Cognitive Reserve Modifies the Relationship Between Neural Function, Neural Injury and Upper-Limb Recovery After Stroke.

OBJECTIVE: To investigate whether cognitive reserve modifies the relationship between functional connectivity, lesion volume, stroke severity and upper-limb motor impairment and recovery in stroke survivors. METHODS: Ten patients with first-ever ischemic middle cerebral artery stroke completed the Cognitive Reserve Index Questionnaire at baseline. Upper-limb motor impairment and functional connectivity were assessed using the Fugl-Meyer Assessment and electroencephalography respectively at baseline and 3-months post-stroke. A debiased weighted phase lag index was computed to estimate functional connectivity between electrodes. Partial least squares (PLS) regression identified a connectivity model that maximally predicted variance in the degree of upper-limb impairment. Regression models were generated to determine whether cognitive reserve modified the relationship between neural function (functional connectivity), neural injury (lesion volume), stroke severity (National Institutes of Health Stroke Scale) and upper-limb motor impairment at baseline and recovery at 3-months (Fugl-Meyer Assessment). RESULTS: The addition of cognitive reserve to a regression model with a dependent variable of upper-limb motor recovery and independent variables of functional connectivity between the ipsilesional motor cortex and parietal cortex, stroke severity and lesion volume improved model efficiency (∆BIC=-7.07) despite not reaching statistical significance (R2=0.90, p=0.07). Cognitive reserve did not appear to improve regression models examining motor impairment at baseline. CONCLUSIONS: Preliminary observations suggest cognitive reserve might modify the relationship between neural function, neural injury, stroke severity and upper-limb motor recovery. Further investigation of cognitive reserve in motor recovery post-stroke appears warranted.

BDNF Val66Met moderates episodic memory decline and tau biomarker increases in early sporadic Alzheimer's disease.

OBJECTIVE: Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been shown to moderate rates of cognitive decline in preclinical sporadic Alzheimer's disease (AD; i.e., Aß + older adults), and pre-symptomatic autosomal dominant Alzheimer's disease (ADAD). In ADAD, Met66 was also associated with greater increases in CSF levels of total-tau (t-tau) and phosphorylated tau (p-tau181). This study sought to determine the extent to which BDNF Val66Met is associated with changes in episodic memory and CSF t-tau and p-tau181 in Aß + older adults in early-stage sporadic AD. METHOD: Aß + Met66 carriers (n = 94) and Val66 homozygotes (n = 192) enrolled in the Alzheimer's Disease Neuroimaging Initiative who did not meet criteria for AD dementia, and with at least one follow-up neuropsychological and CSF assessment, were included. A series of linear mixed models were conducted to investigate changes in each outcome over an average of 2.8 years, covarying for CSF Aß42, APOE ε4 status, sex, age, baseline diagnosis, and years of education. RESULTS: Aß + Met66 carriers demonstrated significantly faster memory decline (d = 0.33) and significantly greater increases in CSF t-tau (d = 0.30) and p-tau181 (d = 0.29) compared to Val66 homozygotes, despite showing equivalent changes in CSF Aß42. CONCLUSIONS: These findings suggest that reduced neurotrophic support, which is associated with Met66 carriage, may increase vulnerability to Aß-related tau hyperphosphorylation, neuronal dysfunction, and cognitive decline even prior to the emergence of dementia. Additionally, these findings highlight the need for neuropsychological and clinicopathological models of AD to account for neurotrophic factors and the genes which moderate their expression.

Associations between multidomain modifiable dementia risk factors with AD biomarkers and cognition in middle-aged and older adults.

This study aimed to determine associations between modifiable dementia risk factors (MDRF), across domains mood symptomatology, lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology, with cognition, beta-amyloid (Aß) and tau, and brain volume. Middle-aged/older adults (n=82) enrolled in a sub-study of the Healthy Brain Project completed self-report questionnaires and a neuropsychological battery. Cerebrospinal fluid levels of Aß 1-42, total tau (t-tau), and phosphorylated tau (p-tau181) (Roche Elecsys), and MRI markers of hippocampal volume and total brain volume were obtained. Participants were classified as no/single domain risk (≤1 domains) or multidomain risk (≥2 domains). Compared to the no/single domain risk group, the multidomain risk group performed worse on the Preclinical Alzheimer's Cognitive Composite (d=0.63, p=.005), and Executive Function (d=0.50, p=.016), and had increased p-tau181 (d=0.47, p=.042) and t-tau (d=0.54, p=.021). In middle-aged/older adults, multidomain MDRFs were related to increases in tau and worse cognition, but not Aß or brain volume. Findings suggest that increases in AD biomarkers are apparent in midlife, particularly for individuals with greater burden, or variety of MDRFs.

Multidomain modifiable dementia risk factors are associated with poorer cognition in midlife.

OBJECTIVE: Studies of modifiable dementia risk factors (MDRFs) generally consider MDRFs individually, despite strong evidence that they co-occur in adult populations. In a large sample of middle-aged adults, this study aimed to determine the frequency and co-occurrence of MDRFs, spanning five domains (mood symptomatology, risky lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology). The relationship between number of domains in which MDRFs were reported with cognitive performance and subjective cognitive concerns was then determined. METHOD: Middle-aged adults (n = 1,610) enrolled in the Healthy Brain Project and completed self-report surveys about their health and lifestyle. Participants also completed the Cogstate Brief Battery and the Cognitive Function Instrument, a measure of subjective ratings of cognition. Participants were classified according to number of domains (mood symptomatology, risky lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology) in which they reported at least one MDRF (0-5). Age, sex, education, and ethnicity were adjusted for in analyses. RESULTS: Most individuals (66.5%) reported MDRFs in two or more domains. Compared with individuals displaying no MDRFs, individuals with MDRFs in 3-5 domains showed worse learning/working memory performance and greater subjective cognitive concerns, with the magnitude of these differences moderate-to-large (d = 0.30-0.93). Individuals displaying MDRFs in five domains also showed worse attention/psychomotor function (d = 0.58) compared to those displaying no MDRFs. CONCLUSIONS: These findings may suggest that multidomain MDRFs are highly frequent in middle-aged adults and are related to poorer cognition. This supports that modifiable dementia risk is multidimensional and raises the possibility that multidomain behavioral intervention trials in middle-aged adults may be useful to delay or prevent cognitive impairment or decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Validation of a digit symbol substitution test for use in supervised and unsupervised assessment in mild Alzheimer's disease.

INTRODUCTION: The Digit-Symbol-Substitution Test (DSST) is used widely in neuropsychological investigations of Alzheimer's Disease (AD). A computerized version of this paradigm, the DSST-Meds, utilizes medicine-date pairings and has been developed for administration in both supervised and unsupervised environments. This study determined the utility and validity of the DSST-Meds for measuring cognitive dysfunction in early AD. METHOD: Performance on the DSST-Meds was compared to performance on the WAIS Coding test, and a computerized digit symbol coding test (DSST-Symbols). The first study compared supervised performance on the three DSSTs versions in cognitively unimpaired (CU) adults (n = 104). The second compared supervised DSST performance between CU (n = 60) and mild-symptomatic AD (mild-AD, n = 79) groups. The third study compared performance on the DSST-Meds between unsupervised (n= 621) and supervised settings. RESULTS: In Study 1, DSST-Meds accuracy showed high correlations with the DSST-Symbols accuracy (r = 0.81) and WAIS-Coding accuracy (r = 0.68). In Study 2, when compared to CU adults, the mild-AD group showed lower accuracy on all three DSSTs (Cohen's d ranging between 1.39 and 2.56) and DSST-Meds accuracy was correlated moderately with Mini-Mental State Examination scores (r = 0.44, p < .001). Study 3 observed no difference in DSST-meds accuracy between supervised and unsupervised administrations. CONCLUSION: The DSST-Meds showed good construct and criterion validity when used in both supervised and unsupervised contexts and provided a strong foundation to investigate the utility of the DSST in groups with low familiarity to neuropsychological assessment.

Cardiovascular Risk Associated with Poorer Memory in Middle-Aged Adults from the Healthy Brain Project.

BACKGROUND: Midlife cardiovascular risk factors (CVRF) are associated with reduced cognition and an increased risk of dementia. OBJECTIVE: To further investigate this association using remote unsupervised online assessment of cognition and cardiovascular risk in middle-aged adults; and to explore the extent to which the association is altered by carriage of the APOE ɛ4 allele. METHODS: The Healthy Brain Project is an online cohort of middle-aged cognitively unimpaired adults (40-70 years) who have undergone cognitive assessment and provided self-reports of demographic and health history. Cardiovascular risk was determined by ascertaining history of hypertension, hypercholesterolemia, diabetes mellitus, overweight (body mass index≥25), and current cigarette smoking. Participants (n = 2,480) were then grouped based on the number of reported CVRF into no CVRF, 1, 2, and≥3 CVRF. Associations between the number of CVRF as a continuous variable, CVRF group, and each individual CVRF with composite measures of attention, memory and subjective cognitive function were investigated. RESULTS: Higher number of CVRF was associated with poorer attention (ß= -0.042, p = 0.039) and memory (ß= -0.080, p < 0.001), but not with subjective cognitive function. When considered individually, current smoking (ß= -0.400, p = 0.015), diabetes (ß= -0.251, p = 0.023), and hypercholesterolemia (ß= -0.109, p = 0.044) were independently associated with poorer memory performance. APOE ɛ4 carriers with≥1 CVRF performed worse on memory than ɛ4 carriers with no CVRFs (ß(SE) = 0.259(0.077), p = 0.004). This was not observed in ɛ4 non-carriers. CONCLUSION: In cognitively normal middle-aged adults, CVRF were associated with poorer cognition, particularly in the memory domain. These results support feasibility of online assessment of cardiovascular risk for cognitive impairment.

The relationship between cognitive engagement and better memory in midlife.

INTRODUCTION: Engagement in cognitively stimulating work and activities may slow cognitive decline and dementia. We examined the individual and combined associations of four cognitive engagement indices (educational attainment, occupational complexity, social engagement, and cognitively stimulating leisure activities) with objective and subjective cognition. METHODS: Middle-aged adults (n = 1864) enrolled in the Healthy Brain Project completed the Cogstate Brief Battery, the Cognitive Function Instrument, and self-report questionnaires of cognitive engagement. RESULTS: Educational attainment and leisure activity engagement were individually associated with memory performance. Participants were classified based on whether they rated highly in zero to four cognitive engagement indices. Compared to participants with no indices, participants with two or more indices performed moderately better on memory. DISCUSSION: Results suggest that greater variety of cognitive engagement across different areas of life is related to better memory in midlife. Possible explanation for this relationship may be increased opportunity for enhancing cognitive reserve, but further investigations are required.

Differential Effects of APOE and Modifiable Risk Factors on Hippocampal Volume Loss and Memory Decline in Aß- and Aß+ Older Adults.

BACKGROUND AND OBJECTIVES: This prospective study sought to determine the association of modifiable/nonmodifiable components included in the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score with hippocampal volume (HV) loss and episodic memory (EM) decline in cognitively normal (CN) older adults classified as brain ß-amyloid (Aß) negative (Aß-) or positive (Aß+). METHODS: Australian Imaging, Biomarkers and Lifestyle study participants (age 58-91 years) who completed ≥2 neuropsychological assessments and a brain Aß PET scan (n = 592) were included in this study. We computed the CAIDE risk score (age, sex, APOE ε4 status, education, hypertension, body mass index [BMI], hypercholesterolemia, physical inactivity) and a modifiable CAIDE risk score (CAIDE-MR; education, hypertension, BMI, hypercholesterolemia, physical inactivity) for each participant. Aß+ was classified using Centiloid >25. Linear mixed models assessed interactions between each CAIDE score, Aß group, and time on HV loss and EM decline. Age, sex, and APOE ε4 were included as separate predictors in CAIDE-MR models to assess differential associations. Exploratory analyses examined relationships between individual modifiable risk factors and outcomes in Aß- cognitively normal (CN) adults. RESULTS: We observed a significant Aß group × CAIDE × time interaction on HV loss (ß [SE] = -0.04 [0.01]; p < 0.000) but not EM decline (ß [SE] = -2.33 [9.96]; p = 0.98). Decomposition revealed a significant CAIDE × time interaction in Aß+ participants only. When modifiable/nonmodifiable CAIDE components were considered separately, we observed a significant Aß group × CAIDE-MR × time interaction on EM decline only (ß [SE] = 3.03 [1.18]; p = 0.01). A significant CAIDE-MR score × time interaction was observed in Aß- participants only. Significant interactions between APOE ε4 and age × time on HV loss and EM decline were observed in both groups. Exploratory analyses in Aß- CN participants revealed a significant interaction between BMI × time on EM decline (ß [SE] = -3.30 [1.43]; p = 0.02). DISCUSSION: These results are consistent with studies showing that increasing age and APOE ε4 are associated with increased rates of HV loss and EM decline. In Aß- CN adults, lower prevalence of modifiable cardiovascular risk factors was associated with less HV loss and EM decline over ∼10 years, suggesting interventions to reduce modifiable cardiovascular risk factors could be beneficial in this group.

Protocol for a Mixed-Methods Process Evaluation of BetterBrains: A Person-Centered Online Intervention to Delay Cognitive Decline in Adults at Risk of Dementia.

BACKGROUND: The BetterBrains Randomized Controlled Trial (RCT) will evaluate the effectiveness of an online, person-centered, risk factor management, coaching intervention in community-dwelling, healthy adults at risk of cognitive decline. Multi-component interventions are challenging to evaluate due to program complexity and personalization to individual needs and contexts. This paper describes a multi-level process evaluation conducted alongside the BetterBrains RCT. OBJECTIVE: To understand how and why the BetterBrains intervention was effective or ineffective at reducing cognitive decline in healthy adults whilst considering the context in which it was implemented. METHODS: 1,510 non cognitively-deteriorated community-dwelling adults aged 40-70 years old at risk of cognitive decline will be recruited and randomly assigned to the intervention or control group. All BetterBrains intervention participants, coaches, and the research team will be included in the evaluation. A mixed-methods design will be used, guided by The Framework for Implementation Fidelity and the program logic model. Data will be sourced from interviews, focus groups, surveys, BetterBrains coach notes, participant weekly check-in surveys, and audio recordings of intervention coaching sessions. Quantitative data will be analyzed via descriptive and inferential statistics and qualitative data will be analyzed using content and thematic analysis. RESULTS: The process evaluation will provide information about contextual and influencing factors related to the implementation of BetterBrains and the RCT outcomes. CONCLUSION: Understanding how BetterBrains was implemented and its associated impacts will inform the translation of the program into community and clinical settings, providing easy access to online, personalized dementia prevention services.

An Online, Person-Centered, Risk Factor Management Program to Prevent Cognitive Decline: Protocol for A Prospective Behavior-Modification Blinded Endpoint Randomized Controlled Trial.

BACKGROUND: Several modifiable risk factors for dementia have been identified, although the extent to which their modification leads to improved cognitive outcomes remains unclear. OBJECTIVE: The primary aim is to test the hypothesis that a behavior modification intervention program targeting personalized risk factors prevents cognitive decline in community-dwelling, middle-aged adults with a family history of dementia. METHODS: This is a prospective, risk factor management, blinded endpoint, randomized, controlled trial, where 1510 cognitively normal, community-dwelling adults aged 40-70 years old will be recruited. Participants will be screened for risk factors related to vascular health (including physical inactivity), mental health, sleep, and cognitive/social engagement. The intervention is an online person-centered risk factor management program: BetterBrains. Participants randomized to intervention will receive telehealth-based person-centered goal setting, motivational interviewing, and follow-up support, health care provider communication and community linkage for management of known modifiable risk factors of dementia. Psychoeducational health information will be provided to both control and intervention groups. RESULTS: The primary outcome is favorable cognitive performance at 24-months post-baseline, defined as the absence of decline on one or more of the following cognitive tests: (a) Cogstate Detection, (b) Cogstate One Card Learning, (c) Cogstate One Back, and (d) Cognitive Function Instrument total score. CONCLUSION: We will test the hypothesis that the BetterBrains intervention program can prevent cognitive decline. By leveraging existing community services and using a risk factor management pathway that tailors the intervention to each participant, we maximize likelihood for engagement, long-term adherence, and for preserving cognitive function in at-risk individuals.

Unstable world: Recent experience affects spatial perception.

An accurate perception of the space surrounding us is central for effective and safe everyday functioning. Understanding the factors influencing spatial perception is therefore vital. Here, we first confirm previous reports that our cultural reading habits shape the perception of space. Twenty-four left-to-right readers (tested in Australia) and 23 right-to-left readers (tested in Israel) over-attend to information presented on the left and right side of space, respectively. We then show that this cultural bias is highly malleable. By employing a simple mirror-reading task prior to the spatial judgments, we demonstrate that the supposed cultural bias can be easily overridden. These findings question hardwired, lateralisation models of spatial-attentional biases and highlight the need for a dynamic model that takes into account hemispheric lateralisation, cultural habits and situational context.

Cognitive Reserve as an Emerging Concept in Stroke Recovery.

Stroke is a leading cause of death and disability. It is a complex and largely heterogeneous condition. Prognosis for variations in impairment and recovery following stroke continues to be challenging and inaccurate, highlighting the need to examine the influence of other currently unknown variables to better predict and understand interindividual differences in stroke impairment and recovery. The concept of "cognitive reserve," a feature of brain function said to moderate the relationship between brain pathology and clinical outcomes, might provide a partial explanation. This review discusses the potential significance of cognitive reserve in the context of stroke, with reference to reduced burden of disability poststroke, health promotion, intervention and secondary prevention of cognitive impairment, ease and challenges of translation into clinical practice, prognosis and prediction of recovery, and clinical decisions and trial stratification. Discussions from the review aim to encourage stroke clinicians and researchers to better consider the role of premorbid, lifestyle-related variables, such as cognitive reserve, in facilitating successful neurological outcomes and recovery following stroke.

Does rTMS reduce depressive symptoms in young people who have not responded to antidepressants?

AIM: Depression is common in young people, and there is a need for safe, effective treatments. This study examined the efficacy of repetitive transcranial magnetic stimulation in a sample of young people aged 17 to 25 years. METHODS: This retrospective study included 15 people aged 17 to 25 years referred by their private psychiatrists affiliated with Ramsay Health Care, South Australia Mental Health Services. All patients met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for treatment-resistant Major Depressive Disorder. Eleven patients received right unilateral treatment and four patients received bilateral treatment. Patients were assessed at baseline and after treatment. RESULTS: There was a significant improvement on the Hamilton Rating Scale for Depression (t(14) = 4.71, P < 0.0001); Montgomery-Åsperg Depression Rating Scale (t(14) = 3.96, P < 0.01) and the Zung Self-Rating Depression Scale (t(14) = 4.13, P < 0.01). There was no difference in response by gender or age. The response rates in these young people did not differ significantly from those of adults aged 25 to 82 years. CONCLUSION: This open label, naturalistic study suggests that repetitive transcranial magnetic stimulation is an effective treatment in young adults who have treatment-resistant depression. Randomized sham-controlled studies are needed to further investigate the efficacy of this treatment in this age group.

Visual compensation in cervical dystonia.

Introduction: Visual-spatial processing can be affected in people with cervical dystonia (CD). These impairments have almost exclusively been observed in laboratory studies, but the impact of visuo-spatial impairments on daily activities is unclear. Here, we investigated how people living with CD visually explore the environment. Method: 21 participants (10 patients and 11 controls) walked a designated course searching for targets while their eye movements were tracked by the means of eye tracking glasses. In addition, all participants performed an extensive battery of spatial neglect tests. Results: People with CD visually compensated for their lateral head position. That is, they made more eye movements towards the side opposite their lateral head position. No evidence for or against spatial asymmetries were detected in a range of behavioral measures (target detection, standard neglect battery tests) on a group level. Yet, single patients showed a neglect-like pattern. One patient with a right torticollis failed to detect most left-sided targets when walking. Conclusion: In general, participants seem to adequately compensate for the deviated head posture when judging spatial stimuli. However, the insufficient spatial exploration in one patient with a valid driving license should raise awareness in clinicians to potential visuo-spatial problems in people living with CD. An interesting question arising from our findings is whether people with CD and marked visuo-spatial deficits would benefit from scanning training, as is employed in stroke rehabilitation.