Classification of Mild Cognitive Impairment and Alzheimer's Disease Using Manual Motor Measures.

INTRODUCTION: Manual motor problems have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), but the specific aspects that are affected, their neuropathology, and potential value for classification modeling is unknown. The current study examined if multiple measures of motor strength, dexterity, and speed are affected in MCI and AD, related to AD biomarkers, and are able to classify MCI or AD. METHODS: Fifty-three cognitively normal (CN), 33 amnestic MCI, and 28 AD subjects completed five manual motor measures: grip force, Trail Making Test A, spiral tracing, finger tapping, and a simulated feeding task. Analyses included (1) group differences in manual performance; (2) associations between manual function and AD biomarkers (PET amyloid ß, hippocampal volume, and APOE ε4 alleles); and (3) group classification accuracy of manual motor function using machine learning. RESULTS: Amnestic MCI and AD subjects exhibited slower psychomotor speed and AD subjects had weaker dominant hand grip strength than CN subjects. Performance on these measures was related to amyloid ß deposition (both) and hippocampal volume (psychomotor speed only). Support vector classification well-discriminated control and AD subjects (area under the curve of 0.73 and 0.77, respectively) but poorly discriminated MCI from controls or AD. CONCLUSION: Grip strength and spiral tracing appear preserved, while psychomotor speed is affected in amnestic MCI and AD. The association of motor performance with amyloid ß deposition and atrophy could indicate that this is due to amyloid deposition in and atrophy of motor brain regions, which generally occurs later in the disease process. The promising discriminatory abilities of manual motor measures for AD emphasize their value alongside other cognitive and motor assessment outcomes in classification and prediction models, as well as potential enrichment of outcome variables in AD clinical trials.

Evidence and sources of placebo effects in transcranial direct current stimulation during a single session of visuospatial working memory practice.

Transcranial direct current stimulation (tDCS) can be used to non-invasively augment cognitive training. However, the benefits of tDCS may be due in part to placebo effects, which have not been well-characterized. The purpose of this study was to determine whether tDCS can have a measurable placebo effect on cognitive training and to identify potential sources of this effect. Eighty-three right-handed adults were randomly assigned to one of three groups: control (no exposure to tDCS), sham tDCS, or active tDCS. The sham and active tDCS groups were double-blinded. Each group performed 20 min of an adapted Corsi Block Tapping Task (CBTT), a visuospatial working memory task. Anodal or sham tDCS was applied during CBTT training in a right parietal-left supraorbital montage. After training, active and sham tDCS groups were surveyed on expectations about tDCS efficacy. Linear mixed effects models showed that the tDCS groups (active and sham combined) improved more on the CBTT with training than the control group, suggesting a placebo effect of tDCS. Participants' tDCS expectations were significantly related to the placebo effect, as was the belief of receiving active stimulation. This placebo effect shows that the benefits of tDCS on cognitive training can occur even in absence of active stimulation. Future tDCS studies should consider how treatment expectations may be a source of the placebo effect in tDCS research, and identify ways to potentially leverage them to maximize treatment benefit.

White Matter Microstructure Analysis in Subjective Memory Complaints and Cognitive Impairment: Insights from Diffusion Kurtosis Imaging and Free-Water DTI.

Background: Dementia is characterized by a cognitive decline in memory and other domains that lead to functional impairments. As people age, subjective memory complaints (SMC) become common, where individuals perceive cognitive decline without objective deficits on assessments. SMC can be an early sign and may precede amnestic mild cognitive impairment (MCI), which frequently advances to Alzheimer's disease (AD). Objective: This study aims to investigate white matter microstructure in individuals with SMC, in cognitively impaired (CI) cohorts, and in cognitively normal individuals using diffusion kurtosis imaging (DKI) and free water imaging (FWI). The study also explores voxel-based correlations between DKI/FWI metrics and cognitive scores to understand the relationship between brain microstructure and cognitive function. Methods: Twelve healthy controls (HCs), ten individuals with SMC, and eleven CI individuals (MCI or AD) were enrolled in this study. All participants underwent MRI 3T scan and the BNI Screen (BNIS) for Higher Cerebral Functions. Results: The mean kurtosis tensor and anisotropy of the kurtosis tensor showed significant differences across the three groups, indicating altered white matter microstructure in CI and SMC individuals. The free water volume fraction (f) also revealed group differences, suggesting changes in extracellular water content. Notably, these metrics effectively discriminated between the CI and HC/SMC groups. Additionally, correlations between imaging metrics and BNIS scores were found for CI and SMC groups. Conclusions: These imaging metrics hold promise in discriminating between individuals with CI and SMC. The observed differences indicate their potential as sensitive and specific biomarkers for early detection and differentiation of cognitive decline.

Age and sex effects on Super G performance are consistent across internet devices.

There have been recent advances in the application of online games that assess motor skill acquisition/learning and its relationship to age and biological sex, both of which are associated with dementia risk. While this online motor learning assessment (called Super G), along with other computer-based cognitive tests, was originally developed to be completed on a computer, many people (including older adults) have been shown to access the internet through a mobile device. Thus, to improve the generalizability of our online motor skill learning game, it must not only be compatible with mobile devices but also yield replicable effects of various participant characteristics on performance relative to the computer-based version. It is unknown if age and sex differentially affect game performance as a function of device type (keyboard versus touchscreen control). Thus, the purpose of this study was to investigate if device type modifies the established effects of age and sex on performance. Although there was a main effect of device on performance, this effect did not alter the overall relationship between performance vs. age or sex. This establishes that Super G can now effectively be extended to both computer and mobile platforms to further test for dementia risk factors.

Delayed and More Variable Unimanual and Bimanual Finger Tapping in Alzheimer's Disease: Associations with Biomarkers and Applications for Classification.

BACKGROUND: Despite reports of gross motor problems in mild cognitive impairment (MCI) and Alzheimer's disease (AD), fine motor function has been relatively understudied. OBJECTIVE: We examined if finger tapping is affected in AD, related to AD biomarkers, and able to classify MCI or AD. METHODS: Forty-seven cognitively normal, 27 amnestic MCI, and 26 AD subjects completed unimanual and bimanual computerized tapping tests. We tested 1) group differences in tapping with permutation models; 2) associations between tapping and biomarkers (PET amyloid-ß, hippocampal volume, and APOEɛ4 alleles) with linear regression; and 3) the predictive value of tapping for group classification using machine learning. RESULTS: AD subjects had slower reaction time and larger speed variability than controls during all tapping conditions, except for dual tapping. MCI subjects performed worse than controls on reaction time and speed variability for dual and non-dominant hand tapping. Tapping speed and variability were related to hippocampal volume, but not to amyloid-ß deposition or APOEɛ4 alleles. Random forest classification (overall accuracy = 70%) discriminated control and AD subjects, but poorly discriminated MCI from controls or AD. CONCLUSIONS: MCI and AD are linked to more variable finger tapping with slower reaction time. Associations between finger tapping and hippocampal volume, but not amyloidosis, suggest that tapping deficits are related to neuropathology that presents later during the disease. Considering that tapping performance is able to differentiate between control and AD subjects, it can offer a cost-efficient tool for augmenting existing AD biomarkers.

Placebo effects of transcranial direct current stimulation on motor skill acquisition.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique used in neurorehabilitation to enhance motor training. However, its benefits to motor training can be difficult to reproduce across research studies. It is possible that the observed benefits of tDCS are not directly related to the intervention itself but rather to the brain-mind responses elicited by the treatment context, commonly known as a placebo effect. This study investigated the presence of a placebo effect of tDCS on motor training and explored potential underlying factors. Sixty-eight participants who were right-handed were randomly assigned to active tDCS, sham tDCS, or a no-stimulation control group. Double-blind active or sham tDCS was applied to the right primary motor cortex, while the unblinded control group received no stimulation. All participants completed 30 training trials of a functional upper-extremity motor task. Participants' beliefs of tDCS, along with their prior knowledge of tDCS, were also collected. There was no significant difference in the amount of improvement on the motor task between the active and sham tDCS groups; however, both active and sham tDCS groups improved more than the control group, indicating a placebo effect. More motor task improvement was also associated with higher beliefs of tDCS (regardless of whether active or sham tDCS was received). This demonstrates a measurable placebo effect of tDCS on motor training, driven at least in part by treatment expectations or beliefs. Future tDCS studies should control for beliefs and other placebo-related factors.

Establishing the Validity and Reliability of an Online Motor Learning Game: Applications for Alzheimer's Disease Research Within MindCrowd.

Objective: Motor practice effects (i.e., improvements in motor task performance with practice) are emerging as a unique variable that can predict Alzheimer's disease (AD) progression and biomarker positivity. However, the tasks used to study motor practice effects have involved face-to-face assessment, making them difficult to integrate into large internet-based cohorts that represent the next generation of AD research. The purpose of this study was to validate an online computer game against its in-lab version, which has been shown previously to characterize motor practice effects. Materials and Methods: This study leveraged young adult participants within the MindCrowd electronic cohort, a large nationwide cohort for AD research collected entirely through the internet. Validation compared performance on the online version among MindCrowd users against an age-matched cohort's performance on an in-lab version using a different controller (Xbox 360 controller joystick for in-lab sample versus keyboard arrow keys for online sample). Results: Data indicated that the rate of skill acquisition among MindCrowd users were not significantly different from those of the in-lab cohort. Furthermore, the contact-to-consent rate observed in this study (although low) was similar to that of other online AD cohorts. Conclusion: Overall, this study demonstrates that implementing online games designed to study and measure motor practice effects into online research cohorts is feasible and valid. Future research will explore how online game performance is associated with age and dementia risk factors that may help further an understanding of AD.

Volumetric regional MRI and neuropsychological predictors of motor task variability in cognitively unimpaired, Mild Cognitive Impairment, and probable Alzheimer's disease older adults.

INTRODUCTION: The mechanisms linking motor function to Alzheimer's disease (AD) progression have not been well studied, despite evidence of AD pathology within motor brain regions. Thus, there is a need for new motor measure that is sensitive and specific to AD. METHODS: In a sample of 121 older adults (54 cognitive unimpaired [CU], 35 amnestic Mild Cognitive Impairment [aMCI], and 32 probable mild AD), intrasubject standard deviation (ISD) across six trials of a novel upper-extremity motor task was predicted with volumetric regional gray matter and neuropsychological scores using classification and regression tree (CART) analyses. RESULTS: Both gray matter and neuropsychological CART models indicated that motor task ISD (our measure of motor learning) was related to cortical regions and cognitive test scores associated with memory, executive function, and visuospatial skills. CART models also accurately distinguished motor task ISD of MCI and probable mild AD from CU. DISCUSSION: Variability in motor task performance across practice trials may be valuable for understanding preclinical and early-stage AD.

Mediation Analysis of the Effect of Visuospatial Memory on Motor Skill Learning in Older Adults.

There is high inter-individual variability in motor skill learning among older adults. Identifying the nature of these individual differences remains challenging due to interactions between participant characteristics (e.g., age, cognition) and task-related factors (e.g., nature of task, level of skill pre-training), making it difficult to determine plausibly causal relationships. This study addresses these competing explanations by using mediation analysis to examine plausible causal inference between visuospatial memory and one-month retention of both gross and fine motor components of a functional upper-extremity task following training. Results suggest that better visuospatial memory results in more retention of fine but not gross motor skill, expanding on previous correlational studies in older adults and informing future interventions for maximizing motor learning in geriatric populations.

Efficacy of Corsi Block Tapping Task training for improving visuospatial skills: a non-randomized two-group study.

Even though impaired visuospatial abilities can negatively affect daily functioning, there are very few training programs that attempt to improve visuospatial abilities. The purpose of this study was to examine if a single training session with a computerized version of the Corsi Block Tapping Task could improve mental rotation skills. Fifty-three young adults were assigned to one of two groups: (1) control group (mean age = 21.4; 10 females), who had 20 min of rest after their baseline assessment, or (2) training group (mean age = 21.5; 17 females), who had 20 min of training on the Corsi Block Tapping Task after their baseline assessment. The primary outcome was reaction time on a computer-based mental rotation task, and it was assessed both before and after the rest or training. There was a significant interaction between time (pre vs. post) and group (control vs. training) on mental rotation performance (p = 0.04), with the training group performing on average 124 ms faster on accurate trials than the control group at post-test. This preliminary study suggested that improving mental rotation may be feasible through targeted cognitive training. Future studies will consider multiple sessions of Corsi Block Tapping Task training to maximize training benefits (i.e., dose-response), as well as longer term retention in cognitively intact and impaired individuals.

Rey-Osterrieth complex figure recall scores and motor skill learning in older adults: A non-linear mixed effect model-based analysis.

Age-related declines in motor learning are well documented. Visuospatial memory has been proposed as a key factor explaining age-related declines in sensorimotor adaptation, but most studies have not used standardized visuospatial memory tests nor controlled for age-related visuospatial memory declines. The present study explores the relationship between visuospatial memory and motor learning in older adults while also controlling for age and utilizing a standardized visuospatial memory test. Forty-nine nondemented older adults repetitively practiced a functional upper-extremity motor task and were re-assessed one week later. Training data were modeled with mixed-effect exponential decay functions, with parameters representing amount of performance change, rate of improvement, and final performance. Age and visuospatial memory were included as possible covariates for the parameter measuring rate of improvement (τ). After controlling for age, higher visuospatial memory scores were associated with faster rates of skill acquisition and better short-term retention one week later. These associations with visuospatial memory were dependent, however, on the level of initial skill. These findings suggest that the extent of re-learning motor skills in geriatric physical rehabilitation may depend on intact visuospatial memory.

Personalized practice dosages may improve motor learning in older adults compared to "standard of care" practice dosages: A randomized controlled trial.

Standard dosages of motor practice in clinical physical rehabilitation are insufficient to optimize motor learning, particularly for older patients who often learn at a slower rate than younger patients. Personalized practice dosing (i.e., practicing a task to or beyond one's plateau in performance) may provide a clinically feasible method for determining a dose of practice that is both standardized and individualized, and may improve motor learning. The purpose of this study was to investigate whether personalized practice dosages [practice to plateau (PtP) and overpractice (OVP)] improve retention and transfer of a motor task, compared to low dose [LD] practice that mimics standard clinical dosages. In this pilot randomized controlled trial (NCT02898701, ClinicalTrials.gov), community-dwelling older adults (n = 41, 25 female, mean age 68.9 years) with a range of balance ability performed a standing serial reaction time task in which they stepped to specific targets. Presented stimuli included random sequences and a blinded repeating sequence. Participants were randomly assigned to one of three groups: LD (n = 15, 6 practice trials equaling 144 steps), PtP (n = 14, practice until reaching an estimated personal plateau in performance), or OVP (n = 12, practice 100% more trials after reaching an estimated plateau in performance). Measures of task-specific learning (i.e., faster speed on retention tests) and transfer of learning were performed after 2-4 days of no practice. Learning of the random sequence was greater for the OVP group compared to the LD group (p = 0.020). The OVP (p = 0.004) and PtP (p = 0.010) groups learned the repeated sequence more than the LD group, although the number of practice trials across groups more strongly predicted learning (p = 0.020) than did group assignment (OVP vs. PtP, p = 0.270). No group effect was observed for transfer, although significant transfer was observed in this study as a whole (p < 0.001). Overall, high and personalized dosages of postural training were well-tolerated by older adults, suggesting that this approach is clinically feasible. Practicing well-beyond standard dosages also improved motor learning. Further research should determine the clinical benefit of this personalized approach, and if one of the personalized approaches (PtP vs. OVP) is more beneficial than the other for older patients.

Using whole-brain diffusion tensor analysis to evaluate white matter structural correlates of delayed visuospatial memory and one-week motor skill retention in nondemented older adults: A preliminary study.

Skill retention is important for motor rehabilitation outcomes. Recent work has demonstrated that delayed visuospatial memory performance may predict motor skill retention in older and neuropathological populations. White matter integrity between parietal and frontal cortices may explain variance in upper-extremity motor learning tasks and visuospatial processes. We performed a whole-brain analysis to determine the white matter correlates of delayed visuospatial memory and one-week motor skill retention in nondemented older adults. We hypothesized that better frontoparietal tract integrity would be positively related to better behavioral performance. Nineteen participants (age>58) completed diffusion-weighted imaging, then a clinical test of delayed visuospatial memory and 50 training trials of an upper-extremity motor task; participants were retested on the motor task one week later. Principal component analysis was used to create a composite score for each participant's behavioral data, i.e. shared variance between delayed visuospatial memory and motor skill retention, which was then entered into a voxel-based regression analysis. Behavioral results demonstrated that participants learned and retained their skill level after a week of no practice, and their delayed visuospatial memory score was positively related to the extent of skill retention. Consistent with previous work, neuroimaging results indicated that regions within bilateral anterior thalamic radiations, corticospinal tracts, and superior longitudinal fasciculi were related to better delayed visuospatial memory and skill retention. Results of this study suggest that the simple act of testing for specific cognitive impairments prior to therapy may identify older adults who will receive little to no benefit from the motor rehabilitation regimen, and that these neural regions may be potential targets for therapeutic intervention.

Improving Prediction of Amyloid Deposition in Mild Cognitive Impairment With a Timed Motor Task.

Cortical amyloid deposition is one of the hallmark biomarkers of Alzheimer's disease (AD). However, given how cost- and time-intensive amyloid imaging can be, there is a continued need for a low-cost, non-invasive, and accessible enrichment strategy to pre-screen individuals for their likelihood of amyloid prior to imaging. Previous work supports the use of coordinated limb movement as a potential screening tool, even after controlling for cognitive and daily function. Thirty-six patients diagnosed with amnestic mild cognitive impairment over the age of 65 underwent 18F-Flutemetamol amyloid-positron emission tomography (PET) imaging and then completed a timed motor task involving upper limb coordination. This task takes ∼5 minutes to administer and score. Multivariate linear regression and receiver operator characteristic analyses showed that including motor task performance improved model prediction of amyloid burden. Results support the rationale for including functional upper extremity motor assessment as a cost- and time-effective means to screen participants for amyloid deposition.

Association Between Motor Task Performance and Hippocampal Atrophy Across Cognitively Unimpaired, Amnestic Mild Cognitive Impairment, and Alzheimer's Disease Individuals.

Hippocampal atrophy is a widely used biomarker for Alzheimer's disease (AD), but the cost, time, and contraindications associated with magnetic resonance imaging (MRI) limit its use. Recent work has shown that a low-cost upper extremity motor task has potential in identifying AD risk. Fifty-four older adults (15 cognitively unimpaired, 24 amnestic mild cognitive impairment, and 15 AD) completed six motor task trials and a structural MRI. Several measures of motor task performance significantly predicted bilateral hippocampal volume, controlling for age, sex, education, and memory. Thus, this motor task may be an affordable, non-invasive screen for AD risk and progression.

Remote, Unsupervised Functional Motor Task Evaluation in Older Adults across the United States Using the MindCrowd Electronic Cohort.

COVID-19 has impacted the ability to evaluate motor function in older adults, as motor assessments typically require face-to-face interaction. One hundred seventy-seven older adults nationwide completed an unsupervised functional upper-extremity assessment at home. Data were compared to data from an independent sample of community-dwelling older adults (N = 250) assessed in lab. The effect of age on performance was similar between the in-lab and at-home groups. Practice effects were also similar. Assessing upper-extremity motor function remotely is feasible and reliable in community-dwelling older adults. This test offers a practical solution for telehealth practice and other research involving remote or geographically isolated individuals.

Cognitive and neural predictors of speech comprehension in noisy backgrounds in older adults.

Older adults often experience difficulties comprehending speech in noisy backgrounds, which hearing loss does not fully explain. It remains unknown how cognitive abilities, brain networks, and age-related hearing loss may uniquely contribute to speech in noise comprehension at the sentence level. In 31 older adults, using cognitive measures and resting-state fMRI, we investigated the cognitive and neural predictors of speech comprehension with energetic (broadband noise) and informational masking (multi-speakers) effects. Better hearing thresholds and greater working memory abilities were associated with better speech comprehension with energetic masking. Conversely, faster processing speed and stronger functional connectivity between frontoparietal and language networks were associated with better speech comprehension with informational masking. Our findings highlight the importance of the frontoparietal network in older adults' ability to comprehend speech in multi-speaker backgrounds, and that hearing loss and working memory in older adults contributes to speech comprehension abilities related to energetic, but not informational masking.

Generalizing the predictive relationship between 1-month motor skill retention and Rey-Osterrieth Delayed Recall scores from nondemented older adults to individuals with chronic stroke: a short report.

Motor learning is fundamental to motor rehabilitation outcomes. There is growing evidence from non-neurological populations supporting the role of visuospatial memory function in motor learning, but current predictive models of motor recovery of individuals with stroke generally exclude cognitive measures, thereby overlooking the potential link between motor learning and visuospatial memory. Recent work has demonstrated that a clinical test of visuospatial memory (Rey-Osterrieth Complex Figure Delayed Recall) may predict 1-month skill learning in older adults; however, whether this relationship persists in individuals with chronic stroke remains unknown. The purpose of this short report was to validate previous findings using Rey-Osterrieth Complex Figure Delayed Recall test scores to predict motor learning and determine if this relationship generalized to a set of individuals post-stroke. Two regression models (one including Delayed Recall scores and one without) were trained using data from non-stroke older adults. To determine the extent to which Delayed Recall test scores impacted prediction accuracy of 1-month skill learning in older adults, we used leave-one-out cross-validation to evaluate the prediction error between models. To test if this predictive relationship generalized to individuals with chronic ischemic stroke, we then tested each trained model on an independent stroke dataset. Results indicated that in both stroke and older adult datasets, inclusion of Delayed Recall scores explained significantly more variance of 1-month skill performance than models that included age, education, and baseline motor performance alone. This proof-of-concept suggests that the relationship between delayed visuospatial memory and 1-month motor skill performance generalizes to individuals with chronic stroke, and supports the idea that visuospatial testing may provide prognostic insight into clinical motor rehabilitation outcomes.

Remote, unsupervised functional motor task evaluation in older adults across the United States using the MindCrowd electronic cohort.

The COVID-19 pandemic has impacted the ability to evaluate motor function in older adults, as motor assessments typically require face-to-face interaction. This study tested whether motor function can be assessed at home. One hundred seventy-seven older adults nationwide (recruited through the MindCrowd electronic cohort) completed a brief functional upper-extremity assessment at home and unsupervised. Performance data were compared to data from an independent sample of community-dwelling older adults (N=250) assessed by an experimenter in-lab. The effect of age on performance was similar between the in-lab and at-home groups for both the dominant and non-dominant hand. Practice effects were also similar between the groups. Assessing upper-extremity motor function remotely is feasible and reliable in community-dwelling older adults. This test offers a practical solution in response to the COVID-19 pandemic and telehealth practice and other research involving remote or geographically isolated individuals.