Poor self-rated health is associated with faster cognitive decline and greater small vessel disease in older adults with type 2 diabetes.

OBJECTIVE: Self-rated health (SRH) is a predictor for poor health outcomes and cognition. Older adults with type 2 diabetes mellitus (T2D) have multi-morbidity and greater cognitive impairment. In the present study we investigated the association of SRH with cognitive decline and brain pathology in older adults with T2D. METHODS: Participants (n = 1122) were from the Israel Diabetes and Cognitive Decline study, and SRH was categorised as low (n = 202), moderate (n = 400) or high (n = 520). Cognition was measured by four cognitive domains: episodic memory, executive functions, language, and attention/working memory. Global cognition was the average of the cognitive domains. Statistical models adjusted for sociodemographic, cardiovascular, and clinical variables. In a randomly selected subsample (n = 230) that had magnetic resonance imaging, we examined relationships between baseline SRH and brain characteristics (white matter hyperintensities [WMHs], hippocampal, and total grey matter [GM] volumes). RESULTS: Low SRH was associated with a decline in executive functions, which accelerated over time when compared to high SRH (est = -0.0036; p = <0.001). Compared to high SRH, low SRH was associated with a faster decline in global cognition (est = -0.0024; p = 0.009). Low SRH at baseline was associated with higher volumes of WMHs (est = 9.8420; p < 0.0008). SRH was not associated with other cognitive domains, or with hippocampal and total GM. CONCLUSIONS: Low SRH is associated with cognitive decline in T2D older adults and may serve as a risk assessment. WMHs may represent an underlying mechanism.

Associations of cortical SPP1 and ITGAX with cognition and common neuropathologies in older adults.

INTRODUCTION: The secreted phosphoprotein 1 (SPP1) gene expressed by CD11c+ cells is known to be associated with microglia activation and neuroinflammatory diseases. As most studies rely on mouse models, we investigated these genes and proteins in the cortical brain tissue of older adults and their role in Alzheimer's disease (AD) and related disorders. METHODS: We leveraged protein measurements, single-nuclei, and RNASeq data from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) of over 1200 samples for association analysis. RESULTS: Expression of SPP1 and its encoded protein osteopontin were associated with faster cognitive decline and greater odds of common neuropathologies. At single-cell resolution,  integrin subunit alpha X (ITGAX) was highly expressed in microglia, where specific subpopulations were associated with AD and cerebral amyloid angiopathy. DISCUSSION: The study provides evidence of SPP1 and ITGAX association with cognitive decline and common neuropathologies identifying a microglial subset associated with disease.

A feasibility study of the combination of intranasal insulin with oral semaglutide for cognition in older adults with metabolic syndrome at high dementia risk- Study rationale and design.

INTRODUCTION: We present the rationale and design of a double-blind placebo-controlled feasibility trial combining intranasal insulin (INI) with semaglutide, a GLP-1 receptor agonist, to improve cognition in older adults with metabolic syndrome (MetS) and mild cognitive impairment (MCI). Since both INI and dulaglutide have beneficial effects on the cerebrovascular disease (CVD), we anticipate that improved CVD will underlie the hypothesized cognitive benefits. METHODS: This 12-months trial will include 80 older adults aged > 60 with MetS and MCI, randomized to 4 groups: INI/oral semaglutide, intranasal placebo/oral semaglutide, INI/oral placebo, and intranasal placebo/oral placebo. Feasibility of combining INI with semaglutide will be tested by examining the ease of use of INI (20IU, twice/day) with semaglutide (14 once daily), adherence, and safety profile are the efficacy of combination therapy on global cognition and neurobiological markers: cerebral blood flow, cerebral glucose utilization, white matter hyperintensities, Alzheimer's related blood biomarkers and expression of insulin signaling proteins measured in brain-derived exosomes. Efficacy will be assessed for the intent-to-treat sample. DISCUSSION: This feasibility study is anticipated to provide the basis for a multi-center large-scale randomized clinical trial (RCT) of the cognitive benefits of the combination of INI with semaglutide in individuals enriched for CVD and at high dementia risk.

Neuroticism is associated with increase in depression symptoms over time in older adults with type 2 diabetes.

OBJECTIVES: The likelihood of depression symptoms in those with type 2 diabetes (T2D) is high. Psychological risk factors enhancing comorbidity of depression symptoms in T2D are yet to be determined. The present study examines the cross-sectional and longitudinal relationship between personality traits and distinct depression dimensions in older adults with T2D. METHODS: Participants were older adults (age ≥65yeas) with T2D from the Israel Diabetes and Cognitive Decline (IDCD) study (N = 356), with complete data on depression [Geriatric Depression Scale (GDS) - 15 item version] and its dimensions- namely, dysphoric mood, apathy, hopelessness, memory complains and anxiety, and on personality [Big Five Inventory (BFI)]. Logistic and mixed linear regression models examined cross-sectional and longitudinal associations while adjusting for socio-demographics, cognition, cardiovascular and diabetes-related factors. RESULTS: Cross-sectionally, high neuroticism was associated with high scores in total GDS and in all depression-dimensions, except memory complaints. Higher extroversion was associated with lower total GDS and with lower scores on all depression dimensions, except anxiety. High levels of neuroticism were associated with increase in total number of depression symptoms over time. CONCLUSIONS: In older adults with T2D, neuroticism and extroversion are associated with most depression dimensions suggesting that these traits relate to a global depression symptomatology rather than to any specific dimension or phenomenology. High neuroticism was associated with increase in depression symptoms over time, highlighting its role in the development of depression symptoms in older adults with T2D.

Amyloid deposition and small vessel disease are associated with cognitive function in older adults with type 2 diabetes.

Diabetes is associated with cognitive decline, but the underlying mechanisms are complex and their relationship with Alzheimer's Disease biomarkers is not fully understood. We assessed the association of small vessel disease (SVD) and amyloid burden with cognitive functioning in 47 non-demented older adults with type-2 diabetes from the Israel Diabetes and Cognitive Decline Study (mean age 78Y, 64% females). FLAIR-MRI, Vizamyl amyloid-PET, and T1W-MRI quantified white matter hyperintensities as a measure of SVD, amyloid burden, and gray matter (GM) volume, respectively. Mean hemoglobin A1c levels and duration of type-2 diabetes were used as measures of diabetic control. Cholesterol level and blood pressure were used as measures of cardiovascular risk. A broad neuropsychological battery assessed cognition. Linear regression models revealed that both higher SVD and amyloid burden were associated with lower cognitive functioning. Additional adjustments for type-2 diabetes-related characteristics, GM volume, and cardiovascular risk did not alter the results. The association of amyloid with cognition remained unchanged after further adjustment for SVD. Our findings suggest that SVD and amyloid pathology may independently contribute to lower cognitive functioning in non-demented older adults with type-2 diabetes, supporting a multimodal approach for diagnosing, preventing, and treating cognitive decline in this population.

The association between regional adiposity, cognitive function, and dementia-related brain changes: a systematic review.

Background: Adiposity has been previously associated with cognitive impairment and Alzheimer's disease and related disorders (ADRD). Body mass index (BMI) is the most common measure of global adiposity, but inconsistent results were found since it is a global measurement. BMI does not represent regional fat distribution which differs between sexes, race, and age. Regional fat distribution may contribute differently to cognitive decline and Alzheimer's disease (AD)-related brain changes. Fat-specific targeted therapies could lead to personalized improvement of cognition. The goal of this systematic review is to explore whether regional fat depots, rather than central obesity, should be used to understand the mechanism underlying the association between adiposity and brain. Methods: This systematic review included 33 studies in the English language, conducted in humans aged 18 years and over with assessment of regional adiposity, cognitive function, dementia, and brain measures. We included only studies that have assessed regional adiposity using imaging technics and excluded studies that were review articles, abstract only or letters to editor. Studies on children and adolescents, animal studies, and studies of patients with gastrointestinal diseases were excluded. PubMed, PsychInfo and web of science were used as electronic databases for literature search until November 2022. Results: Based on the currently available literature, the findings suggest that different regional fat depots are likely associated with increased risk of cognitive impairment, brain changes and dementia, especially AD. However, different regional fat depots can have different cognitive outcomes and affect the brain differently. Visceral adipose tissue (VAT) was the most studied regional fat, along with liver fat through non-alcoholic fatty liver disease (NAFLD). Pancreatic fat was the least studied regional fat. Conclusion: Regional adiposity, which is modifiable, may explain discrepancies in associations of global adiposity, brain, and cognition. Specific regional fat depots lead to abnormal secretion of adipose factors which in turn may penetrate the blood brain barrier leading to brain damage and to cognitive decline.

A feasibility study of the combination of intranasal insulin with dulaglutide for cognition in older adults with metabolic syndrome at high dementia risk - Study rationale and design.

INTRODUCTION: We present the rationale and design of a double-blind placebo-controlled feasibility trial combining intranasal insulin (INI) with dulaglutide, a GLP-1 receptor agonist, to improve cognition in older adults with metabolic syndrome (MetS) and mild cognitive impairment (MCI). Since both INI and dulaglutide have beneficial effects on the cerebrovascular disease (CVD), we anticipate that improved CVD will underlie the hypothesized cognitive benefits. METHODS: This 12-months trial will include 80 older adults aged > 60 with MetS and MCI, randomized to 4 groups: INI/dulaglutide injection, intranasal placebo/dulaglutide injection, INI/placebo injection, and intranasal placebo/placebo injection. Feasibility of combining INI with dulaglutide will be tested by examining the ease of use of INI (20IU, twice/day) with dulaglutide (1.5 mg/week), adherence, and safety profile are the efficacy of combination therapy on global cognition and neurobiological markers: cerebral blood flow, cerebral glucose utilization, white matter hyperintensities, Alzheimer's related blood biomarkers and expression of insulin signaling proteins measured in brain-derived exosomes. Efficacy will be assessed for the intent-to-treat sample. DISCUSSION: This feasibility study is anticipated to provide the basis for a multi-center large-scale randomized clinical trial of the cognitive benefits of the combination of INI with dulaglutide in individuals enriched for CVD and at high dementia risk.

Blood Biomarkers in Neurodegenerative Diseases: Implications for the Clinical Neurologist.

Blood-based biomarkers offer a major advance in the clinical evaluation of neurodegenerative diseases. Currently, research studies have reported robust assays of blood markers for the detection of amyloid and tau pathologies specific to Alzheimer disease (amyloid-ß peptides, and p-tau) and nonspecific blood markers of neuronal (neurofilament light, ß-synuclein, and ubiquitin-C-terminal-hydrolase-L1) and glial degeneration (glial fibrillary acidic protein) that can measure key pathophysiologic processes in several neurodegenerative diseases. In the near future, these markers may be used for screening, diagnosis, or disease and treatment response monitoring. Blood-based biomarkers for neurodegenerative diseases have been rapidly implemented in research, and they have the potential to enter clinical use soon in different clinical settings. In this review, we will describe the main developments and their potential implications for the general neurologist.

Consumption of Ultra-Processed Food and Cognitive Decline among Older Adults With Type-2 Diabetes.

BACKGROUND: Ultra-processed food (UPF) consumption is related to increased morbidity and mortality. However, knowledge on its association with cognitive function is lacking. In this longitudinal study, we examined the associations between UPF intake and cognitive decline in older adults with type-2 diabetes (T2D). METHODS: The sample included initially nondemented T2D older adults (≥65 years), from the Israel Diabetes and Cognitive Decline study, who had complete information on nutrition at baseline and at least 3 cognitive assessments (mean follow-up 5.3 ± 1.5 years). Nutritional intake was evaluated by a validated Food-Frequency Questionnaire, and foods were categorized as UPF based on NOVA classification. Percent of calories from UPF were calculated from total caloric consumption in total and specific food groups. Mixed effect models were used to examine the link between UPF intake (top vs bottom quartiles) and change in cognitive function overall and in specific domains, adjusting for potential confounders. RESULTS: Of the total sample (N = 568; mean age 71.3 ± 4.5 years, 60% men), 141 consumed >31% kcal from UPF (top quartile). Greater intake of ultra-processed meat was associated with a faster decline in executive functions and global cognition (ß = -0.041 ± 0.013; p = .002 and ß = -0.026 ± 0.010; p = .011, respectively). Additionally, consumption of ultra-processed oils/spreads was associated with faster decline in executive functions and global cognition (ß = -0.037 ± 0.014; p = .006 and ß = -0.028 ± 0.010; p = .009, respectively). Total UPF consumption and UPF-derived from dairy products and bread/pastries/starch were not associated with cognitive change. CONCLUSION: This study suggests that a high intake of ultra-processed meat and oils/spreads may be associated with accelerated cognitive decline in older individuals with T2D.

Development and validation of virtual reality-based Rey Auditory Verbal Learning Test.

Objective: Translations and adaptations of traditional neuropsychological tests to virtual reality (VR) technology bear the potential to increase their ecological validity since the technology enables simulating everyday life conditions in a controlled manner. The current paper describes our translation of a commonly used neuropsychological test to VR, the Rey Auditory Verbal Learning Test (RAVLT). For this aim, we developed a VR adaptation of the RAVLT (VR-RAVLT) Which is based on a conversation with a secretary in a virtual office using a fully immersive VR system. To validate the VR-RAVLT, we tested its construct validity, its age-related discriminant validity and its test-retest validity in reference to the original gold standard RAVLT (GS-RAVLT). Method: Seventy-eight participants from different age groups performed the GS-RAVLT and the VR-RAVLT tests in a counterbalanced order in addition to other neuropsychological tests. Construct validity was validated using Pearson's correlations coefficients and serial position effects; discriminant validity was validated using receiver operating characteristic area under the curve values and test-retest reliability was validated using intraclass correlation coefficients. Results: Comparing both RAVLTs' format results indicates that the VR-RAVLT has comparable construct, discriminant and test-retest validities. Conclusion: the novel VR-RAVLT and the GS-RAVLT share similar psychometric properties suggesting that the two tests measure the same cognitive construct. This is an indication of the feasibility of adapting the RAVLT to the VR environment. Future developments will employ this approach for clinical diagnosis and treatment.

Choices of (in)action in obesity: Implications for research on treatment and prevention.

The obesity epidemic has crossed social-demographic barriers and is a matter of significant concern. Why do individuals fail to restrain from eating high-calorie foods and fail to follow treatment routines that reduce the risk of health complications? These questions have been addressed through behavioral and brain imaging studies on prefrontal cortex inhibitory mechanisms. Failure to inhibit undesirable behaviors has become a hallmark of obesity. In many life situations, obesity risk is increased by inaction (e.g., not taking blood pressure medication, not following a healthy diet). Risk by inaction has been defined as passive risk-taking, and it is correlated with traits such as procrastination, future time perspective, and cognitive avoidance. To the present, passive tendencies, specifically in the context of risk-taking behaviors, have not been addressed in the obesity literature. We introduce a framework in which active and passive risk-taking behaviors are integrated within the scope of bidirectional models of obesity that describe the brain as both the cause and the consequence of obesity vulnerability. The present perspective aims to foster new research on treatment and prevention, and also on the neurobiology of passive behaviors in obesity and other metabolic conditions.

Optimized Glycopeptide Enrichment Method-It Is All About the Sauce.

Protein glycosylation is a family of posttranslational modifications that play a crucial role in many biological pathways and diseases. The enrichment and analysis of such a diverse family of modifications are very challenging because of the number of possible glycan-peptide combinations. Among the methods used for the enrichment of glycopeptides, boronic acid never lived up to its promise. While most studies focused on improving the affinity of the boronic acids to the sugars, we discovered that the buffer choice is just as important for successful enrichment if not more so. We show that an amine-less buffer allows for the best glycoproteomic coverage, in human plasma and brain specimens, improving total quantified glycopeptides by over 10-fold, and reaching 1598 N-linked glycopeptides in the brain and 737 in nondepleted plasma. We speculate that amines compete with the glycans for boronic acid binding, and therefore the elimination of them improved the method significantly.

Thicker macula in asymptomatic APOE Ɛ4 middle-aged adults at high AD risk.

INTRODUCTION: We compared retinal layers' thickness between apolipoprotein E (APOE) Ɛ4 carriers and non-carriers in a cohort of cognitively normal middle-aged adults enriched for Alzheimer's disease (AD) risk. METHODS: Participants (N = 245) underwent spectral domain optical coherence tomography. Multivariate analyses of covariance adjusting for age, sex, education, and best corrected vision acuity was used to compare retinal thickness between APOE groups. RESULTS: Participants' mean age was 59.60 (standard deviation = 6.42) with 66.4% women and 32.2% APOE Ɛ4 carriers. Greater macular full thickness was observed in APOE Ɛ4 carriers compared to non-carriers (P = .017), reaching statistical significance for the inner and outer nasal (P = .009 and P = .005, respectively), inner superior (P = .041), and inner and outer inferior (P = .013 and P = .033, respectively) sectors. The differences between APOE groups were mainly driven by the ganglion cell layer (P < .05) and the inner plexiform layer (P < .05). DISCUSSION: A thicker macula is observed already in midlife asymptomatic APOE Ɛ4 carriers at high AD risk.

Stability in BMI over time is associated with a better cognitive trajectory in older adults.

OBJECTIVE: Evidence on simultaneous changes in body mass index (BMI) and cognitive decline, which better reflect the natural course of both health phenomena, is limited. METHODS: We capitalized on longitudinal data from 15,977 initially non-demented elderly from the Alzheimer's Disease Centers followed for 5 years on average. Changes in BMI were defined as (1) last minus first BMI, (2) mean of all follow-up BMIs minus first BMI, and (3) standard deviation of BMI change from baseline and all follow-up visits (representing variability). RESULTS: Participants with significant changes in BMI (increase or decrease of ≥5%), or who had greater variability in BMI, had faster cognitive decline. This pattern was consistent irrespective of normal (BMI < 25; N = 5747), overweight (25 ≤ BMI < 30; N = 6302), or obese (BMI ≥ 30; N = 3928) BMI at baseline. CONCLUSIONS: Stability in BMI predicts better cognitive trajectories suggesting clinical value in tracking BMI change, which is simple to measure, and may point to individuals whose cognition is declining.

Dynamic regulation of N6,2'-O-dimethyladenosine (m6Am) in obesity.

The prevalent m6Am mRNA cap modification was recently identified as a valid target for removal by the human obesity gene FTO along with the previously established m6A mRNA modification. However, the deposition and dynamics of m6Am in regulating obesity are unknown. Here, we investigate the liver m6A/m methylomes in mice fed on a high fat Western-diet and in ob/ob mice. We find that FTO levels are elevated in fat mice, and that genes which lost m6Am marking under obesity are overly downregulated, including the two fatty-acid-binding proteins FABP2, and FABP5. Furthermore, the cellular perturbation of FTO correspondingly affect protein levels of its targets. Notably, generally m6Am- but not m6A-methylated genes, are found to be highly enriched in metabolic processes. Finally, we deplete all m6A background via Mettl3 knockout, and unequivocally uncover the association of m6Am methylation with increased mRNA stability, translation efficiency, and higher protein expression. Together, these results strongly implicate a dynamic role for m6Am in obesity-related translation regulation.

Diverse Motor Performances Are Related to Incident Cognitive Impairment in Community-Dwelling Older Adults.

Objective: Late-life cognitive impairment is heterogeneous. This study examined to what extent varied motor performances are differentially associated with incident Alzheimer's dementia (AD) and incident mild cognitive impairment (MCI) in older adults. Design: Nested substudy. Setting: Communities across metropolitan Chicago. Participants: African American (N = 580) and European American (N = 580) adults without dementia, propensity-balanced by age (mean = 73.2; SD = 6.0), sex (78.4% women), education (mean = 15.6; SD = 3.3) and number of follow ups. Measurements: Cognitive status was assessed annually and based in part on a composite measure of global cognition including 17 cognitive tests. A global motor score was based on 10 motor performances from which 4 motor domains were computed including hand dexterity, hand strength, gait function, and leg strength. Results: During 7 years of follow-up, 166 of 1,160 (14.3%) developed AD. In a proportional hazards model controlling for age, sex, education, and race, each 1-SD higher baseline global motor score was associated with about a 20% reduction in the risk of AD (hazard ratio: 0.81; 95% CI: 0.68, 0.97). Higher baseline motor function was also associated with decreased risk of incident MCI (hazard ratio: 0.79; 95% CI: 0.68, 0.92). Hand dexterity, hand strength and gait function but not leg strength were associated with incident AD and MCI. When including all four motor domains in the same model, results remained the same for incident MCI, while for incident AD, the association with hand strength remained significant. Conclusion: Diverse motor performances are associated with late-life cognitive impairment. Further work is needed to identify specific motor performances that may differentiate adults at risk for future MCI or AD dementia.

Effect of Advanced Glycation End Products on Cognition in Older Adults with Type 2 Diabetes: Results from a Pilot Clinical Trial.

BACKGROUND: Dietary advanced glycation end-products (AGEs) are linked to cognitive decline. However, clinical trials have not tested the effect of AGEs on cognition in older adults. OBJECTIVE: The aim of the current pilot trial was to examine the feasibility of an intervention to reduce dietary AGEs on cognition and on cerebral blood flow (CBF). METHODS: The design is a pilot randomized controlled trial of dietary AGEs reduction in older adults with type 2 diabetes. Seventy-five participants were randomized to two arms. The control arm received standard of care (SOC) guidelines for good glycemic control; the intervention arm, in addition to SOC guidelines, were instructed to reduce their dietary AGEs intake. Global cognition and CBF were assessed at baseline and after 6 months of intervention. RESULTS: At baseline, we found a reverse association between AGEs and cognitive functioning, possibly reflecting the long-term toxicity of AGEs on the brain. There was a significant improvement in global cognition at 6 months in both the intervention and SOC groups which was more prominent in participants with mild cognitive impairment. We also found that at baseline, higher AGEs were associated with increased CBF in the left inferior parietal cortex; however, 6 months of the AGEs lowering intervention did not affect CBF levels, despite lowering AGEs exposure in blood. CONCLUSION: The current pilot trial focused on the feasibility and methodology of intervening through diet to reduce AGEs in older adults with type 2 diabetes. Our results suggest that participants with mild cognitive impairment may benefit from an intensive dietary intervention.

Trajectories of depression symptoms over time differ by APOE4 genotype in older adults with type 2 diabetes.

OBJECTIVES: The APOE-ε4 genotype has been associated with old-age depression, but this relationship has been rarely investigated in type 2 diabetes (T2D) older adults, who are at significantly increased risk for depression, a major contributor to T2D complications. We examined whether trajectories of depression symptoms over time differ by APOE-ε4 genotype in older adults with T2D. METHODS: Participants (n = 754 [13.1% APOE-ε4 carrier]s) were from the longitudinal Israel Diabetes and Cognitive Decline (IDCD) study. They were initially cognitively normal and underwent evaluations of depression approximately every 18 months using the 15-item version of the Geriatric Depression Scale (GDS) and the depression subscale of the Neuropsychiatric Inventory (NPI). APOE was defined as a dichotomy of ε4 carriers and non-carriers. We used Hierarchical Linear Mixed Models (HLMM) that modeled the effects of APOE status on repeated GDS and NPI-depression scores in an unadjusted model (Model 1), adjusting for demographic factors (Model 2) and additionally adjusting for cardiovascular factors and global cognition (Model 3). RESULTS: Participants' mean age was 71.37 (SD = 4.5); 38.2% female. In comparison to non-carriers, APOE-ε4 carriers had lower mean GDS scores (ß = -0.46, p = 0.018) and lower NPI-depression scores (ß = -0.170, p = 0.038) throughout all study follow period. The groups did not differ in the slope of change over time in GDS (ß = -0.005, p = 0.252) or NPI-depression (ß = -0.001, p = 0.994) scores. Additional adjustment for cardiovascular factors and global cognition did not alter these results. CONCLUSIONS: In older adults with T2D, APOE-ε4 carriers have less depressive symptoms in successive measurements suggesting they may be less susceptible to depression.

Multimodal immersive trail making-virtual reality paradigm to study cognitive-motor interactions.

BACKGROUND: Neuropsychological tests of executive function have limited real-world predictive and functional relevance. An emerging solution for this limitation is to adapt the tests for implementation in virtual reality (VR). We thus developed two VR-based versions of the classic Color-Trails Test (CTT), a well-validated pencil-and-paper executive function test assessing sustained (Trails A) and divided (Trails B) attention-one for a large-scale VR system (DOME-CTT) and the other for a portable head-mount display VR system (HMD-CTT). We then evaluated construct validity, test-retest reliability, and age-related discriminant validity of the VR-based versions and explored effects on motor function. METHODS: Healthy adults (n = 147) in three age groups (young: n = 50; middle-aged: n = 80; older: n = 17) participated. All participants were administered the original CTT, some completing the DOME-CTT (14 young, 29 middle-aged) and the rest completing the HMD-CTT. Primary outcomes were Trails A and B completion times (tA, tB). Spatiotemporal characteristics of upper-limb reaching movements during VR test performance were reconstructed from motion capture data. Statistics included correlations and repeated measures analysis of variance. RESULTS: Construct validity was substantiated by moderate correlations between the'gold standard' pencil-and-paper CTT and the VR adaptations (DOME-CTT: tA 0.58, tB 0.71; HMD-CTT: tA 0.62, tB 0.69). VR versions showed relatively high test-retest reliability (intraclass correlation; VR: tA 0.60-0.75, tB 0.59-0.89; original: tA 0.75-0.85, tB 0.77-0.80) and discriminant validity (area under the curve; VR: tA 0.70-0.92, tB 0.71-0.92; original: tA 0.73-0.95, tB 0.77-0.95). VR completion times were longer than for the original pencil-and-paper test; completion times were longer with advanced age. Compared with Trails A, Trails B target-to-target VR hand trajectories were characterized by delayed, more erratic acceleration and deceleration, consistent with the greater executive function demands of divided vs. sustained attention; acceleration onset later for older participants. CONCLUSIONS: The present study demonstrates the feasibility and validity of converting a neuropsychological test from two-dimensional pencil-and-paper to three-dimensional VR-based format while preserving core neuropsychological task features. Findings on the spatiotemporal morphology of motor planning/execution during the cognitive tasks may lead to multimodal analysis methods that enrich the ecological validity of VR-based neuropsychological testing, representing a novel paradigm for studying cognitive-motor interactions.