Cognitive Outcome Measures Research Articles

Comparing therapeutic‐focused ultrasound (TFUS) in conjunction with bosutinib versus independent TFUS administration among Alzheimer’s patients

AbstractBackgroundTo date, there are limited therapeutic options for the treatment or symptomatic relief of degenerative dementia [1]. There has been growing interest in the class of medications known as tyrosine kinase inhibitors, such as bosutinib, as a therapeutic intervention for dementia [2]. Ongoing clinical and preclinical trials also suggest focused ultrasound may yield therapeutic potential for patients with neurodegenerative conditions such as Alzheimer’s disease [3‐5]. Focused ultrasound may be used as an independent therapeutic intervention or adjunctively to facilitate delivery of medicine. The present study compares the efficacy of focused ultrasound as an independent intervention to the efficacy of focused ultrasound combined with bosutinib, using several outcome measures to demonstrate accuracy.MethodsStructural and functional imaging were used to navigate cerebral and subcortical ultrasound targets for 13 patients (9 female; Mage = 72.08 years, SDage = 9.30 years), 7 of which received therapeutic ultrasound as an independent intervention, and the remaining 6 received both therapeutic ultrasound in conjunction with bosutinib. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Montreal Cognitive Assessment [MoCA].ResultsThe combination of therapeutic ultrasound with bosutinib was associated with 66% of patients maintaining or improving their Clinical Dementia Rating scale during the eight‐week protocol, whereas therapeutic ultrasound as a stand alone intervention showed 43% of patients maintaining or improving their Clinical Dementia Rating scale. Similarly, 67% of patients who underwent the combination intervention maintained or improved their MoCA scores, and of the patients who only received therapeutic ultrasound, 57% maintained or improved their MoCA scores.ConclusionsThe results of these comparisons suggest a combination of medication and therapeutic ultrasound may have a more positive outcome than therapeutic ultrasound alone. Clinical studies have shown that this ultrasound technology has been successfully applied for small molecules [6]. This technique of tailored targeting for each patient’s brain in conjunction with medication may represent a significant advancement to the field. Future studies should explore this combination.

P.0713 Effectiveness and safety of vortioxetine in real-world clinical practice in China: results from the prospective RELIEVE China study

Vortioxetine, a novel antidepressant for the treatment of major depressive disorder (MDD), is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and serotonin (5-HT) transporter (SERT) inhibitor. Here we review its preclinical and clinical properties and discuss translational aspects. Vortioxetine increases serotonergic, noradrenergic, dopaminergic, cholinergic, histaminergic and glutamatergic neurotransmission in brain structures associated with MDD. These multiple effects likely derive from its interaction with 5-HT-receptor-mediated negative feedback mechanisms controlling neuronal activity. In particular, 5-HT3 receptors may play a prominent role, since their blockade i) increases pyramidal neuron activity by removing 5-HT3 receptor-mediated excitation of GABA interneurons, and ii) augments SSRI effects on extracellular 5-HT. However, modulation of the other 5-HT receptor subtypes also likely contributes to vortioxetine's pharmacological effects. Preclinical animal models reveal differences from SSRIs and SNRIs, including antidepressant-like activity, increased synaptic plasticity and improved cognitive function. Vortioxetine had clinical efficacy in patients with MDD: 11 placebo-controlled studies (including one in elderly) with efficacy in 8 (7 positive, 1 supportive), 1 positive active comparator study plus a positive relapse prevention study. In two positive studies, vortioxetine was superior to placebo in pre-defined cognitive outcome measures. The clinically effective dose range (5–20 mg/day) spans ~50 to >80% SERT occupancy. SERT and 5-HT3 receptors are primarily occupied at 5 mg, while at 20 mg, all targets are likely occupied at functionally relevant levels. The side-effect profile is similar to that of SSRIs, with gastrointestinal symptoms being most common, and a low incidence of sexual dysfunction and sleep disruption possibly ascribed to vortioxetine's receptor modulation.

A randomised placebo‐controlled study on the effects of anthocyanins for maintaining cognitive functioning in individuals at increased risk for dementia

AbstractBackgroundAnthocyanins are found in dark berries, that have antioxidant and anti‐inflammatory effects and can cross the blood‐brain barrier. This study aims to evaluate the safety and efficacy of anthocyanins in modifying key dementia‐related mechanisms and maintaining cognitive functioning in older people at risk for dementia.MethodWe conducted a 24‐week randomised, double‐blind, placebo‐controlled Phase II study. A total of 208 participants aged 60‐80 years with cardiometabolic disorders (n=143) or mild cognitive impairment (n=68), were randomised to either purified anthocyanins (Medox® capsules, 320mg/day) or placebo for 24 weeks. The primary outcome is the Quality of episodic memory score, a composite measure from the online cognitive test battery CogTrack®, administered monthly. Secondary outcomes include other cognitive scores, neuroimaging (MRI and FDG‐PET), blood and CSF biomarkers. Medication compliance was measured by counting returned capsules, and anthocyanin metabolite levels will be measured in serum and CSF. Longitudinal measures of Quality of episodic memory will be subject to Mixed Model for Repeated Measures ANCOVA. Cognitive data are currently being analysed but still blinded.ResultTreatment groups are shown in Table 1. Retention in the study was very good; only one participant discontinued the study due to adverse event (AE), diarrhoea, another four due to pre‐defined protocol deviation (Figure 1). AEs were reported in 34 participants, five of which were serious adverse event (hospitalisation for constipation, hypertension, MRI finding of acute ischemic stroke at final assessment, and two anginas). There were minor differences in the proportions of participants reporting AEs (18 vs 15%; p=0.58). There were no notable changes in safety blood tests and the medication compliance was high (median 98% of planned doses, IQR 93‐99%).ConclusionThis is one of the most ambitious trials of anthocyanins and cognitive impairment. Anthocyanin capsules were well‐tolerated and safe, with no significant differences in adverse events between the treatment groups. The analysis of the cognitive outcome measures is ongoing, and the results will be presented at the meeting. The study may contribute to further improvement of intervention strategies to prevent or delay the onset of dementia, including a potential decision to take anthocyanins toward phase III trials.

Neuroimaging Biomarkers Predicting the Efficacy of Multimodal Rehabilitative Intervention in the Alzheimer's Dementia Continuum Pathology.

In this work we aimed to identify neural predictors of the efficacy of multimodal rehabilitative interventions in AD-continuum patients in the attempt to identify ideal candidates to improve the treatment outcome. Subjects in the AD continuum who participated in a multimodal rehabilitative treatment were included in the analysis [n = 82, 38 Males, mean age = 76 ± 5.30, mean education years = 9.09 ± 3.81, Mini Mental State Examination (MMSE) mean score = 23.31 ± 3.81]. All subjects underwent an MRI acquisition (1.5T) at baseline (T0) and a neuropsychological evaluation before (T0) and after intervention (T1). All subjects underwent an intensive multimodal cognitive rehabilitation (8–10 weeks). The MMSE and Neuropsychiatric Inventory (NPI) scores were considered as the main cognitive and behavioral outcome measures, and Delta change scores (T1–T0) were categorized in Improved (ΔMMSE > 0; ΔNPI < 0) and Not Improved (ΔMMSE ≤ 0; ΔNPI ≥ 0). Logistic Regression (LR) and Random Forest classification models were performed including neural markers (Medial Temporal Brain; Posterior Brain (PB); Frontal Brain (FB), Subcortical Brain indexes), neuropsychological (MMSE, NPI, verbal fluencies), and demographical variables (sex, age, education) at baseline. More than 50% of patients showed a positive effect of the treatment (ΔMMSE > 0: 51%, ΔNPI < 0: 52%). LR model on ΔMMSE (Improved vs. Not Improved) indicate a predictive role for MMSE score (p = 0.003) and PB index (p = 0.005), especially the right PB (p = 0.002) at baseline. The Random Forest analysis correctly classified 77% of cognitively improved and not improved AD patients. Concerning the NPI, LR model on ΔNPI (Improved vs. Not Improved) showed a predictive role of sex (p = 0.002), NPI (p = 0.005), PB index (p = 0.006), and FB index (p = 0.039) at baseline. The Random Forest reported a classification accuracy of 86%. Our data indicate that cognitive and behavioral status alone are not sufficient to identify best responders to a multidomain rehabilitation treatment. Increased neural reserve, especially in the parietal areas, is also relevant for the compensatory mechanisms activated by rehabilitative treatment. These data are relevant to support clinical decision by identifying target patients with high probability of success after rehabilitative programs on cognitive and behavioral functioning.

Optimizing Cognitive Assessment Outcome Measures for Alzheimer's Disease by Matching Wordlist Memory Test Features to Scoring Methodology.

Cognitive assessment with wordlist memory tests is a cost-effective and non-invasive method of identifying cognitive changes due to Alzheimer's disease and measuring clinical outcomes. However, with a rising need for more precise and granular measures of cognitive changes, especially in earlier or preclinical stages of Alzheimer's disease, traditional scoring methods have failed to provide adequate accuracy and information. Well-validated and widely adopted wordlist memory tests vary in many ways, including list length, number of learning trials, order of word presentation across trials, and inclusion of semantic categories, and these differences meaningfully impact cognition. While many simple scoring methods fail to account for the information that these features provide, extensive effort has been made to develop scoring methodologies, including the use of latent models that enable capture of this information for preclinical differentiation and prediction of cognitive changes. In this perspective article, we discuss prominent wordlist memory tests in use, their features, how different scoring methods fail or successfully capture the information these features provide, and recommendations for emerging cognitive models that optimally account for wordlist memory test features. Matching the use of such scoring methods to wordlist memory tests with appropriate features is key to obtaining precise measurement of subtle cognitive changes.

Exploring the Effect of Combined Transcranial and Intra-Oral Photobiomodulation Therapy Over a Four-Week Period on Physical and Cognitive Outcome Measures for People with Parkinson's Disease: A Randomized Double-Blind Placebo-Controlled Pilot Study.

Neuroprotection against Parkinson's disease degeneration by photobiomodulation has been reported in animal models but no true placebo-controlled human studies have been published. To understand if photobiomodulation therapy can produce clinically significant differences in physical performance measures in people with Parkinson's disease; and what frequency of treatment is necessary to initiate clinical change. In a participant and assessor-blinded, randomized, placebo-controlled pilot study, 22 participants received either sham and/or active laser photobiomodulation (904 nm, 60 mW/diode, 50 Hz) for 33 s to each of 21 points at the cranium and intra-orally, on one, two or three times/week for 4 weeks. Two treatment phases were separated by a 4-week wash-out (Phase 2). Upper and lower limb physical outcome measures were assessed before and after each treatment phase. The Montreal Cognitive Assessment was evaluated prior to treatment Phase 1, and at the end of treatment Phase 3. Montreal Cognitive Assessment remained stable between start and end of study. No measures demonstrated statistically significant changes. With regular treatment, the spiral (writing) test and the dynamic step test were most sensitive to change in a positive direction; and the 9-hole peg test demonstrated a minimum clinically important difference worthy of further investigation in a larger, adequately powered clinical trial. A placebo effect was noted. The results support the notion that combined transcranial and intra-oral photobiomodulation therapy needs to be applied at least 2 to 3 times per week for at least four weeks before some improvement in outcome measures becomes evident. Longer courses of treatment may be required.

Working memory training efficacy in COPD: the randomised, double-blind, placebo-controlled Cogtrain trial.

BackgroundCognitive impairment is highly prevalent in COPD and is associated with a sedentary lifestyle, unhealthy diet and increased cognitive stress susceptibility. Enhancement of cognitive performance by working memory training (WMT) may reverse these effects. Therefore, this study aimed to investigate the efficacy of WMT in COPD on cognitive performance, healthy lifestyle behaviours and cognitive stress susceptibility.MethodsThe double-blind randomised, placebo-controlled Cogtrain trial consisted of a 12-week training phase comprising 30 active or sham WMT sessions, followed by a second 12-week maintenance phase with 12 sessions. Measurements took place at baseline and after the first and second phases. The primary outcome was cognitive performance. Secondary outcomes were the recall of prespecified healthy lifestyle goals, physical capacity and activity, dietary quality and cognitive stress susceptibility. Motivation towards exercising and healthy eating and psychological wellbeing were exploratory outcomes.ResultsSixty-four patients with moderate COPD (45% male, aged 66.2±7.2 years, median forced expiratory volume in 1 s 60.6% predicted) were randomised. WMT significantly increased patients’ performance on the trained tasks in the first phase, which remained stable in the second phase. Of the 17 cognitive outcome measures, only one measure of memory improved after the first phase and one measure of reaction time after the second phase. This intervention did not influence physical capacity and activity, recall of prespecified healthy lifestyle goals, psychological wellbeing or cognitive stress susceptibility.ConclusionWMT improved performance on the trained tasks but not overall cognitive performance, healthy lifestyle behaviours or cognitive stress susceptibility in patients with COPD.

Association between discrepancy in objective and subjective cognitive abilities and treatment response in patients with major depressive disorder: A CAN-BIND-1 study report

BackgroundMajor Depressive Disorder (MDD) is characterized by objective and subjective cognitive deficits. Discrepancies between objective and subjective cognitive performance can reflect under- to over-estimations of cognitive abilities, and these discrepancies are referred to as cognitive self-appraisals. Despite evidence that low self-appraisals are associated with depression, the modifiability of self-appraisals and their association with treatment outcome remains unclear. The current study examined whether self-appraisals change following antidepressant treatment. Furthermore, we investigated the association of self-appraisals with treatment outcome. MethodsAs part of the CAN-BIND-1 clinical trial, 154 patients with MDD completed measures of objective and subjective cognitive abilities, depressive symptoms, and functional outcomes (work productivity, psychosocial functioning, and quality of life) at baseline and post-escitalopram treatment. Self-appraisals were calculated based on discrepancies between objective and subjective cognitive abilities, with higher scores indicating overestimation of cognitive abilities. ResultsBaseline self-appraisals were not predictive of treatment outcomes. However, self-appraisals increased from pre- to post-treatment. Moreover, pre-post treatment increases in self-appraisals were associated with positive treatment response and remission, decreases in depressive symptoms, and improvements in work productivity, psychosocial functioning, and quality of life. LimitationsThe pre-post intervention design precluded examining the temporal precedence of change in self-appraisals versus depressive symptoms and functional outcomes. ConclusionsFindings are the first to demonstrate that self-appraisals are treatment-sensitive and are associated with treatment outcomes and recovery from MDD. Cognitive self-appraisals may represent a key marker of treatment response and a valuable target for assessment and intervention, as well as a potential mechanism underlying risk and recovery.

Amyloid-β and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials.

Alzheimer’s disease and Lewy body diseases are the most common causes of neurodegeneration and dementia. Amyloid-beta (Aβ) and alpha-synuclein (αSyn) are two key proteins involved in the pathogenesis of these neurodegenerative diseases. Immunotherapy aims to reduce the harmful effects of protein accumulation by neutralising toxic species and facilitating their removal. The results of the first immunisation trial against Aβ led to a small percentage of meningoencephalitis cases which revolutionised vaccine design, causing a shift in the field of immunotherapy from active to passive immunisation. While the vast majority of immunotherapies have been developed for Aβ and tested in Alzheimer’s disease, the field has progressed to targeting other proteins including αSyn. Despite showing some remarkable results in animal models, immunotherapies have largely failed final stages of clinical trials to date, with the exception of Aducanumab recently licenced in the US by the FDA. Neuropathological findings translate quite effectively from animal models to human trials, however, cognitive and functional outcome measures do not. The apparent lack of translation of experimental studies to clinical trials suggests that we are not obtaining a full representation of the effects of immunotherapies from animal studies. Here we provide a background understanding to the key concepts and challenges involved in therapeutic design. This review further provides a comprehensive comparison between experimental and clinical studies in Aβ and αSyn immunotherapy and aims to determine the possible reasons for the disconnection in their outcomes.

Effective non-pharmacological interventions for cancer related cognitive impairment in adults (excluding central nervous system or head and neck cancer): systematic review and meta-analysis.

Cancer-related cognitive impairment (CRCI) is prevalent in cancer survivors, and impairments affect daily living tasks and overall wellbeing. This review aimed to identify and evaluate published randomized controlled trials (RCTs) of interventions to manage CRCI in adult populations, to analyze their effectiveness and to investigate the quality of the studies. Seven databases were searched (Medline, Scopus, CINAHL, AMED, PsychINFO, OTseeker, and the Cochrane Database of Systematic Reviews), including years 2005-2020, for randomized controlled trials (RCTs) investigating interventions to address cognition for adults with cancer. The final search was conducted in February 2021. The quality of studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for RCTs. Meta-analysis used comprehensive meta-analysis software. The study protocol was registered with PROSPERO (registration N. CRD42017076868). A total of 45 studies involving 4727 participants examined interventions for CRCI and met selection criteria. Categories of interventions included cognitive training-based intervention (N.=15), cognitive behavior therapy (CBT) (N.=4), physical activity (N.=16) and other supportive therapies (N.=10). Meta-analysis indicated beneficial overall effects for all categories of interventions: cognitive training (standardized mean difference [SMD]=0.41, 95% CI: 0.28-0.53, I2=88.87%); CBT (SMD=0.30, 95% CI: 0.14-0.46, I2=44.86%); physical activity (SMD=0.27, 95% CI: 0.20-0.35, I2=37.67%); and supportive therapies (SMD=0.27, 95% CI: 0.16-0.39, I2=64.94%). Studies used self-report cognitive outcome measures and neurocognitive testing, or a mixture. Findings suggest that effective intervention for CRCI exist, and cognitive training is consistently supported as an effective intervention; however, a high level of heterogeneity was found. CRCI research is currently dominated by breast cancer survivors, and quality research is also needed to address the broader population of cancer survivors who experience CRCI.

Outcome Measures for Dementia With Lewy Body Clinical Trials: A Review.

Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias. Clinical trials for individuals with DLB are increasing. We aimed to identify commonly used outcome measures for trials in DLB. A pragmatic literature search of PubMed and clinicaltrials.gov identified interventional studies including populations with DLB. Studies were included if they enrolled participants with DLB and met the National Institutes of Health criteria for a clinical trial. Data were collected using standardized forms. Outcome measures were categorized according to core and supportive features of DLB. After de-duplication, 58 trials were identified. The most common cognitive outcome measures were the Mini Mental State Examination (n=24) and Cognitive Drug Research computerized Assessment System (n=5). The Clinician's Assessment of Fluctuations was the most commonly used measure for fluctuations (n=4). Over half of studies used the Neuropsychiatric Inventory to assess behavioral symptoms (n=31). The Unified Parkinson's Disease Rating Scale was frequently used for motor assessment (n=23). Clinical trial outcomes used in DLB are rarely validated in this population and some lack face validity. There is a need to validate existing scales in DLB and develop DLB-specific outcome measures.

From the Clinic to the Laboratory, and Back Again: Investigations on Cannabinoids and Endocannabinoid System Modulators for Treating Schizophrenia

The present mini-review focuses on animal models of schizophrenia that have explored the effects of cannabidiol (CBD; a non-psychoactive component of cannabis) or the pharmacological manipulation of the endocannabinoid system on behavioral and cognitive outcome measures. First, results of some relevant clinical studies in this area are summarized, and then pre-clinical work on animal models of schizophrenia based on NMDA receptor antagonism or neurodevelopmental manipulations are discussed. A brief overview is given of the theoretical framework on which these models are based, along with a concise summary of results that have been obtained. Clinical results using CBD for schizophrenia seem promising and its effects in animal models of schizophrenia support its potential as a useful pharmacotherapy. Animal models have been paramount for elucidating the actions of CBD and the function of the endocannabinoid system and for identifying novel pharmacological targets, such as cannabinoid receptors and anandamide. However, more attention needs to be placed on defining and applying independent variables and outcome measures that are comparable between pre-clinical and clinical studies. The objective of this review is, on the one hand, to emphasize the potential of such models to predict clinical response to experimental drugs, and on the other hand, to highlight areas in which research on such models could be improved.

Investigating neurophysiological markers of impaired cognition in schizophrenia

Cognitive impairment is highly prevalent in schizophrenia and treatment options are severely limited. A greater understanding of the pathophysiology of impaired cognition would have broad implications, including for the development of effective treatments. In the current study we used a multimodal approach to identify neurophysiological markers of cognitive impairment in schizophrenia. Fifty-seven participants (30 schizophrenia, 27 controls) underwent neurobiological assessment (electroencephalography [EEG] and Transcranial Magnetic Stimulation combined with EEG [TMS-EEG]) and assessment of cognitive functioning using an n-back task and the MATRICS Consensus Cognitive Battery. Neurobiological outcome measures included oscillatory power during a 2-back task, TMS-related oscillations and TMS-evoked potentials (TEPs). Cognitive outcome measures were d prime and accurate reaction time on the 2-back and MATRICS domain scores. Compared to healthy controls, participants with schizophrenia showed significantly reduced theta oscillations in response to TMS, and trend level decreases in task-related theta and cortical reactivity (i.e. reduced N100 and N40 TEPs). Participants with schizophrenia also showed significantly impaired cognitive performance across all measures. Correlational analysis identified significant associations between cortical reactivity and TMS-related oscillations in both groups; and trend level associations between task-related oscillations and impaired cognition in schizophrenia. The current study provides experimental support for possible neurophysiological markers of cognitive impairment in schizophrenia. The potential implications of these findings, including for treatment development, are discussed.

Is there a bidirectional association between sedentary behaviour and cognitive decline in older adults? Findings from the Irish Longitudinal Study on Ageing.

Research on whether sedentary behaviour (SB) is related to cognitive decline in older individuals is conflicting, potentially caused by methodological differences in previous studies. To inform public health policies, we analysed both the forward and reverse association across four-years between subjective TV time and objectively-measured SB and four cognitive outcome measures in older adults. The Irish Longitudinal Study on Ageing (TILDA) quantified time spent watching TV using a questionnaire and objective physical activity patterns with a GENEActiv accelerometer. Mixed model analysis examined whether these two measures of SB related to changes in cognitive function (immediate and delayed recall, MMSE, and animal naming task) during a four-year follow-up period. Furthermore, the reverse association between changes in cognition over the preceding four years and SB was investigated. We included 1,276 participants (67 ± 9 years). Longitudinally, every hour of objective SB per day was associated with a −0.01 (95%CI = −0.03;−0.00) lower MMSE score per year. Reversely, a worse decline in immediate and delayed recall over the preceding waves was related to slightly more objective SB (B = −0.24 (95%CI = −0.41;−0.07)) and TV time (B = −0.25 (95%CI = −0.48;−0.03)) at the end of those four years. To conclude, in healthy older individuals, higher levels of objective SB are related to cognitive decline across a four-year follow-up, although the magnitude and clinical relevance are questionable. As preceding cognitive decline is associated with more SB across follow-up, this suggests that a bidirectional association is plausible.

Yoga Interventions Used for the Rehabilitation of Stroke, Parkinson's Disease, and Multiple Sclerosis: A Scoping Review of Clinical Research.

Objectives: The current body of literature was reviewed to compile and describe yoga interventions that have been applied in clinical research and neurologic rehabilitation settings with patients affected by stroke, Parkinson's disease (PD), and multiple sclerosis (MS). Design: Available literature on yoga therapy (YT) was mapped following a five-stage framework to identify key concepts, knowledge gaps, and evidence to inform practice. Publications were identified through Medline, CINAHL, EMBASE, and PsycINFO. Selected studies required subjects with a clinical diagnosis of stroke, PD, and MS to participate in a yoga intervention and have physical, cognitive, and/or psychosocial outcome measures assessed. Results: A total of 50 studies were included in this review. Study characteristics, patient demographics, description of the yoga intervention, reported outcome measures and the main findings were extracted from the studies. Conclusion: Implementing YT in neurorehabilitation can help health care professionals integrate a more holistic approach that addresses the fundamental physical and psychological challenges of living with a chronic and debilitating neurologic disorder. The included studies described yogic interventions consisting of group or individual therapy sessions lasting 60-75 min that were carried out one to three times per week for 8-12 consecutive weeks across all three conditions. All studies described in this scoping review used different yoga protocols confirming the lack of specific interventional parameters available for implementing yoga into the rehabilitation of individuals affected by stroke, PD, or MS.

IMPLICITNESS AND EXPLICITNESS IN COGNITIVE ABILITIES AND CORRECTIVE FEEDBACK

AbstractThis aptitude–treatment interaction study investigated the extent to which explicit and implicit cognitive abilities are differentially related to learning outcomes under two corrective feedback conditions. One hundred and thirteen intermediate English learners of Spanish were randomly assigned to an implicit feedback (recast), explicit feedback (explicit correction), or control group after completing tests from two aptitude batteries (High-Level Language Aptitude Battery [Hi-LAB] and LLAMA). Linguistic improvement on noun-adjective gender agreement and Differential Object Marking was assessed using grammaticality judgment and oral production tasks. Results showed that implicit but not explicit abilities were relevant for the acquisition of gender agreement under implicit feedback as measured by grammaticality judgments. In contrast, explicit but not implicit abilities were relevant for the acquisition of object marking under explicit feedback as measured by oral production. These results lent support to a double dissociation, but they also suggested higher-order interaction effects between the type of cognitive ability, outcome measure, and target structure.

Cortical involvement determines impairment 30 years after a clinically isolated syndrome.

Many studies report an overlap of MRI and clinical findings between patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), which in part is reflective of inclusion of subjects with variable disease duration and short periods of follow-up. To overcome these limitations, we examined the differences between RRMS and SPMS and the relationship between MRI measures and clinical outcomes 30 years after first presentation with clinically isolated syndrome suggestive of multiple sclerosis. Sixty-three patients were studied 30 years after their initial presentation with a clinically isolated syndrome; only 14% received a disease modifying treatment at any time point. Twenty-seven patients developed RRMS, 15 SPMS and 21 experienced no further neurological events; these groups were comparable in terms of age and disease duration. Clinical assessment included the Expanded Disability Status Scale, 9-Hole Peg Test and Timed 25-Foot Walk and the Brief International Cognitive Assessment For Multiple Sclerosis. All subjects underwent a comprehensive MRI protocol at 3 T measuring brain white and grey matter (lesions, volumes and magnetization transfer ratio) and cervical cord involvement. Linear regression models were used to estimate age- and gender-adjusted group differences between clinical phenotypes after 30 years, and stepwise selection to determine associations between a large sets of MRI predictor variables and physical and cognitive outcome measures. At the 30-year follow-up, the greatest differences in MRI measures between SPMS and RRMS were the number of cortical lesions, which were higher in SPMS (the presence of cortical lesions had 100% sensitivity and 88% specificity), and grey matter volume, which was lower in SPMS. Across all subjects, cortical lesions, grey matter volume and cervical cord volume explained 60% of the variance of the Expanded Disability Status Scale; cortical lesions alone explained 43%. Grey matter volume, cortical lesions and gender explained 43% of the variance of Timed 25-Foot Walk. Reduced cortical magnetization transfer ratios emerged as the only significant explanatory variable for the symbol digit modality test and explained 52% of its variance. Cortical involvement, both in terms of lesions and atrophy, appears to be the main correlate of progressive disease and disability in a cohort of individuals with very long follow-up and homogeneous disease duration, indicating that this should be the target of therapeutic interventions.

Postural stability is a valid and meaningful disability metric in progressive MS with potential for use in neuroprotective therapy trials

BackgroundBalance impairment is observed in up to 70% of people with MS (pwMS) and worsens with disease progression. Posturography using a force platform is the current gold standard in the measurement of balance. However, posturography has not been adequately studied or widely accepted for use as a disability outcome measure for pwMS. Importantly, the recent emergence of both successful and failed neuroprotective therapy trials in progressive MS has emphasised the need for new disability outcome measures for people with progressive MS. The main objectives of this study were to evaluate the clinical validity, reliability and feasibility of posturography as a disability metric in progressive MS. MethodsThis was a prospective cross-sectional study. We recruited 73 people with progressive MS (age 18–65 years, EDSS 3.5–6.0). Participants stood in the centre of a force platform, feet comfortably apart, under various conditions: (i) eyes open (EO), (ii) eyes closed (EC) – a single task, each lasting ninety seconds; and simultaneous EO with a cognitive test: (iii) N-Back, a three-minute test whereby participants were instructed to click the mouse when two identical letters were displayed consecutively on a screen, (iv) Sustained Attention Response Task, a five-minute test whereby participants were instructed to click the mouse for every number “1″ to “9″ except “3″ – i.e., dual-tasks. Additionally, we performed a battery of validated physical and cognitive outcome measures. Posturographic data was processed using Matlab. Statistical analysis was performed using SPSS version 26. We used multiple linear regression modelling to determine whether significant univariate correlations between posturography and clinical metrics were independent of covariates that may influence the associations seen. A two-tailed significance level of 0.05 was used. ResultsOf 73 participants, mean age 52.4 (8.5) years, mean MS disease duration 13.8 (10.3) years, median EDSS 5.0 (IQR 4.0–6.0), 44 (60.4%) were female. EO-Path-Length independently predicted upper extremity function (9-Hole-Peg-Test) with a larger effect size (adjusted R2=20.0%, p = 0.001) than that for walking measures (Timed 25-Foot Walk, adjusted R2=1.6%, p = 0.01; Two-Minute Walk Test, adjusted R2=7.2%, p = 0.002), while controlling for age, disease duration, height, weight, and sex. The addition of EO-Mediolateral-Displacement to the MS Functional Composite (MSFC) created a four-component z-score that increased the variance explained for quality of life (QOL) by 62.1%. Postural stability was significantly lower with mediolateral vs anteroposterior direction of sway, removal of vision, increased body weight, male sex, and fampridine use. Postural stability improved during dual-tasks compared to EO single task. Posturography detected significant worsening of balance over a single prolonged stance. ConclusionPostural stability independently predicted a wide range of clinical metrics including upper extremity function, walking ability, cognition and QOL, therefore establishing construct and concurrent validity as a disability outcome measure for people with progressive MS. Additionally, posturography is a quantitative, non-invasive, quick-and-easy-to-administer, and highly sensitive device, demonstrating its high feasibility for use as a time- and resource-efficient disability metric in neuroprotective therapy trials for progressive MS.

Age-at-Onset and APOE-Related Heterogeneity in Pathologically Confirmed Sporadic Alzheimer Disease.

To characterize age-related clinical heterogeneity in Alzheimer disease (AD) and determine whether it is modified by APOE genotype or concomitant non-AD pathology, we analyzed data from 1,750 patients with sporadic, pathologically confirmed severe AD. In this retrospective cohort study, regression and mixed effects models assessed effects of estimated age at onset, APOE genotype, and their interaction on standardized clinical, cognitive, and pathologic outcome measures from the National Alzheimer's Coordinating Center database. A bimodal distribution of age at onset frequency in APOE ε4- cases showed best separation at age 63. Using this age cutoff, cases were grouped as ε4- early-onset AD (EOAD) (n = 169), ε4+ EOAD (n = 273), ε4- late-onset AD (LOAD) (n = 511), and ε4+ LOAD (n = 797). Patients with EOAD were more likely than patients with LOAD to present with noncognitive behavioral or motor symptoms or nonmemory cognitive complaints, and had more executive dysfunction, but less language impairment on objective cognitive testing. Age at onset and ε4- genotype were independently associated with lower baseline Mini-Mental State Examination scores and greater functional impairment and patients with EOAD had faster cognitive and functional decline than patients with LOAD regardless of APOE genotype. Patients with EOAD were more likely than patients with LOAD to receive a non-AD clinical diagnosis even though they were more likely to have pure AD without concomitant vascular or other non-AD neurodegenerative pathology. Early-onset sporadic AD is associated with a greater likelihood of an atypical, non-memory-dominant clinical presentation, especially in the absence of the APOE ε4 allele, which may lead to misattribution to non-AD underlying pathology.

Effect of Reading Rehabilitation for Age-Related Macular Degeneration on Cognitive Functioning: Protocol for a Nonrandomized Pre-Post Intervention Study.

BackgroundAge-related vision impairments and dementia both become more prevalent with increasing age. Research into the mechanisms of these conditions has proposed that some of their causes (eg, macular degeneration/glaucoma and Alzheimer’s disease) could be symptoms of an underlying common cause. Research into sensory-cognitive aging has provided data that sensory decline may be linked to the progression of dementia through reduced sensory stimulation. While hearing loss rehabilitation may have a beneficial effect on cognitive functioning, there are no data available on whether low vision rehabilitation, specifically for reading, could have a beneficial effect on cognitive health.ObjectiveThe research questions are: (1) Does low vision rehabilitation reduce reading effort? (2) If so, does reduced reading effort increase reading activity, and (3) If so, does increased reading activity improve cognitive functioning? The primary objective is to evaluate cognition before, as well as at 6 months and 12 months after, 3 weeks of low vision reading rehabilitation using magnification in individuals with age-related macular degeneration, with or without coexisting hearing impairments. We hypothesize that improvements postrehab will be observed at 6 months and maintained at 12 months for participants with vision loss and less so for those with dual sensory loss. The secondary objective is to correlate participant characteristics with all cognitive outcomes to identify which may play an important role in reading rehabilitation.MethodsWe employ a quasiexperimental approach (nonrandomized, pre-post intervention study). A 3x3 design (3 groups x 3 time points) allows us to examine whether cognitive performance will change before and after 6 months and 12 months of a low vision reading intervention, when comparing 75 low vision and 75 dual sensory impaired (vision & hearing) participants to 75 age-matched healthy controls. The study includes outcome measures of vision (eg, reading acuity and speed), cognition (eg, short-term and long-term memory, processing speed), participant descriptors, demographics, and clinical data (eg, speech perception in noise, mental health).ResultsThe study has received approval, and recruitment began on April 24, 2019. As of March 4, 2021, 38 low vision and 7 control participants have been enrolled. Lockdown forced a pause in recruitment, which will recommence once the COVID-19 crisis has reached a point where face-to-face data collection with older adults becomes feasible again.ConclusionsEvidence of protective effects caused by reading rehabilitation will have a considerable impact on the vision rehabilitation community and their clients as well as all professionals involved in the care of older adults with or without dementia. If we demonstrate that reading rehabilitation has a beneficial effect on cognition, the demand for rehabilitation services will increase, potentially preventing cognitive decline across groups of older adults at risk of developing macular degeneration.Trial RegistrationClinicalTrials.gov NCT04276610; Unique Protocol ID: CRIR-1284-1217; https://clinicaltrials.gov/ct2/show/NCT04276610International Registered Report Identifier (IRRID)DERR1-10.2196/19931