Decline In Motor Function Research Articles

PCR174 Characterizing Progressive Disease Burden amid Heterogeneity: Data Visualizations for Ambulatory Motor Function in Duchenne Muscular Dystrophy (DMD)

DMD is an X-linked recessive disorder that causes progressive loss of muscle function in affected patients. Given variation in ages at symptom onset and rates of motor function decline, we aimed to develop data visualizations characterizing typical patterns of disease progression amid heterogeneity.

Decreased gray matter volume in the right middle temporal gyrus associated with cognitive dysfunction in preeclampsia superimposed on chronic hypertension.

The effects of preeclampsia superimposed on chronic hypertension (CHTN-PE) on the structure and function of the human brain are mostly unknown. The purpose of this study was to examine altered gray matter volume (GMV) and its correlation with cognitive function in pregnant healthy women, healthy non-pregnant individuals, and CHTN-PE patients. Twenty-five CHTN-PE patients, thirty-five pregnant healthy controls (PHC) and thirty-five non-pregnant healthy controls (NPHC) were included in this study and underwent cognitive assessment testing. A voxel-based morphometry (VBM) approach was applied to investigate variations in brain GMV among the three groups. Pearson's correlations between mean GMV and the Stroop color-word test (SCWT) scores were calculated. Compared with the NPHC group, the PHC and CHTN-PE groups showed significantly decreased GMV in a cluster of the right middle temporal gyrus (MTG), and the GMV decrease was more significant in the CHTN-PE group. There were significant differences in the Montreal Cognitive Assessment (MoCA) and Stroop word scores among the three groups. Notably, the mean GMV values in the right MTG cluster were not only significantly negatively correlated with Stroop word and Stroop color scores but also significantly distinguished CHTN-PE patients from the NPHC and PHC groups in receiver operating characteristic curve analysis. Pregnancy may cause a decrease in local GMV in the right MTG, and the GMV decrease is more significant in CHTN-PE patients. The right MTG affects multiple cognitive functions, and combined with the SCWT scores, it may explain the decline in speech motor function and cognitive flexibility in CHTN-PE patients.

Pose detection using deep learning for gait assessment

This approach of gait analysis helps in solving the problems associated with the health of aged people by concentrating on the frailty and senility syndromes that affect elderly individuals. Deterioration of cognitive and motor abilities is a common result of ageing and has an effect on elderly people's quality of life. Some studies have connected these changes in gait patterns to the decline in cognitive and motor function. As a result, gait analysis is a useful tool for diagnosing senility and frailty diseases. By transferring the pose estimation data to a correct statistical analysis, gait analysis can be carried out utilizing machine learning and computer vision approach, allowing physiotherapists to analyse and treat patients accordingly. The main problem observed is that physiotherapists will analyse stroke patients' walking patterns on their own. As a result, this approach solves the problem by providing an accurate result of the observation. As everything is computerised, proper treatment can be provided with accurate data. A physiotherapist could also use machine learning classification techniques to analyse and classify the observed disorder and correct it. Our study mainly focuses on using machine learning approach instead of traditional sensor based or consultation just by vision. This will serve as a newer and better proposition of the same.

Patient and procedural risk factors for decline in lower-extremity motor scores following adult spinal deformity surgery.

The purpose of this study was to discern factors that differentiate patients who experience postoperative lower-extremity motor function decline in the early postoperative period. Adult spinal deformity (ASD) patients who were enrolled in a multicenter, observational, and prospectively collected study from 2018 to 2021 at 18 spinal deformity centers in North America were queried. Eligible participants met at least one of the following radiographic and/or procedural inclusion criteria: pelvic incidence minus lumbar lordosis (PI-LL) ≥ 25°, T1 pelvic angle (T1PA) ≥ 30°, sagittal vertical axis (SVA) ≥ 15 cm, thoracic scoliosis ≥ 70°, thoracolumbar scoliosis ≥ 50°, global coronal malalignment ≥ 7 cm, 3-column osteotomy, spinal fusion ≥ 12 levels, and/or age ≥ 65 years with ≥ 7 levels of instrumentation. Patients with an inflammatory or autoimmune disease and those who were incarcerated or pregnant were excluded, as were non-English speakers. Only patients with baseline and 6-week postoperative lower-extremity motor score (LEMS) were analyzed. Patient information, including demographic data, operative data, patient-reported outcomes, and radiographic parameters, were collected. Univariate and multivariable logistic regression models were built to quantify the degree to which a patient's postoperative LEMS decline was related to demographic and clinical characteristics. In total, 205 patients (mean age 61.5 years, mean total instrumented levels 12.6, 67.3% female, 54.2% primary cases, 79.5% with pelvic fixation) were evaluated. Of these 205 patients, 32 (15.5%) experienced LEMS decline in the perioperative period. These patients were older (p = 0.0014) and had greater BMI (p = 0.0176), higher frailty scores (p = 0.047), longer operating room times (p = 0.033), and greater estimated blood loss (p < 0.0001), and they were more frequently observed to have intraoperative neurophysiological monitoring (IONM) changes (p = 0.018). The deteriorated cohort had greater C7SVA at baseline (p = 0.0028) but were comparable in terms of all other radiographic parameters. No radiographic differences were seen between the groups at the 6-week visit; however, the deteriorated cohort experienced greater change in PI-LL (p < 0.0001), lumbar lordosis (p = 0.0461), C7SVA (p = 0.0004), and T1PA (p < 0.0001). Multivariate logistic regression demonstrated that the presence of IONM changes and each degree of negative change in T1PA conferred 3.71 (95% CI 1.01-13.42) and 1.09 (1.01-1.19) greater odds of postoperative LEMS deterioration, respectively. In this study, 15.6% of ASD patients incurred LEMS decline in the perioperative period. The magnitude of change in global sagittal alignment, specifically T1PA, was the strongest independent predictor of LEMS decline, which has implications for surgical planning, patient counseling, and clinical research.

Coenzyme Q10 supplementation improves the motor function of middle-aged mice by restoring the neuronal activity of the motor cortex

Physiological aging causes motor function decline and anatomical and biochemical changes in the motor cortex. We confirmed that middle-aged mice at 15–18 months old show motor function decline, which can be restored to the young adult level by supplementing with mitochondrial electron transporter coenzyme Q10 (CoQ10) as a water-soluble nanoformula by drinking water for 1 week. CoQ10 supplementation concurrently improved brain mitochondrial respiration but not muscle strength. Notably, we identified an age-related decline in field excitatory postsynaptic potential (fEPSP) amplitude in the pathway from layers II/III to V of the primary motor area of middle-aged mice, which was restored to the young adult level by supplementing with CoQ10 for 1 week but not by administering CoQ10 acutely to brain slices. Interestingly, CoQ10 with high-frequency stimulation induced NMDA receptor-dependent long-term potentiation (LTP) in layer V of the primary motor cortex of middle-aged mice. Importantly, the fEPSP amplitude showed a larger input‒output relationship after CoQ10-dependent LTP expression. These data suggest that CoQ10 restores the motor function of middle-aged mice by improving brain mitochondrial function and the basal fEPSP level of the motor cortex, potentially by enhancing synaptic plasticity efficacy. Thus, CoQ10 supplementation may ameliorate the age-related decline in motor function in humans.

Microstructure of Brain Nuclei in Early Parkinson's Disease: Longitudinal Diffusion Kurtosis Imaging.

Diffusion kurtosis imaging provides in vivo measurement of microstructural tissue characteristics and could help guide management of Parkinson's disease. To investigate longitudinal diffusion kurtosis imaging changes on magnetic resonance imaging in the deep grey nuclei in people with early Parkinson's disease over two years, and whether they correlate with disease progression. We conducted a longitudinal case-control study of early Parkinson's disease. 262 people (Parkinson's disease: n = 185, aged 67.5±9.1 years; 43% female; healthy controls: n = 77, aged 66.6±8.1 years; 53% female) underwent diffusion kurtosis imaging and clinical assessment at baseline and two-year timepoints. We automatically segmented five nuclei, comparing the mean kurtosis and other diffusion kurtosis imaging indices between groups and over time using repeated-measures analysis of variance, and Pearson correlation with the two-year change in Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III. At baseline, mean kurtosis was higher in Parkinson's disease than controls in the substantia nigra, putamen, thalamus and globus pallidus when adjusting for age, sex, and levodopa equivalent daily dose (p < 0.027). These differences grew over two years, with mean kurtosis increasing for the Parkinson's disease group while remaining stable for the control group; evident in significant "group ×time" interaction effects for the putamen, thalamus and globus pallidus (ηp2= 0.08-0.11, p < 0.015). However, we did not detect significant correlations between increasing mean kurtosis and declining motor function in the Parkinson's disease group. Diffusion kurtosis imaging of specific grey matter structures shows abnormal microstructure in PD at baseline and abnormal progression in PD over two years.

Cognitive Decline and Mood Alterations in the Mouse Model of Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is a hereditary disorder, caused by an expansion of polyglutamine in the ataxin-2 protein. Although the mutant protein is expressed throughout all the cell and organ types, the cerebellum is primarily affected. The disease progression is mainly accompanied by a decline in motor functions. However, the disturbances in cognitive abilities and low mental state have also been reported in patients. Recent evidence suggests that the cerebellar functionality expands beyond the motor control. Thus, the cerebellum turned out to be involved into the language, verbal working, and spatial memory; executive functions such as working memory, planning, organizing, and strategy formation; and emotional processing. Here, we used the transgenic SCA2-58Q mice to evaluate their anxiety, cognitive functions, and mood alterations. The expression of the mutant ataxin-2 specifically in the cerebellar Purkinje cells (PCs) in SCA2-58Q mice allowed us to study the direct involvement of the cerebellum into the cognitive and affective control. We determined that SCA2-58Q mice exhibit anxiolytic behavior, decline in spatial memory, and a depressive-like state. Our results support the idea of cerebellar involvement in cognitive control and the handling of emotions.

α-Synuclein and Mechanisms of Epigenetic Regulation.

Synucleinopathies are a group of neurodegenerative diseases with common pathological lesions associated with the excessive accumulation and abnormal intracellular deposition of toxic species of α-synuclein. The shared clinical features are chronic progressive decline of motor, cognitive, and behavioral functions. These disorders include Parkinson's disease, dementia with Lewy body, and multiple system atrophy. Vigorous research in the mechanisms of pathology of these illnesses is currently under way to find disease-modifying treatment and molecular markers for early diagnosis. α-Synuclein is a prone-to-aggregate, small amyloidogenic protein with multiple roles in synaptic vesicle trafficking, neurotransmitter release, and intracellular signaling events. Its expression is controlled by several mechanisms, one of which is epigenetic regulation. When transmitted to the nucleus, α-synuclein binds to DNA and histones and participates in epigenetic regulatory functions controlling specific gene transcription. Here, we discuss the various aspects of α-synuclein involvement in epigenetic regulation in health and diseases.

Optimizing the Effect of tDCS on Motor Sequence Learning in the Elderly.

One of the most visible effects of aging, even in healthy, normal aging, is a decline in motor performance. The range of strategies applicable to counteract this deterioration has increased. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique that can promote neuroplasticity, has recently gained attention. However, knowledge about optimized tDCS parameters in the elderly is limited. Therefore, in this study, we investigated the effect of different anodal tDCS intensities on motor sequence learning in the elderly. Over the course of four sessions, 25 healthy older adults (over 65 years old) completed the Serial Reaction Time Task (SRTT) while receiving 1, 2, or 3 mA of anodal or sham stimulation over the primary motor cortex (M1). Additionally, 24 h after stimulation, motor memory consolidation was assessed. The results confirmed that motor sequence learning in all tDCS conditions was maintained the following day. While increased anodal stimulation intensity over M1 showed longer lasting excitability enhancement in the elderly in a prior study, the combination of higher intensity stimulation with an implicit motor learning task showed no significant effect. Future research should focus on the reason behind this lack of effect and probe alternative stimulation protocols.

Asperuloside, the bioactive compound in the edible Eucommia ulmoides male flower, delays muscle aging by daf-16 mediated improvement in mitochondrial dysfunction.

Muscle aging is accompanied by a progressive decline in motor performance and mitochondrial function, yet fundamental treatments for this disorder remain sparse. The search for active compounds from natural dietary products that promote muscular health has attracted considerable interest. Although the male flowers of Eucommia ulmoides Oliv., an emerging resource of plant-based food, have healthspan-promoting efficacy, it's still unclear whether they or their main active compounds (iridoids) could improve muscle aging. We compared the effects of three iridoids on motion status during different aging processes in Caenorhabditis elegans (C. elegans). Additionally, we further investigated the roles and mechanisms of the iridoid-rich floral extract (EUFE) and the most active monomer on nematode age-related muscle hypofunction exacerbated by high fat. We found that EUFE and asperuloside (Asp) significantly improved motility and muscular health and reduced lipid accumulation at appropriate concentrations. Compared to normal mitochondria against muscle disorder, Asp delayed the deterioration of mitochondrial function, morphology, or related metabolism during aging. Meanwhile, Asp regulated the mitochondrial quality control (MQC) network, mainly activating mitophagy, which was associated with increased mRNA and protein expression of lgg-1 and dct-1. Mechanistically, Asp promoted the expression and nuclear localization of the DAF-16 protein, an upstream regulator of the above two autophagy-related genes. The defective mutant and RNA interference further suggested that daf-16 mediated the ameliorative effects of Asp on muscle aging and mitochondrial dysfunction. These results provide potential evidence for the preventive application and functional food development of E. ulmoides male flowers and asperuloside against muscle aging.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

Timed Up and Go Testに着目した新しい運動評価方法の開発

[Purpose] The purpose of this study was to investigate the usefulness of centrifugal acceleration as an indicator for screening early motor function decline using a simple movement measurement system we developed. [Participants and Methods] We measured the Timed Up and Go test (TUG) time using a simple movement measurement system, and investigated frailty in 25 independent healthy elderly people living in the community. [Results] A correlation was found between TUG times and the number of steps taken, and centrifugal accelerations in all subjects. There was no significant difference between the robust and frail groups’ TUG times, but there was a significant difference in centrifugal acceleration. [Conclusion] Centrifugal acceleration may be a more detailed indicator of motor function decline in the elderly.

MR-spectroscopy in metachromatic leukodystrophy: A model free approach and clinical correlation

Background and purposeMetachromatic leukodystrophy (MLD) is a lysosomal enzyme deficiency disorder leading to demyelination and subsequently to a progressive decline in cognitive and motor function. It affects mainly white matter where changes during the course of the disease can be visualized on T2-weighted MRI as hyperintense areas. Associated changes in brain metabolism can be quantified by MR spectroscopy (MRS) and may give complementary information as biomarkers for disease characterisation and progression. Our study aimed to further investigate the correlation of MRS with clinical parameters for motor and cognitive function by using a model free MRS analysis approach that would be precise and straightforward to implement. Materials and methods53 MRS datasets derived from 29 patients (10 late-infantile, 19 juvenile) and 12 controls were acquired using a semi-LASER CSI sequence covering a slice through the centrum semiovale above the corpus callosum. We defined four regions of interest in the white matter (frontal white matter [FWM] and the cortico-spinal tract [CST] area, each left and right) and one in cortical grey matter. Spectra were analysed using a model and fitting free approach by calculating the definite integral of 10 intervals which were distributed along the whole spectrum. These 10 intervals were orientated towards the main peaks of the metabolites N-acetylaspartate (NAA), creatine, myo-inositol, choline, glutamine/glutamate and aspartate to approximately attribute changes in the intervals to corresponding metabolites. Their ratios to the main creatine peak integral were correlated with clinical parameters assessing motor and cognitive abilities. Furthermore, in a post-hoc analysis, NAA levels of a subset of 21 MR datasets were correlated to NAA levels in urine measured by 1H (proton) nuclear magnetic resonance (NMR) spectroscopy.The applied interval integration method was validated in the control cohort against the standard approach, using spectral profile templates of known metabolites (LCModel). Both methods showed good agreement, with coefficients of variance being slightly lower for our approach compared to the related LCModel results. Moreover, the new approach was able to extract information out of the frequency range around the main peaks of aspartate and glutamine where LCModel showed only few usable values for the respective metabolites. ResultsMLD spectra clearly differed from controls. The most pronounced differences were found in white matter (much less in grey matter), with larger values corresponding to main peaks of myo-inositol, choline and aspartate, and smaller values associated with NAA and glutamine. Late-infantile patients had more severe changes compared to later-onset patients, especially in intervals corresponding to NAA, aspartate, myo-inositol, choline and glutamine.There was a high correlation of several intervals in the corticospinal tract region with motor function (with the most relevant interval corresponding to NAA peak with a correlation coefficient of −0.75; p < 0.001), while cognitive function, by means of IQ, was found to be most correlating in frontal white matter corresponding to the NAA peak (r = 0.84, p < 0.001).The post-hoc analysis showed that the main NAA peak interval correlated negatively with the NAA in urine (r = −0.584, p < 0.001). ConclusionThe applied model and fitting free interval integration approach to analyse MRS data of a semi-LASER sequence at 3T suits well to detect and quantify pathological changes in MLD patients through the different courses of the disease and correlates well with clinical symptoms while showing smaller dimensions of variation compared to the more sophisticated single metabolite analysis using LCModel. NAA seems the most clinically meaningful biomarker to use in this context. Its correlation with urine measurements further underlines its potential as a clinically and biologically useful parameter of disease progression in MLD.

Anti-α-synuclein c-terminal antibodies block PFF uptake and accumulation of phospho-synuclein in preclinical models of Parkinson's disease

Parkinson's disease (PD), a neurodegenerative disease affecting dopaminergic (DA) neurons, is characterized by decline of motor function and cognition. Dopaminergic cell loss is associated with accumulation of toxic alpha synuclein aggregates. As DA neuron death occurs late in the disease, therapeutics that block the spread of alpha synuclein may offer functional benefit and delay disease progression. To test this hypothesis, we generated antibodies to the C terminal region of synuclein with high nanomolar affinity and characterized them in in vitro and in vivo models of spread. Interestingly, we found that only antibodies with high affinity to the distal most portion of the C-terminus robustly reduced uptake of alpha synuclein preformed fibrils (PFF) and accumulation of phospho (S129) alpha synuclein in cell culture. Additionally, the antibody treatment blocked the spread of phospho (S129) alpha synuclein associated-pathology in a mouse model of synucleinopathy. Blockade of neuronal PFF uptake by different antibodies was more predictive of in vivo activity than their binding potency to monomeric or oligomeric forms of alpha synuclein. These data demonstrate that antibodies directed to the C-terminus of the alpha synuclein have differential effects on target engagement and efficacy. Furthermore, our data provides additional support for the development of alpha synuclein antibodies as a therapeutic strategy for PD patients.

Characteristics of frailty phenotype in Chinese nursing home population and significance of motor function indicators in frailty assessment.

The objectives of this study were to analyze the distribution characteristics of frailty phenotypes in older adults of Chinese nursing homes, and to compare some motor function characteristics of older adults in nursing homes between frailty and non-frailty, to determine which motor function and frailty are related. This cross-sectional study included 177 older adults living in nursing homes. Frailty was diagnosed by Fried's phenotype, and motor function assessment characteristics (including muscle tone, ROM, and balance) were also evaluated. Chi-square and logistic regression analyses were performed. Frailty prevalence was 53% in nursing homes in big Chinese cities (average age 82.0 ± 6.1). Low levels of physical activity (90.4% in frail elder), decreased handgrip strength (98.9% in frail elder) and slowed walking speed (100% in frail elder) were the 3 main components of the frailty phenotype of frail adults in nursing homes in China. It is worth noting that 74.7% of the non-frail elders also had reduced handgrip strength. Further analysis showed that balance (P < .001), muscle tone (upper, P = .028, lower, P = .001) and the range of motion (P < .001) were associated with frailty in older adults. The frailty of the elders in Chinese nursing homes was characterized by the decline of motor function. And surprisingly, both frail and non-frail elders were found to have poor strength. Frail nursing home seniors also have body muscle tone, range of motion and balance problems. The elderly of China should focus on strength, stretch and balance training to improve motor function, especially strength training, which is important for prevention frailty.

A longitudinal study of creatine kinase and creatinine levels in Duchenne muscular dystrophy.

Management of Duchenne muscular dystrophy (DMD) has entered an era featuring novel treatments. Trackable noninvasive biomarkers could improve disease progression monitoring and drug effect detection. Our aim in this study was to measure changes in selected noninvasive biomarkers and assess their relationship to age and motor function. We retrospectively studied 555 patients with DMD who had at least 12 months of treatment of glucocorticoids and were not enrolled in trials of potential disease-modifying therapies. We extracted biomarker data of serum creatine kinase (CK), serum creatinine (Cr), urine Cr, and urine Cr/urine osmolality (osm), as well as functional data for age at loss of ambulation and Functional Motor Scale (FMS) values from patients' clinical records. Data were analyzed using linear mixed-model analyses. CK, serum Cr, urine Cr, and urine Cr/urine osm all decreased with declining motor function. CK consistently decreased and FMS score consistently worsened with age without clear inflection points. There was an increased odds ratio for LOA with lower values of CK, serum Cr, urine Cr, and urine Cr/urine osm, most notably for urine Cr. Although individual biomarker values are challenging to directly apply clinically, our study has demonstrated that trends over time may complement functional measures in the assessment of individuals with DMD. Future studies could elucidate predictive utility of these biomarkers in assessing motor function changes in DMD.

At Crossroads in a Virtual City: Effect of Spatial Disorientation on Gait Variability and Psychophysiological Response among Healthy Older Adults

Introduction: Aging has been associated with a decline in cognitive and motor performance, often expressed in multitasking situations, which could include wayfinding. A major challenge to successful wayfinding is spatial disorientation, occurring mostly at crossings. Although gait changes have been observed in various dual-task conditions, little is known about the effect of disorientation on gait and psychophysiological response among older adults during wayfinding. The study aimed at identifying the effect of spatial disorientation on gait variability and psychophysiological response among healthy older adults during wayfinding in a controlled environment. Method: We analyzed data of 28 participants (age 70.8 ± 4.6, 18 female), 14 experimental and 14 controls. Participants performed a wayfinding task consisting of 14 major decision points (7 intersections) within a virtual environment (VE) projected on a 180° screen while walking on a self-paced treadmill equipped with a marker-based optical motion-capture system. The VE was held constant for the controls and manipulated for the experimental participants. Disorientation was identified based on a customized annotation scheme. Variability in gait, including the coefficient of variation (CV), was measured as the primary endpoint. Psychophysiological response measures, including heart rate variability (RMSSD) and skin conductance response (SCR), were continuously monitored as secondary endpoints and estimates of cognitive effort. Linear Mixed Effects models were applied to hypothesis-driven outcome measures extracted from decision points. Results: Walking speed and step length decreased when disoriented (p < 0.05), while stride time, stance time, walking speed CV, stance time CV, SCR amplitude, and SCR count increased when disoriented (p < 0.05). A higher RMSSD was associated with being disoriented at crossings (p < 0.05). SCR count was greater in the older experimental group (p < 0.001), including when disoriented (p < 0.001). Discussion/Conclusion: The results provide evidence for the impact of spatial disorientation on changes in gait pattern and psychophysiological response among older adults during wayfinding. Location also had implications for the effect of disorientation on gait and cognitive effort. This gives further insight into the substrates of real-world navigation challenges among older adults, with an emphasis on viable features for designing situation-adaptive interventional devices aiding independent mobility.

Poorer dexterity is associated with underlying Alzheimer’s disease brain pathology

AbstractBackgroundThere has been increasing recognition for the decline of motor function in Alzheimer’s disease (AD) progression and its substantial role in disease morbidity. However, less is known about regional pathology burden—including amyloid‐β and tau protein deposition and cortical trophy—and its relationship to motor performance. Here investigate this relationship using standardized motor function assessment tools.MethodParticipants along a control‐to‐impaired continuum were enrolled in the Alzheimer’s Disease Connectome Project and underwent T1‐weighted MRI (N=206), with a subset undergoing [C‐11]PiB (N=61) and [F‐18 ]Flortaucipir PET (N=58) (Table 1) imaging for amyloid and tau pathology, respectively. T1‐weighted scans were processed using Freesurfer to estimate regional cortical thickness. [C‐11]PiB distribution volume ratios (DVR; cerebellar GM reference region) and [F‐18] Flortaucipir standardized uptake value ratios (SUVr; inferior cerebellar GM reference region) were assessed. Regions of interest (ROI) for analysis included the parahippocampal, entorhinal, motor, and frontal regions. Motor function was assessed utilizing NIH toolbox tests including the 2‐minute walking, 9‐hole pegboard dexterity, and dynamometer grip strength assessments. Motor performance was analyzed using participants uncorrected standardized scores. Scores were collected from participant‐reported dominant hand assessments. Multiple linear regression models tested relationships between AD biomarker burden and motor performance while controlling for age and sex of participants.ResultIncreased amyloid‐β (β‐0.42, p‐value: &lt;0.05) and tau (β: ‐0.53, p‐value: &lt;0.05) burden in primary motor cortices were associated with worse dexterity scores independent of age and sex. Grip strength did not show a significant correlation to cortical amyloid‐β (β: ‐0.14, p‐value 0.33) or tau burden (β: 0.23, p‐value: 0.36). Higher cortical thickness in primary motor regions were associated with higher dexterity (β: 0.21, p‐value &lt;0.0001) and 2‐minute walking scores (β: 0.24, p‐value &lt;0.001). When controlling for age and sex, grip strength predicted decreasing cortical thickness (β: 0.01, p‐value: &lt;0.001) (Table 2).ConclusionLower dexterity performance may be driven by elevated AD pathological burden and cortical thinning in cortical motor regions. Further research into motor performance and clinical disease manifestation is needed to determine the diagnostic utility of fine motor assessment as a predictor of motor decline in individuals with Alzheimer’s disease pathology.

The association of gabapentin initiation and neurocognitive changes in older adults with normal cognition.

Background: Gabapentin is increasingly prescribed to older adults, which raises concerns about its potential to cause neurocognitive changes. Therefore, we aimed to examine the association of gabapentin use with neurocognitive changes (i.e., cognitive decline, functional status decline, and motor function change) in older adults. Methods: We conducted a retrospective cohort study using the National Alzheimer's Coordinating Center Uniform Data Set (UDS; September 2005-March 2021 data freeze). From the eligible sample (≥age 65 years), we identified cognitively normal new-users of gabapentin and the visit they initiated gabapentin (i.e., index visit). Initiators were matched to randomly selected nonusers on year of UDS enrollment and visit number from enrollment to index. Cognitive decline was defined as any increase in the Clinical Dementia Rating global score (CDRGLOB) and as a 1-point increase in CDR sum of boxes (CDR-SB). Functional status decline was defined as a 3-point increase in the sum of the Functional Activities Questionnaire (FAQ) and as 0.3-point increase in mean FAQ. Decline in motor function was defined as new clinician reports of gait disorder, falls, and slowness. To mitigate confounding and selection bias, we used joint stabilized inverse probability of treatment weights and stabilized inverse probability of censoring weights. All analyses were conducted comparing index to index+1 and index+2 visits. Results: From the eligible UDS participants (N = 23,059), we included 480 initiators (mean age [SD]: 78.7 [6.9]; male 34.4%); 4,320 nonusers (78.3 [7.0]; 34.4%). Gabapentin initiation was significantly associated with cognitive/functional status decline: worsening CDRGLOB at index+1 visit (odds ratio [95% confidence interval]: 1.55 [1.07, 2.25]); CDR-SB at index+1 visit (1.94 [1.22, 3.09]); and mean of FAQ at index+2 visit (1.78 [1.12, 2.83]). After excluding initiators with extant motor dysfunction (n = 21), we identified 459 initiators (78.7 [6.9]; 34.0%) and 4,131 nonusers (78.2 [6.9]; 34.7%); in this sample, gabapentin initiation was associated with increased falls at the index+2 visit (2.51 [1.19, 5.31]). Conclusion: Gabapentin initiation was significantly associated with deleterious neurocognitive changes among older adults with initially normal cognition. Further studies are needed to examine the risk/benefit of prescribing gabapentin in older adults.

The importance of early diagnosis and views on newborn screening in metachromatic leukodystrophy: results of a Caregiver Survey in the UK and Republic of Ireland

Metachromatic Leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). MLD causes progressive loss of motor function and severe decline in cognitive function, leading to premature death. Early diagnosis of MLD provides the opportunity to begin treatment before the disease progresses and causes severe disability. MLD is not currently included in newborn screening (NBS) in the UK.This study consisted of an online survey, and follow-up semi-structured interviews open to MLD patients or caregivers, aged 18 years and over. The aims of the study were to understand the importance of early diagnosis and to establish the views of families and caregivers of patients with MLD on NBS.A total of 24 patients took part in the survey, representing 20 families (two families had two children with MLD, one family had three children with MLD). Following on from the survey, six parents participated in the interviews. Our data showed diagnostic delay from first symptoms was between 0 and 3 years, with a median of 1 year (n = 18); during this time deterioration was rapid, especially in earlier onset MLD. In patients with late infantile MLD (n = 10), 50% were wheelchair dependent, 30% were unable to speak, and 50% were tube fed when a diagnosis of MLD was confirmed. In patients with early juvenile MLD (n = 5), over half used a wheelchair some of the time, had uncontrollable crying, and difficulty speaking (all 60%) before or at the time of diagnosis. A high degree of support was expressed for NBS among caregivers, 95% described it as very or extremely important and 86% believed detection of MLD at birth would have changed their child’s future. One parent expressed their gratitude for an early diagnosis as a result of familial MLD screening offered at birth and how it had changed their child’s future: “It did and it absolutely has I will be forever grateful for his early diagnosis thanks to his older sister.”The rapid rate of deterioration in MLD makes it an essential candidate for NBS, particularly now the first gene therapy (Libmeldy™) has been approved by the European Medicines Agency. Libmeldy™ has also been recommended as a treatment option in England and Wales by the National Institute for Health and Care Excellence (NICE) and is being made available to patients in Scotland via the Scottish Medicines Consortium’s ultra-orphan pathway.