Early mild traumatic brain injury (mTBI or concussion sustained between 0 and 5 years old) can lead to post-concussive symptoms, behavioral changes, and cognitive difficulties. Although school-age children (6–17 years old) experience similar consequences, severe neuropsychological deficits are not common, and the majority have no persisting symptoms after one month. Thus, there may be value in focusing on what characterizes optimal functioning (or wellness) after mTBI, but this has not been explored in young children. This study documents the evolution and predictors of optimal functioning after early mTBI.

Participants were 190 children aged 18 – 60 months with mTBI (n = 69), orthopedic injury (OI; n = 50), or typical development (TDC; n = 71). Optimal functioning was defined as: (1) no clinically significant behavioral problems; (2) no cognitive difficulties; (3) no persisting post-concussive symptoms; (4) average quality of life or better. Predictors related to sociodemographic, injury, child, and caregiver characteristics included number of acute symptoms, child sex, age, temperament, maternal education, parent-child attachment and interaction quality, and parenting stress.

Fewer children with mTBI had optimal functioning over 6 and 18-months post-injury compared to those with OI and TDC. Higher parent-child interaction quality and lower child negative affectivity temperament independently predicted optimal functioning.

Children who sustain early mTBI are less likely to exhibit optimal functioning than their peers in the long-term. Parent-child interaction quality could be a potential intervention target for promoting optimal function.

To explore the relationship between age, education, sex, and ApoE4 (+) status to brain volume among a cohort with amnestic mild cognitive impairment (aMCI).

One hundred and twenty-three participants were stratified into Hispanic (n = 75) and White non-Hispanic (WNH, N = 48). Multiple linear regression analyses were conducted with age, education, sex, and ApoE4 status as predictor variables and left and right combined MRI volumes of the hippocampus, parahippocampus, and entorhinal cortex as dependent variables. Variations in head sizes were corrected by normalization with a total intracranial volume measurement.

Bonferroni-corrected results indicated that when controlling for ApoE4 status, education, and age, sex was a significant predictor of hippocampal volume among the Hispanic group (β = .000464, R2 = .196, p < .01) and the WNH group (β = .000455, R2 = .195, p < .05). Education (β = .000028, R2 = .168, p < .01) and sex (β = .000261, R2 = .168, p < .01) were significant predictors of parahippocampal volume among the Hispanic MCI group when controlling for the effects of ApoE4 status and age. One-way ANCOVAs comparing hippocampal and parahippocampal volume between males and females within groups revealed that females had significantly larger hippocampal volumes (p < .05). Hispanic females had significantly larger hippocampal (p < .001) and parahippocampal (p < .05) volume compared to males. No sex differences in parahippocampal volume were noted among WNHs.

Biological sex, rather than ApoE4 status, was a greater predictor of hippocampal volume among Hispanic and WNH females. These findings add to the mixed literature on sex differences in dementia research and highlight continued emphasis on ethnic populations to elucidate on neurodegenerative disparities.

Blood-based biomarkers offer a more feasible alternative to Alzheimer’s disease (AD) detection, management, and study of disease mechanisms than current in vivo measures. Given their novelty, these plasma biomarkers must be assessed against postmortem neuropathological outcomes for validation. Research has shown utility in plasma markers of the proposed AT(N) framework, however recent studies have stressed the importance of expanding this framework to include other pathways. There is promising data supporting the usefulness of plasma glial fibrillary acidic protein (GFAP) in AD, but GFAP-to-autopsy studies are limited. Here, we tested the association between plasma GFAP and AD-related neuropathological outcomes in participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC).

This sample included 45 participants from the BU ADRC who had a plasma sample within 5 years of death and donated their brain for neuropathological examination. Most recent plasma samples were analyzed using the Simoa platform. Neuropathological examinations followed the National Alzheimer’s Coordinating Center procedures and diagnostic criteria. The NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Measures of GFAP were log-transformed. Binary logistic regression analyses tested the association between GFAP and autopsy-confirmed AD status, as well as with semi-quantitative ratings of regional atrophy (none/mild versus moderate/severe) using binary logistic regression. Ordinal logistic regression analyses tested the association between plasma GFAP and Braak stage and CERAD neuritic plaque score. Area under the curve (AUC) statistics from receiver operating characteristics (ROC) using predicted probabilities from binary logistic regression examined the ability of plasma GFAP to discriminate autopsy-confirmed AD status. All analyses controlled for sex, age at death, years between last blood draw and death, and APOE e4 status.

Of the 45 brain donors, 29 (64.4%) had autopsy-confirmed AD. The mean (SD) age of the sample at the time of blood draw was 80.76 (8.58) and there were 2.80 (1.16) years between the last blood draw and death. The sample included 20 (44.4%) females, 41 (91.1%) were White, and 20 (44.4%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having autopsy-confirmed AD (OR=14.12, 95% CI [2.00, 99.88], p=0.008). ROC analysis showed plasma GFAP accurately discriminated those with and without autopsy-confirmed AD on its own (AUC=0.75) and strengthened as the above covariates were added to the model (AUC=0.81). Increases in GFAP levels corresponded to increases in Braak stage (OR=2.39, 95% CI [0.71-4.07], p=0.005), but not CERAD ratings (OR=1.24, 95% CI [0.004, 2.49], p=0.051). Higher GFAP levels were associated with greater temporal lobe atrophy (OR=10.27, 95% CI [1.53,69.15], p=0.017), but this was not observed with any other regions.

The current results show that antemortem plasma GFAP is associated with non-specific AD neuropathological changes at autopsy. Plasma GFAP could be a useful and practical biomarker for assisting in the detection of AD-related changes, as well as for study of disease mechanisms.

This study is based on long-term follow-up of participants in a randomized double-blind sham surgery-controlled trial (1995–1999) designed to determine the effectiveness of implantation of human embryonic mesencephalic tissue containing dopamine neuron precursors into the brains of patients with advanced Parkinson’s disease (PD). We investigated differences between long-term survivors and nonsurvivors at baseline in order to contribute to information regarding optimal patient selection for upcoming stem cell trials.

Forty participants were randomly assigned to receive either neural implantation or sham surgery. Thirty-four patients who ultimately received the implant were followed periodically with the most recent assessment occurring in 2015–2016. Demographic information, neurological measures, positron emission tomography (PET) imaging, neuropsychological assessments, and a personality assessment were included in the current analyses. T-tests were used to compare survivors and nonsurvivors. Logistic regression analyses examined predictors of survivorship.

Five of six survivors were female. They were younger than nonsurvivors (p = .03) and more neuropsychologically “intact” across a broad range of cognitive areas (significance levels ranged from <.001 to .045). There were no differences between survivors and nonsurvivors off medications at baseline on neurological or PET assessments. Survivors reported more “Openness to Experience” (p = .004) than nonsurvivors. Using empirically derived predictor variables, results of logistic regression analyses indicated that Animal Naming (cognitive task) and Openness to Experience (personality variable) were the strongest predictors of survivorship.

Variables to consider when selecting participants for future cell-based therapies include being “intact” neuropsychologically, level of Openness to Experience, younger age, and inclusion of women.

Extensive research shows that tests of executive functioning (EF) predict instrumental activities of daily living (IADLs) but are nevertheless often criticized for having poor ecological validity. The Modified Six Elements Test (MSET) is a pencil-and-paper test that was developed to mimic the demands of daily life, with the assumption that this would result in a more ecologically valid test. Although the MSET has been extensively validated in its ability to capture cognitive deficits in various populations, support for its ability to predict functioning in daily life is mixed. This study aimed to examine the MSET’s ability to predict IADLs assessed via three different modalities relative to traditional EF measures.

Participants (93 adults aged 60 – 85) completed the MSET, traditional measures of EF (Delis-Kaplan Executive Function System; D-KEFS), and self-reported and performance-based IADLs in the lab. Participants then completed three weeks of IADL tasks at home, using the Daily Assessment of Independent Living and Executive Skills (DAILIES) protocol.

The MSET predicted only IADLs completed at home, while the D-KEFS predicted IADLs across all three modalities. Further, the D-KEFS predicted home-based IADLs beyond the MSET when pitted against each other, whereas the MSET did not contribute beyond the D-KEFS.

Traditional EF tests (D-KEFS) appear to be superior to the MSET in predicting IADLs in community-dwelling older adults. The present results argue against replacing traditional measures with the MSET when addressing functional independence of generally high-functioning and cognitive healthy older adult patients.

To examine neuropsychological functioning as a predictor of psychosocial adjustment difficulties at discharge from a postacute residential rehabilitation facility for traumatic brain injury (TBI) and depression as a potential mediator.

A retrospective record review was conducted of 172 adults who received rehabilitation services for TBI. Individuals completed a full battery of neuropsychological tests, depression assessment, and functional assessments at admission. Functional assessments were also obtained at discharge.

A two-phase structural equation model analysis was performed. The first phase specified a good fitting model of a cognitive functioning (CF) latent construct with four indicators of cognitive domains measuring verbal fluency, cognitive flexibility, verbal learning, and working memory. Worse CF was associated with greater psychosocial adjustment impairment at discharge, but not related to depression. Psychosocial adjustment impairment at admission was positively associated with depression when controlling for CF, however depression did not predict psychosocial adjustment at discharge. Thus, depression was not found to be a significant mediator of psychosocial adjustment impairment at discharge.

Results provide support for neuropsychological functioning at the start of postacute rehabilitation for TBI as an important predictor of psychosocial functioning difficulties that remain upon discharge and highlights the need to examine mechanisms beyond depression.

The ability to remotely monitor cognitive skills is increasing with the ubiquity of smartphones. The Mobile Toolbox (MTB) is a new measurement system that includes measures assessing Executive Functioning (EF) and Processing Speed (PS): Arrow Matching, Shape-Color Sorting, and Number-Symbol Match. The purpose of this study was to assess their psychometric properties.

MTB measures were developed for smartphone administration based on constructs measured in the NIH Toolbox® (NIHTB). Psychometric properties of the resulting measures were evaluated in three studies with participants ages 18 to 90. In Study 1 (N = 92), participants completed MTB measures in the lab and were administered both equivalent NIH TB measures and other external measures of similar cognitive constructs. In Study 2 (N = 1,021), participants completed the equivalent NIHTB measures in the lab and then took the MTB measures on their own, remotely. In Study 3 (N = 168), participants completed MTB measures twice remotely, two weeks apart.

All three measures exhibited very high internal consistency and strong test-retest reliability, as well as moderately high correlations with comparable NIHTB tests and moderate correlations with external measures of similar constructs. Phone operating system (iOS vs. Android) had a significant impact on performance for Arrow Matching and Shape-Color Sorting, but no impact on either validity or reliability.

Results support the reliability and convergent validity of MTB EF and PS measures for use across the adult lifespan in remote, self-administered designs.

The Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) is well validated and commonly used to assess difficulties in everyday functioning regarding dementia. To facilitate interpretation and clinical implementation across different European countries, we aim to provide normative data and a diagnostic cutoff for dementia.

Cross-sectional data from Dutch Brain Research Registry (N = 1,064; mean (M) age = 62 ± 11 year; 69.5% female), European Medial Information Framework-Alzheimer’s Disease 90 + (N = 63; Mage = 92 ± 2 year; 52.4% female), and European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (N = 247; Mage = 63 ± 7 year; 72.1% female) were used. The generalized additive models for location, scale, and shape framework were used to obtain normative values (Z-scores). The beta distribution was applied, and combinations of age, sex, and educational attainment were modeled. The optimal cutoff for dementia was calculated using area under receiver operating curves (AUC-ROC) and Youden Index, using data from Amsterdam Dementia Cohort (N = 2,511, Mage = 64 ± 8 year, 44.4% female).

The best normative model accounted for a cubic-like decrease of IADL performance with age that was more pronounced in low compared to medium/high educational attainment. The cutoff for dementia was 1.85 standard deviation below the population mean (AUC = 0.97; 95% CI [0.97–0.98]).

We provide regression-based norms for A-IADL-Q and a diagnostic cutoff for dementia, which help improve clinical assessment of IADL performance across European countries.

Despite associations between hypoglycemia and cognitive performance using cross-sectional and experimental methods (e.g., Insulin clamp studies), few studies have evaluated this relationship in a naturalistic setting. This pilot study utilizes an EMA study design in adults with T1D to examine the impact of hypoglycemia and hyperglycemia, measured using CGM, on cognitive performance, measured via ambulatory assessment.

Twenty adults with T1D (mean age 38.9 years, range 26-67; 55% female; 55% bachelor’s degree or higher; mean HbA1c = 8.3%, range 5.4% - 12.5%), were recruited from the Joslin Diabetes Center at SUNY Upstate Medical University. A blinded Dexcom G6 CGM was worn during everyday activities while completing 3-6 daily EMAs using personal smartphones. EMAs were delivered between 9 am and 9 pm, for 15 days. EMAs included 3 brief cognitive tests developed by testmybrain.org and validated for brief mobile administration (Gradual Onset CPT d-prime, Digit Symbol Matching median reaction time, Multiple Object Tracking percent accuracy) and self-reported momentary negative affect. Day-level average scores were calculated for the cognitive and negative affect measures. Hypoglycemia and hyperglycemia were defined as the percentage of time spent with a sensor glucose value <70 mg/dL or > 180 mg/dL, respectively. Daytime (8 am to 9 pm) and nighttime (9 pm to 8 am) glycemic excursions were calculated separately. Multilevel models estimated the between- and within-person association between the night prior to, or the same day, time spent in hypoglycemia or hyperglycemia and cognitive performance (each cognitive test was modeled separately). To evaluate the effect of between-person differences, person-level variables were calculated as the mean across the study and grand-mean centered. To evaluate the effect of within-person fluctuations, day-level variables were calculated as deviations from these person-level means.

Within-person fluctuations in nighttime hypoglycemia were associated with daytime processing speed. Specifically, participants who spent a higher percentage of time in hypoglycemia than their average percentage the night prior to assessment performed slower than their average performance on the processing speed test (Digit Symbol Matching median reaction time, b = 94.16, p = 0.042), while same day variation in hypoglycemia was not associated with variation in Digit Symbol Matching performance. This association remained significant (b = 97.46, p = 0.037) after controlling for within-person and between-person effects of negative affect. There were no significant within-person associations between time spent in hyperglycemia and Digit Symbol Matching, nor day/night hypoglycemia or hyperglycemia and Gradual Onset CPT or Multiple Object Tracking.

Our findings from this EMA study suggest that when individuals with T1D experience more time in hypoglycemia at night (compared to their average), they have slower processing speed the following day, while same day hypoglycemia and hyperglycemia does not similarly impact processing speed performance. These results showcase the power of intensive longitudinal designs using ambulatory cognitive assessment to uncover novel determinants of cognitive variation in real world settings that have direct clinical applications for optimizing cognitive performance. Future research with larger samples is needed to replicate these findings.

Digital cognitive assessments (DCAs) provide insight into cognition and behavior that remains inaccessible through standard assessment approaches. However, the availability of DCAs and the requisite toolkits to extract and analyze meaningful features from these datasets are largely constrained to technical specialists or through fee-for-service commercial entities. The NKI- Rockland Sample provides a large- scale lifespan data sample featuring DCAs, and also openly shares its DCA tasks through the open-source MindLogger platform along with pipelines for feature extraction and analyses. Here we present normative performance from a digital version of Archimedes Spiral Drawing.

NKI-RS2 participants were largely drawn from the existing NKI-RS participant pool (n= 1,500), aged 885. The NKI-RS2 is in year 1 of data collection; here, we report on a subset of participants (n= 9) who performed a digitized version of the Archimedes Spiral Drawing task. This graphomotor task with well-established research and clinical utility in movement disordered populations was adapted for use for off-the-shelf tablet devices. The NKI-RS2 implements these tasks on an Apple iPad Pro2, sampling participant drawing at 120Hz, and featuring pixel- and millisecond- level resolution for all tasks. On the Spiral Drawing and Recall Tests participants traced five Archimedes spirals from the center outward through four windings presented on the iPad. They were then asked to replicate the spiral freehand three times. From these spiral drawings, we extracted time to completion, distance covered, speed/ speed variability, rotational smoothness, number of crossings, mean absolute error, bias, and goodness of fit to the ideal Archimedes spiral.

Comparing the tracing and recall conditions, participants showed significantly faster drawing speed (t[8]=5.32, p< .001), more variable drawing speed (t[8]=5.93, p< .001), reduced goodness of fit to the template t[8]=4.99, p< .002, and reduced rotational smoothness (t[8]=7.43, p< .0003) in the recall conditions. Collapsing across conditions, age predicted more variable drawing speed: t[8]= 2.77 p< .019, greater tracing error (t[8] = 2.69, p< .0227), and reduced rotational smoothness (t[8] = 2.67, p< .024). Between conditions, age predicts a greater increase in drawing speed variability (t[8] = 9.76, p< .0006).

Using the open source MindLogger platform and off-the-shelf digital tablets, we were able to replicate classic paper and pen neuropsychological tests. By adapting these tasks to DCA, we were able to extract meaningful features that are not otherwise accessible (drawing speed, variability, etc.), or that would require additional hardware solutions (e.g., dwell time). By making these tasks and their processing pipelines available, the NKI-RS2 can facilitate the democratization of DCA and DCA analysis to a broader range of researchers and clinicians.

It is unclear how agenesis of the corpus callosum (ACC), a congenital brain malformation defined by complete or partial absence of the corpus callosum, impacts language development. fMRI studies of middle childhood suggest that the corpus callosum plays a role in the interhemispheric language network (Bartha-Doering et al., 2020), and that reduced interhemispheric functional connectivity is correlated with worse language abilities in children with ACC (Bartha-Doering et al., 2021). Additionally, accumulating evidence suggests structural abnormalities of the corpus callosum play a role in neurodevelopmental disorders. While children who go on to receive an autism spectrum disorder (ASD) diagnosis may show early signs of altered word and gesture acquisition (Iverson et al., 2018), the same is not known about ACC. This study examined language development during the second year of life in children with ACC in comparison to neurotypical control participants, as well as other children at elevated risk of ASD.

The MacArthur-Bates Communicative Development Inventories (MCDI): Words and Gestures scales were administered to parents of 74 children with isolated ACC at 12, 18 and 24 months of age. Children whose first language was not English and children who were bilingual were excluded. Comparison groups consisted of individuals with a low familial likelihood of ASD (LL- n=140) and individuals with high familial likelihood of ASD who do and do not have a confirmed ASD diagnosis (HL+ n=68, HL- n=256).

Compared to LL controls, the ACC group produced fewer words at 18 and 24 months of age, and demonstrated fewer words understood at all three timepoints. Similarly, compared to the HL- group, the ACC group demonstrated fewer words produced and understood at 18 months of age, and fewer words produced at 24 months of age. The ACC and HL+ groups did not differ in words produced or words understood at any timepoint.

Overall, infants with ACC demonstrated delayed vocabulary expansion from 12 to 24 months of age. These findings illustrate the role of callosal connectivity in the development of language across the first 2 years of life, and highlight the need for support and interventions that target vocabulary production and comprehension.

Fluoride exposure has been associated with thyroid dysfunction, but fluoride's impact on thyroid function in pregnancy is unclear, especially during early gestation when the fetus is dependent on maternal thyroid hormone. We examined the potential thyroid-disrupting effects of maternal fluoride exposure in pregnancy and tested whether thyroid disruption in pregnancy mediates the association between maternal fluoride exposure and child intelligence quotient (IQ) among Canadian mother-child dyads living in areas with optimal fluoridation.

We measured fluoride concentrations in drinking water and in spot urine samples collected in each trimester from pregnant women enrolled in the Maternal-Infant Research on Environmental Chemicals study. We also measured thyroid hormone (thyroid stimulating hormone [TSH], free thyroxine [FT4], and total thyroxine [TT4]) levels during the first trimester of pregnancy and categorized women as euthyroid (n=1301), subclinical hypothyroid (n=100), or primary hypothyroid (n=28). Those categorized as primary hypothyroid were combined with an additional 79 women who reported clinical diagnoses at time of study enrolment (total n=107). In a sample of 1508 women, we used logistic regression to estimate the association between fluoride exposure and risk of either subclinical or primary hypothyroidism, separately, and linear regression to estimate associations between fluoride exposure and women's thyroid hormone levels (TSH, FT4, TT4). We tested effect modification by child sex and thyroid peroxidase (TPO) antibody status. In a subsample of 439 mother-child pairs, we measured child Full-Scale IQ (FSIQ) at 3-4 years of age using the Wechsler Preschool and Primary Scale of Intelligence. We used linear regression to test associations between maternal hypothyroidism or thyroid hormone levels, and children's FSIQ scores. Finally, mediation analysis in the counterfactual framework was used to estimate the proportion of the effect of maternal fluoride exposure on child FSIQ mediated by maternal hypothyroidism, through evaluation of the natural direct (not through hypothyroidism) and indirect (through hypothyroidism) effects.

Using categorical measures of thyroid status, a 0.5 mg/L increase in water fluoride concentration was associated with a 1.64 (95% confidence interval [CI], 1.04 to 2.58) increased odds of primary hypothyroidism. This association was stronger among women with normal TPO antibody levels (< 5.61 IU/mL) (odds ratio, 2.80; 95% CI, 1.24 to 6.36). In contrast, we did not find a significant association between maternal urinary fluoride and hypothyroidism. For continuous measures of thyroid hormone levels, a 1 mg/L increase in maternal urinary fluoride was associated with a 35% (p=0.01) increase in TSH among women pregnant with a female fetus. In our subsample analyses, children born to women with primary hypothyroidism had lower FSIQ than children of euthyroid women, especially among boys (B, 8.78; 95% CI, -16.78 to -0.79). In contrast, maternal TSH, FT4, and TT4 levels were not significantly associated with child FSIQ scores. Maternal primary hypothyroidism did not significantly mediate the relationship between maternal water fluoride concentration and child FSIQ (p natural indirect effect= .35).

Fluoride in drinking water may increase the risk of hypothyroidism in pregnancy. Thyroid dysfunction in pregnancy may be one mechanism underlying developmental neurotoxicity of fluoride.

Exercise has been found to be important in maintaining neurocognitive health. However, the effect of exercise intensity level remains relatively underexplored. Thus, to test the hypothesis that self-paced high-intensity exercise and cardiorespiratory fitness (peak aerobic capacity; VO2peak) increase grey matter (GM) volume, we examined the effect of a 6-month exercise intervention on frontal lobe GM regions that support the executive functions in older adults.

Ninety-eight cognitively normal participants (age = 69.06 ± 5.2 years; n = 54 female) were randomised into either a self-paced high- or moderate-intensity cycle-based exercise intervention group, or a no-intervention control group. Participants underwent magnetic resonance imaging and fitness assessment pre-intervention, immediately post-intervention, and 12-months post-intervention.

The intervention was found to increase fitness in the exercise groups, as compared with the control group (F = 9.88, p = <0.001). Changes in pre-to-post-intervention fitness were associated with increased volume in the right frontal lobe (β = 0.29, p = 0.036, r = 0.27), right supplementary motor area (β = 0.30, p = 0.031, r = 0.29), and both right (β = 0.32, p = 0.034, r = 0.30) and left gyrus rectus (β = 0.30, p = 0.037, r = 0.29) for intervention, but not control participants. No differences in volume were observed across groups.

At an aggregate level, six months of self-paced high- or moderate-intensity exercise did not increase frontal GM volume. However, experimentally-induced changes in individual cardiorespiratory fitness was positively associated with frontal GM volume in our sample of older adults. These results provide evidence of individual variability in exercise-induced fitness on brain structure.