Discrete Relationships between Spatiotemporal Gait Characteristics and Domain-Specific Neuropsychological Performance in Midlife.

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.

Gait Characteristics and Cognitive Function in Middle-Aged Adults with and without Type 2 Diabetes Mellitus: Data from ENBIND.

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.

Neurophysiological correlates of dual tasking in people with Parkinson's disease and freezing of gait.

Freezing of gait in people with Parkinson's disease (PwP) is associated with executive dysfunction and motor preparation deficits. We have recently shown that electrophysiological markers of motor preparation, rather than decision-making, differentiate PwP with freezing of gait (FOG +) and without (FOG -) while sitting. To examine the effect of locomotion on these results, we measured behavioural and electrophysiological responses in PwP with and without FOG during a target response time task while sitting (single-task) and stepping-in-place (dual-task). Behavioural and electroencephalographic data were acquired from 18 PwP (eight FOG +) and seven young controls performing the task while sitting and stepping-in-place. FOG + had slower response times while stepping compared with sitting. However, response times were significantly faster while stepping compared with sitting for controls. Electrophysiological responses showed no difference in decision-making potentials (centroparietal positivity) between groups or conditions but there were differences in neurophysiological markers of response inhibition (N2) and motor preparation (lateralized readiness potential, LRP) in FOG + while performing a dual-task. This suggests that the addition of a second complex motor task (stepping-in-place) impacts automatic allocation of resources in FOG +, resulting in delayed response times. The impact of locomotion on the generation of the N2 and LRP potentials, particularly in freezers, indirectly implies that these functions compete with locomotion for resources. In the setting of multiple complex tasks or cognitive impairment, severe motor dysfunction may result, leading to freezing of gait.

Baseline Association of Motoric Cognitive Risk Syndrome With Sustained Attention, Memory, and Global Cognition.

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.

Motor preparation rather than decision-making differentiates Parkinson's disease patients with and without freezing of gait.

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.

The Impact of Common Inhaler Errors on Drug Delivery: Investigating Critical Errors with a Dry Powder Inhaler.

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.

Predicting asthma exacerbations employing remotely monitored adherence.

This Letter investigated the efficacy of a decision-support system, designed for respiratory medicine, at predicting asthma exacerbations in a multi-site longitudinal randomised control trial. Adherence to inhaler medication was acquired over 3 months from patients with asthma employing a dose counter and a remote monitoring adherence device which recorded participant's inhaler use: n = 184 (23,656 audio files), 61% women, age (mean ± sd) 49.3 ± 16.4. Data on occurrence of exacerbations was collected at three clinical visits, 1 month apart. The relative risk of an asthma exacerbation for those with good and poor adherence was examined employing a univariate and multivariate modified Poisson regression approach; adjusting for age, gender and body mass index. For all months dose counter adherence was significantly (p < 0.01) higher than remote monitoring adherence. Overall, those with poor adherence had a 1.38 ± 0.34 and 1.42 ± 0.39 (remotely monitored) and 1.25 ± 0.32 and 1.18 ± 0.31 (dose counter) higher relative risk of an exacerbation in model 1 and model 2, respectively. However, this was not found to be statistically significantly different. Remotely monitored adherence holds important clinical information and future research should focus on refining adherence and exacerbation measures. Decision-support systems based on remote monitoring may enhance patient-physician communication, possibly reducing preventable adverse events.

A Method to Calculate Adherence to Inhaled Therapy that Reflects the Changes in Clinical Features of Asthma.

RATIONALE: Currently, studies on adherence to inhaled medications report average adherence over time. This measure does not account for variations in the interval between doses, nor for errors in inhaler use. OBJECTIVES: To investigate whether adherence calculated as a single area under the (concentration-time) curve (AUC) measure, incorporating the interval between doses and inhaler technique, was more reflective of patient outcomes than were current methods of assessing adherence. METHODS: We attached a digital audio device (INhaler Compliance Assessment) to a dry powder inhaler. This recorded when the inhaler was used, and analysis of the audio data indicated if the inhaler had been used correctly. These aspects of inhaler use were combined to calculate adherence over time, as an AUC measure. Over a 3-month period, a cohort of patients with asthma was studied. Adherence to a twice-daily inhaler preventer therapy using this device and clinical measures were assessed. MEASUREMENTS AND MAIN RESULTS: Recordings from 239 patients with severe asthma were analyzed. Average adherence that was based on the dose counter was 84.4%, whereas the ratio of expected to observed accumulated AUC, actual adherence, was 61.8% (P < 0.01). Of all the adherence measures, only adherence calculated as AUC reflected changes in asthma quality of life, ß-agonist reliever use, and peak expiratory flow over the 3 months (P < 0.05 compared with other measures of adherence). CONCLUSIONS: Adherence that incorporates the interval between doses and inhaler technique, and calculated as AUC, is more reflective of changes in quality of life and lung function than are the currently used measures of adherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01529697).

A protocol for a randomised clinical trial of the effect of providing feedback on inhaler technique and adherence from an electronic device in patients with poorly controlled severe asthma.

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.

Dual Motor-Cognitive Virtual Reality Training Impacts Dual-Task Performance in Freezing of Gait.

Freezing of gait (FOG), an episodic gait disturbance characterized by the inability to generate effective stepping, occurs in more than half of Parkinson's disease patients. It is associated with both executive dysfunction and attention and becomes most evident during dual tasking (performing two tasks simultaneously). This study examined the effect of dual motor-cognitive virtual reality training on dual-task performance in FOG. Twenty community dwelling participants with Parkinson's disease (13 with FOG, 7 without FOG) participated in a pre-assessment, eight 20-minute intervention sessions, and a post-assessment. The intervention consisted of a virtual reality maze (DFKI, Germany) through which participants navigated by stepping-in-place on a balance board (Nintendo, Japan) under time pressure. This was combined with a cognitive task (Stroop test), which repeatedly divided participants' attention. The primary outcome measures were pre- and post-intervention differences in motor (stepping time, symmetry, rhythmicity) and cognitive (accuracy, reaction time) performance during single- and dual-tasks. Both assessments consisted of 1) a single cognitive task 2) a single motor task, and 3) a dual motor-cognitive task. Following the intervention, there was significant improvement in dual-task cognitive and motor parameters (stepping time and rhythmicity), dual-task effect for those with FOG and a noteworthy improvement in FOG episodes. These improvements were less significant for those without FOG. This is the first study to show benefit of a dual motor-cognitive approach on dual-task performance in FOG. Advances in such virtual reality interventions for home use could substantially improve the quality of life for patients who experience FOG.

Relative association of processing speed, short-term memory and sustained attention with task on gait speed: a study of community-dwelling people 50 years and older.

BACKGROUND: For single gait tasks, associations have been reported between gait speed and cognitive domains. However, few studies have evaluated if this association is altered in dual gait tasks given gait speed changes with complexity and nature of task. We evaluated relative contributions of specific elements of cognitive function (including sustained attention and processing speed) to dual task gait speed in a nationally representative population of community-dwelling adults over 50 years. METHODS: Gait speed was obtained using the GaitRite walkway during three gait tasks: single, cognitive (alternate letters), and motor (carrying a filled glass). Linear regression models, adjusted for covariates, were constructed to predict the relative contributions of seven neuropsychological tests to gait speed differences and to investigate gait task effects. RESULTS: The mean age and gait speed of the population (n = 4,431, 55% women) was 62.4 years (SD = 8.2) and 135.85 cm/s (SD = 20.20, single task), respectively. Poorer processing speed, short-term memory, and sustained attention were major cognitive contributors to slower gait speed for all gait tasks. Both dual gait tasks were robust to covariate adjustment and had a significant additional executive function element not found for the single gait task. CONCLUSIONS: For community-dwelling older adults processing speed, short-term memory and sustained attention were independently associated with gait speed for all gait tasks. Dual gait tasks were found to highlight specific executive function elements. This result forms a baseline value for dual task gait speed.

A method to assess adherence in inhaler use through analysis of acoustic recordings of inhaler events.

RATIONALE: Poor adherence to inhaler use can be due to poor temporal and/or technique adherence. Up until now there has been no way of reliably tracking both these factors in everyday inhaler use. OBJECTIVES: This paper introduces a device developed to create time stamped acoustic recordings of an individual's inhaler use, in which empirical evidence of temporal and technique adherence in inhaler use can be monitored over time. The correlation between clinical outcomes and adherence, as determined by this device, was compared for temporal adherence alone and combined temporal and technique adherence. FINDINGS: The technology was validated by showing that the doses taken matched the number of audio recordings (r2 = 0.94, p<0.01). To demonstrate that audio analysis of inhaler use gives objective information, in vitro studies were performed. These showed that acoustic profiles of inhalations correlated with the peak inspiratory flow rate (r2 = 0.97, p<0.01), and that the acoustic energy of exhalations into the inhaler was related to the amount of drug removed. Despite training, 16% of participants exhaled into the mouthpiece after priming, in >20% of their inhaler events. Repeated training reduced this to 7% of participants (p = 0.03). When time of use was considered, there was no evidence of a relationship between adherence and changes in AQLQ (r2 = 0.2) or PEFR (r2 = 0.2). Combining time and technique the rate of adherence was related to changes in AQLQ (r2 = 0.53, p = 0.01) and PEFR (r2 = 0.29, p = 0.01). CONCLUSIONS: This study presents a novel method to objectively assess how errors in both time and technique of inhaler use impact on clinical outcomes. TRIAL REGISTRATION: EudraCT 2011-004149-42.

Measurement of attention during movement: acquisition of ambulatory EEG and cognitive performance from healthy young adults.

Non-invasive methods of recording human electro-cortical brain dynamics during normal daily activities would have far-reaching clinical benefits. The literature suggests a strong link between gait and cognition, where attention is seen to play a central role. This study investigated if clinically useful electrophysiological measures of attention can be collected using an auditory oddball task in ecological/non-clinic environments through analysis of the amplitude and latency of auditory P3 event related potentials (ERPs). Electrophysiological (EEG, EOG, EMG) recordings were taken for 7 healthy subjects while presented with an auditory oddball task. Data was recorded in control, static (seated) and dynamic (fixed cycling) experimental conditions. Recordings were also taken for two subjects during treadmill walking. P3 ERPs were calculated and data analysis showed that peak amplitude and component latency remained stable across all experimental conditions. For the Cz electrode position there were 0.2-2% P3 amplitude and 3-9% P3 latency differences. P3 amplitude and latency also remained stable between experimental conditions for all electrode locations. This result opens up the possibility to quantitatively investigate the interaction between gait and attention during the ageing process but also in movement disorders such as freezing of gait in Parkinson's disease.

Variance between walking speed and neuropsychological test scores during three gait tasks across the Irish Longitudinal study on Aging (TiLDA) dataset.

This study investigated the relationship between neuropsychological test scores and gait speed in three gait tasks using baseline cross-sectional data from 4694 healthy adults (54% women, age (mean±sd) 62.4±8.2) from The Irish Longitudinal study on Aging (TiLDA). Global cognition, short term memory, speed of processing, executive function and sustained attention were measured by a detailed battery of neuropsychological tests. Gait speed was recorded from a GaitRite™ pressure sensing mat during a single walk and two dual walking tasks; dual cognitive walk (alternate letters) and dual motor walk (carrying a glass of water). Correlations between neuropsychological test scores and the three gait speed outcomes were investigated using univariate and multiple linear regressions models; firstly adjusting for age, gender, height, education and depression only and then including all neuropsychological test scores in the same regression model and adjusting as previously. It was found that short term memory, speed of processing and attention were significantly correlated with gait speed in all three gait conditions, with global cognition and executive function also significantly correlated with gait speed in the dual cognitive walk. The nature and complexity of the task performed affected gait speed with the addition of the cognitive task while walking causing a larger reduction in gait speed than the addition of the motor task. This indicates that for this healthy nationally representative population sample there is a link between neural processes involved in movement and cognition and this association differs depending on the gait task performed.