Abstract Gait is a scalable biomarker of functional, physical, and brain health, but most studies rely on gait speed alone. Here, we developed and validated gait age clocks that estimate age from multidimensional gait features and quantify deviations as gait age gaps, with gaps >0 (<0) for accelerated (delayed) aging. We included data from 5,681 participants, including healthy controls and clinical groups (Parkinson’s disease, neurodegenerative diseases, stroke, diabetes, fallers, and frailty). Normative models trained in healthy controls showed robust age prediction ( r =0.851, p <0.001), and full gait models outperformed gait speed alone (ΔR 2 =0.175). Gaps captured accelerated aging across neurological and physical conditions, tracked Parkinson’s disease severity, and were associated with frailty, physical performance, white matter hyperintensities, and geriatric depression. Gait age gaps are also related to brain aging, risk/protective lifestyle factors, and mortality risk. These findings support gait age gaps as an interpretable biomarker for aging, risk stratification, and clinical monitoring.

Abstract Background Midlife risk factors such as Type 2 Diabetes Mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life, with executive function, memory and attention domains often affected first. Spatiotemporal gait characteristics are increasingly recognised as biomarkers of neurocognitive function and later dementia risk. Methods Using an automated walkway, 24 spatiotemporal gait parameters were examined across 5 domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions. Neurocognitive function was measured using a neuropsychological assessment battery. Linear regression was used assess the relationship between each gait parameter across the three walks and cognitive function. Results 102 middle-aged adults underwent assessment, 65 with uncomplicated T2DM (57.5 ± 8.0 years; 40% female) and 37 healthy controls (57.0 ± 8.3 years; 62.1% female). T2DM was associated with significant changes in gait phases and rhythm domains at usual-pace, and greater gait variability observed during maximal-pace and dual-task. In the overall cohort, both gait pace and rhythm domains were associated with memory and executive function during usual pace walking. At maximal-pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual-task, associations between gait variability and delayed memory and executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Conclusion This supports the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals. Discrete associations were seen between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms, in addition to single-task usual-pace gait, may be important in cognitively unimpaired populations with risk factors for later cognitive decline - with the aim of identifying individuals who may benefit most from potential preventative interventions.

Midlife risk factors such as type 2 diabetes mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life with executive function, memory, and attention domains often affected first. Spatiotemporal gait characteristics are emerging as important integrative biomarkers of neurocognitive function and of later dementia risk. We examined 24 spatiotemporal gait parameters across five domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions in 102 middle-aged adults with (57.5 ± 8.0 years; 40% female) and without (57.0 ± 8.3 years; 62.1% female) T2DM. Neurocognitive function was measured using a neuropsychological assessment battery. T2DM was associated with significant changes in gait phases and rhythm domains at usual pace, and greater gait variability observed during maximal pace and dual tasks. In the overall cohort, both the gait pace and rhythm domains were associated with memory and executive function during usual pace. At maximal pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual task, associations between gait variability and both delayed memory/executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Principal components analysis identified a consistent association of slower gait pace (step/stride length) and increased gait variability during maximal-pace walking with poorer memory and executive function performance. These data support the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals and reveal discrete associations between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms may be important in cognitively unimpaired populations with risk factors for later cognitive decline—with the aim of identifying individuals who may benefit from potential preventative interventions.

Type 2 Diabetes Mellitus (T2DM) in midlife is associated with a greater risk of dementia in later life. Both gait speed and spatiotemporal gait characteristics have been associated with later cognitive decline in community-dwelling older adults. Thus, the assessment of gait characteristics in uncomplicated midlife T2DM may be important in selecting-out those with T2DM at greatest risk of later cognitive decline. We assessed the relationship between Inertial Motion Unit (IMUs)-derived gait characteristics and cognitive function assessed via Montreal Cognitive Assessment (MoCA)/detailed neuropsychological assessment battery (CANTAB) in middle-aged adults with and without uncomplicated T2DM using both multivariate linear regression and a neural network approach. Gait was assessed under (i) normal walking, (ii) fast (maximal) walking and (iii) cognitive dual-task walking (reciting alternate letters of the alphabet) conditions. Overall, 138 individuals were recruited (n = 94 with T2DM; 53% female, 52.8 ± 8.3 years; n = 44 healthy controls, 43% female, 51.9 ± 8.1 years). Midlife T2DM was associated with significantly slower gait velocity on both slow and fast walks (both p < 0.01) in addition to a longer stride time and greater gait complexity during normal walk (both p < 0.05). Findings persisted following covariate adjustment. In analyzing cognitive performance, the strongest association was observed between gait velocity and global cognitive function (MoCA). Significant associations were also observed between immediate/delayed memory performance and gait velocity. Analysis using a neural network approach did not outperform multivariate linear regression in predicting cognitive function (MoCA) from gait velocity. Our study demonstrates the impact of uncomplicated T2DM on gait speed and gait characteristics in midlife, in addition to the striking relationship between gait characteristics and global cognitive function/memory performance in midlife. Further studies are needed to evaluate the longitudinal relationship between midlife gait characteristics and later cognitive decline, which may aid in selecting-out those with T2DM at greatest-risk for preventative interventions.

AIMS:To establish the impact of uncomplicated type 2 diabetes on cognitive and neuropsychological performance in midlife. METHODS:We performed a cross-sectional study of middle-aged adults with uncomplicated type 2 diabetes and a cohort of healthy control participants. General cognition was assessed using the Montreal Cognitive Assessment test and neuropsychological assessment was undertaken using a detailed neuropsychological assessment battery. RESULTS:A total of 152 participants (102 with type 2 diabetes and 50 controls) were recruited (mean age 52 ± 8 years, 51% women). Participants with midlife type 2 diabetes were more than twice as likely to make an error on the Montreal Cognitive Assessment test [incidence rate ratio 2.44 (95% CI 1.54 to 3.87); P < 0.001]. Further, type 2 diabetes was also associated with significantly lower memory composite score [β: -0.20 (95% CI -0.39 to -0.01); P = 0.04] and paired associates learning score [β: = -1.97 (95% CI -3.51, -0.43); P = 0.01] on the neuropsychological assessment battery following adjustment for age, sex, BMI, educational attainment and hypercholesterolaemia. CONCLUSIONS:Even in midlife, type 2 diabetes was associated with small but statistically significant cognitive decrements. These statistically significant decrements, whilst not clinically significant in terms of objective cognitive impairment, may have important implications in selecting out individuals most at risk of later cognitive decline for potential preventative interventions in midlife.

AbstractBackgroundMidlife Type 2 Diabetes Mellitus (T2DM) is associated with an increased risk of dementia in later life. Despite this, few studies have examined the utility of midlife biomarkers to predict later cognitive decline in T2DM. We evaluated the association between dual‐task gait speed and cognitive performance in midlife T2DM as part of ENBIND Study.MethodParticipants with midlife T2DM and matched healthy controls were recruited. Participants with T2DM only included if they had no micro/macrovascular complications of T2DM. Cognition was assessed using the Montreal Cognitive Assessment (MoCA) and computerised neuropsychological assessment battery (CANTAB®). Gait was assessed using both stopwatch and accelerometry across four tasks: (i) self‐selected (usual) gait speed, (ii) maximal gait speed and (iii) dual‐task gait speed (reciting alternate letters of the alphabet). Appropriate univariate statistics in addition to Poisson and linear models were used to analyse results.Results102 cognitively‐intact middle‐aged (52 ± 7.9 years) adults with (N = 71) and without (N = 31) T2DM were recruited. T2DM was associated with a greater likelihood of error on the MoCA (IRR = 2.36, 1.53‐3.64, p<0.001) which persisted after covariate adjustment. T2DM was associated with poorer performance on reaction/movement time, executive function, attention and visuospatial memory tasks, however results were attenuated by covariate adjustment. T2DM was associated with slower gait speed on all three tasks (all p<0.001). Overall, self‐selected, maximal and dual‐task speed were associated with greater likelihood of error on the MoCA (all p<0.001). However, after robust adjustment for covariates, only the association for Dual Task Cost (DTC) persisted (p = 0.021). A DTC*T2DM interaction was not significant.ConclusionsThe current analysis showed diminished cognitive and gait performance in midlife T2DM vs. healthy controls. We observed significant associations between gait performance on the addition of a dual task and general cognitive function. This association, whilst greater in T2DM, was not T2DM specific and adds further evidence for the association between dual task‐gait and cognitive performance in midlife. Our findings support the ongoing exploration and use of gait as a physiological biomarker of overall cognitive function and warrants longitudinal investigation in this high risk group.

Abstract Background Type 2 Diabetes (T2DM) in midlife is associated with a greater risk of dementia in later life. The longitudinal ENBIND Study is examining novel approaches to biomarker discovery in this high-risk group which may help identify those at greatest risk Methods Non-demented participants with midlife T2DM (no micro/macrovascular complications) and matched controls were recruited. Following detailed health/diabetes assessment, general cognitive (MoCA) and computerised neuropsychological (CANTAB) assessment were performed. Gait was assessed by stopwatch and accelerometers across several tasks including self-selected and maximal gait speed in addition to a dual-task cognitive paradigm (reciting alternate letters of the alphabet). Bloods were analysed for C-Reactive Protein (CRP) and glycated haemoglobin (HbA1c). Between group differences were analysed using t-tests/non-parametric equivalents and linear regression used for multivariate analysis. Results Sixty participants with T2DM (51.9 +/- 8.4 yrs) and 30 matched controls (52.3 +/- 7.9 yrs) were recruited. Controlling for demographic and cardiovascular covariates, T2DM was associated with a lower MoCA score, slower self-selected, maximal and dual-task gait speed (all p<0.05). Maximal gait speed (p =0.006) but not self-selected gait speed (p =0.47) was associated with poorer cognitive function. On multivariate analysis of the dual-task difference, both T2DM and lower MoCA score were associated with a poorer performance, (p<0.001, p= 0.003). Overall, performance in the lowest vs highest quartile on the dual-task gait paradigm was associated with a significantly poorer performance on the MoCA (p<0.001; median 27 vs 29). On multivariate analysis of laboratory parameters, higher CRP levels were associated with slower maximal (p =0.041) and dual-task (p=0.033) gait performance. Conclusion Midlife T2DM is associated with poorer cognitive performance. Gait speed, and in particular dual-task gait speed, correlate strongly with general cognitive performance. Future work will tease out the specific domains of gait and cognition which are affected, and assess longitudinally in this high-risk group.

BACKGROUND:Researchers, using checklists, have identified that 30%-90% of patients make errors in inhaler use. It is not certain whether these errors affect the delivery of medication. We have developed an electronic monitor (INCA™) that records audio each time an inhaler is used, providing objective information on inhaler technique. The aim of this study was to assess the effect that correctly identified inhaler errors, with the INCA device, have on drug delivery.METHODS:This was a prospective study of healthy volunteers using a salbutamol Diskus™. The inclusion criteria allowed for the recruitment of healthy participants who were nonfrequent users of Salbutamol. Each participant was assigned to one control "phase" first and two/three subsequent error "phases." Each phase consisted of six doses of the drug taken 6 hours apart, and the participants' blood was drawn before and 25 minutes after doses one and six. This allowed us to sample their trough and peak serum salbutamol levels.RESULTS:Fourteen healthy volunteers were studied. The inhaler technique errors simulated in this study included exhaling into the device after drug priming but before inhalation, low inspiratory flow, multiple inhalations, low breath hold, missed doses, and wrong inhaler position. Only the exhalation error, low inspiratory flow, and missed doses led to a significant reduction in serum salbutamol levels. After six doses of the exhalation error, there was a 62% reduction in peak salbutamol levels. Low inspiratory flow led to a 52% reduction in peak salbutamol levels and a 78% reduction in trough levels. Missed doses led to a 37% reduction in trough salbutamol levels.CONCLUSIONS:These findings confirm that technique errors affect drug delivery. Furthermore, we were able to identify that the most critical technique errors with the Diskus inhaler are exhalation into the device before inhalation, poor inspiratory flow, and missing doses.

Background: Quantitative gait analysis shows promise as an adjunct to routine clinical examination.However, interpretation of results from gait analysis can be complex.Specifically, collinearity between characteristics of gait (e.g.speed, stride length) and noise introduced by the specific testing conditions can lead to over-fitting of interpretations and

OBJECTIVES:Slow gait has been shown to be a good predictor of declining cognitive function in healthy older adults. Motoric cognitive risk (MCR) syndrome is a new construct incorporating slow gait and subjective cognitive complaints in individuals without dementia who have preserved activities of daily living. This analysis investigated the prevalence of MCR and factors associated with MCR in a nationally representative population. In addition, cross-sectional associations between MCR and cognitive domains, an relationship yet to be fully elucidated in literature, was investigated. MEASUREMENTS:Participants completed a comprehensive neuropsychological assessment and gait analysis at a health assessment center. Logistic regression was employed to examine associated health factors. Composite scores reflecting global cognition, memory, sustained attention, executive function, and processing speed were constructed using neuropsychological test scores. Associations between MCR and these composites were quantified using multivariate generalized linear modelling. All analyses were weighted to be nationally representative. SETTING:Community-dwelling adults in The Irish Longitudinal Study on Aging (TILDA) completed an interview and a center-based health assessment. PARTICIPANTS:Participants aged 60 years and over (n = 2151, age; mean: 67.84 years, range: 60-93) were included. Participants with a Mini-Mental State Examination score of below 24, a diagnosis of serious memory impairment, Parkinson disease, dementia, or Alzheimer disease were excluded. RESULTS:MCR prevalence was estimated at 2.56% (95% confidence interval 1.97, 3.31). Significant risk factors for MCR were antidepressant use [odds ratio (OR) 4.46, P < .001], self-reported poor vision (OR 4.92, P < .05), and obesity (OR 2.29, P < .01). Individuals with MCR performed worse on tests that assess memory (B: -0.58, P < .001), global cognition (B: -0.42, P < .001), and sustained attention (B: -0.34, P < .05) with robust adjustment made for confounding demographic and health variables. CONCLUSIONS:MCR is characterized by strong negative associations with global cognition, attention, and memory. This may be indicative of the underlying pathology of MCR. The effect of antidepressant use on MCR is novel and may represent an important consideration in future studies.

Objective: Freezing of gait (FOG) is a brief, episodic phenomenon affecting over half of people with Parkinson's disease (PD) and leads to significant morbidity. The pathophysiology of FOG remains poorly understood but is associated with deficits in cognitive function and motor preparation.Method: We studied 20 people with PD (10 with FOG, 10 without FOG) and performed a timed response target detection task while electroencephalographic data were acquired. We analysed the data to detect and examine cortical markers of cognitive decision making (P3b or centroparietal positivity, CPP) and motor readiness potential. We analysed current source density (CSD) to increase spatial resolution and allow identification of distinct signals.Results: There was no difference in the P3b/CPP response between people with PD with and without FOG, suggesting equivalent cognitive processing with respect to decision-making. However, the FOG group had significant difference with an earlier onset and larger amplitude of the lateralized readiness potential. Furthermore, the amplitude of the lateralised readiness potential correlated strongly with total Frontal Assessment Battery score.Conclusions: The difference in lateralized readiness potentials may reflect excessive recruitment of lateral premotor areas to compensate for dysfunction of the supplementary motor area and resultant loss of automatic motor control. This early, excessive recruitment of frontal networks occurs in spite of equivalent motor scores and reaction times between groups.Significance: The saturation of frontal processing mechanisms could help explain deficits in attentional set-shifting, dual-tasking and response inhibition which are frequently reported in FOG. (C) 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

INTRODUCTION:In clinical practice, it is difficult to distinguish between patients with refractory asthma from those with poorly controlled asthma, where symptoms persist due to poor adherence, inadequate inhaler technique or comorbid diseases. We designed an audio recording device which, when attached to an inhaler, objectively identifies the time and technique of inhaler use, thereby assessing both aspects of adherence. This study will test the hypothesis that feedback on these two aspects of adherence when passed on to patients improves adherence and helps clinicians distinguish refractory from difficult-to-control asthma.METHODS:This is a single, blind, prospective, randomised, clinical trial performed at 5 research centres. Patients with partially controlled or uncontrolled severe asthma who have also had at least one severe asthma exacerbation in the prior year are eligible to participate. The effect of two types of nurse-delivered education interventions to promote adherence and inhaler technique will be assessed. The active group will receive feedback on their inhaler technique and adherence from the new device over a 3-month period. The control group will also receive training in inhaler technique and strategies to promote adherence, but no feedback from the device. The primary outcome is the difference in actual adherence, a measure that incorporates time and technique of inhaler use between groups at the end of the third month. Secondary outcomes include the number of patients who remain refractory despite good adherence, and differences in the components of adherence after the intervention. Data will be analysed on an intention-to-treat and a per-protocol basis. The sample size is 220 subjects (110 in each group), and loss to follow-up is estimated at 10% which will allow results to show a 10% difference (0.8 power) in adherence between group means with a type I error probability of 0.05.TRIAL REGISTRATION NUMBER:NCT01529697; Pre-results.