Gray matter loss relates to dual task gait in Lewy body disorders and aging.

BACKGROUND: Within the spectrum of Lewy body disorders (LBD), both Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by gait and balance disturbances, which become more prominent under dual-task (DT) conditions. The brain substrates underlying DT gait variations, however, remain poorly understood in LBD. OBJECTIVE: To investigate the relationship between gray matter volume loss and DT gait variations in LBD. METHODS: Seventy-nine participants including cognitively unimpaired PD, PD with mild cognitive impairment, PD with dementia (PDD), or DLB and 20 cognitively unimpaired controls were examined across a multi-site study. PDD and DLB were grouped together for analyses. Differences in gait speed between single and DT conditions were quantified by dual task cost (DTC). Cortical, subcortical, ventricle, and cerebellum brain volumes were obtained using FreeSurfer. Linear regression models were used to examine the relationship between gray matter volumes and DTC. RESULTS: Smaller amygdala and total cortical volumes, and larger ventricle volumes were associated with a higher DTC across LBD and cognitively unimpaired controls. No statistically significant interaction between group and brain volumes were found. Adding cognitive and motor covariates or white matter hyperintensity volumes separately to the models did not affect brain volume and DTC associations. CONCLUSION: Gray matter volume loss is associated with worse DT gait performance compared to single task gait, across cognitively unimpaired controls through and the LBD spectrum. Impairment in DT gait performance may be driven by age-related cortical neurodegeneration.

Effects of Exercise Alone or Combined With Cognitive Training and Vitamin D Supplementation to Improve Cognition in Adults With Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Exercise, cognitive training, and vitamin D may enhance cognition in older adults with mild cognitive impairment (MCI). Objective: To determine whether aerobic-resistance exercises would improve cognition relative to an active control and if a multidomain intervention including exercises, computerized cognitive training, and vitamin D supplementation would show greater improvements than exercise alone. Design, Setting, and Participants: This randomized clinical trial (the SYNERGIC Study) was a multisite, double-masked, fractional factorial trial that evaluated the effects of aerobic-resistance exercise, computerized cognitive training, and vitamin D on cognition. Eligible participants were between ages 65 and 84 years with MCI enrolled from September 19, 2016, to April 7, 2020. Data were analyzed from February 2021 to December 2022. Interventions: Participants were randomized to 5 study arms and treated for 20 weeks: arm 1 (multidomain intervention with exercise, cognitive training, and vitamin D), arm 2 (exercise, cognitive training, and placebo vitamin D), arm 3 (exercise, sham cognitive training, and vitamin D), arm 4 (exercise, sham cognitive training, and placebo vitamin D), and arm 5 (control group with balance-toning exercise, sham cognitive training, and placebo vitamin D). The vitamin D regimen was a 10 000 IU dose 3 times weekly. Main Outcomes and Measures: Primary outcomes were changes in ADAS-Cog-13 and Plus variant at 6 months. Results: Among 175 randomized participants (mean [SD] age, 73.1 [6.6] years; 86 [49.1%] women), 144 (82%) completed the intervention and 133 (76%) completed the follow-up (month 12). At 6 months, all active arms (ie, arms 1 through 4) with aerobic-resistance exercise regardless of the addition of cognitive training or vitamin D, improved ADAS-Cog-13 when compared with control (mean difference, -1.79 points; 95% CI, -3.27 to -0.31 points; P = .02; d = 0.64). Compared with exercise alone (arms 3 and 4), exercise and cognitive training (arms 1 and 2) improved the ADAS-Cog-13 (mean difference, -1.45 points; 95% CI, -2.70 to -0.21 points; P = .02; d = 0.39). No significant improvement was found with vitamin D. Finally, the multidomain intervention (arm 1) improved the ADAS-Cog-13 score significantly compared with control (mean difference, -2.64 points; 95% CI, -4.42 to -0.80 points; P = .005; d = 0.71). Changes in ADAS-Cog-Plus were not significant. Conclusions and Relevance: In this clinical trial, older adults with MCI receiving aerobic-resistance exercises with sequential computerized cognitive training significantly improved cognition, although some results were inconsistent. Vitamin D supplementation had no effect. Our findings suggest that this multidomain intervention may improve cognition and potentially delay dementia onset in MCI. Trial Registration: ClinicalTrials.gov Identifier: NCT02808676.

Combining exercise with cognitive training and vitamin D3 to improve functional brain connectivity (FBC) in older adults with mild cognitive impairment (MCI). Results from the SYNERGIC trial.

Changes in functional brain connectivity (FBC) may indicate how lifestyle modifications can prevent the progression to dementia; FBC identifies areas that are spatially separate but temporally synchronized in their activation and is altered in those with mild cognitive impairment (MCI), a prodromal state between healthy cognitive aging and dementia. Participants with MCI were randomly assigned to one of five study arms. Three times per week for 20-weeks, participants performed 30-min of (control) cognitive training, followed by 60-min of (control) physical exercise. Additionally, a vitamin D3 (10,000 IU/pill) or a placebo capsule was ingested three times per week for 20-weeks. Using the CONN toolbox, we measured FBC change (Post-Pre) across four statistical models that collapsed for and/or included some or all study arms. We conducted Pearson correlations between FBC change and changes in physical and cognitive functioning. Our sample included 120 participants (mean age: 73.89 ± 6.50). Compared to the pure control, physical exercise (model one; p-False Discovery Rate (FDR) < 0.01 & < 0.05) with cognitive training (model two; p-FDR = < 0.001), and all three interventions combined (model four; p-FDR = < 0.01) demonstrated an increase in FBC between regions of the Default-Mode Network (i.e., hippocampus and angular gyrus). After controlling for false discovery rate, there were no significant correlations between change in connectivity and change in cognitive or physical function. Physical exercise alone appears to be as efficacious as combined interventional strategies in altering FBC, but implications for behavioral outcomes remain unclear.

Dual-task gait and white matter hyperintensities in Lewy body diseases: An exploratory analysis.

Background: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are part of a spectrum of Lewy body disorders, who exhibit a range of cognitive and gait impairments. Cognitive-motor interactions can be examined by performing a cognitive task while walking and quantified by a dual task cost (DTC). White matter hyperintensities (WMH) on magnetic resonance imaging have also been associated with both gait and cognition. Our goal was to examine the relationship between DTC and WMH in the Lewy body spectrum, hypothesizing DTC would be associated with increased WMH volume. Methods: Seventy-eight participants with PD, PD with mild cognitive impairment (PD-MCI), PD with dementia or DLB (PDD/DLB), and 20 cognitively unimpaired participants were examined in a multi-site study. Gait was measured on an electronic walkway during usual gait, counting backward, animal fluency, and subtracting sevens. WMH were quantified from magnetic resonance imaging using an automated pipeline and visual rating. A median split based on DTC was performed. Models included age as well as measures of global cognition and cardiovascular risk. Results: Compared to cognitively unimpaired participants, usual gait speed was lower and DTC was higher in PD-MCI and PDD/DLB. Low DTC participants had higher usual gait speed. WMH burden was greater in high counting DTC participants. Frontal WMH burden remained significant after adjusting for age, cardiovascular risk and global cognition. Conclusion: Increased DTC was associated with higher frontal WMH burden in Lewy body disorders after adjusting for age, cardiovascular risk, and global cognition. Higher DTC was associated with age.

Frailty and functional brain connectivity (FBC) in older adults with mild cognitive impairment (MCI): baseline results from the SYNERGIC Trial.

Functional brain connectivity (FBC), or areas that are anatomically separate but temporally synchronized in their activation, represent a sensitive biomarker for monitoring dementia progression. It is unclear whether frailty is associated with FBC in those at higher risk of progression to dementia (e.g., mild cognitive impairment -MCI-) and if sex plays a role. We used baseline data from the SYNERGIC trial, including participants with MCI that received brain MRI. In this cross-sectional analyses (n = 100), we measured frailty using a deficit accumulation frailty index. Using the CONN toolbox, we assessed FBC of networks and regions of interest across the entire connectome. We used Pearson's correlation to investigate the relationship between FBC and frailty index in the full sample and by sex. We also divided the full sample and each sex into tertiles based upon their frailty index score and then assessed between-tertile differences in FBC. The full sample (cluster: size = 291 p-FDR < 0.05) and males (cluster: size = 993 and 451 p-FDR < 0.01) demonstrated that increasing (stronger) connectivity between the right hippocampus and clusters in the temporal gyrus was positively correlated with increasing (worse) frailty. Males also demonstrated between-tertile differences in right hippocampus connectivity to clusters in the lateral occipital cortex (cluster: size = 289 p-FDR < 0.05). Regardless of frailty status, females demonstrated stronger within-network connectivity of the Default-Mode (p = 0.024). Our results suggest that increasing (worse) frailty was associated with increasing (stronger) connectivity between regions not typically linked, which may reflect a compensation tactic by the plastic brain. Furthermore, the relationship between the two variables appears to differ by sex. Our results may help elucidate why specific individuals progress to a dementia syndrome. NCT02808676. https://www.clinicaltrials.gov/ct2/show/NCT02808676.

Large-scale frontoparietal theta, alpha, and beta phase synchronization: A set of EEG differential characteristics for freezing of gait in Parkinson's disease?

Freezing of gait (FOG) is a complex gait disturbance in Parkinson's disease (PD), during which the patient is not able to effectively initiate gait or continue walking. The mystery of the FOG phenomenon is still unsolved. Recent studies have revealed abnormalities in cortical activities associated with FOG, which highlights the importance of cortical and cortical-subcortical network dysfunction in PD patients with FOG. In this paper, phase-locking value (PLV) of eight frequency sub-bands between 0.05 Hz and 35 Hz over frontal, motor, and parietal areas [during an ankle dorsiflexion (ADF) task] is used to investigate EEG phase synchronization. PLV was investigated over both superficial and deeper networks by analyzing EEG signals preprocessed with and without Surface Laplacian (SL) spatial filter. Four groups of participants were included: PD patients with severe FOG (N = 5, 5 males), PD patients with mild FOG (N = 7, 6 males), PD patients without FOG (N = 14, 13 males), and healthy age-matched controls (N = 13, 10 males). Fifteen trials were recorded from each participant. At superficial layers, frontoparietal theta phase synchrony was a unique feature present in PD with FOG groups. At deeper networks, significant dominance of interhemispheric frontoparietal alpha phase synchrony in PD with FOG, in contrast to beta phase synchrony in PD without FOG, was identified. Alpha phase synchrony was more distributed in PD with severe FOG, with higher levels of frontoparietal alpha phase synchrony. In addition to FOG-related abnormalities in PLV analysis, phase-amplitude coupling (PAC) analysis was also performed on frequency bands with PLV abnormalities. PAC analysis revealed abnormal coupling between theta and low beta frequency bands in PD with severe FOG at the superficial layers over frontal areas. At deeper networks, theta and alpha frequency bands show high PAC over parietal areas in PD with severe FOG. Alpha and low beta also presented PAC over frontal areas in PD groups with FOG. The results introduced significant phase synchrony differences between PD with and without FOG and provided important insight into a possible unified underlying mechanism for FOG. These results thus suggest that PLV and PAC can potentially be used as EEG-based biomarkers for FOG.

Profiles of Motor-Cognitive Interference in Parkinson's Disease-The Trail-Walking-Test to Discriminate between Motor Phenotypes.

Background and Aims. Most research on Parkinson's disease (PD) focuses on describing symptoms and movement characteristics. Studies rarely focus on the early detection of PD and the search for suitable markers of a prodromal stage. Early detection is important, so treatments that may potentially change the course of the disease can be attempted early on. While gait disturbances are less pronounced in the early stages of the disease, the prevalence, and severity increase with disease progression. Therefore, postural instability and gait difficulties could be identified as sensitive biomarkers. The aim was to evaluate the discriminatory power of the Trail-Walking Test (TWT; Schott, 2015) as a potential diagnostic instrument to improve the predictive power of the clinical evaluation concerning the severity of the disease and record the different aspects of walking. Methods. A total of 20 older healthy (M = 72.4 years, SD = 5.53) adults and 43 older adults with PD and the motor phenotypes postural instability/gait difficulty (PIGD; M = 69.7 years, SD = 8.68) and tremor dominant (TD; M = 68.2 years, SD = 8.94) participated in the study. The participants performed a motor-cognitive dual task (DT) of increasing cognitive difficulty in which they had to walk a given path (condition 1), walk to numbers in ascending order (condition 2), and walk to numbers and letters alternately and in ascending order (condition 3). Results. With an increase in the cognitive load, the time to complete the tasks (seconds) became longer in all groups, F(1.23, 73.5) = 121, p < 0.001, ɳ2p = 0.670. PIGD showed the longest times in all conditions of the TWT, F(2, 60) = 8.15, p < 0.001, ɳ2p = 0.214. Mutual interferences in the cognitive and motor domain can be observed. However, clear group-specific patterns cannot be identified. A differentiation between the motor phenotypes of PD is especially feasible with the purely motor condition (TWT-M; AUC = 0.685, p = 0.44). Conclusions. PD patients with PIGD must be identified by valid, well-evaluated clinical tests that allow for a precise assessment of the disease's individual fall risk, the severity of the disease, and the prognosis of progression. The TWT covers various aspects of mobility, examines the relationship between cognitive functions and walking, and enables differentiation of the motor phenotypes of PD.

Protocol for SYNchronising Exercises, Remedies in GaIt and Cognition at Home (SYNERGIC@Home): feasibility of a home-based double-blind randomised controlled trial to improve gait and cognition in individuals at risk for dementia.

INTRODUCTION: Physical exercise and cognitive training have the potential to enhance cognitive function and mobility in older adults at risk of Alzheimer's disease and related dementia (ADRD), but little is known about the feasibility of delivering multidomain interventions in home settings of older adults at risk of ADRD. This study aims to assess the feasibility of home-based delivery of exercise and cognitive interventions, and to evaluate the relationship between participants' intervention preferences and their subsequent adherence. Secondary objectives include the effect of the interventions on ADRD risk factors, including frailty, mobility, sleep, diet and psychological health. METHODS AND ANALYSIS: The SYNchronising Exercises, Remedies in GaIt and Cognition at Home (SYNERGIC@Home) feasibility trial is a randomised control trial that follows a 2×2 factorial design, with a 16-week home-based intervention programme (3 sessions per week) of physical exercises and cognitive training. Participants will be randomised in blocks of four to one of the following four arms: (1) combined exercise (aerobic and resistance)+cognitive training (NEUROPEAK); (2) combined exercise+control cognitive training (web searching); (3) control exercise (balance and toning)+cognitive training; and (4) control exercise+control cognitive training. SYNERGIC@Home will be implemented through video conferencing. Baseline and post-intervention assessments at 4-month and 10-month follow-up will include measures of cognition, frailty, mobility, sleep, diet and psychological health. Primary feasibility outcome is adherence to the interventions. Primary analytic outcome is the relationship between pre-allocation preference for a given intervention and subsequent adherence to the allocated intervention. A series of secondary analytic outcomes examining the potential effect of the individual and combined interventions on cognitive, mobility and general well-being will be measured at baseline and follow-up. ETHICS AND DISSEMINATION: Ethics approval was granted by the relevant research ethics boards. Findings of the study will be presented to stakeholders and published in peer-reviewed journals and at provincial, national and international conferences. TRIAL REGISTRATION NUMBER: NCT04997681, Pre-results.

Feasibility of online PD SAFEx™ exercise rehabilitation for symptom improvements of Parkinson's disease: A pilot study.

BACKGROUND: Parkinson's Disease (PD) is a neurodegenerative disorder affecting both motor and cognitive symptoms. While medications show some improvement in motor symptoms, cognitive symptoms can worsen. In-person exercise programs, such as PD SAFEx™, are an important adjunct therapy in improving symptoms. However, coronavirus disease 2019 (COVID-19) limited in-person exercise interventions. Therefore, there is a need to investigate the effectiveness of online exercise delivery. OBJECTIVE: To identify (1) whether an online exercise intervention can achieve similar results to an identical in-person intervention and (2) if online PD SAFEx™ can alter the cognitive decline of PD patients. METHODS: 20 participants with idiopathic PD participated in a 12-week online PD SAFEx™ program and were compared to 73 participants from in-person PD SAFEx™. The primary outcome measure was the Unified Parkinson's Disease Rating Scale-III measured before/after intervention. Three secondary cognitive measures were collected with the online group. RESULTS: Main effect of time on UPDRS-III scores of both groups were found (F(1,92) = 35.555, p < 0.001). No interaction was found between in-person and online groups (F(1,1) = 0.052, p = 0.820). TMT B in the online group showed significant improvements in executive function (F(1,17) = 7.095, p = 0.016). CONCLUSIONS: Online and in-person PD SAFEx™ both achieved clinically significant UPDRS-III improvement and are statistically equivalent. Online PD SAFEx™ reduced cognitive symptoms seen during COVID-19.

An equation to calculate UPDRS motor severity for online and rural assessments of Parkinson's.

OBJECTIVE: Management of PD has largely been affected by COVID-19. Due to the restrictions posed by COVID-19, there has been a shift from in-person to online forms of assessment. This presents a challenge as not all motor symptoms can be assessed virtually. Two of the four cardinal symptoms of PD (rigidity and postural instability) cannot be assessed virtually using the gold-standard Unified Parkinson's Disease Rating Scale (UPDRS-III). As a result, an accurate total motor severity score can not be computed from the remaining subsections. Recently, one study stated that in order for accurate scores to be calculated, only three sections could be absent. Virtually, six sections are unable to be evaluated with online assessments. This inability to compute a total motor severity score may result in poor disease management. Thus, in this study a regression equation was developed to predict total motor severity scores from partial scores. METHODS: Total motor severity scores (UPDRS-III) from N = 234 individuals with idiopathic Parkinson's were retrospectively analyzed. In order to conduct a linear regression analysis predictor and outcome variables were created. The variables were then used for the linear regression. The equation was then tested on an independent data set N = 1168. RESULTS: The regression analysis resulted in the equation to predict total motor symptom severity of PD. CONCLUSIONS: In conclusion, the developed equation will be very useful for outreach in rural communities, as well as the continued remote management of PD during COVID-19 and beyond.

Movement-related EEG signatures associated with freezing of gait in Parkinson's disease: an integrative analysis.

Freezing of gait is the most severe gait deficit associated with Parkinson's disease and significantly affects patients' independence and consequently their quality of life. The lack of a clear understanding of its underlying neurophysiological mechanism has resulted in limited effectiveness of the current treatment options. In this study, we investigated EEG features over (pre-)supplementary motor area and primary motor cortex during a simple cue-based ankle dorsiflexion movement. These features include movement-related cortical potentials (0.05-5 Hz) and brain oscillations (1-50 Hz). Electromyogram signal from the tibialis anterior muscle of the dominant foot was used to determine the movement onset. The EEG features before, during and following the onset of the movement were compared among three groups of participants: patients with freezing (N = 14, 11 males), patients without freezing (N = 14, 13 males) and healthy age-matched controls (N = 13, 10 males) with 15 recorded trials for each individual. Additionally, Parkinson's disease patients with freezing of gait were separated into mild (N = 7) and severe cases (N = 5), so that EEG features associated with freezing severity could be investigated. The results indicated significant differences between patients with severe freezing of gait compared to healthy controls and patients without freezing of gait. In addition, patients with mild and severe freezing represented cortical activity differences. For patients with freezing, the initial component of movement-related cortical potential is significantly lower than that of the healthy controls (P = 0.002) and is affected by the severity of freezing. Furthermore, a striking absence of beta frequency band (12-35 Hz) desynchronization was observed in patients with freezing, especially low-beta frequency band over Cz, before the movement, which was also associated with the severity of the freezing of gait. Low-beta (13-20 Hz) and high-beta (21-35 Hz) frequency band activities represented unique features for each group. Beta event-related desynchronization over Cz present in healthy controls prior to movement onset, was partially replaced by the theta band (4-8 Hz) synchrony in patients with freezing. Patients with severe freezing also represented some level of theta band synchronization over contralateral supplementary motor area. This suggests the involvement of cognitive processing over the motor cortex in controlling cue-based voluntary movement as a compensatory mechanism associated with freezing of gait. The EEG features identified in this study are indicative of important freezing of gait clinical characteristics such as severity and contribute to a better understanding of the underlying neurophysiology of the mysterious phenomenon of freezing of gait.

Boxing vs Sensory Exercise for Parkinson's Disease: A Double-Blinded Randomized Controlled Trial.

Background. Exercise is increasingly becoming recognized as an important adjunct to medications in the clinical management of Parkinson's disease (PD). Boxing and sensory exercise have shown immediate benefits, but whether they continue beyond program completion is unknown. This study aimed to investigate the effects of boxing and sensory training on motor symptoms of PD, and whether these benefits remain upon completion of the intervention. Methods. In this 20-week double-blinded randomized controlled trial, 40 participants with idiopathic PD were randomized into 2 treatment groups, (n = 20) boxing or (n = 20) sensory exercise. Participants completed 10 weeks of intervention. Motor symptoms were assessed at (week 0, 10, and 20) using the Unified Parkinson's Disease Rating Scale (UPDRS-III). Data were analyzed using SPSS, and repeated-measures ANOVA was conducted. Results. A significant interaction effect between groups and time were observed F(1, 39) = 4.566, P = .036, where the sensory group improved in comparison to the boxing group. Post hoc analysis revealed that in comparison to boxing, the effects of exercise did not wear off at washout (week 20) P < .006. Conclusion. Future rehabilitation research should incorporate similar measures to explore whether effects of exercise wear off post intervention.

Detecting Sensitive Mobility Features for Parkinson's Disease Stages Via Machine Learning.

BACKGROUND: It is not clear how specific gait measures reflect disease severity across the disease spectrum in Parkinson's disease (PD). OBJECTIVE: To identify the gait and mobility measures that are most sensitive and reflective of PD motor stages and determine the optimal sensor location in each disease stage. METHODS: Cross-sectional wearable-sensor records were collected in 332 patients with PD (Hoehn and Yahr scale I-III) and 100 age-matched healthy controls. Sensors were adhered to the participant's lower back, bilateral ankles, and wrists. Study participants walked in a ~15-meter corridor for 1 minute under two walking conditions: (1) preferred, usual walking speed and (2) walking while engaging in a cognitive task (dual-task). A subgroup (n = 303, 67% PD) also performed the Timed Up and Go test. Multiple machine-learning feature selection and classification algorithms were applied to discriminate between controls and PD and between the different PD severity stages. RESULTS: High discriminatory values were found between motor disease stages with mean sensitivity in the range 72%-83%, specificity 69%-80%, and area under the curve (AUC) 0.76-0.90. Measures from upper-limb sensors best discriminated controls from early PD, turning measures obtained from the trunk sensor were prominent in mid-stage PD, and stride timing and regularity were discriminative in more advanced stages. CONCLUSIONS: Applying machine-learning to multiple, wearable-derived features reveals that different measures of gait and mobility are associated with and discriminate distinct stages of PD. These disparate feature sets can augment the objective monitoring of disease progression and may be useful for cohort selection and power analyses in clinical trials of PD. © 2021 International Parkinson and Movement Disorder Society.

Rehabilitation of Falls in Parkinson's Disease: Self-Perception vs. Objective Measures of Fall Risk.

Falls are an important cause of injury and increased hospital/long-term care facility stays and has been reported in 70% of people with Parkinson's disease (PD), yet there is limited effectiveness of medications for reducing falls. As an adjunct, many exercise therapies succeed in objectively reducing the number of falls, but this may not translate to improved quality of life (QOL). Importantly, self-perceived fall risk has a greater influence on activities of daily living and QOL, making it important to evaluate in the rehabilitation of PD. The purpose of this study was to examine the influence of a 10-week exercise intervention (PD SAFE × TM) on self-perceived (according to balance confidence measures) and objective measures of gait that are commonly linked to fall risk in PD. Participants (N = 44) with PD completed PD SAFE × TM. Pre-/post-assessment involved the Activities-specific Balance Confidence Scale (perception), objective falls characteristics (stride time, stride width, stride length, and stride variability), and symptom severity (Unified Parkinson's Disease Rating Scale motor subsection III (UPDRS-III)) after participants were stratified into a mild (no-balance impairment) vs. severe (balance impairment) groups. Overall disease severity (F (1, 43) = 8.75, p < 0.003) and all objective fall parameters improved (p < 0.05) in both groups, yet self-perceived fall risk improved in only the severe PD group F (1, 43) = 9.86, p < 0.022. Given that self-perceived fall risk and objective fall risk both play a role in the quality of life, identifying strategies to improve both aspects may be important in improving the overall quality of life.

Investigating Therapies for Freezing of Gait Targeting the Cognitive, Limbic, and Sensorimotor Domains.

BACKGROUND: Freezing of gait (FOG) is arguably the most disabling motor symptom experienced with Parkinson's disease (PD), but treatments are extremely limited due to our poor understanding of the underlying mechanisms. Three cortical domains are postulated in recent research (ie, the cognitive, limbic, and sensorimotor domains), thus, treatments targeting these mechanisms of FOG may potentially be effective. Cognitive training, cognitive behavioral therapy (CBT, a well-known anxiety intervention), and proprioceptive training may address the cognitive, limbic, and sensorimotor domains, respectively. OBJECTIVE: To investigate whether these 3 treatments could improve functional outcomes of FOG. METHODS: In a single-blind, randomized crossover design, 15 individuals with PD and FOG were randomized into different, counterbalanced orders of receiving the interventions. Each consisted of eight 1-hour sessions, twice weekly for 4 weeks. FOG severity was assessed as the primary outcome using a novel gait paradigm that was aimed at evoking FOG when the cognitive, limbic, or sensorimotor domains were independently challenged. RESULTS: FOG severity significantly improved after the cognitive intervention, with strong trends toward improvement specifically in the baseline and cognitive-challenge assessment conditions. CBT, as the anxiety intervention, resulted in significantly worse FOG severity. In contrast, proprioceptive training significantly improved FOG severity, with consistent trends across all conditions. CONCLUSIONS: The cognitive and proprioceptive treatments appeared to improve different aspects of FOG. Thus, either of these interventions could potentially be a viable treatment for FOG. However, although the results were statistically significant, they could be sensitive to the relatively small number of participants in the study. Considering the significant results together with nonsignificant trends in both FOG and gait measures, and given equal time for each intervention, proprioceptive training produced the most consistent indications of benefits in this study. (clinicaltrials.gov NCT03065127).

Gait variability across neurodegenerative and cognitive disorders: Results from the Canadian Consortium of Neurodegeneration in Aging (CCNA) and the Gait and Brain Study.

INTRODUCTION: Gait impairment is common in neurodegenerative disorders. Specifically, gait variability-the stride-to-stride fluctuations in distance and time-has been associated with neurodegeneration and cognitive impairment. However, quantitative comparisons of gait impairments across the cognitive spectrum of dementias have not been systematically investigated. METHODS: Older adults (N = 500) with subjective cognitive impairment, Parkinson disease (PD), mild cognitive impairment (MCI), PD-MCI, Alzheimer's disease (AD), PD-dementia, Lewy body dementia, and frontotemporal dementia, as well cognitive normal controls, who were assessed for their gait and cognitive performance. RESULTS: Factor analyses grouped 11 quantitative gait parameters and identified four independent gait domains: rhythm, pace, variability, and postural control, for group comparisons and classification analysis. Among these domains, only high gait variability was associated with lower cognitive performance and accurately discriminated AD from other neurodegenerative and cognitive conditions. DISCUSSION: Our findings indicate that high gait variability is a marker of cognitive-cortical dysfunction, which can help to identify Alzheimer's disease dementia.

Pupil light reflex in Parkinson's disease patients with and without freezing of gait symptoms.

PURPOSE: Freezing of gait (FOG) is considered as a motor disorder that affects some Parkinson's disease (PD) patients; however, sensory systems may also be involved in FOG. The pupil light reflex (PLR) is a reliable measure of the autonomic nervous system. Different dilation and constriction pupil parameters may be used to investigate the integrity of the autonomic nervous system in PD patients with and without FOG symptoms. This study aimed to look at the integrity of autonomic nervous system and to investigate the nonmotor functions mediated by the cholinergic system in Parkinson's patients with and without FOG symptoms. METHODS: Constriction and dilation pupil light reflexes were measured by using a handheld pupillometer. Twenty-two patients with FOG symptoms, 25 patients without FOG symptoms, and 25 aged-matched healthy controls participated in this study. RESULTS: The results showed that most of the constriction parameters and dilation latency of both patient groups differed significantly from healthy controls. FOG patients showed larger pupil size under light condition and larger deficits in constriction latency than nonFOG patients. Both the groups of PD patients had longer dilation latencies than healthy controls. CONCLUSION: This study suggests that the cholinergic autonomic nervous system is affected in PD patients more than the adrenergic system. FOG patients had larger impairments in nondopaminergic mediated functions such as pupil light reflexes, which suggests that FOG patients have greater impairment in functions that involve cholinergic neurotransmitters.

Movement Related Cortical Potentials in Parkinson's Disease Patients with Freezing of Gait.

Parkinson's disease (PD) is a complex neurode-generative disorder that results into poverty of movements. Freezing of gait (FOG) is a common and severely incapacitating symptom of PD. However, the underlying neurophysiological mechanism of FOG is still unclear. Electroencephalogram (EEG) as a non-invasive brain signal measurement method has been repeatedly used to reveal the pathological reasons behind PD. Since PD affects movement abilities, one particular type of EEG pattern called Movement-related cortical potential (MRCP), which was shown to be related to the generation of movement intention, can be a useful tool in PD research. However, most MRCP studies in PD area focus on the upper-limb movement like finger movement, to the best knowledge of the authors, no study explored MRCP characteristics during lower extremity movement in PD patients, particularly PD patients with FOG. This paper intends to investigate the relationship between the characteristics of MRCP and FOG by comparing MRCP signals among three groups: healthy controls group, PD patients without FOG group, and PD patients with FOG group. These three groups of participants were recruited based on age-matching and gender proportion matching criteria. During the experiment, the Electromyography (EMG) from the tibialis anterior (TA) muscle and EEG were recorded when performing ankle dorsiflexion (AD) by the dominant foot. MRCP signals were extracted from EEG data based on the muscle activities in the TA muscle of the dominant foot. The results of this study show that, during lower limb activities, MRCP shares considerable similarities between PD patients and healthy participants. However, the amplitude of MRCP in PD patients (with and without FOG) is lower compared to the healthy participants. In addition, direct observations from the results show that MRCP from PD patients with FOG has higher amplitude but more variability in terms of amplitude and latency than those from PD patients without FOG.

Behavioural manifestations and associated non-motor features of freezing of gait: A narrative review and theoretical framework.

Over the past decade, non-motor related symptoms and provocative contexts have offered unique opportunities to gain insight into the potential mechanisms that may underpin freezing of gait (FOG) in Parkinson's disease (PD). While this large body of work has informed several theoretical models, to date, few are capable of explaining behavioural findings across multiple domains (i.e. cognitive, sensory-perceptual and affective) and in different behavorial contexts. As such, the exact nature of these interrelationships and their neural basis remain quite enigmatic. Here, the non-motor, behavioural evidence for cognitive, sensory-perceptual and affective contributors to FOG are reviewed and synthesized by systematically examining (i) studies that manipulated contextual environments that provoke freezing of gait, (ii) studies that uncovered factors that have been proposed to contribute to freezing, and (iii) studies that longitudinally tracked factors that predict the future development of freezing of gait. After consolidating the evidence, we offer a novel perspective for integrating these multi-faceted behavioural patterns and identify key challenges that warrant consideration in future work.