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.

Don't be late! Postponing cognitive decline and preventing early unemployment in people with multiple sclerosis: a study protocol.

BACKGROUND: Up to 65% of people with multiple sclerosis (PwMS) develop cognitive deficits, which hampers their ability to work, participating in day-to-day life and ultimately reducing quality of life (QoL). Early cognitive symptoms are often less tangible to PwMS and their direct environment and are noticed only when symptoms and work functioning problems become more advanced, i.e., when (brain) damage is already advanced. Treatment of symptoms at a late stage can lead to cognitive impairment and unemployment, highlighting the need for preventative interventions in PwMS. AIMS: This study aims to evaluate the (cost-) effectiveness of two innovative preventative interventions, aimed at postponing cognitive decline and work functioning problems, compared to enhanced usual care in improving health-related QoL (HRQoL). METHODS: Randomised controlled trial including 270 PwMS with mild cognitive impairment, who have paid employment ≥ 12 h per week and are able to participate in physical exercise (Expanded Disability Status Scale < 6.0). Participants are randomised across three study arms: 1) 'strengthening the brain' - a lifestyle intervention combining personal fitness, mental coaching, dietary advice, and cognitive training; 2) 'strengthening the mind' - a work-focused intervention combining the capability approach and the participatory approach in one-on-one coaching by trained work coaches who have MS themselves; 3) Control group-receiving general information about cognitive impairment in MS and receiving care as usual. Intervention duration is four months, with short-term and long-term follow-up measurements at 10 and 16 months, respectively. The primary outcome measure of the Don't be late! intervention study will be HRQoL as measured with the 36-item Short Form. Secondary outcomes include cognition, work related outcomes, physical functioning, structural and functional brain changes, psychological functioning, and societal costs. Semi-structured interviews and focus groups with stakeholders will be organised to qualitatively reflect on the process and outcome of the interventions. DISCUSSION: This study seeks to prevent (further) cognitive decline and job loss due to MS by introducing tailor-made interventions at an early stage of cognitive symptoms, thereby maintaining or improving HRQoL. Qualitative analyses will be performed to allow successful implementation into clinical practice. TRIAL REGISTRATION: Retrospectively registered at ClinicalTrials.gov with reference number NCT06068582 on 10 October 2023.

Don't be late! Timely identification of cognitive impairment in people with multiple sclerosis: a study protocol.

BACKGROUND: Cognitive impairment occurs in up to 65% of people with multiple sclerosis (PwMS), negatively affecting daily functioning and health-related quality of life. In general, neuropsychological testing is not part of standard MS-care due to insufficient time and trained personnel. Consequently, a baseline assessment of cognitive functioning is often lacking, hampering early identification of cognitive decline and change within a person over time. To assess cognitive functioning in PwMS in a time-efficient manner, a BICAMS-based self-explanatory digital screening tool called the Multiple Screener©, has recently been developed. The aim of the current study is to validate the Multiple Screener© in a representative sample of PwMS in the Netherlands. Additionally, we aim to investigate how cognitive functioning is related to psychological factors, and both work and societal participation. METHODS: In this cross-sectional multicentre study, 750 PwMS (aged 18-67 years) are included. To obtain a representative sample, PwMS are recruited via 12 hospitals across the Netherlands. They undergo assessment with the Minimal Assessment of Cognitive Functioning in MS (MACFIMS; reference-standard) and the Multiple Screener©. Sensitivity, specificity, and predictive values for identifying (mild) cognitive impairment are determined in a subset of 300 participants. In a second step, the identified cut-off values are tested in an independent subset of at least 150 PwMS. Moreover, test-retest reliability for the Multiple Screener© is determined in 30 PwMS. Information on psychological and work-related factors is assessed with questionnaires. DISCUSSION: Validating the Multiple Screener© in PwMS and investigating cognition and its determinants will further facilitate early identification and adequate monitoring of cognitive decline in PwMS.

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.

Developmental and age differences in visuomotor adaptation across the lifespan.

In the present cross-sectional study, we examined age and sex differences in sensorimotor adaptation. We tested 253 individuals at a local science museum (NEMO Science Museum, Amsterdam). Participants spanned a wide age range (8-70 years old; 54% male), allowing us to examine effects of both development and healthy aging within a single study. Participants performed a visuomotor adaptation task in which they had to adapt manual joystick movements to rotated visual feedback. We assessed the rate of adaptation following the introduction of the visual perturbation (both for early and later stages of adaptation), and the rate of de-adaptation following its removal. Results showed reliable adaptation patterns which did not differ by sex. We observed a quadratic relationship between age and both early adaptation and de-adaptation rates, with younger and older adults exhibiting the fasted adaptation rates. Our findings suggest that both younger and older age are associated with poorer strategic, cognitive processes involved in adaptation. We propose that developmental and age differences in cognitive functions and brain properties may underlie these effects on sensorimotor functioning.

Testing the dopamine overdose hypothesis in action control: A study in people with Parkinson's disease.

Prior work on patients with Parkinson's disease (PD) has shown that the administration of dopaminergic medication in the early to intermediate stages of PD benefits (motor) functions associated with the dopamine-depleted dorsal striatal circuitry but may 'overdose' and interfere with (cognitive) functions associated with the relatively intact ventral striatal circuitry. The present study aimed to elucidate this so-called dopamine overdose hypothesis for the action control domain. Using a within-subject design in a sample of 13 people with PD, we evaluated the effect of dopaminergic medication on two cognitive processes underlying goal-directed behaviour, namely action selection and initiation through event binding and conflict adaptation. We also investigated whether individual differences in the magnitude of medication effects were associated across these processes. Results showed no indications that dopaminergic medication affects action selection and initiation or conflict adaptation in PD patients. Additionally, we observed no correlations between both cognitive processes nor between individual differences in medication effects. Our findings do not support the notion that dopaminergic medication modulates action control processes, suggesting that the dopamine overdose hypothesis may only apply to a specific set of cognitive processes and should potentially be refined.

Effects of exploring a novel environment on memory across the lifespan.

Exploration of a novel environment has been shown to promote memory formation in healthy adults. Studies in animals have suggested that such novelty-induced memory boosts are mediated by hippocampal dopamine. The dopaminergic system is known to develop and deteriorate over the lifespan, but so far, the effects of novelty on memory across the lifespan have not yet been investigated. In the current study, we had children, adolescents, younger, and older adults (n = 439) explore novel and previously familiarized virtual environments to pinpoint the effects of spatial novelty on declarative memory in humans across different age groups. After exploration, words were presented while participants performed a deep or shallow encoding task. Incidental memory was quantified in a surprise test. Results showed that participants in the deep encoding condition remembered more words than those in the shallow condition, while novelty did not influence this effect. Interestingly, however, children, adolescents and younger adults benefitted from exploring a novel compared to a familiar environment as evidenced by better word recall, while these effects were absent in older adults. Our findings suggest that the beneficial effects of novelty on memory follow the deterioration of neural pathways involved in novelty-related processes across the lifespan.

Neural correlates of risky decision making in Parkinson's disease patients with impulse control disorders.

Some patients with Parkinson's disease (PD) experience impulse control disorders (ICDs), characterized by deficient voluntary control over impulses, drives, or temptations regarding excessive hedonic behavior. The present study aimed to better understand the neural basis of impulsive, risky decision making in PD patients with ICDs by disentangling potential dysfunctions in decision and outcome mechanisms. We collected fMRI data from 20 patients with ICDs and 28 without ICDs performing an information gathering task. Patients viewed sequences of bead colors drawn from hidden urns and were instructed to infer the majority bead color in each urn. With each new bead, they could choose to either seek more evidence by drawing another bead (draw choice) or make an urn-inference (urn choice followed by feedback). We manipulated risk via the probability of bead color splits (80/20 vs. 60/40) and potential loss following an incorrect inference ($10 vs. $0). Patients also completed the Barratt Impulsiveness Scale (BIS) to assess impulsivity. Patients with ICDs showed greater urn choice-specific activation in the right middle frontal gyrus, overlapping the dorsal premotor cortex. Across all patients, fewer draw choices (i.e., more impulsivity) were associated with greater activation during both decision making and outcome processing in a variety of frontal and parietal areas, cerebellum, and bilateral striatum. Our findings demonstrate that ICDs in PD are associated with differences in neural processing of risk-related information and outcomes, implicating both reward and sensorimotor dopaminergic pathways.

Trait Anxiety as a Risk Factor for Impulse Control Disorders in de novo Parkinson's Disease.

BACKGROUND: In addition to the well-known motor symptoms, patients with Parkinson's disease (PD) also frequently experience disabling non-motor symptoms including impulse control disorders (ICDs). ICDs are characterized by a loss of voluntary control over impulses, drives, or temptations regarding excessive hedonic behavior. OBJECTIVE: The present study examined whether depression and anxiety in de novo PD patients predict the prospective development of ICDs. METHODS: We selected 330 de novo PD patients from the Parkinson's Progression Markers Initiative database who were free of ICDs at the start of the study. ICD presence at baseline and follow-up assessments was evaluated via the shortened version of the Questionnaire for Impulsive-Compulsive Disorders (QUIP-S). Baseline depression and anxiety were measured via the Geriatric Depression Scale (GDS-15) and State-Trait-Anxiety Inventory (STAI-Y), respectively. RESULTS: A total of 149 participants (45.2%) developed an ICD at follow-up and average time of ICD onset was 35 months after baseline. Results of a Cox regression analysis showed that STAI-Y scores but not GDS-15 scores significantly predicted ICD presence. Specifically, scores reflecting higher trait anxiety were associated with an increased risk of developing an ICD. This effect was not confounded by age, gender or UPDRS motor score. We also replicated the well-established result that dopamine agonist use is predictive of ICDs. CONCLUSION: Our findings indicate that higher anxiety levels in de novo PD patients represent a risk factor for ICD development during the course of the disorder. This highlights the need for early and routine based anxiety screening in these patients.

Novelty exposure induces stronger sensorimotor representations during a manual adaptation task.

Active exploration of novel spatial environments enhances memory for subsequently presented explicit, declarative information in humans. These effects have been attributed to novelty promoting dopamine release via mesolimbic dopaminergic pathways in the brain. As procedural motor learning has been linked to dopamine as well, we predict that novelty effects extend to this domain. To test this hypothesis, the present study examined whether spatial novelty exploration benefits subsequent sensorimotor adaptation. Participants explored either two different virtual environments (i.e., novelty condition; n = 210) or two identical environments (i.e., familiar condition; n = 253). They then performed a manual adaptation task in which they had to adapt joystick movements to a visual perturbation. We assessed the rate of adaptation following the introduction of this perturbation, and the rate of deadaptation following its removal. While results showed reliable adaptation patterns and similar adaptation rates across both conditions, individuals in the novelty condition showed slower deadaptation. This suggests that exposure to spatial novelty induced stronger sensorimotor representations during adaptation, potentially through novelty-induced dopaminergic effects in mesocortical and/or nigrostriatal pathways. Novelty exposure may be employed to promote motor learning on tasks that require precision movements in altered sensory contexts, for example, in astronauts moving in microgravity or patients with impaired motor processing.

Cognition in Motion: Evidence for Intact Action Control With Healthy Aging.

OBJECTIVES: Healthy aging is associated with impairments in motor functioning. Such functioning is not limited to the physical execution of actions, but also involves cognitive processes that allow for goal-directed behavior. The present study examined whether aging affects 2 of such cognitive components that control motor functioning, namely action planning and action adaptation, and whether age effects are associated across components. METHOD: A group of 103 participants aged 18-82 years performed 2 tasks that have previously been linked to action planning and adaptation, respectively. RESULTS: Despite observations that aging was associated with slower and less accurate responses, Bayesian models showed evidence indicating that older age was not associated with poorer action planning and conflict adaptation. DISCUSSION: These findings challenge the view that healthy aging is associated with a general deficit in motor functioning and suggest that some cognitive aspects of motor control may be relatively spared.

Cognitive and Affective Theory of Mind in Healthy Aging.

BACKGROUND: Previous studies on the effect of healthy aging on Theory of Mind (ToM) have produced mixed results. A possible explanation may be that different ToM components and types of inference have not systematically been considered. This study examined the effect of aging on ToM by assessing both first and second order cognitive and affective components within a single task. METHODS: We compared performance of young (M = 18.3y) and older adults (M = 61.0y) on the Yoni task. This task allows for a within-subject assessment of both first and second order cognitive and affective ToM. RESULTS: We observed that older adults had longer reaction times than young adults across cognitive and affective first order items. For second order items, this age difference was larger for affective than cognitive items. Results showed no indications that these findings could be explained by age differences in speed/accuracy trade-offs. CONCLUSION: Our findings suggest that decision processes underlying ToM are slower in older adults on both first and second order inferences, but that age differences in these processes between cognitive and affective ToM are selective to second order inferences. We propose that the observed age differences may be associated with cortical and mental changes that occur with aging.

Neural Dedifferentiation across the Lifespan in the Motor and Somatosensory Systems.

Age-related declines in sensorimotor performance have been linked to dedifferentiation of neural representations (i.e., more widespread activity during task performance in older versus younger adults). However, it remains unclear whether changes in neural representations across the adult lifespan are related between the motor and somatosensory systems, and whether alterations in these representations are associated with age declines in motor and somatosensory performance. To investigate these issues, we collected functional magnetic resonance imaging and behavioral data while participants aged 19-76 years performed a visuomotor tapping task or received vibrotactile stimulation. Despite one finding indicative of compensatory mechanisms with older age, we generally observed that 1) older age was associated with greater activity and stronger positive connectivity within sensorimotor and LOC regions during both visuomotor and vibrotactile tasks; 2) increased activation and stronger positive connectivity were associated with worse performance; and 3) age differences in connectivity in the motor system correlated with those in the somatosensory system. Notwithstanding the difficulty of disentangling the relationships between age, brain, and behavioral measures, these results provide novel evidence for neural dedifferentiation across the adult lifespan in both motor and somatosensory systems and suggest that dedifferentiation in these two systems is related.

Age-Related Reductions in Tactile and Motor Inhibitory Function Start Early but Are Independent.

Aging is associated with declines in motor and somatosensory function. Some of these motor declines have been linked to age-related reductions in inhibitory function. Here we examined whether tactile surround inhibition also changes with age and whether these changes are associated with those in the motor domain. We tested a group of 56 participants spanning a wide age range (18-76 years old), allowing us to examine when age differences emerge across the lifespan. Participants performed tactile and motor tasks that have previously been linked to inter- and intra-hemispheric inhibition in the somatosensory and motor systems. The results showed that aging is associated with reductions in inhibitory function in both the tactile and motor systems starting around 40 years of age; however, age effects in the two systems were not correlated. The independent effects of age on tactile and motor inhibitory function suggest that distinct mechanisms may underlie age-related reductions in inhibition in the somatosensory and motor systems.

Learning to be in control involves response-specific mechanisms.

Conflict adaptation refers to our ability to modulate our attention in line with changing situational demands, so we can engage in goal-directed behavior. While there is ample evidence demonstrating that such adaptation in conflict tasks can be captured using different response modalities, it remains unknown whether these effects rely on domain-general mechanisms applied to different response modalities, or are the result of more inherently response-specific processes. Here, we used an individual-differences approach to evaluate whether conflict adaptation in two highly similar tasks using different response modalities are related. Specifically, participants performed two versions of a Stroop task, one in which they responded via key presses and one in which they responded via mouse movements. In both tasks, we manipulated the item-specific proportion of (in)congruent trials (80% vs. 20% congruent). This allowed us to evaluate the item-specific proportion congruency (ISPC) effect, a hallmark indicator of conflict adaptation. ISPC effects were observed in both response modalities. However, we found no indications that individual differences in the ISPC effects of the two response modalities were related. This raises the question whether findings from studies on conflict adaptation measured by different modalities can reliably be compared. Furthermore, these results suggest that response modality plays a more integrative role in these adaptive processes, rather than being the mere output of a domain-general control mechanism. This is consistent with contingency learning accounts of the ISPC effect and associative learning models of cognitive control.

The effect of dopaminergic medication on conflict adaptation in Parkinson's disease.

Parkinson's disease (PD) is a neurological disorder associated primarily with motor symptoms such as tremor, slowness of movement, and difficulties with gait and balance. Most patients take dopaminergic medication to improve their motor functions. Previous studies reported indications that such medication can impair higher cognitive functions (cf. dopamine overdose hypothesis). In the present study, we examined the effect of medication status on conflict adaptation. PD patients performed a Stroop task in which we manipulated the proportion of congruent and incongruent items, thereby allowing us to explore conflict adaptation. The use of mouse movements allowed us to examine the action dynamics of conflict adaptation in PD, and their sensitivity to dopaminergic medication. Each patient performed the same task twice: once without making changes to their regular medication regime, and once after overnight withdrawal from their medication. Results showed that medication improved mouse movements and alleviated motor symptoms. Moreover, patients' mouse movements were modulated as a function of the proportion congruency manipulation, revealing conflict adaptation in PD, which was unaffected by medication status. The present study extends earlier work on conflict adaptation in PD where reduced transient (trial-by-trial) conflict adaptation was observed ON compared to OFF medication (Duthoo et al., 2013, Neuropsychology, 27, 556). Our findings suggest that more sustained cognitive control processes may not be sensitive to dopamine overdose effects.