Cognitive Outcome Measures Research Articles

Immersive Technology for Cognitive-Motor Training in Parkinson's Disease.

Background: Parkinson’s disease (PD) is a neurodegenerative disease in which the progressive loss of dopaminergic neurons (DA) leads to initially sporadic and eventually widespread damage of the nervous system resulting in significant musculoskeletal and cognitive deterioration. Loss of motor function alongside increasing cognitive impairment is part of the natural disease progression. Gait is often considered an automatic activity; however, walking is the result of a delicate balance of multiple systems which maintain the body’s center of mass over an ever-changing base of support. It is a complex motor behavior that requires components of attention and memory to prevent falls and injury. In addition, evidence points to the critical role of salient visual information to gait adaptability. There is a growing understanding that treatment for PD needs to address movement as it occurs naturally and walking needs to be practiced in more complex environments than traditional therapy has provided.MethodsIn this single-blinded randomized-controlled pilot study, an immersive treadmill training was piloted to determine feasibility and preliminary efficacy on gait and cognition in people with PD. Eighteen participants with Hoehn and Yahr stages I-III PD were randomized to either an intervention or a waitlist control group. Following baseline data collection, the intervention group trained for 30 min, three times/week for 4 weeks on a split belt treadmill combined with a first-person immersive video game targeting visuospatial skills and working memory. Assessment was repeated after 4 weeks of training for the experimental group and 1-month after baseline for the control group. Primary motor outcomes were captured with the APDM Opal sensors during 6 MWT, TUG, and TUG Cognitive. Secondary outcomes of cognition were measured with the Montreal Cognitive Assessment (MoCA), Verbal Fluency (Fruit, Vegetable, and Animal) and the Symbol Digit Modality Test (SDMT). Within subject differences were calculated using the Wilcoxon Signed Ranked Test and between subject comparisons were analyzed using the Mann Whitney U-test.ResultsThis novel treadmill training program was well-tolerated with all participants in the intervention group completing 4 weeks of training three times a week without any adverse effects. After immersive cognitive motor training, the experimental group made clinically relevant improvements in gait speed and walking distance during the 6 MWT while members of the control group showed no change or decreased gait speed and walking distance over the 1-month trial. In addition, the experimental group demonstrated significant improvement for the TUG Cognitive (p = 0.05) and those changes were greater than the control group (between group p = 0.040). The experimental group also improved scores on MoCA (p = 0.007) and SDMT (p = 0.01) cognitive outcome measures while the control group did not.ConclusionThe use of immersive gaming technology to engage specific areas of cognition related to gait is feasible in PD. The treadmill training program paired with a customized interactive video game improved walking velocity in addition to non-significant but consistent improvements in other gait measures and cognitive performance in participants with early to mid-stage PD.

Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort.

Background and ObjectivesDisease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic).MethodsC9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage.ResultsA total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1.DiscussionWe confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language, and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive end points for measuring treatment effects as well as characterizing the best time window for starting treatment.

Mindfulness and music interventions in the workplace: assessment of sustained attention and working memory using a crowdsourcing approach

BackgroundOccupational stress has huge financial as well as human costs. Application of crowdsourcing might be a way to strengthen the investigation of occupational mental health. Therefore, the aim of the study was to assess Danish employees’ stress and cognition by relying on a crowdsourcing approach, as well as investigating the effect of a 30-day mindfulness and music intervention.MethodsWe translated well-validated neuropsychological laboratory- and task-based paradigms into an app-based platform using cognitive games measuring sustained attention and working memory and measuring stress via. Cohen’s Perceived Stress Scale. A total of 623 healthy volunteers from Danish companies participated in the study and were randomized into three groups, which consisted of a 30-day intervention of either mindfulness or music, or a non-intervention control group.ResultsParticipants in the mindfulness group showed a significant improvement in the coefficient of sustained attention, working memory capacity and perceived stress (p < .001). The music group showed a 38% decrease of self-perceived stress. The control group showed no difference from pre to post in the survey or cognitive outcome measures. Furthermore, there was a significant correlation between usage of the mindfulness and music app and elevated score on both the cognitive games and the perceived stress scale.ConclusionThe study supports the nascent field of crowdsourcing by being able to replicate data collected in previous well-controlled laboratory studies from a range of experimental cognitive tasks, making it an effective alternative. It also supports mindfulness as an effective intervention in improving mental health in the workplace.

Adult Cognitive Outcomes Following Childhood Mild Traumatic Brain Injury: A Scoping Review.

This review aimed to (1) summarize the existing literature regarding cognitive outcomes in adults with a history of pediatric mild traumatic brain injury (mTBI) and (2) identify gaps in the literature to provide directions for future research. Participants sustained mTBI in childhood (0-17 years of age) and underwent cognitive assessment in adulthood (older than 18 years) at least 1 year postinjury. MEDLINE Ovid and PsycINFO Ovid databases were searched to identify original research studies that examined adult cognitive outcomes after childhood mTBI. Cognitive outcome measures assessed memory, attention, visuospatial abilities, processing speed, comprehension, reasoning, intellectual functioning, and executive functioning. Outcome measures ranged from self-reported cognitive symptoms to objective testing. A total of 4216 articles were screened, leading to the inclusion of 6 published studies for review (3 prospective cohort and 3 retrospective cohort), with 131 537 participants (mTBI = 6724; controls = 123 823). Review of the included articles suggests that adults with a history of childhood mTBI perform within the average range expected for adult cognitive functioning, although they may perform more poorly than non-head-injured comparison groups on a variety of cognitive measures. Injury-related factors, such as requiring electroencephalography within 24 hours of injury and posttraumatic amnesia lasting longer than 30 minutes, may be associated with variability in adult cognitive outcomes. The weight of the available evidence suggests that childhood mTBI does not have a significant impact on adult cognitive functioning. However, further research is needed to provide a more comprehensive understanding of the long-term cognitive outcomes of childhood mTBI and to identify predictors of those outcomes in adulthood.

Repeated Measures of Cognitive and Affective Learning Outcomes in Simulation Debriefing

Introduction. To better support the development of domain expertise, there has been considerable interest in the instructional strategies that afford opportunities for problem solving. Simulation-based learning includes case-based activities that support learners' transition into practice through experience and reflective debriefing. Review of the Literature. Simulation-based learning serves as a means for learners to practice psychomotor, affective, and cognitive skills. Although the literature suggests this is an effective strategy for supporting problem-solving skills, much of the literature is focused on measuring cognitive outcomes within a single case. As such, very few studies have simultaneously investigated (a) how debriefing in simulation-based education supports problem solving and (b) the degree to which cognitive and affective learning outcomes are variable throughout the problem-solving process. Methodology. To address this gap, this repeated-measures study examined the role of debriefing strategies in simulation-based learning experiences, which was designed to practice both cognitive and affective skills. In the control condition, participants were given 2 simulation-based laboratory instructional sessions and then assessed on cognitive (problem representation and solution generation) and affective learning (perceived self-efficacy) outcomes. In the comparison condition, participants engaged in debriefing sessions after each of the 2 simulation-based laboratory instructional sessions. For the cognitive outcomes, participants were assessed using the Think-Aloud Standardized Patient Examination instrument, which measured problem representation and solution generation. Acute care confidence survey was used to measure perceived self-efficacy. Results. The study found statistically significant gaps in early-stage measures of cognitive problem representation, but no difference was found in solution generation or perceived self-efficacy measures. Conclusion. This study reinforces the importance of debriefing in simulation-based education. Specifically, this study suggests that cognitive learning outcomes are variable during the problem-solving process, but affective learning outcomes are more fixed and may need more targeted debriefing.

The Use of Home-Based Nonimmersive Virtual Reality to Encourage Physical and Cognitive Exercise in People With Mild Cognitive Impairment: A Feasibility Study.

Individuals with mild cognitive impairment are at risk of cognitive and physical decline. Virtual reality (VR) exercise may provide beneficial physical and cognitive exercise. The objectives of this study were to assess the feasibility and safety of home-based VR exercise and to provide pilot data for physical and cognitive efficacy. Eleven individuals with mild cognitive impairment (seven males/four females, average 78 years old, and average 3 years since diagnosis) performed a 30-min home-based VR exercise program 5 days a week for 6 weeks. The VR platform was successfully installed in participants' homes, and all participants were able to learn the VR program and progress. Participants completed 99% of the prescribed exercise. There were no major adverse events. Most participants enjoyed the VR program and reported physical benefits; fewer reported cognitive benefits. No physical or cognitive outcome measures showed change after 6 weeks. Home-based VR exercise is safe and feasible in individuals with mild cognitive impairment.

Association of Emerging β-Amyloid and Tau Pathology With Early Cognitive Changes in Clinically Normal Older Adults.

Alzheimer disease (AD) clinical trials are moving earlier in the disease process according to emerging signs of β-amyloid (Aβ) and tau pathology. If early treatment is the right time for intervention, it is critical to find the right test to optimize cognitive outcome measures for clinical trials. We sought to identify cognitive measures associated with the earliest detectable signs of emerging Aβ and tau pathology. One hundred twelve clinically normal adults with longitudinal Pittsburgh compound B (PiB)-PET, 18F-flortaucipir (FTP)-PET, and cognitive data for ≥7 years were included from the Harvard Aging Brain Study (HABS). Analyses assessed those initially classified as PiB- (less than Centiloid [CL] 20) and then expanded to include PiB+ individuals up to CL40, the approximate threshold beyond which neocortical tau proliferation begins. Separate linear mixed-effects models assessed the effects of emerging global Aβ (PiB slope) and tau (baseline FTP level and FTP slope) in the entorhinal and inferior temporal (IT) cortices on multiple cognitive tasks and the Preclinical Alzheimer's Cognitive Composite (PACC) over time. Steeper PiB slopes were associated with declining processing speed (Digit Symbol Substitution Test [DSST], Trail Making Test Part A) in those <CL20 and expanded to include learning/memory retrieval (FCSRT-FR], Selective Reminding Test Total Recall [SRT-tr], Logical Memory Immediate Recall) in the <CL40 group. FTP had limited effects under CL20, with only rising right IT FTP slope related to declining FCSRT-FR and SRT-tr learning/memory retrieval. When we expanded to include those initially <CL40, rising FTP level or slope was related to declines across all tasks, and PiB slope effects on memory retrieval but not DSST score were reduced. A composite measure of processing speed and memory retrieval tasks provided the strongest prediction of decline under CL40, while PACC score remained optimal at high levels of Aβ (>CL40). Early, Aβ-mediated cognitive slowing was detected for processing speed measures, while early memory retrieval declines were associated with emerging Aβ and tau pathology. Composites of these measures may help determine whether anti-Aβ or anti-tau therapies administered at the first signs of pathology might preserve cognitive function. This study provides Class I evidence that in clinically normal older adults, emerging PET-detected AD pathology is associated with declining processing speeds and memory retrieval.

Cognitive predictors of social adjustment in pediatric brain tumor survivors treated with photon versus proton radiation therapy.

Pediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes. Survivors who underwent PRT (n=38) or XRT (n=20) participated in a neurocognitive evaluation >1year post radiotherapy. Group differences in cognitive and social functioning were assessed using analysis of covariance (ANCOVA). Regression analyses examined predictors of peer relations and social skills. Age at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p>.05). XRT participants were younger at diagnosis (XRT M=5.0years, PRT M=7.6years) and further out from radiotherapy (XRT M=8.7years, PRT M=4.6years). The XRT group performed worse than the PRT group on measures of processing speed (p=.01) and verbal memory (p<.01); however, social outcomes did not differ by radiation type. The proportion of survivors with impairment in peer relations and social skills exceeded expectation; χ2 (1)=38.67, p<.001; χ2 (1)=5.63, p<.05. Household poverty predicted peer relation difficulties (t=2.18, p<.05), and verbal memory approached significance (t=-1.99, p=.05). Tumor diameter predicted social skills (t=-2.07, p<.05). Regardless of radiation modality, survivors are at risk for social challenges. Deficits in verbal memory may place survivors at particular risk. Results support monitoring of cognitive and social functioning throughout survivorship, as well as consideration of sociodemographic risk factors.

Effects of a multimodal approach to food art therapy on people with mild cognitive impairment and mild dementia.

Food art therapy (FAT) has multiple modalities in which cognition, emotion, and social changes are stimulated. The purpose of this study was to design a multimodal approach to a food art therapy (MM-FAT) program and identify its effects on cognitive ability, daily living functioning, depression, self-esteem, self-efficacy, self-expression, and social functioning in individuals with mild cognitive impairment (MCI) and mild dementia by employing a mixed methods research design. The participants included 39 patients from a public dementia care centre in Seoul, Korea. The intervention group, which comprised 20 participants, received 12 MM-FAT sessions 3 times a week for 4 weeks, and the control group, which included 19 participants, received usual care. The MM-FAT program was evaluated based on its effectiveness on cognitive, daily living, emotional, and social functioning outcome measures at three time points using repeated measures analysis of variance. Semi-structured interviews (n=9) were conducted to evaluate the overall experience of the MM-FAT program and its outcomes. The findings reveal that MM-FAT has a positive effect on the cognitive, emotional, and social functioning of individuals with MCI and mild dementia. However, there were no enhancements in individuals' daily living functioning, and the lasting effects of the intervention could not be assessed. Cognition and depression increased significantly at the end of the MM-FAT program. Self-expression and self-efficacy were significantly higher in the MM-FAT group than in the control group. The semi-structured interviews revealed improvements in participants' behaviour, communication, and interaction. This mixed methods study focused on individuals with MCI or mild dementia contributes to an understanding of the effectiveness of a FAT program employing a multimodal approach. Despite the COVID-19 pandemic, the study was able to enrich the effects of MM-FAT on cognitive, emotional, and social functioning through qualitative findings.

Including Arts in Rehabilitation Enhances Outcomes in the Psychomotor, Cognitive, and Affective Domains: A Scoping Review.

The purpose of this scoping review was to analyze the published literature regarding the use of art in the context of rehabilitation for consideration in physical therapy. The CINAHL, PsycArticles, APA PsycInfo, Art Index, Music Index, Cochrane Reviews, and PubMed electronic databases were accessed. Inclusion and exclusion criteria were established and utilized to determine study eligibility. Study details were extracted from each article by researchers using a systematic format. Summation of journal type, participants, dosing and type of intervention, setting and interventionist, outcome domains, and study results were included. Out of 1452 studies, 76 were included for extraction. Of these studies, most had outcome measures aligned with the psychomotor and affective domains of learning (n = 66). Very few studies had outcome measures with psychomotor and cognitive domains (n = 2) or psychomotor, affective, and cognitive outcome measures (n = 8). Regarding the arts used, music, dance, or both were used in 77 instances. Fewer studies reported using creative arts therapy, singing, theater, writing, and rhythm (n = 17). Of the 76 studies analyzed, 74 reported a within-group treatment effect. The arts effectively enhance physical therapist practice; therefore, it is recommended that physical therapists continue to seek collaboration with art professionals and explore the use of arts in practice. Findings demonstrate that combining the arts with physical therapist practice amplifies not only psychomotor but affective and cognitive outcomes as well. The arts have applicability across broad populations (eg, chronic pain, neurologic dysfunction, respiratory conditions). This study supports that physical therapist education and practice should embrace the arts as a collaborative modality to promote enhanced psychomotor, affective, and cognitive outcomes.

A cognitively enhanced online Tai Ji Quan training intervention for community-dwelling older adults with mild cognitive impairment: A feasibility trial

BackgroundThis study examines the feasibility, acceptability, and safety of a newly developed cognitive-enhancing Tai Ji Quan training intervention, delivered via remote videoconferencing, for older adults with mild cognitive impairment (MCI).MethodsIn a three-arm feasibility trial, community-dwelling older adults with MCI (N = 69; mean age = 74.6 years, 57% women) were randomized to a cognitively enhanced Tai Ji Quan (n = 23), standard Tai Ji Quan (n = 22), or stretching group (n = 24) and participated in a 60-minute online exercise session via Zoom, twice weekly for 16 weeks. Participants were recruited primarily in the state of Oregon through mass mailing and word of mouth. The primary outcomes were intervention feasibility (with respect to recruitment, online intervention delivery, fidelity and compliance, and attrition and retention rates), acceptability, and safety. We also assessed feasibility of online data collection and test-retest reliability and explored preliminary trends on secondary outcomes that included global cognitive function, dual-task cost, and domain-specific cognition function.ResultsThe study had an average recruitment rate of 55%. Feasibility was demonstrated by the overall successful online program implementation, with good fidelity, acceptable compliance (76%), and excellent retention (94%). The cognitively enhanced Tai Ji Quan intervention was shown to be acceptable to participants as well as safe, with no major intervention-related moderate/severe events. At week 16, the group receiving cognitively enhanced Tai Ji Quan training showed a positive trend in the cognitive function and dual-task outcome measures whereas the group receiving standard Tai Ji Quan training exhibited positive trends on global and domain-specific cognitive measures.ConclusionsPreliminary findings of this pilot study indicate the feasibility, acceptability, and safety of a tailored, cognitively enhanced Tai Ji Quan training intervention delivered remotely to home settings via videoconferencing for community-dwelling older adults with MCI.Trial registrationClinicaltrials.gov identifier NCT04070703

Co-creating a local environmental epidemiology study: the case of citizen science for investigating air pollution and related health risks in Barcelona, Spain

BackgroundWhile the health risks of air pollution attract considerable attention, both scholarly and within the general population, citizens are rarely involved in environmental health research, beyond participating as data subjects. Co-created citizen science is an approach that fosters collaboration between scientists and lay people to engage the latter in all phases of research. Currently, this approach is rare in environmental epidemiology and when co-creation processes do take place, they are often not documented. This paper describes the first stages of an ongoing co-created citizen science epidemiological project in Barcelona (Spain), that included identifying topics that citizens wish to investigate as regards air pollution and health, formulating their concerns into research questions and co-designing the study protocol. This paper also reflects key trade-offs between scientific rigor and public engagement and provides suggestions to consider when applying citizen science to environmental health studies.MethodsExperts created an online survey and analyzed responses with descriptive statistics and qualitative coding. A pop-up intervention was held to discuss with citizens their concerns about air pollution and health. Later on, a community meeting was organized to narrow down the research topics and list potential research questions. In an online survey, citizens were asked to vote for the research question they would like to investigate with the experts. A workshop was held to choose a study design in which citizens would like to partake to answer their preferred research question.ResultsAccording to 488 respondents from the first survey, cognitive and mental health were the main priorities of investigation. Based on the second survey, with 27% of the votes from 556 citizens, the most popular research question was, “How does air pollution together with noise and green/blue spaces affect mental health?”. The study design selected was an observational study in which citizens provide daily repeated measures of different cognitive and mental health outcomes and relate them to the air pollution concentrations.ConclusionsBased on the co-creation activities and the results obtained, we conclude that applying citizen science in an environmental health project is valuable for researchers despite some challenges such as engaging citizens and maximizing representativity.

Adverse childhood experiences interact with inflammation and menopause transition stage to predict verbal memory in women

ObjectiveWomen with more adverse childhood experiences (ACEs) may face a triple threat of risk factors for cognitive concerns during the menopause transition: reduced estradiol, increased inflammation, and early life stress sequelae. Our objective was to determine the extent to which ACEs and peripheral basal inflammatory markers associate with verbal memory across the menopause transition. MethodsPenn Ovarian Aging cohort participants (n ​= ​167) were assessed for ACEs (low (0–1) or high (≥2)) and had remaining stored blood samples at study end assayed for interleukin (IL)-6, IL-1-beta (IL-1β), C-reactive protein (CRP), and tumor necrosis factor alpha (TNF-α). Annual assessment included a verbal memory test (the Buschke Selective Reminding Test) and menopause stage determination. To estimate the effects of menopause stage, ACEs, and cytokines on verbal memory, repeated cognitive outcome measures were modeled in generalized estimating equations. Covariates included body mass index, smoking, race, education, age at baseline, and baseline verbal memory performance. Cytokine levels were log-transformed. ResultsAdvancing menopause stage was associated with worse performance on immediate verbal recall and delayed verbal recall (ps ​< ​0.001). During perimenopause, higher ACE exposure was associated with worse immediate verbal recall at higher levels of TNF-α (slope difference p ​= ​0.041). ConclusionsInflammation may mechanistically link ACEs and verbal memory for high ACE women during perimenopause. Reducing inflammation for these individuals may have positive impact on verbal memory across the menopause transition.

Cognitive outcome measures for tracking Alzheimer's disease in Down syndrome.

Down syndrome (DS) is now viewed as a genetic type of Alzheimer's disease (AD), given the near-universal presence of AD pathology in middle adulthood and the elevated risk for developing clinical AD in DS. As the field of DS prepares for AD clinical intervention trials, there is a strong need to identify cognitive measures that are specific and sensitive to the transition from being cognitively stable to the prodromal (e.g., Mild Cognitive Impairment-Down syndrome) and clinical AD (e.g., Dementia) stages of the disease in DS. It is also important to determine cognitive measures that map onto biomarkers of early AD pathology during the transition from the preclinical to the prodromal stage of the disease, as this transition period is likely to be targeted and tracked in AD clinical trials. The present chapter discusses the current state of research on cognitive measures that could be used to screen/select study participants and as potential outcome measures in future AD clinical trials with adults with DS. In this chapter, we also identify key challenges that need to be overcome and questions that need to be addressed by the DS field as it prepares for AD clinical trials in the coming years.

Postural neurologic deficits after decompressive craniectomy: A case series of sinking skin flap syndrome in traumatic brain injury.

Hemicraniectomy to manage raised intracranial pressure following traumatic brain injury (TBI) has improved survival but may increase the incidence of Sinking Skin Flap Syndrome (SSFS). SSFS is a clinical syndrome in which patients with craniectomy develop objective neurologic abnormalities due to the pressure of the atmosphere on the unprotected brain, often presenting with postural headaches and neurologic deficits that localize to the craniectomy site. Previously thought to be a rare complication of craniectomy after TBI, evidence suggests SSFS is under-recognized. To describe the clinical and radiographic features leading to diagnosis and the impact of temporizing and definitive management of SSFS on outcomes in inpatients with moderate/severe TBI. Two patients' symptoms, qualitative behaviour observation, physical and cognitive outcome measures, and neuroimaging pre- and post-temporizing measures and cranioplasty are presented. Both patients demonstrated partial improvements with temporizing measures and substantial improvements in functional, cognitive, physical, and rehabilitation outcomes from the cranioplasty and resolution of SSFS. Rehabilitation care providers are critical to the timely diagnosis and management of SSFS, including the use of temporizing measures and advocacy for definitive treatment with cranioplasty. These cases highlight the diverse clinical presentations and importance of SSFS diagnosis to improve patient outcomes.

Development of treatments for Down syndrome

Down syndrome is caused by an extra copy (or, rarely, an extra segment) of chromosome 21. The phenotype of Down syndrome is variable, but common to all individuals with the syndrome is some degree of intellectual disability. 1 Antonarakis SE Skotko BG Rafii MS et al. Down syndrome. Nat Rev Dis Primers. 2020; 6: 9 Crossref PubMed Scopus (92) Google Scholar Alzheimer's disease pathology is seen both at autopsy and by amyloid PET in all adults with Down syndrome by the age of 40 years, putting this population at especially high risk of developing early-onset Alzheimer's disease. However, there are no pharmacological treatments for either intellectual disability or Alzheimer's disease in people with Down syndrome. Safety, efficacy, and tolerability of memantine for cognitive and adaptive outcome measures in adolescents and young adults with Down syndrome: a randomised, double-blind, placebo-controlled phase 2 trialMemantine was well tolerated, but cognition-enhancing effects were not recorded with a 20 mg/day dose in adolescents and young adults with Down syndrome. Exploratory analyses point to a need for future work. Full-Text PDF

Safety, efficacy, and tolerability of memantine for cognitive and adaptive outcome measures in adolescents and young adults with Down syndrome: a randomised, double-blind, placebo-controlled phase 2 trial

Down syndrome is a chromosomal disorder with considerable neurodevelopmental impact and neurodegenerative morbidity. In a pilot trial in young adults with Down syndrome, memantine (a drug approved for Alzheimer's disease) showed a significant effect on a secondary measure of episodic memory. We aimed to test whether memantine would improve episodic memory in adolescents and young adults with Down syndrome. We did a randomised, double-blind, placebo-controlled phase 2 trial with a parallel design, stratified by age and sex. Participants (aged 15-32 years) with either trisomy 21 or complete unbalanced translocation of chromosome 21 and in general good health were recruited from the community at one site in Brazil and another in the USA. Participants were randomly assigned (1:1) to receive either memantine (20 mg/day orally) or placebo for 16 weeks. Computer-generated randomisation tables for both sites (allocating a placebo or drug label to each member of a unique pair of participants) were centrally produced by an independent statistician and were shared only with investigational pharmacists at participating sites until unblinding of the study. Participants and investigators were masked to treatment assignments. Neuropsychological assessments were done at baseline (T1) and week 16 (T2). The primary outcome measure was change from baseline to week 16 in the California Verbal Learning Test-second edition short-form (CVLT-II-sf) total free recall score, assessed in the per-protocol population (ie, participants who completed 16 weeks of treatment and had neuropsychological assessments at T1 and T2). Linear mixed effect models were fit to data from the per-protocol population. Safety and tolerability were monitored and analysed in all participants who started treatment. Steady-state concentrations in plasma of memantine were measured at the end of the trial. This study is registered at ClinicalTrials.gov, number NCT02304302. From May 13, 2015, to July 22, 2020, 185 participants with Down syndrome were assessed for eligibility and 160 (86%) were randomly assigned either memantine (n=81) or placebo (n=79). All participants received their allocated treatment. Linear mixed effect models were fit to data from 149 (81%) participants, 73 in the memantine group and 76 in the placebo group, after 11 people (eight in the memantine group and three in the placebo group) discontinued due to COVID-19 restrictions, illness of their caregiver, adverse events, or low compliance. The primary outcome measure did not differ between groups (CVLT-II-sf total free recall score, change from baseline 0·34 points [95% CI -0·98 to 1·67], p=0·61). Memantine was well tolerated, with infrequent mild-to-moderate adverse events, the most common being viral upper respiratory infection (nine [11%] participants in the memantine group and 12 [15%] in the placebo group) and transient dizziness (eight [10%] in the memantine group and six [8%] in the placebo group). No serious adverse events were observed. Amounts of memantine in plasma were substantially lower than those considered therapeutic for Alzheimer's disease. Memantine was well tolerated, but cognition-enhancing effects were not recorded with a 20 mg/day dose in adolescents and young adults with Down syndrome. Exploratory analyses point to a need for future work. Alana Foundation. For the Portuguese translation of the abstract see Supplementary Materials section.

Modifications in response to the COVID‐19 pandemic in a multimodal intervention trial to prevent cognitive impairment in older women with cardiovascular disease

BackgroundCognitive impairment disproportionately affects women compared to men, and cardiovascular disease (CVD) increases risk. Physical activity and cognitive training may have synergistic effects on cognition when delivered together. However, no multimodal intervention has targeted older women (≥65) with CVD or has utilized a scalable lifestyle approach. Our study seeks to evaluate the efficacy of MindMoves, a 24‐week multimodal intervention, on cognition and serum biomarkers in 254 older women with CVD. However, effects of the COVID‐19 pandemic complicated implementation of our original in‐person trial protocol. The purpose of this paper is to describe protocol modifications made by our interdisciplinary team in response to COVID‐19,MethodWe employ a 2x2 factorial randomized controlled trial design to determine independent and combined efficacies of Mind (cognitive training with BrainHQ) and Move (lifestyle physical activity with goal self‐monitoring and nurse‐led group meetings) interventions. Outcome measures of cognition and serum biomarkers (brain‐derived neurotrophic factor, vascular endothelial growth factor, insulin‐like growth factor 1) are collected at baseline, 24, 48, and 72 weeks. Nurse scientists oversee interventions, cardiologists refer women ≥65 years with CVD and no cognitive impairment from clinics, and a cognitive neurologist and neuropsychologist oversee outcome measures. Pandemic‐related protocol changes were implemented to maximize study integrity and participant/staff safety. Targeted mailings were added to in‐person recruitment strategies. Screening activities shifted to phone. In‐person data collection was modified for phone/virtual settings, including accelerometer mailing (device measure of physical activity), neurocognitive tests validated for phone use, and home‐based participant‐administered dried blood spot collection for serum biomarkers. Women are now provided and trained to use iPad tablets to complete intervention activities virtually (e.g., Move group meetings).ResultThe anticipated number of participants (19) in the first cohort was recruited without disruption, in the original timeline. Participants completed all phone‐based questionnaires and mailed devices were returned. Randomization occurred as planned. Intervention activities are ongoing, including phone‐based orientations and ≥90% attendance at virtual meetings.ConclusionThe modified trial protocol is being successfully implemented during the COVID‐19 pandemic. Results will demonstrate efficacy of pivoting from in‐person to virtual delivery of a lifestyle‐focused multimodal intervention in at‐risk older women with CVD.

Metabolic and cerebrovascular effects of gemfibrozil treatment: A randomized, placebo‐controlled, double‐blind, phase II clinical trial for dementia prevention

AbstractBackground“Fibrates” (PPAR‐alpha agonists) are lipid lowering agents that are widely known to improve metabolic parameters and potentially reduce cerebrovascular (CVD) disease burden. We conducted a parallel‐design, double‐blind, placebo‐controlled clinical trial of gemfibrozil targeting predementia AD (NCT02045056). An administrative supplement funded by the NIH/NIA allowed us to evaluate metabolic and CVD outcomes that may contribute to mixed AD‐CVD cognitive decline.MethodPatients with prodromal AD (CDR 0‐0.5) were randomized to receive gemfibrozil (600 mg twice daily) or placebo for 48 weeks. Metabolic and CVD endpoints included: 1) metabolic parameters including plasma glucose, HgbA1c, cholesterol, triglyceride levels, and inflammatory plasma biomarker profiles and 2) MRI imaging biomarkers including white matter hyperintensity (WMH) volumes, DTI, and ASL measures.ResultPrimary outcomes of the study reported previously include an excellent safety profile, CNS penetration, as well as trends for reducing Ab42 levels (0=0.063), hippocampal atrophy (p=0.15), and decline on the CANS‐MCI cognitive battery (MMTM p&lt;0.01). Metabolic and cerebrovascular effects of gemfibrozil treatment included significant improvements in plasma glucose (p&lt;0.001), lipid levels (p&lt;0.001), and trends in CVD imaging biomarkers including reductions in WMH volumes (p=0.33), accompanied by ASL perfusion increases in the dorsolateral prefrontal cortex (p=0.13), hippocampus (p=0.10) and posterior cingulate cortex (p=0.16). Attenuation of reductions in the anti‐inflammatory cytokine IL‐13 (p&lt;0.05) and increases in proinflammatory TNFa (p=0.08) were evident in the treatment group.ConclusionThe overlap in disease mechanisms and possible therapeutics for prevention of dementia caused by AD and or CVD is remarkable. These pathologies frequently coexist in the aging population and appear to act additively as well as synergistically, It is quite possible that the beneficial effects seen on cognitive outcome measures in this study might be more related to metabolic and CVD influences than on the direct effects influencing AD pathways that were the target of this clinical intervention. Strong consideration of incorporating metabolic and CVD outcomes in AD trials may help us disentangle the conundrum of risks and treatments for both CVD and AD that are the leading causes of dementia worldwide today.

Cortical structure and episodic memory profiles in APOE ε4: Resilience and vulnerability for cognitive impairment

AbstractBackgroundThe apolipoprotein E (APOE)‐ε4 allele represents the greatest genetic risk factor for late‐onset Alzheimer’s disease (AD). Identifying a resilience profile that might mitigate medial temporal lobe atrophy in enriched genetic risk may explain differences between individuals’ susceptibility to AD pathology.Method742 older adults from OASIS‐3 were stratified by APOE genotype status (423 ε3ε3 carriers; 271 ε3ε4 carriers and 48 ε4ε4 carriers) and classified as cognitively normal (74%) or with mild cognitive dysfunction (26%) using the clinical dementia rating scale (CDR) score. Neuropsychological screening measured general cognitive function, depression and psychiatric symptoms. Episodic memory, processing speed and naming ability were included as cognitive outcome measures. Cortical structure was measured using FreeSurfer. General linear models determined the main effects of APOE and cognitive status on relative regional volumes (regional volume divided by total intracranial volume) and cognition. APOE x cognitive status interactions were followed up with linear models to assess the effects of APOE in the cognitively normal and impaired groups separately.ResultAs expected main effects of APOE and cognitive status were observed on hippocampal, amygdala and entorhinal volumes. Greater effects of APOE were found on all regions in individuals with cognitive dysfunction, except on the entorhinal cortex. Significant interactions between APOE and cognitive status revealed that the left precuneus and superior frontal volumes were preserved in cognitively normal homozygote and heterozygote ε4 carriers with entorhinal atrophy, but were reduced in cognitively impaired ε4 carriers, controlling for age and sex. We found a similar interactive effect of APOE and cognitive status on episodic memory, with superior memory in cognitively normal e4ε4 carriers, and memory impairment in cognitively impaired e4ε4carriers, compared to their respective cognitive normal and impaired ε3ε3 counterparts.ConclusionCortical and subcortical atrophic signatures were identified for cognitively normal and impaired ε4 carriers. Structural integrity of the precuneus and superior frontal cortices may protect against cognitive dysfunction, even if medial temporal atrophy is present. Thus, our results indicate that the structural integrity of frontal‐parietal lobes may provide resilience against cognitive impairment in the face of ε4‐related decline in medial temporal structures.