Considering equity in priority setting using transmission models: Recommendations and data needs.

OBJECTIVES: Disease transmission models are used in impact assessment and economic evaluations of infectious disease prevention and treatment strategies, prominently so in the COVID-19 response. These models rarely consider dimensions of equity relating to the differential health burden between individuals and groups. We describe concepts and approaches which are useful when considering equity in the priority setting process, and outline the technical choices concerning model structure, outputs, and data requirements needed to use transmission models in analyses of health equity. METHODS: We reviewed the literature on equity concepts and approaches to their application in economic evaluation and undertook a technical consultation on how equity can be incorporated in priority setting for infectious disease control. The technical consultation brought together health economists with an interest in equity-informative economic evaluation, ethicists specialising in public health, mathematical modellers from various disease backgrounds, and representatives of global health funding and technical assistance organisations, to formulate key areas of consensus and recommendations. RESULTS: We provide a series of recommendations for applying the Reference Case for Economic Evaluation in Global Health to infectious disease interventions, comprising guidance on 1) the specification of equity concepts; 2) choice of evaluation framework; 3) model structure; and 4) data needs. We present available conceptual and analytical choices, for example how correlation between different equity- and disease-relevant strata should be considered dependent on available data, and outline how assumptions and data limitations can be reported transparently by noting key factors for consideration. CONCLUSIONS: Current developments in economic evaluations in global health provide a wide range of methodologies to incorporate equity into economic evaluations. Those employing infectious disease models need to use these frameworks more in priority setting to accurately represent health inequities. We provide guidance on the technical approaches to support this goal and ultimately, to achieve more equitable health policies.

Disease severity and prefrontal cortex activation during obstacle negotiation among patients with Parkinson's disease: Is it all as expected?

BACKGROUND: Previous reports indicate that patients with Parkinson's disease (PD) activate the prefrontal cortex (PFC) during complex activities such as obstacle negotiation to compensate for impaired motor function. However, the influence of disease severity on PFC activation has not been systematically evaluated. Here, we examined the effects of disease severity on PFC activation during obstacle negotiation. METHODS: 74 patients with PD (age 68.26 ± 7.54 yrs; 62.2% men) were divided into three groups based on Hoehn and Yahr stages. All patients walked along an obstacle course while negotiating anticipated and unanticipated obstacles (long/low available response time) at heights of 50 mm and 100 mm. PFC activation was measured using functional near-infrared spectroscopy (fNIRS) and was compared between groups and tasks using mixed model analyses. RESULTS: Participants with more advanced PD (i.e., Hoehn & Yahr 3) had higher PFC activation levels when negotiating anticipated obstacles, compared to participants with milder PD (i.e., Hoehn & Yahr 1, 2) (p < 0.001). Moreover, higher LEDD correlated with higher prefrontal activation during the higher anticipated obstacle. In contrast, during the negotiation of unanticipated obstacles, the differences in PFC activation were not associated with disease severity in a linear manner. CONCLUSIONS: The present study suggests that with increased disease severity, patients with PD rely more on the PFC when negotiating anticipated obstacles, perhaps to compensate for attention and motor deficits. These findings support the role of cognition in fall risk and the need to improve attention and cognition in fall prevention programs, especially among patients with more advanced disease.

Which obstacle attributes place additional demands on higher-level cognitive function in patients with Parkinson's disease?

BACKGROUND: Previous reports show that patients with Parkinson's disease (PD) rely on prefrontal activation to compensate for impaired motor function during complex activities such as obstacle negotiation. However, the influence of the properties of the obstacles on prefrontal activation has not been systematically evaluated. Here, we examined the effects of obstacle height and anticipation time on prefrontal activation in patients with PD and older adults. METHODS: 34 patients with PD (age: 67.4 ± 5.7 years; 14 women) and 26 older adults (age: 71.3 ± 8.9 years; 11 women) walked in an obstacle course while negotiating anticipated and unanticipated obstacles (long/short available time response, ART) at heights of 50 mm and 100 mm. Prefrontal activation was measured using functional Near-Infrared Spectroscopy (fNIRS); obstacle negotiation performance was measured using Kinect cameras. RESULTS: PD patients showed greater increases in prefrontal activation during and after obstacle crossing compared to the older adults (p < 0.001). Obstacle height affected prefrontal activity only when crossing anticipated obstacles (ARTxheight interaction, p = 0.011), in which case higher obstacles were accompanied by higher prefrontal activity. PD patients showed higher levels of activation during unanticipated obstacles, compared to older adults (groupXART: p = 0.015). Different correlations between prefrontal activation and obstacle negotiation strategies were observed in patients and controls. CONCLUSIONS: These results point to the use of prefrontal activation as a compensatory mechanism in PD. Moreover, the higher activation observed when negotiating more challenging obstacles suggests that there is greater reliance on cognitive resources in these demanding situations that may contribute to the higher risk of falls in PD patients.

A multi-modal virtual reality treadmill intervention for enhancing mobility and cognitive function in people with multiple sclerosis: Protocol for a randomized controlled trial.

BACKGROUND: Gait and cognitive impairments are common in individuals with Multiple Sclerosis (MS) and can interfere with everyday function. Those with MS have difficulties executing cognitive tasks and walking simultaneously, a reflection of dual-task interference. Therefore, dual-task training may improve functional ambulation. Additionally, using technology such as virtual reality can provide personalized rehabilitation while mimicking real-world environments. The purpose of this randomized controlled trial is to establish the benefits of a combined cognitive-motor virtual reality training on MS symptoms compared to conventional treadmill training. METHODS: This study will be a single-blinded, two arm RCT with a six-week intervention period. 144 people with MS will be randomized into a treadmill training alone group or treadmill training with virtual reality group. Both groups will receive 18 sessions of training while walking on a treadmill, with the virtual reality group receiving feedback from the virtual system. Primary outcome measures include dual-task gait speed and information processing speed, which will be measured prior to training, one-week post-training, and three months following training. DISCUSSION: This study will provide insight into the ability of a multi-modal cognitive-motor intervention to reduce dual-task cost and to enhance information processing speed in those with MS. This is one of the first studies that is powered to understand whether targeted dual-task training can improve MS symptoms and increase functional ambulation. We anticipate that those in the virtual reality group will have a significantly greater increase in dual-task gait speed and information processing speed than those achieved via treadmill training alone.

Deterioration of specific aspects of gait during the instrumented 6-min walk test among people with multiple sclerosis.

Prolonged walking is typically impaired among people with multiple sclerosis (pwMS), however, it is unclear what the contributing factors are or how to evaluate this deterioration. We aimed to determine which gait features become worse during sustained walking and to examine the clinical correlates of gait fatigability in pwMS. Fifty-eight pwMS performed the 6-min walk test while wearing body-fixed sensors. Multiple gait domains (e.g., pace, rhythm, variability, asymmetry and complexity) were compared across each minute of the test and between mild- and moderate-disability patient groups. Associations between the decline in gait performance (i.e., gait fatigability) and patient-reported gait disability, fatigue and falls were also determined. Cadence, stride time variability, stride regularity, step regularity and gait complexity significantly deteriorated during the test. In contrast, somewhat surprisingly, gait speed and swing time asymmetry did not change. As expected, subjects with moderate disability (n = 24) walked more poorly in most gait domains compared to the mild-disability group (n = 34). Interestingly, a group × fatigue interaction effect was observed for cadence and gait complexity; these measures decreased over time in the moderate-disability group, but not in the mild group. Gait fatigability rate was significantly correlated with physical fatigue, gait disability, and fall history. These findings suggest that sustained walking affects specific aspects of gait, which can be used as markers for fatigability in MS. This effect on gait depends on the degree of disability, and may increase fall risk in pwMS. To more fully understand and monitor correlates that reflect everyday walking in pwMS, multiple domains of gait should be quantified.

A new approach to quantifying the EEG during walking: Initial evidence of gait related potentials and their changes with aging and dual tasking.

BACKGROUND: The electroencephalogram (EEG) can be a useful tool to investigate the neurophysiology of gait during walking. Our aims were to develop an approach that identify and quantify event related potentials (ERPs) during a gait cycle and to examine the effects of aging and dual tasking on these gait related potentials (GRPs). METHODS: 10 young and 10 older adults walked on a treadmill while wearing a wireless 20-channels EEG and accelerometers on the ankles. Each heel strike extracted from the accelerometers was used as an event to which the electrical brain activity pattern was locked. The subjects performed usual and dual task walking that included an auditory oddball task. GRPs amplitude and latency were computed, and a new measure referred to as Amplitude Pattern Consistency (APC) was developed to quantify the consistency of these GRP amplitudes within a gait cycle. The results were compared between and within groups using linear mixed model analysis. RESULTS: The electrical pattern during a gait cycle consisted of two main positive GRPs. Differences in these GRPs between young and older adults were observed in Pz and Cz. In Pz, older adults had higher GRPs amplitude (p = 0.006, p = 0.010), and in Cz lower APC (p = 0.025). Alterations were also observed between the walking tasks. Both groups showed shorter latency during oddball walking compared to usual walking in Cz (p = 0.040). In addition, the APC in Cz was correlated with gait speed (r = 0.599, p = 0.011) in all subjects and with stride time variability in the older adults (r = -0.703, p = 0.023). CONCLUSIONS: This study is the first to define specific gait related potentials within a gait cycle using novel methods for quantifying waveforms. Our findings show the potential of this approach to be applied broadly to study the EEG during gait in a variety of contexts. The observed changes in GRPs with aging and walking task and the relationship between GRPs and gait may suggest the neurophysiologic foundation for studying walking and for developing new approaches for improving gait.

Age-associated changes in obstacle negotiation strategies: Does size and timing matter?

INTRODUCTION: Tripping over an obstacle is one of the most common causes of falls among older adults. However, the effects of aging, obstacle height and anticipation time on negotiation strategies have not been systematically evaluated. METHODS: Twenty older adults (ages: 77.7±3.4years; 50% women) and twenty young adults (age: 29.3±3.8years; 50% women) walked through an obstacle course while negotiating anticipated and unanticipated obstacles at heights of 25mm and 75mm. Kinect cameras captured the: (1) distance of the subject's trailing foot before the obstacles, (2) distance of the leading foot after the obstacles, (3) clearance of the leading foot above the obstacles, and (4) clearance of the trailing foot above the obstacles. Linear-mix models assessed changes between groups and conditions. RESULTS: Older adults placed their leading foot closer to the obstacle after landing, compared to young adults (p<0.001). This pattern was enhanced in high obstacles (group*height interaction, p=0.033). Older adults had lower clearance over the obstacles, compared to young adults (p=0.007). This was more pronounced during unanticipated obstacles (group*ART interaction, p=0.003). The distance of the leading foot and clearance of the trailing foot after the obstacles were correlated with motor, cognitive, and functional abilities. CONCLUSIONS: These findings suggest that there are age-related changes in obstacle crossing strategies that are dependent on the specific characteristics of the obstacle. The results have important implications for clinical practice, suggesting that functional exercise should include obstacle negotiation training with variable practice of height and available response times. Further studies are needed to better understand the effects of motor and cognitive abilities.

Altered brain activation in complex walking conditions in patients with Parkinson's disease.

INTRODUCTION: Behavioral studies suggest that deficits in cognitive domains and sensory-motor processes associated with Parkinson's disease (PD) impair the ability to walk in complex environments. However, the neural correlates of locomotion in complex environments are still unclear. METHODS: Twenty healthy older adults (mean age 69.7 ± 1.3 yrs) and 20 patients with PD (mean age 72.9 ± 1.6 yrs; disease duration: 6.8 ± 1.3 yrs; UPDRSIII: 29.8 ± 2.4) were asked to imagine themselves walking while in the MRI scanner. Three imagined walking tasks, i.e., usual walking, obstacle negotiation, and navigation were performed. Watching the same virtual scenes without imagining walking served as control tasks. Whole brain analyses were used. RESULTS: Compared to usual walking, both groups had increased activation during obstacle negotiation in middle occipital gyrus (MOG) (pFWEcorr<0.001), middle frontal gyrus (MFG) (pFWEcorr<0.005), and cerebellum (pFWEcorr<0.001). Healthy older adults had higher activation in precuneus and MOG (pFWEcorr<0.023) during navigation, while no differences were observed in patients with PD. Between group comparisons revealed that patients with PD had a significantly higher activation in usual walking and obstacle negotiation (pFWEcorr<0.039) while during navigation task, healthy older adults had higher activation (pFWEcorr<0.047). CONCLUSIONS: Patients with PD require greater activation during imagined usual walking and obstacle negotiation than healthy older adults. This increased activation may reflect a compensatory attempt to overcome inefficient neural activation in patients with PD. This increased activation may reduce the functional reserve needed during more demanding tasks such as during navigation which may contribute to the high prevalence of falls and dual tasking difficulties among patients with PD.

The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease.

GBA mutations are among the most common genetic risk factors for Parkinson disease (PD) worldwide. We aimed to identify genetic modifiers of the age at onset (AAO) in GBA-associated PD. The study included a genome-wide discovery phase, including a cohort of 79 patients with the GBA p.N370S mutation, and candidate validation and replication analyses of 8 SNPs in patients with mild (n = 113) and severe (n = 41) GBA mutations. Genotyping was performed using the Affymetrix human SNP 6.0 array and TaqMan assays. In the genome-wide phase, none of the SNPs passed the genome-wide significance threshold. Eight SNPs were selected for further analysis from the top hits. In all GBA-associated PD patients (n = 153), the BIN1 rs13403026 minor allele was associated with an older AAO (12.4 ± 5.9 years later, p = 0.0001), compared to patients homozygous for the major allele. Furthermore, the AAO was 10.7 ± 6.8 years later in patients with mild GBA mutations, (p = 0.005, validation group), and 17.1 ± 2.5 years later in patients with severe GBA mutations (p = 0.01, replication). Our results suggest that alterations in the BIN1 locus, previously associated with Alzheimer disease, may modify the AAO of GBA-associated PD. More studies in other populations are required to examine the role of BIN1-related variants in GBA-associated PD.

Introducing a new definition of a near fall: intra-rater and inter-rater reliability.

Near falls (NFs) are more frequent than falls, and may occur before falls, potentially predicting fall risk. As such, identification of a NF is important. We aimed to assess intra and inter-rater reliability of the traditional definition of a NF and to demonstrate the potential utility of a new definition. To this end, 10 older adults, 10 idiopathic elderly fallers, and 10 patients with Parkinson's disease (PD) walked in an obstacle course while wearing a safety harness. All walks were videotaped. Forty-nine video segments were extracted to create 2 clips each of 8.48 min. Four raters scored each event using the traditional definition and, two weeks later, using the new definition. A fifth rater used only the new definition. Intra-rater reliability was determined using Kappa (K) statistics and inter-rater reliability was determined using ICC. Using the traditional definition, three raters had poor intra-rater reliability (K<0.054, p>0.137) and one rater had moderate intra-rater reliability (K=0.624, p<0.001). With the traditional definition, inter-rater reliability between the four raters was moderate (ICC=0.667, p<0.001). In contrast, the new NF definition showed high intra-rater (K>0.601, p<0.001) and excellent inter-rater reliability (ICC=0.815, p<0.001). A priori, it is easy to distinguish falls from usual walking and NFs, but it is more challenging to distinguish NFs from obstacle negotiation and usual walking. Therefore, a more precise definition of NF is required. The results of the present study suggest that the proposed new definition increases intra and inter-rater reliability, a critical step for using NFs to quantify fall risk.

Transcranial sonography and functional imaging in glucocerebrosidase mutation Parkinson disease.

BACKGROUND: Heterozygous glucocerebrosidase (GBA) mutations are the leading genetic risk factor for Parkinson disease, yet imaging correlates, particularly transcranial sonography, have not been extensively described. METHODS: To determine whether GBA mutation heterozygotes with Parkinson disease demonstrate hyperechogenicity of the substantia nigra, transcranial sonography was performed in Ashkenazi Jewish Parkinson disease subjects, tested for the eight most common Gaucher disease mutations and the LRRK2 G2019S mutation, and in controls. [(18)F]-fluorodeoxyglucose or [(18)F]-fluorodopa positron emission tomography is also reported from a subset of Parkinson disease subjects with heterozygous GBA mutations. RESULTS: Parkinson disease subjects with heterozygous GBA mutations (n = 23) had a greater median maximal area of substantia nigral echogenicity compared to controls (n = 34, aSNmax = 0.30 vs. 0.18, p = 0.007). There was no difference in median maximal area of nigral echogenicity between Parkinson disease groups defined by GBA and LRRK2 genotype: GBA heterozygotes; GBA homozygotes/compound heterozygotes (n = 4, aSNmax = 0.27); subjects without LRRK2 or GBA mutations (n = 32, aSNmax = 0.27); LRRK2 heterozygotes/homozygotes without GBA mutations (n = 27, aSNmax = 0.28); and GBA heterozygotes/LRRK2 heterozygotes (n = 4, aSNmax = 0.32, overall p = 0.63). In secondary analyses among Parkinson disease subjects with GBA mutations, maximal area of nigral echogenicity did not differ based on GBA mutation severity or mutation number. [(18)F]-fluorodeoxyglucose (n = 3) and [(18)F]-fluorodopa (n = 2) positron emission tomography in Parkinson disease subjects with heterozygous GBA mutations was consistent with findings in idiopathic Parkinson disease. CONCLUSIONS: Both transcranial sonography and positron emission tomography are abnormal in GBA mutation associated Parkinson disease, similar to other Parkinson disease subjects.

Improvement of balance after audio-biofeedback. A 6-week intervention study in patients with progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease with no sufficient treatment options to date. The most devastating symptom is the loss of balance with consecutive falls. Based on the observation that postural control improved in patients with vestibular dysfunction after audio-biofeedback training, we tested the effects of this training in PSP patients. Eight PSP patients were included into an uncontrolled 6-week intervention trial. The focus of the training was the improvement of posture and dynamic balance by using audio-biofeedback. The device was well accepted. No adverse events occurred. A significant improvement in the Berg Balance Scale was observed (T2 vs. T1, p=0.016), which remained significant at the 4-week follow-up (T3 vs. T1, p=0.008). Significant improvement of the Parkinson's disease questionnaire was demonstrated. No significant changes were found in the Timed Up-and-Go Test, the Five Chair Rise Test, and in specific clinical scales. To our knowledge, the present study is the first to demonstrate that audio-biofeedback training with PSP patients is associated with improvements of balance and psychosocial aspects.

LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease.

GBA and LRRK2 mutations increase susceptibility to Parkinson disease (PD), which is characterized by various disabling symptoms. An extended cohort of 600 Ashkenazi PD patients was screened for the LRRK2 G2019S and for eight GBA mutations. Reported initial symptoms were compared between three genotypic groups of patients: carriers of GBA mutations, carriers of LRRK2 G2019S mutation, and non-carriers. More LRRK2 G2019S carriers reported muscle stiffness (rigidity, p = 0.007) and balance disturbances (p = 0.008), while more GBA mutation carriers reported slowness (bradykinesia, p = 0.021). These results suggest distinct effects of LRRK2 or GBA mutations on the initial symptoms of PD.

Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

Is heart rate variability related to gait impairment in patients with Parkinson's disease? A pilot study.

BACKGROUND AND PURPOSE: Impairments in gait and autonomic function are common in patients with Parkinson's disease (PD). These are likely independent symptoms, based on different etiologic mechanisms. However, a few recent reports have observed an association between motor function, in particular gait impairment, and autonomic function in PD. In those studies, the Unified Parkinson's Disease Rating Scale (UPDRS) was used to evaluate gait and motor function. The present study was performed to further examine this putative relationship using quantitative measures of autonomic function and gait in order to shed light on the underlying pathophysiology of these symptoms. METHODS: Nine healthy young, 15 healthy elderly and 18 PD patients were studied. Heart rate variability (HRV) measures were collected during rest. Gait speed, swing time and swing time variability were measured during a 1-min walk at comfortable speed. The motor portion of the UPDRS was also evaluated in all subjects. RESULTS: HRV values were highest in the young adults, intermediate in the healthy elderly controls, and lowest in the PD patients. Gait measures tended to deteriorate with age and were significantly worse in the PD patients, compared to the elderly controls. HRV was not correlated with any measure of gait performance (p>0.129) nor with the UPDRS-motor score (p>0.147). DISCUSSION AND CONCLUSIONS: The present findings support the idea that gait and autonomic function impairments co-exist in PD, but their etiology is based on distinct pathophysiological pathways, with minimal overlap.

Virtual reality-based approaches to enable walking for people poststroke.

Several approaches have been developed and implemented to use virtual reality for rehabilitation of walking for people poststroke. The purpose of this article is to compare and contrast these approaches by describing the virtual reality technology and evaluating the evidence to support its use. Early findings are encouraging but await verification, refinement, and extension.