regression in 47 patients with MECP2 duplication syndrome (MDS) and reviewed these characteristics in over 280 MDS published cases., Methods: The institutional review board approved this retrospective review of medical records and case histories of patients with MDS., Results: The average age at enrollment was 10 ± 7 years. Patients with epilepsy were older (13 ± 7 years vs 8 ± 5 years, p = 0.004) and followed for a longer time (11.8 ± 6.5 years vs 6.3 ± 4.2 years, p = 0.003) than patients without a seizure disorder. Epilepsy affected 22/47 (47%) patients with MDS. It was treatment-refractory and consistent with epileptic encephalopathy in 18/22 (82%) cases. Lennox-Gastaut syndrome (LGS) was present in 12/22 (55%) patients and manifested between late childhood and adulthood in 83% of cases. The emergence of neurologic regression coincided with the onset of epilepsy. The MECP2 duplication size and gene content did not correlate with epilepsy presence, type, age at onset, or treatment responsiveness., Conclusion: Epilepsy in MDS is common, often severe, and medically refractory. LGS occurs frequently and may have a late onset. Developmental regression often follows the onset of epilepsy. The MECP2 duplication extent and gene content do not discriminate between patients with or without epilepsy. Our findings inform clinical care and family counseling with respect to early epilepsy recognition, diagnosis, specialty referral, and implementation of aggressive seizure therapy to minimize detrimental effect of uncontrolled seizures on cognitive functions or preexisting neurologic deficits., (© 2018 American Academy of Neurology.)

As part of the American Society of Anesthesiology Brain Health Initiative goal of improving perioperative brain health for older patients, over 30 experts met at the fifth International Perioperative Neurotoxicity Workshop in San Francisco, CA, in May 2016, to discuss best practices for optimizing perioperative brain health in older adults (ie, >65 years of age). The objective of this workshop was to discuss and develop consensus solutions to improve patient management and outcomes and to discuss what older adults should be told (and by whom) about postoperative brain health risks. Thus, the workshop was provider and patient oriented as well as solution focused rather than etiology focused. For those areas in which we determined that there were limited evidence-based recommendations, we identified knowledge gaps and the types of scientific knowledge and investigations needed to direct future best practice. Because concerns about perioperative neurocognitive injury in pediatric patients are already being addressed by the SmartTots initiative, our workshop discussion (and thus this article) focuses specifically on perioperative cognition in older adults. The 2 main perioperative cognitive disorders that have been studied to date are postoperative delirium and cognitive dysfunction. Postoperative delirium is a syndrome of fluctuating changes in attention and level of consciousness that occurs in 20%-40% of patients >60 years of age after major surgery and inpatient hospitalization. Many older surgical patients also develop postoperative cognitive deficits that typically last for weeks to months, thus referred to as postoperative cognitive dysfunction. Because of the heterogeneity of different tools and thresholds used to assess and define these disorders at varying points in time after anesthesia and surgery, a recent article has proposed a new recommended nomenclature for these perioperative neurocognitive disorders. Our discussion about this topic was organized around 4 key issues: preprocedure consent, preoperative cognitive assessment, intraoperative management, and postoperative follow-up. These 4 issues also form the structure of this document. Multiple viewpoints were presented by participants and discussed at this in-person meeting, and the overall group consensus from these discussions was then drafted by a smaller writing group (the 6 primary authors of this article) into this manuscript. Of course, further studies have appeared since the workshop, which the writing group has incorporated where appropriate. All participants from this in-person meeting then had the opportunity to review, edit, and approve this final manuscript; 1 participant did not approve the final manuscript and asked for his/her name to be removed.

Purpose of Review: When describing clinical or experimental traumatic brain injury (TBI), the adjectives 'mild,' 'moderate' and 'severe' are misleading. 'Mild' clinical TBI frequently results in long-term disability. 'Severe' rodent TBI actually resembles mild or complicated mild clinical TBI., Recent Findings: Many mild TBI patients appear to have recovered completely but have postconcussive symptoms, deficits in cognitive and executive function and reduced cerebral blood flow. After moderate TBI, 31.8% of patients died or were discharged to skilled nursing or hospice. Among survivors of moderate and severe TBI, 44% were unable to return to work. On MRI, 88% of mild TBI patients have evidence of white matter damage, based on measurements of fractional anisotropy and mean diffusivity/apparent diffusion coefficient. After sports concussion, clinically recovered patients have abnormalities in functional connectivity on functional MRI. Methylphenidate improved fatigue and cognitive impairment and, combined with cognitive rehabilitation, improved memory and executive functioning. In comparison to clinical TB, because the entire spectrum of experimental rodent TBI, although defined as moderate or severe, more closely resembles mild or complicated mild clinical TBI., Summary: Many patients after mild or moderate TBI suffer long-term sequelae and should be considered a major target for translational research. Treatments that improve outcome in rodent TBI, even when the experimental injuries are defined as severe, might be most applicable to mild or moderate TBI.

The left dorsolateral prefrontal cortex (DLPFC) is involved in the experience and modulation of pain, and may be an important node linking pain and cognition. Repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC can reduce chronic and experimental pain. However, whether left DLPFC rTMS can influence the development of chronic pain is unknown. Using repeated intramuscular injection of nerve growth factor to induce the development of sustained muscle pain (lasting weeks), 30 healthy individuals were randomized to receive 5 consecutive daily treatments of active or sham left DLPFC rTMS, starting before the first nerve growth factor injection on day 0. Muscle soreness and pain severity were collected daily for 14 days and disability on every alternate day. Before the first and 1 day after the last rTMS session, anxiety, depression, affect, pain catastrophizing, and cognitive performance on the attention network test were assessed. Left DLPFC rTMS treatment compared with sham was associated with reduced muscle soreness, pain intensity, and painful area (P < 0.05), and a similar trend was observed for disability. These effects were most evident during the days rTMS was applied lasting up to 3 days after intervention. Depression, anxiety, pain catastrophizing, and affect were unchanged. There was a trend toward improved cognitive function with rTMS compared with sham (P = 0.057). These data indicate that repeated left DLPFC rTMS reduces the pain severity in a model of prolonged muscle pain. The findings may have implications for the development of sustained pain in clinical populations.