Physical, sensory, and cognitive function are all related to successful aging, quality of life, and independence in older age. Decline in cognitive function, in particular, can create difficulty in many Instrumental Activities of Daily Living such as driving and other aspects of everyday function. Loss of driving competence can subsequently lead to depression, isolation, loss of independence and reduced quality of life. Results from a large randomized controlled trial investigating the long-term impact of Speed of Processing Training will be presented demonstrating the impact of such training on cognitive and everyday function. Speed of Processing Training is an adaptive cognitive intervention administered on a computer that improves visual attention, and has been shown to enhance the connections needed for visual attention using task-driven and resting state fMRI.

The ACTIVE clinical trial recruited a volunteer sample of 2,832 community dwelling older adults between the ages of 65 and 94 years at six different field sites in six different states. This study evaluated the impact of three cognitive interventions targeted at improving cognitive and everyday function which served as contract control conditions for each other. Participants were randomly assigned to speed of processing training, reasoning training, memory training, or a no-contact control group. Follow-up testing was collected in person for ten years, and at twenty years final archival data was collected from the Departments of Motor Vehicles at each of the six field sites, as well as the Medicare/Medicaid data across the twenty years since enrollment. Outcomes included measures of cognitive function, measures of IADL (including crash involvement and driving cessation), and secondary outcomes of mobility (falls, driving habits, life space), quality of life, mortality and health conditions (from Medicare Records).

Results will be presented with respect to everyday function including several longitudinal measures of mobility: number of miles driven per year and driving difficulty, rates of driving cessation, and crash involvement. Random effects modelling, cox proportional hazards, and rate ratios will be presented illustrating the positive impact of cognitive training on these outcome measures. In particular, Speed of Processing Training was found to sustain driving competence with respect to continued driving relative to other types of training, and to reduce the risk of crash involvement over ten years. Furthermore, decline in Speed of Processing was the only cognitive measure predictive of crash involvement longitudinally in the no-contact control group. Positive benefits were also observed for Health Related Quality of Life (HRQoL), and depression.

The ACTIVE clinical trial, among other studies, has demonstrated that cognitive training can have long-term positive benefit on the everyday abilities, quality of life, and continued independence of older adults.

Cognitive impairment is observed in up to two-thirds of persons with Multiple Sclerosis (MS). Impairments in cognitive processing speed (PS) is the most prevalent cognitive disturbance, occurs early in the course of disease and is strongly associated with disease progression, various brain parameters and everyday life functional activities. As such, cognitive rehabilitation for PS impairments should be an integral part of MS treatment and management. The current study examines the efficacy of Speed of Processing Training (SOPT) to improve processing speed (PS) in individuals with Multiple Sclerosis (MS). SOPT was chosen because of its significant positive results in the aging populations.

This double-blind, placebo-controlled randomized clinical trial included 84 participants with clinically definite MS and impaired PS, 43 in the treatment group and 41 in the placebo control group. Outcomes included changes in the Useful Field of View (UFOV) and neuropsychological evaluation (NPE) including measure of PS (e.g., Pattern Comparison and Letter Comparison). Participants completed a baseline NPE and a repeat NPE post-treatment. Treatment consisted of 10 sessions delivered twice per week for 5 weeks. After the 5 weeks, the treatment group was randomized to booster sessions or no contact. Long-term follow-up assessments were completed 6 months after completion of treatment. The primary outcome were tests of PS including UFOV and neuropsychological testing.

A significant effect of SOPT was observed on both the UFOV (large effect) and Pattern Comparison with a similar pattern of results noted on Letter Comparison, albeit at a trend level. The treatment effect was maintained 6-months later. The impact of booster sessions was not significant. Correlations between degree of improvement on the UFOV and the number of levels completed within each training task were significant for both Speed and Divided Attention indicating that completion of more levels of training correlated with greater benefit.

SOPT is effective for treating PS deficits in MS with benefit documented on both the UFOV and a neuropsychological measure of PS. Less benefit was observed as the outcome measures became more distinct in cognitive demands from the treatment. Long-term maintenance was observed. The number of training levels completed within the 10-sessions exerted a significant impact on treatment benefit, with more levels completed resulting in greater benefit.

CI Cognitive Therapy (CICT) is a combination of behavioral techniques derived from CI Movement Therapy (CIMT) modified to apply to the cognitive domain, and Speed of (Cognitive) Processing Training (SOPT). SOPT is effective in improving cognitive function in the treatment setting and driving ability in everyday situations. The data concerning the effect of SOPT on other cognition-based instrumental activities of daily living (IADL) in everyday situations is incomplete. The strengths of CIMT, based on its Transfer Package (TP), are to facilitate 1) transfer of improved function from the treatment setting to IADL in everyday settings, and 2) long-term retention of the improved performance of IADL. This study sought to determine in a preliminary case series whether the TP of CI Movement Therapy combined with SOPT would have the same effect on a wide range of impaired cognition-based ADL.

Participants were 6 adults with chronic stroke: mean chronicity = 36.2 months, (range, 16-56 months); mean age = 59.7 years, (range, 47-55); 1 female; 3 African American and 3 European American. Five had mild cognitive impairment, while one had moderate impairment. Participants received 35 hours of outpatient treatment in 10-15 sessions distributed over 2-6 weeks, depending on the participants’ availability. Sessions began with 1 hour of SOPT training followed by training of cognition-based ADL by the process of shaping, a common method in the behavior analysis field. Other behavior analysis methods employed in the TP of CI Movement Therapy were used, including: 1) behavior contracting, daily assignment of homework, participation of a family member in the training and monitoring process, daily administration of a structured interview assessing amount and quality of performance of 30 IADL, problem solving to overcome perceived (or real) barriers to performance of IADL. Participants were given daily homework assignments in follow-up and were contacted in periodic, pre-arranged phone calls to determine status, compliance and problem-solve.

All six participants showed marked improvement on the SOPT test similar to that in the Ball et al studies. However, here transfer to IADL outside the treatment setting was substantial. On the main real-world outcome, the Canadian Occupational Performance Measure (COPM), there were increases of 2.7±1.3 and 2.1±1.6 on the two scales (d’s = 1.9 & 1.3, respectively). (Changes on the COPM > 2 points are considered clinically meaningful and changes in d’ >.8 are considered large). On two other real-word measures, the Cognitive Task Activity Log (CTAL) and inventory of Improved and New Cognitive Activities (INCA), there was a marked increase during the acquisition phase of training. There was no loss in retention over the 6-16 months (mean = 12.2) of follow-up to date. Instead, the INCA showed strong further improvement after the end of treatment-setting training, especially in the New Activities Not Performed Since Before Stroke Onset category, going from a mean of 8.2 after training to 14.6 at the end of follow-up.

These very preliminary results suggest that CICT may be an efficacious therapy for mild to moderate cognitive impairment in chronic stroke and possibly other disorders.

Persistent brain fog is common in adults with Post-Acute Sequelae of SARS-CoV-2 infection (PASC), in whom it causes distress and in many cases interferes with performance of instrumental activities of daily living (IADL) and return-to-work. There are no interventions with rigorous evidence of efficacy for this new, often disabling condition. The purpose of this pilot is to evaluate the efficacy, on a preliminary basis, of a new intervention for this condition termed Constraint-Induced Cognitive therapy (CICT). CICT combines features of two established therapeutic approaches: cognitive speed of processing training (SOPT) developed by the laboratory of K. Ball and the Transfer Package and task-oriented training components of Constraint-Induced Movement therapy developed by the laboratory of E. Taub and G. Uswatte.

Participants were > 3 months after recovery from acute COVID symptoms and had substantial brain fog and impairment in IADL. Participants were randomized to CICT immediately or after a 3-month delay. CICT involved 36 hours of outpatient therapy distributed over 4-6 weeks. Sessions had three components: (a) videogamelike training designed to improve how quickly participants process sensory input (SOPT), (b) training on IADLs following shaping principles, and (c) a set of behavioral techniques designed to transfer gains from the treatment setting to daily life, i.e., the Transfer Package. The Transfer Package included (a) negotiating a behavioral contract with participants and one or more family members about the responsibilities of the participants, family members, and treatment team; (b) assigning homework during and after the treatment period; (c) monitoring participants’ out-of-session behavior; (d) supporting problem-solving by participants and family members about barriers to performance of IADL; and (e) making follow-up phone calls. IADL performance, brain fog severity, and cognitive impairment were assessed using validated, trans-diagnostic measures before and after treatment and three months afterwards in the immediate-CICT group and on parallel occasions in the delayed-CICT group (aka waitlist controls).

To date, five were enrolled in the immediate-CICT group; four were enrolled in the wait-list group. All had mild cognitive impairment, except for one with moderate impairment in the immediate-CICT group. Immediate-CICT participants, on average, had large reductions in brain fog severity on the Mental Clutter Scale (MCS, range = 0 to 10 points, mean change = -3.7, SD = 2.0); wait-list participants had small increases (mean change = 1.0, SD = 1.4). Notably, all five in the immediate-CICT group had clinically meaningful improvements (i.e., changes > 2 points) in performance of IADL outside the treatment setting as measured by the Canadian Occupational Performance Measure (COPM) Performance scale; only one did in the wait-list group. The advantage for the immediate-CICT group was very large on both the MCS and COPM (d’s = 1.7, p’s < .05). In follow-up, immediate-CICT group gains were retained or built-upon.

These preliminary findings warrant confirmation by a large-scale randomized controlled trial. To date, CICT shows high promise as an efficacious therapy for brain fog due to PASC. CICT participants had large, meaningful improvements in IADL performance outside the treatment setting, in addition to large reductions in brain fog severity.

Interpretation of neuropsychological (NP) tests depends on the quality of the normative standards available for the tests. Co-norming across tests is necessary when interpreting differences between scores on different tests. The relevance of specific norms for an individual examinee further depends on multiple design features of the standardization studies, including: when the studies were conducted, sampling strategy, inclusion/exclusion criteria, age, sex/gender, education, race and ethnicity, socioeconomic status, and region. This paper examines the standardization studies of the most widely used NP tests, identifies their strengths and weaknesses, and makes recommendations for interpretive caveats based on these analyses.

We reviewed the standardization strategies and coded information about the sampling frames, inclusion/exclusion criteria, stratification methods, demographic characteristics, and sample sizes overall and within each stratum where relevant. These methods were applied to the WAIS-IV, WMS-IV, CVLT3, D-KEFS, Pearson Advanced Clinical Solutions (ACS), Rey Complex Figure Test, WCST, Symbol Digit Modalities Test, RBANS, BVMT-R, HVLT, Halstead-Reitan (“Heaton et al”) Norms for Boston Naming, Finger Tapping, Grooved Pegboard), MOANS, and MOAANS (Boston Naming, Trail Making Test, Judgement of Line Orientation). We calculated multiple indexes for each test, including standard errors and confidence intervals for scaled scores.

Most tests used age only as a stratification factor, providing “age corrected” scores for selected age bands. The sample sizes for the age strata range from 1 to ∼200 but were usually less than 100 participants/stratum. Sex differences were rarely reported and some studies had markedly uneven distributions of sex. Education was not used as a stratification factor in any study, and few norms attempted corrections for education. The possible interactions of age and education on test scores are seldom reported and cell sizes for combinations of age and education may be too small to enable robust estimates of scores, especially at lower levels of education and older ages. The possible impact of race and ethnicity are rarely interrogated except in ACS, Heaton and MOAANS norms, which all focus on “African American” participants. Discrepancies in scores across ACS, Heaton and MOAANS suggest marked sampling differences.

Existing norms have major limitations which may impact the clinical assessment of individuals and result in inappropriate treatment recommendations as well as lead to inappropriate classification in clinical trials, which may include score “cutoffs” based on widely used normative standards. Most norms use only age as a stratification factor, despite robust impacts of education on scores. Race and ethnicity are poorly represented, fail to reflect current demographic characteristics of the United States, and existing norms present major conflicts for African American groups, with the same raw scores differing by a full standard deviation depending only on the source of normative data. Sex differences are examined infrequently and it remains unclear to what extent sex or gender differences may affect some scores. There is an urgent need for new, preferably “dynamic” normative standards, that include sampling by socially and demographically meaningful metrics, to provide greater precision in assessment of neuropsychological scores and score discrepancies, and for evaluating the inclusion/exclusion criteria, and criteria for efficacy in clinical trials that use neurocognitive endpoints.

There is a dearth of an appropriate standardized tool to assess neuropsychological functions in rural population, which has low literacy rates, are culturally diverse, and have limited access to healthcare resources. The NIREH Neuropsychological Battery for Rural Population (NINB-RP) is a relatively brief and easy-to-administer battery comprising multiple tests that are modified or adopted as per rural community settings to evaluate verbal learning, fine coordination, attention efficiency, executive task, concentration, and visual attention, mental flexibility, and motor coordination in rural populations. The present study aimed to examine the clinical validity and establish cut-off scores for impairment of neuropsychological functions for different age, gender, and education levels of NINB-RP in a rural community in central India.

This was a prospective cross-sectional study conducted in participants aged > 18 years (n=2952, M: F=1407:1545) recruited through a stratified sampling technique from 23 randomly selected villages from central India. The data of nine neuropsychological tests [(Finger and Tweezer dexterity test (FDT, TDT); Digit Forward and Backward test (DFT, DBT); Serial subtraction test (SST); Trail Making-A and B; Finger Tapping test (FTT); and Letter Digit Substitution test, LDST)] from 215 cognitively impaired and 2737 healthy control subjects were analyzed. The tests were performed in a village school/community hall or an outdoor camp. Independent sample t-test, Chi-square test, and Receiver Operating Characteristic (ROC) curve were used to calculate the area under the curve (AUC), cut-off scores, and sensitivity (ST)/specificity (SP) values for seven conditions, i.e., gender (male vs. female), age groups (up to 49 years and above 50 years); and educational levels (illiterate, intermediate and college). For those variables where ST/SP values were lower than 0.70, a unique cut-off score was calculated for the entire sample, adjusting by age and educational levels.

A significant difference in mean (median) scores between the healthy control and cognitively impaired groups were observed in all tests except Trail Making A and B and LDST. The AUC for most of the tests ranged from 0.70 to 0.81, and the ST/SP values ranged from 69-73% and 65-75%, respectively. The results showed that most tests of NINB-RP reached moderate to good sensitivity and specificity for gender, age and education levels, except for DBT for females, above 50 years, and illiterate and intermediate education groups. FDT for males [AUC: 0.85 (95%CI0.80-0.91], ST/SP=76/82%] and females [(AUC=0.78 (95%CI0.74-0.82), ST/SP=71/70%], TDT for intermediate education group [AUC=0.82 (95%CI0.60-1.00), ST/SP=86/83%] and FTT for less than 49 years age group [AUC=0.75 (95%CI0.67-0.84), ST/SP=71/76%] were the most useful tests to discriminate among healthy control and cognitively impaired rural population.

The present study is an attempt to establish the cut-off scores of a neuropsychological battery for a large rural population in the community setting. The proposed cut-off values might be helpful in clinical assessment in rural areas where clinical neuropsychology services are not readily available. NINB-RP can be a valuable tool for clinical research studies in rural communities. Further studies on similar samples in other countries need to be undertaken.

The Rey Complex Figure (CF) is a popular test to assess visuospatial construction and visual memory, but its broader use in clinical research is limited by scoring complexity. To widen its application, we developed a new CF scoring system similar to the Benson Figure in which 10 primary CF elements are scored according to presence and location. A novel recognition task was also created for each of these 10 items consisting of a 4-choice recognition condition containing the primary rectangle and major interior lines with qualitative variations of target elements as distractors. The current investigation was designed to characterize the relationship between scoring methods and establish whether comparable results are obtained across both traditional and new CF scoring approaches.

Participants from the Emory Health Brain Study (EHBS) who had completed the Rey CF copy during their cognitive study visit were studied. All participants were self-identified as normal, and administered the CF according to our previously published procedure that included the Copy, Immediate Recall (∼ 30 seconds), and 30-minute Delayed Recall (Loring et al., 1990). Following delayed recall, CF recognition was assessed using the Meyers and Myers (1995) recognition followed by the newly developed forced choice recognition. The final sample included 155 participants ranging in age from 51.6 years to 80.0 years (M=64.9, SD=6.6). The average MoCA score was 26.8/30 (SD=6.6).

Mean performance levels across conditions and scoring approaches are included in the table. Correlations between Copy, Immediate Recall, Delayed Recall, and Recognition were calculated to evaluate the relationship between the traditional 18 item/36 point Osterrieth criteria and newly developed CF scoring criteria using both parametric and non-parametric approaches. Pearson correlations demonstrated high agreement between approaches when characterizing performance levels across all CF conditions (Copy r=.72, Immediate Recall r=.87, Delayed Recall r=.90, and Recognition r=.52). Similar correlations were present using non-parametric analyses (Copy ρ=.46, Immediate Recall ρ=.83, Delayed Recall ρ=.91, and Recognition ρ=.42). Table. Mean performance levels across conditions and scoring approaches

The high correlations, particularly for Immediate and Delayed Recall conditions, suggest that the modified simpler scoring system is comparable to the traditional approach, thereby suggesting potential equivalence between scoring methods. When comparing Rey’s original 47 point scoring approach to his 36 point scoring system, Osterrieth (1944) reported a correlation in fifty adults of ρ=.95 and a correlation in twenty 6-year-olds of ρ=.92. In this investigation, lower correlations were observed for copy and recognition conditions, in part representing smaller response distribution across participants. Although these preliminary results are encouraging, to implement the new EHBS scoring method in clinical evaluation, we are developing normative data in participants across the entire EHBS series, many of whom were not administered the new CF Recognition. We are also examining performances in patients undergoing DBS evaluation for Parkinson Disease to explore its clinical sensitivity. Simpler scoring will permit greater CF clinical and research application.

Construction of predictive algorithms of concussion symptom recovery at 4 and 12 weeks post-injury using an evidence-based assessment (EBA) model to guide clinical decision-making, extending the 2016 5P decision rule.

Children and adolescents, ages 8-18 (n=1,551; mean age=12.78; 62% male), followed over 12 weeks in the prospective multicenter cohort study (Predicting Persistent Post-Concussive Problems in Pediatrics, 5P; Zemek et al., 2016). The age-specific PostConcussion Symptom Inventory (PCSI) (8-12, 17 items; 1318 years, 20 items) was completed at six timepoints from the ED and at 1, 2, 4, 8, and 12-weeks post-injury. Logistic regression analysis was applied to the set of key variables including the PCSI Total Retrospective-Adjusted PostInjury Difference (RAPID) scores, patient demographics and pre-injury history, and injury characteristics to predict participant recovery status (Recovered, Not Recovered) at the 4- and 12-week endpoints. The resulting recovery-predictive equations identified the significant sets of variables with symptom scores at four successive post-injury timepoints (ED, 1, 2, 4 weeks). Logistic Regression Threshold values were established at the 90th CI against which individual patient data was applied to determine recovery status. Participants with sub-threshold sums were deemed recovered at the target endpoint (4- or 12-weeks post-injury).

A total of 19 predictive equations were generated for the two age groups across the recovery timeline. Four sets of equations were developed to predict symptom recovery status at 4-weeks post-injury for the two age groups (8-12 AUC=0.679-0.884; 13-18 AUC=0.752-0.909). Prediction of symptom recovery status at 12-weeks post-injury yielded six equations for the 8-12 age group (AUC=0.723-0.825), and five equations for the 13-18 age group (AUC=0.724-0.887). Total PCSI RAPID score was identified as a significant variable in each of these 19 equations. Participant sex was identified as significant in 18 of the 19 constructed equations. Other variables that were identified as significant at varying timepoints included age, pre-injury history of learning disability and migraines, and an early post-injury sign in the ED (answering questions more slowly than usual). Examples of the equations include: Week 1 predicting symptom recovery status at 4-weeks: 8-12 yr group-(Sex*.802)+(week 1 Total RAPID Score*.142)+(Age2* .053)+(-3.851) with AUC=0.808; 13-18 yr group-(Sex*.980)+(Week 1 Total RAPID Score*.071)+(-3.261) with AUC=0.861.

Clinicians’ management of the concussion recovery of children and adolescents can benefit from EBA guidance. The 5P dataset (Zemek et al., 2016) provides an important window into “typical” and “atypical” recovery trajectories, establishing an initial predictive decision rule for a 4-week recovery endpoint, at the ED timepoint only, reporting AUC=0.69. The current study extends the prediction modeling using successive post-injury timepoints reflecting a typical management timeline. Symptom reports from both 1- and 2-weeks post injury with patient demographics/ history predicted symptom recovery status at 4- and 12-weeks post-injury, significantly improve predictive accuracy over the ED timepoint alone. These predictive equations, when applied to the individual patient, can serve to assist the clinician’s understanding of the patients’ recovery trajectory, i.e., on track for a typical or atypical recovery, further informing the intervention strategy.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive decline in motor function in all patients and cognitive impairment in a subset of patients. Evidence suggests that cognitive reserve (CR) may protect against cognitive and motor decline in ALS, but less is known about the impact of specific occupational skills and requirements on clinical outcomes in ALS. We expected that a history of working jobs with more complex cognitive demands would protect against cognitive decline, while jobs that require fine and complex motor skills would protect against motor dysfunction.

Participants were 150 ALS patients recruited from the University of Pennsylvania’s Comprehensive ALS Center. Participants underwent clinical and neuropsychological evaluations within 1 year of ALS diagnosis. Cognitive performance was measured using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), which includes ALS-Specific (e.g., verbal fluency, executive functions, language, social cognition) and NonSpecific (e.g., memory, visuospatial functions) composite scores. Motor functioning was measured using the Penn Upper Motor Neuron (UMN) scale and the ALS Functional Rating Scale (ALS-FRS). Occupational skills and requirements for each participant were assessed using data from the Occupational Information Network (O*NET) Database. O*NET data were assessed using principal components analysis, and 17 factor scores were derived representing distinct worker characteristics (n=5), occupational requirements (n=7), and worker requirements (n=5). These scores were entered as independent variables in multiple linear regression models using ECAS, UMN, and ALS-FRS scores as dependent variables covarying for education.

Preserved ECAS ALS-Specific performance was associated with jobs that involve greater reasoning abilities (ß=2.03, S.E.=0.79, p<.05), analytic skills (ß=3.08, S.E.=0.91, p<.001), and humanities knowledge (ß=1.20, S.E.=0.58, p<.05), as well as less exposure to environmental hazards (ß=-2.42, S.E.=0.76, p<.01) and fewer demands on visualperceptual (ß=-1.75, S.E.=0.73, p<.05) and technical skills (ß=-1.62, S.E.=0.63, p<.05). Preserved ECAS Non-Specific performance was associated with jobs that involve greater exposure to conflict (ß=0.82, S.E.=0.33, p<.05) and social abilities (ß=0.65, S.E.=0.29, p<.05). Jobs involving greater precision skills (ß=1.92, S.E.=0.79, p<.05) and reasoning ability (ß=2.10, S.E.=0.95, p<.05) were associated with greater disease severity on the UMN, while jobs involving more health services knowledge were associated with worse motor functioning on the ALS-FRS (ß=-1.30, S.E.=0.60, p<.05).

Specific occupational skills and requirements show protective effects on cognitive functioning in ALS, while others confer risk for cognitive and motor dysfunction. Preserved cognitive functioning was linked to a history of employment in jobs requiring strong reasoning abilities, social skills, and humanities knowledge, while poorer cognitive functioning was linked to jobs involving a high risk of exposure to environmental hazards and high visuo-perceptual and technical demands. In contrast, we did not find evidence of motor reserve, as no protective effects of occupational skills and requirements were found for motor symptoms, and jobs involving greater precision skills, reasoning abilities, and health services knowledge were linked to worse motor functioning. Our findings offer new insights into how occupational history may protect against cognitive impairment or confer elevated risk for cognitive and motor dysfunction in ALS.

Therapeutics targeting frontotemporal dementia (FTD) are entering clinical trials. There are challenges to conducting these studies, including the relative rarity of the disease. Remote assessment tools could increase access to clinical research and pave the way for decentralized clinical trials. We developed the ALLFTD Mobile App, a smartphone application that includes assessments of cognition, speech/language, and motor functioning. The objectives were to determine the feasibility and acceptability of collecting remote smartphone data in a multicenter FTD research study and evaluate the reliability and validity of the smartphone cognitive and motor measures.

A diagnostically mixed sample of 207 participants with FTD or from familial FTD kindreds (CDR®+NACC-FTLD=0 [n=91]; CDR®+NACC-FTLD=0.5 [n=39]; CDR®+NACC-FTLD>1 [n=39]; unknown [n=38]) were asked to remotely complete a battery of tests on their smartphones three times over two weeks. Measures included five executive functioning (EF) tests, an adaptive memory test, and participant experience surveys. A subset completed smartphone tests of balance at home (n=31) and a finger tapping test (FTT) in the clinic (n=11). We analyzed adherence (percentage of available measures that were completed) and user experience. We evaluated Spearman-Brown split-half reliability (100 iterations) using the first available assessment for each participant. We assessed test-retest reliability across all available assessments by estimating intraclass correlation coefficients (ICC). To investigate construct validity, we fit regression models testing the association of the smartphone measures with gold-standard neuropsychological outcomes (UDS3-EF composite [Staffaroni et al., 2021], CVLT3-Brief Form [CVLT3-BF] Immediate Recall, mechanical FTT), measures of disease severity (CDR®+NACC-FTLD Box Score & Progressive Supranuclear Palsy Rating Scale [PSPRS]), and regional gray matter volumes (cognitive tests only).

Participants completed 70% of tasks. Most reported that the instructions were understandable (93%), considered the time commitment acceptable (97%), and were willing to complete additional assessments (98%). Split-half reliability was excellent for the executive functioning (r’s=0.93-0.99) and good for the memory test (r=0.78). Test-retest reliabilities ranged from acceptable to excellent for cognitive tasks (ICC: 0.70-0.96) and were excellent for the balance (ICC=0.97) and good for FTT (ICC=0.89). Smartphone EF measures were strongly associated with the UDS3-EF composite (ß's=0.6-0.8, all p<.001), and the memory test was strongly correlated with total immediate recall on the CVLT3-BF (ß=0.7, p<.001). Smartphone FTT was associated with mechanical FTT (ß=0.9, p=.02), and greater acceleration on the balance test was associated with more motor features (ß=0.6, p=0.02). Worse performance on all cognitive tests was associated with greater disease severity (ß's=0.5-0.7, all p<.001). Poorer performance on the smartphone EF tasks was associated with smaller frontoparietal/subcortical volume (ß's=0.4-0.6, all p<.015) and worse memory scores with smaller hippocampal volume (ß=0.5, p<.001).

These results suggest remote digital data collection of cognitive and motor functioning in FTD research is feasible and acceptable. These findings also support the reliability and validity of unsupervised ALLFTD Mobile App cognitive tests and provide preliminary support for the motor measures, although further study in larger samples is required.

Interventions using a cognitive training paradigm called the Useful Field of View (UFOV) task have shown to be efficacious in slowing cognitive decline. However, no studies have looked at the engagement of functional networks during UFOV task completion. The current study aimed to (a) assess if regions activated during the UFOV fMRI task were functionally connected and related to task performance (henceforth called the UFOV network), (b) compare connectivity of the UFOV network to 7 resting-state functional connectivity networks in predicting proximal (UFOV) and near-transfer (Double Decision) performance, and (c) explore the impact of network segregation between higher-order networks and UFOV performance.

336 healthy older adults (mean age=71.6) completed the UFOV fMRI task in a Siemens 3T scanner. UFOV fMRI accuracy was calculated as the number of correct responses divided by 56 total trials. Double Decision performance was calculated as the average presentation time of correct responses in log ms, with lower scores equating to better processing speed. Structural and functional MRI images were processed using the default pre-processing pipeline within the CONN toolbox. The Artifact Rejection Toolbox was set at a motion threshold of 0.9mm and participants were excluded if more than 50% of volumes were flagged as outliers. To assess connectivity of regions associated with the UFOV task, we created 10 spherical regions of interest (ROIs) a priori using the WFU PickAtlas in SPM12. These include the bilateral pars triangularis, supplementary motor area, and inferior temporal gyri, as well as the left pars opercularis, left middle occipital gyrus, right precentral gyrus and right superior parietal lobule. We used a weighted ROI-to-ROI connectivity analysis to model task-based within-network functional connectivity of the UFOV network, and its relationship to UFOV accuracy. We then used weighted ROI-to-ROI connectivity analysis to compare the efficacy of the UFOV network versus 7 resting-state networks in predicting UFOV fMRI task performance and Double Decision performance. Finally, we calculated network segregation among higher order resting state networks to assess its relationship with UFOV accuracy. All functional connectivity analyses were corrected at a false discovery threshold (FDR) at p<0.05.

ROI-to-ROI analysis showed significant within-network functional connectivity among the 10 a priori ROIs (UFOV network) during task completion (all pFDR<.05). After controlling for covariates, greater within-network connectivity of the UFOV network associated with better UFOV fMRI performance (pFDR=.008). Regarding the 7 resting-state networks, greater within-network connectivity of the CON (pFDR<.001) and FPCN (pFDR=. 014) were associated with higher accuracy on the UFOV fMRI task. Furthermore, greater within-network connectivity of only the UFOV network associated with performance on the Double Decision task (pFDR=.034). Finally, we assessed the relationship between higher-order network segregation and UFOV accuracy. After controlling for covariates, no significant relationships between network segregation and UFOV performance remained (all p-uncorrected>0.05).

To date, this is the first study to assess task-based functional connectivity during completion of the UFOV task. We observed that coherence within 10 a priori ROIs significantly predicted UFOV performance. Additionally, enhanced within-network connectivity of the UFOV network predicted better performance on the Double Decision task, while conventional resting-state networks did not. These findings provide potential targets to optimize efficacy of UFOV interventions.

General cognitive ability (g) is central to our understanding of human cognition, as it accounts for nearly half of individual differences in performances on diverse cognitive tests. There is growing interest in the brain networks necessary for g because such knowledge could elucidate neural mechanisms of g. Prior work highlighted the association between g and frontoparietal functional networks. However, the specificity of this relationship has been questioned. Moreover, no studies have compared the relative importance of structural and functional networks for g, and most studies have relied on data from neurologically healthy individuals, which limits causal brain-behavior inference. Lesion network mapping (LNM) can overcome such limitations. LNM integrates lesion location and structural and functional brain network data, and allows for inference upon networks necessary for cognitive functions. Here, we used data from three cohorts of patients with focal brain lesions to perform a large-scale LNM study of g. We also compared the relative value of lesion-behavior mapping, and structural and functional LNM, for predicting g across cohorts.

Using data from 402 individuals with chronic, focal brain lesions from the Iowa Neurological Patient Registry, we created a bifactor model to estimate g from the shared variance across neuropsychological tests. To create “cognitive comparisons,” we also estimated the unique aspects of domain-specific abilities (visuospatial processing, memory, and processing speed) by removing domain-general variance from each. Next, we used multivariate lesion-behavior mapping to create statistically weighted maps linking deficits in g and domain-specific abilities to regions of focal brain damage. To perform LNM, the local maxima of the lesion-behavior maps were used as seeds for structural and functional connectivity analyses based on normative diffusion-weighted imaging and resting-state functional connectivity data, respectively. The resulting maps were collapsed using principal components analysis (PCA). We quantified the overlap between each map and the lesion volumes of patients from two validation cohorts (n = 101, n = 100). We used these scores to predict observed g in the validation cohorts while controlling for lesion volume. We also compared the relative predictive value of the lesion-behavior maps, and the structural and functional LNMs.

Lesion-behavior mapping indicated that lesions of left frontal white matter, bilateral frontal operculum/insula, and a region of white matter in the posterior left hemisphere were associated with impairments in g. Across all lesion-behavior mapping and LNM results, only two of the structural LNM maps linked to g were statistically significantly predictive of g in both validation cohorts: a map corresponding to the anterior thalamic radiation, and another corresponding to left frontal pyramidal projections. Both added value beyond lesion-behavior mapping and functional LNM.

The results are notable in several respects: they highlight the importance of structural networks for g, de-emphasize the relevance of functional networks for g, and suggest novel brain circuitry involved in g. Our findings are consistent with animal studies implicating anterior thalamic nuclei in working memory, a cognitive function central to g. Clinically, our study highlights the importance of considering domain-general deficits and the effects of focal lesions on distributed cognitive networks.

Set-shifting/switching tasks, among other measures of executive functioning, are typically thought to represent frontal lobe functioning. However, the neuroanatomical correlates of these tests are not fully established. The aim of this study was to examine associations between individual measures of set-shifting/switching and cortical thickness. We hypothesized that performance on each switching measure would strongly correlate with aggregated cortical thickness within the frontal lobe.

Measures of interest included set-shifting subtests of the Delis-Kaplan Executive Function System (DKEFS): Color-Word Inhibition Switching, Category Switching, and Trail Making Test Number-Letter Switching. Archival data from an outpatient memory disorders clinic were reviewed to identify individuals whose neuropsychological evaluations included the measures of interest and had quality-assessed, volumetric MRI data available (n=243; 53.1% male, 81.9% Caucasian, Mage=72.4, SDage=6.7). Cortical thickness values were generated by FreeSurfer and averages were calculated for both frontal and temporal lobes, separately. Using partial correlations, controlling for age, we explored associations between each switching trial separately with right and left, frontal and temporal cortical thickness. The strength of associations within each lobe were then compared using Fisher's r-to-z transformations.

Category Switching was significantly correlated with left and right hemisphere temporal thickness (r=0.38 and 0.31, respectively), but was not significantly correlated with left or right frontal lobe cortical thickness (r=.12 and .07, respectively). Fisher's r-to-z transformations revealed significantly stronger relationships between Category Switching and temporal thickness, rather than frontal thicknesses. Trails Switching was also significantly correlated with left and right temporal cortical thickness (r=-0.28, and =-0.23, respectively) and bore weaker associations with frontal cortical thickness (r=-.13 and r = -.14 for left and right hemispheres, respectively). In contrast, Color-Word Inhibition-Switching did not show a significant relationship with frontal or temporal cortical thickness.

Contrary to our hypothesis, stronger associations were observed with temporal lobe cortical thickness for Category Switching. Category Switching involves a language production component which could explain the strong association with temporal cortical thickness compared to frontal cortical thickness. Additionally, the pattern of associations between Trails Switching and frontal and temporal thickness was non-specific. Perhaps most striking is the lack of association between each switching measure and frontal cortical thickness, which was unexpected, given that these measures are used to assess executive functioning, broadly localized to the frontal lobe. Future directions involve examining the associations of these measure with subcortical structures and replicating these findings in larger datasets.

White matter hyperintensity (WMH) burden is greater, has a frontal-temporal distribution, and is associated with proxies of exposure to repetitive head impacts (RHI) in former American football players. These findings suggest that in the context of RHI, WMH might have unique etiologies that extend beyond those of vascular risk factors and normal aging processes. The objective of this study was to evaluate the correlates of WMH in former elite American football players. We examined markers of amyloid, tau, neurodegeneration, inflammation, axonal injury, and vascular health and their relationships to WMH. A group of age-matched asymptomatic men without a history of RHI was included to determine the specificity of the relationships observed in the former football players.

240 male participants aged 45-74 (60 unexposed asymptomatic men, 60 male former college football players, 120 male former professional football players) underwent semi-structured clinical interviews, magnetic resonance imaging (structural T1, T2 FLAIR, and diffusion tensor imaging), and lumbar puncture to collect cerebrospinal fluid (CSF) biomarkers as part of the DIAGNOSE CTE Research Project. Total WMH lesion volumes (TLV) were estimated using the Lesion Prediction Algorithm from the Lesion Segmentation Toolbox. Structural equation modeling, using Full-Information Maximum Likelihood (FIML) to account for missing values, examined the associations between log-TLV and the following variables: total cortical thickness, whole-brain average fractional anisotropy (FA), CSF amyloid ß42, CSF p-tau181, CSF sTREM2 (a marker of microglial activation), CSF neurofilament light (NfL), and the modified Framingham stroke risk profile (rFSRP). Covariates included age, race, education, APOE z4 carrier status, and evaluation site. Bootstrapped 95% confidence intervals assessed statistical significance. Models were performed separately for football players (college and professional players pooled; n=180) and the unexposed men (n=60). Due to differences in sample size, estimates were compared and were considered different if the percent change in the estimates exceeded 10%.

In the former football players (mean age=57.2, 34% Black, 29% APOE e4 carrier), reduced cortical thickness (B=-0.25, 95% CI [0.45, -0.08]), lower average FA (B=-0.27, 95% CI [-0.41, -.12]), higher p-tau181 (B=0.17, 95% CI [0.02, 0.43]), and higher rFSRP score (B=0.27, 95% CI [0.08, 0.42]) were associated with greater log-TLV. Compared to the unexposed men, substantial differences in estimates were observed for rFSRP (Bcontrol=0.02, Bfootball=0.27, 994% difference), average FA (Bcontrol=-0.03, Bfootball=-0.27, 802% difference), and p-tau181 (Bcontrol=-0.31, Bfootball=0.17, -155% difference). In the former football players, rFSRP showed a stronger positive association and average FA showed a stronger negative association with WMH compared to unexposed men. The effect of WMH on cortical thickness was similar between the two groups (Bcontrol=-0.27, Bfootball=-0.25, 7% difference).

These results suggest that the risk factor and biological correlates of WMH differ between former American football players and asymptomatic individuals unexposed to RHI. In addition to vascular risk factors, white matter integrity on DTI showed a stronger relationship with WMH burden in the former football players. FLAIR WMH serves as a promising measure to further investigate the late multifactorial pathologies of RHI.

The locus coeruleus (LC) innervates the cerebrovasculature and plays a crucial role in optimal regulation of cerebral blood flow. However, no human studies to date have examined links between these systems with widely available neuroimaging methods. We quantified associations between LC structural integrity and regional cortical perfusion and probed whether varying levels of plasma Alzheimer’s disease (AD) biomarkers (Aß42/40 ratio and ptau181) moderated these relationships.

64 dementia-free community-dwelling older adults (ages 55-87) recruited across two studies underwent structural and functional neuroimaging on the same MRI scanner. 3D-pCASL MRI measured regional cerebral blood flow in limbic and frontal cortical regions, while T1-FSE MRI quantified rostral LC-MRI contrast, a well-established proxy measure of LC structural integrity. A subset of participants underwent fasting blood draw to measure plasma AD biomarker concentrations (Aß42/40 ratio and ptau181). Multiple linear regression models examined associations between perfusion and LC integrity, with rostral LC-MRI contrast as predictor, regional CBF as outcome, and age and study as covariates. Moderation analyses included additional terms for plasma AD biomarker concentration and plasma x LC interaction.

Greater rostral LC-MRI contrast was linked to lower regional perfusion in limbic regions, such as the amygdala (ß = -0.25, p = 0.049) and entorhinal cortex (ß = -0.20, p = 0.042), but was linked to higher regional perfusion in frontal cortical regions, such as the lateral (ß = 0.28, p = 0.003) and medial (ß = 0.24, p = 0.05) orbitofrontal (OFC) cortices. Plasma amyloid levels moderated the relationship between rostral LC and amygdala CBF (Aß42/40 ratio x rostral LC interaction term ß = -0.31, p = 0.021), such that as plasma Aß42/40 ratio decreased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and amygdala perfusion decreased. Plasma ptau181levels moderated the relationship between rostral LC and entorhinal CBF (ptau181 x rostral LC interaction term ß = 0.64, p = 0.001), such that as ptau181 increased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and entorhinal perfusion decreased. For frontal cortical regions, ptau181 levels moderated the relationship between rostral LC and lateral OFC perfusion (ptau181 x rostral LC interaction term ß = -0.54, p = .004), as well as between rostral LC and medial OFC perfusion (ptau181 x rostral LC interaction term ß = -0.53, p = .005), such that as ptau181 increased (i.e., greater pathology), the strength of the positive relationship between rostral LC integrity and frontal perfusion decreased.

LC integrity is linked to regional cortical perfusion in non-demented older adults, and these relationships are moderated by plasma AD biomarker concentrations. Variable directionality of the associations between the LC and frontal versus limbic perfusion, as well as the differential moderating effects of plasma AD biomarkers, may signify a compensatory mechanism and a shifting pattern of hyperemia in the presence of aggregating AD pathology. Linking LC integrity and cerebrovascular regulation may represent an important understudied pathway of dementia risk and may help to bridge competing theories of dementia progression in preclinical AD studies.

White matter hyperintensities (WMH) are a radiological marker of small vessel cerebrovascular disease that are related to cognition and memory decline in aging and Alzheimer’s disease (AD). However, the mechanisms that link WMH to memory impairment and whether they interact with or act independently of AD pathophysiology are unclear. The transentorhinal cortex (BA35) is among the earliest anatomical regions to show tau deposition and subsequent atrophy, and baseline posterior WMH is related to longitudinal cortical thinning of the entorhinal cortex. However, it is unclear whether regional WMH are related to BA35 volume specifically, and whether this relationship is influenced by amyloid-β (Aβ) burden. We hypothesized that WMH in the vascular territory of the posterior cerebral artery (PCA), which perfuses both posterior and medial temporal lobe regions, would be associated with reduced BA35 volume and with lower memory in older adults independently of Aβ.

114 older adults without dementia, aged 60 to 98 years (mean (SD) = 78.31 (11.02), 71 (62.8%) women), were included. Regional WMH volumes were derived from T2-FLAIR images using ANTs, a vascular territory atlas and manual editing. Global Aβ was assessed with 18F-florbetapir PET, using SUVR of a cortical composite region (FBP mean SUVR) with a cerebellar reference region. Total transentorhinal (BA35) volume was derived using T1 and T2-weighted images using ASHS. To assess hippocampal pattern separation ability, an index of episodic memory, participants completed both object (MDT-O) and spatial (MDT-S) versions of a mnemonic discrimination task, with the lure discrimination index as the outcome. Using linear regressions, we first tested for associations among PCA-defined WMH, Aβ, BA35 volume, and MDT-S and MDT-O scores. We then tested whether the relationship between PCA-defined WMH and MDT-O performance was mediated by BA35 volume and whether this mediation was moderated by Aβ. All models adjusted for age, sex, and education.

PCA-defined WMH were related to higher FBP mean SUVR (b=0.287, p=0.042) and lower BA35 volume (b=-0.222, p=0.038). PCA-defined WMH were also negatively related to MDT-O performance (b=-0.229, p=0.044), but not to MDT-S (b=-0.171, p=0.118). FBP mean SUVR was not related to BA35 volume (b=-0.131, p=0.344) or MDT performance (MDT-S: b=-0.138, p=0.348; MDT-O: b=0.059, p=0.690). Furthermore, FBP mean SUVR did not interact with PCA-defined WMH to predict memory performance (interaction b=-0.039, p=0.973), nor BA35 volume (interaction b=-0.140, p=0.894). The association of PCA-defined WMH to MDT-O was fully mediated by BA35 volume (indirect effect b=-0.0005, 95% CI (-0.0014, -0.0003)). This mediation was not moderated by FBP mean SUVR (indirect effect b=-0.00001, 95% CI (-0.001, 0.001)).

We found that PCA-defined WMH were related to memory performance in older adults, and this association is fully mediated by transentorhinal volume. While PCA-defined WMH are related to higher global Aβ burden, there is no interaction between PCA-defined WMH and Aβ on BA35 volume. These findings point to an amyloid-independent vascular pathway towards memory decline in aging and AD. Future work should examine whether the pathway linking PCA-defined WMH to transentorhinal cortex atrophy and subsequent memory decline is mediated by regional tau pathology.

Fetal alcohol spectrum disorder (FASD) is a common neurodevelopmental condition associated with deficits in cognitive functioning (executive functioning [EF], attention, working memory, etc.), behavioral impairments, and abnormalities in brain structure including cortical and subcortical volumes. Rates of comorbid attention-deficit/hyperactivity disorder (ADHD) are high in children with FASD and contribute to significant functional impairments. Sluggish cognitive tempo (SCT) includes a cluster of symptoms (e.g. underactive/slow-moving, confusion, fogginess, daydreaming) found to be related to but distinct from ADHD, and previous research suggests that it may be common in FASD. We explored SCT by examining the relationship between SCT and both brain volumes (corpus callosum, caudate, and hippocampus) and objective EF measures in children with FASD vs. typically developing controls.

This is a secondary analysis of a larger longitudinal CIFASD study that consisted of 35 children with prenatal alcohol exposure (PAE) and 30 controls between the ages of 9 to 18 at follow-up. Children completed a set of cognitive assessments (WISC-IV, DKEFS, & NIH Toolbox) and an MRI scan, while parents completed the Child Behavior Checklist (CBCL), which includes a SCT scale. We examined group differences between PAE and controls in relation to SCT symptoms, EF scores, and subcortical volumes. Then, we performed within-and between-group comparisons with and without controlling for total intracranial volume, age, attention problems, and ADHD problems between SCT and subcortical brain volumes. Finally, we performed correlations between SCT and EF measures for both groups.

Compared to controls, participants with PAE showed significantly more SCT symptoms on the CBCL (t [57] = 3.66, p = 0.0006), more parent-rated attention problems and ADHD symptoms, lower scores across several EF measures (DKEFS Trail-Making and Verbal Fluency; WISC-IV Digit Span, Symbol Search, and Coding; effect sizes ranging from 0.44 to 1.16), and smaller regional volumes in the caudate, hippocampus, and posterior areas of the corpus callosum. In the PAE group, a smaller hippocampus was associated with more SCT symptoms (controlling for parent-rated attention problems and ADHD problems, age, and intracranial volume). However, in the control group, a larger mid posterior and posterior corpus callosum were significantly associated with more SCT symptoms (controlling for parent-rated attention problems, intracranial volume, and age; r [24] = 0.499, p = 0.009; r [24] = 0.517, p = 0.007). In terms of executive functioning, children in the PAE group with more SCT symptoms performed worse on letter sequencing of the Trail-Making subtest (controlling attention problems & ADHD symptoms). In comparison, those in the control group with more SCT symptoms performed better on letter sequencing and combined number letter sequencing of the Trail-Making subtest (controlling attention problems).

Findings suggest that children with FASD experience elevated SCT symptoms compared to typically developing controls, which may be associated with worse performance on EF tasks and smaller subcortical volumes (hippocampus) when taking attention difficulties and ADHD symptoms into account. Additional research into the underlying causes and correlates of SCT in FASD could result in improved tailoring of interventions for this population.

Fetal alcohol spectrum disorder (FASD) is a life-long condition, and few interventions have been developed to improve the neurodevelopmental course in this population. Early interventions targeting core neurocognitive deficits have the potential to confer long-term neurodevelopmental benefits. Time-targeted choline supplementation is one such intervention that has been shown to provide neurodevelopmental benefits that emerge with age during childhood. We present a long-term follow-up study evaluating the neurodevelopmental effects of early choline supplementation in children with FASD approximately 7 years on average after an initial efficacy trial. In this study, we examine treatment group differences in executive function (EF) outcomes and diffusion MRI of the corpus callosum using the Neurite Orientation Dispersion and Density Index (NODDI) biophysical model.

The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2.5- to 5-year-olds with FASD. Participants in this long-term follow-up study included 18 children (9 placebo; 9 choline) seen 7 years on average following initial trial completion. The mean age at follow-up was 11 years old. Diagnoses were 28% fetal alcohol syndrome (FAS), 28% partial FAS, and 44% alcohol-related neurodevelopmental disorder. The follow-up evaluation included measures of executive functioning (WISC-V Picture Span and Digit Span; DKEFS subtests) and diffusion MRI (NODDI).

Children who received choline early in development outperformed those in the placebo group across a majority of EF tasks at long-term follow-up (effect sizes ranged from -0.09 to 1.27). Children in the choline group demonstrated significantly better performance on several tasks of lower-order executive function skills (i.e., DKEFS Color Naming [Cohen's d = 1.27], DKEFS Word Reading [Cohen's d = 1.13]) and showed potentially better white matter microstructure organization (as indicated by lower orientation dispersion; Cohen's d = -1.26) in the splenium of the corpus callosum compared to the placebo group. In addition, when collapsing across treatment groups, higher white matter microstructural organization was associated with better performance on several EF tasks (WISC-V Digit Span; DKEFS Number Sequencing and DKEFS Word Reading).

These findings highlight long-term benefits of choline as a neurodevelopmental intervention for FASD and suggest that changes in white matter organization may represent an important target of choline in this population. Unique to this study is the use of contemporary biophysical modeling of diffusion MRI data in youth with FASD. Findings suggest this neuroimaging approach may be particularly useful for identifying subtle white matter differences in FASD as well as neurobiological responses to early intervention associated with important cognitive functions.

Motor skills have been linked to executive functions (EFs) in typically developing school-, and preschool-age children. Yet fine motor skills have been more consistently correlated with EFs than gross motor skills, perhaps because they are more frequently investigated. Preterm born children are vulnerable to deficits in both gross and fine motor skills, even after exclusion of neurological cases. In addition to motor skills, EFs may also be compromised in preterm born preschoolers. Because premature birth increases the odds for atypical brain development, and since adverse effects on brain functioning tend to yield increased dispersion of performance scores, we wished to determine whether fine and gross motor skills are differentially linked to performance on tasks measuring EF skills in nonhandicapped preschoolers born preterm.

We studied 99 preterm (born < 34 weeks) singleton preschoolers (3-4 years of age; 50 females), all graduates of the Neonatal Intensive Care Unit at William Beaumont Hospital, Royal Oak, MI. Motor skills were assessed with the Peabody Developmental Motor Scales - (Second Edition) which provide Fine and Gross Motor Quotients (FMQ, and GMQ, respectively). Three core EFs were measured: working memory, motor inhibition, and verbal fluency. Working memory skills were assessed with two Clinical Evaluation of Language Fundamentals - Preschool -Second Edition subtests: Recalling Sentences (RS) and Concepts and Following Directions (CFD). Motor inhibition and verbal fluency were assessed with the NEPSY-II Statue and Word Generation (WG) subtests, respectively. Children with a history of moderate to severe intracranial pathology or cerebral palsy were excluded.

We conducted linear regression analyses using scaled scores from the Statue, WG, RS, and CFD subtests as the predicted variables. Predictors of interest were the FMQ and GMQ. We adjusted for sociodemographic factors (SES and sex) and perinatal risk (gestational age, sum of antenatal complications and birth weight SD). The GMQ was significantly associated with all four EF measures (Statue, t(84) = 4.13, p < .001; CFD, t(92) = 3.83, p < .001; WG, t(84) = 3.38, p = .001; RS, t(90) = 3.37, p = .001). The FMQ was significantly associated with three of four EF measures (Statue, t(84) = 3.41, p = .001; CFD, t(92) = 3.97, p < .001; WG, t(84) = 1.96, p = .054; RS, t(90) = 2.91, p = .005).

Both fine and gross motor skills were associated with EF in nonhandicapped preterm-born singletons. Lower motor functioning in either motor domain was linked to reduction in performance on diverse EF measures. It should be emphasized that motor performance contributed to explaining variance in EFs even after statistical adjustment for early medical risk. In addition to the obvious conclusion that motor skills may underpin EF skills, it is likely that early risk factors not captured by the medical risk variables used in our analyses were nonetheless tapped by variability in motor performance. As preschool EFs are essential for subsequent academic performance, the significance of age-appropriate motor development in the preschool age should not be underestimated in our at-risk population.