Proteinopathy and Longitudinal Cognitive Decline in Parkinson Disease.

BACKGROUND AND OBJECTIVES: People with Parkinson disease (PD) commonly experience cognitive decline, which may relate to increased α-synuclein, tau, and ß-amyloid accumulation. This study examines whether the different proteins predict longitudinal cognitive decline in PD. METHODS: All participants (PD n = 152, controls n = 52) were part of a longitudinal study and completed a lumbar puncture for CSF protein analysis (α-synuclein, total tau [tau], and ß-amyloid42 [ß-amyloid]), a ß-amyloid PET scan, and/or provided a blood sample for APOE genotype (ε4+, ε4-), which is a risk factor for ß-amyloid accumulation. Participants also had comprehensive, longitudinal clinical assessments of overall cognitive function and dementia status, as well as cognitive testing of attention, language, memory, and visuospatial and executive function. We used hierarchical linear growth models to examine whether the different protein metrics predict cognitive change and multivariate Cox proportional hazard models to predict time to dementia conversion. Akaike information criterion was used to compare models for best fit. RESULTS: Baseline measures of CSF ß-amyloid predicted decline for memory (p = 0.04) and overall cognitive function (p = 0.01). APOE genotypes showed a significant group (ε4+, ε4-) effect such that ε4+ individuals declined faster than ε4- individuals in visuospatial function (p = 0.03). Baseline ß-amyloid PET significantly predicted decline in all cognitive measures (all p ≤ 0.004). Neither baseline CSF α-synuclein nor tau predicted cognitive decline. All 3 ß-amyloid--related metrics (CSF, PET, APOE) also predicted time to dementia. Models with ß-amyloid PET as a predictor fit the data the best. DISCUSSION: Presence or risk of ß-amyloid accumulation consistently predicted cognitive decline and time to dementia in PD. This suggests that ß-amyloid has high potential as a prognostic indicator and biomarker for cognitive changes in PD.

Distinct progression patterns across Parkinson disease clinical subtypes.

OBJECTIVE: To examine specific symptom progression patterns and possible disease staging in Parkinson disease clinical subtypes. METHODS: We recently identified Parkinson disease clinical subtypes based on comprehensive behavioral evaluations, "Motor Only," "Psychiatric & Motor," and "Cognitive & Motor," which differed in dementia and mortality rates. Parkinson disease participants ("Motor Only": n = 61, "Psychiatric & Motor": n = 17, "Cognitive & Motor": n = 70) and controls (n = 55) completed longitudinal, comprehensive motor, cognitive, and psychiatric evaluations (average follow-up = 4.6 years). Hierarchical linear modeling examined group differences in symptom progression. A three-way interaction among time, group, and symptom duration (or baseline age, separately) was incorporated to examine disease stages. RESULTS: All three subtypes increased in motor dysfunction compared to controls. The "Motor Only" subtype did not show significant cognitive or psychiatric changes compared to the other two subtypes. The "Cognitive & Motor" subtype's cognitive dysfunction at baseline further declined compared to the other two subtypes, while also increasing in psychiatric symptoms. The "Psychiatric & Motor" subtype's elevated psychiatric symptoms at baseline remained steady or improved over time, with mild, steady decline in cognition. The pattern of behavioral changes and analyses for disease staging yielded no evidence for sequential disease stages. INTERPRETATION: Parkinson disease clinical subtypes progress in clear, temporally distinct patterns from one another, particularly in cognitive and psychiatric features. This highlights the importance of comprehensive clinical examinations as the order of symptom presentation impacts clinical prognosis.

Resting-state functional connectivity associated with gait characteristics in people with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is a movement disorder caused by dysfunction in the basal ganglia (BG). Clinically relevant gait deficits, such as decreased velocity and increased variability, may be caused by underlying neural dysfunction. Reductions in resting-state functional connectivity (rs-FC) between networks have been identified in PD compared to controls; however, the association between gait characteristics and rs-FC of brain networks in people with PD has not yet been explored. The present study aimed to investigate these associations. METHODS: Gait characteristics and rs-FC MRI data were collected for participants with PD (N = 50). Brain networks were identified from a set of seeds representing cortical, subcortical, and cerebellar regions. Gait outcomes were correlated with the strength of rs-FC within and between networks of interest. A stepwise regression analysis was also conducted to determine whether the rs-FC strength of brain networks, along with clinical motor scores, were predictive of gait characteristics. RESULTS: Gait velocity was associated with rs-FC within the visual network and between motor and cognitive networks, most notably BG-thalamus internetwork rs-FC. The stepwise regression analysis showed strength of BG-thalamus internetwork rs-FC and clinical motor scores were predictive of gait velocity. CONCLUSION: The results of the present study demonstrate gait characteristics are associated with functional organization of the brain at the network level, providing insight into the neural mechanisms of clinically relevant gait characteristics. This knowledge could be used to optimize the design of gait rehabilitation interventions for people with neurological conditions.

Parkinson disease clinical subtypes: key features & clinical milestones.

OBJECTIVES: Based on multi-domain classification of Parkinson disease (PD) subtypes, we sought to determine the key features that best differentiate subtypes and the utility of PD subtypes to predict clinical milestones. METHODS: Prospective cohort of 162 PD participants with ongoing, longitudinal follow-up. Latent class analysis (LCA) delineated subtypes based on score patterns across baseline motor, cognitive, and psychiatric measures. Discriminant analyses identified key features that distinguish subtypes at baseline. Cox regression models tested PD subtype differences in longitudinal conversion to clinical milestones, including deep brain stimulation (DBS), dementia, and mortality. RESULTS: LCA identified distinct subtypes: "motor only" (N = 63) characterized by primary motor deficits; "psychiatric & motor" (N = 17) characterized by prominent psychiatric symptoms and moderate motor deficits; "cognitive & motor" (N = 82) characterized by impaired cognition and moderate motor deficits. Depression, executive function, and apathy best discriminated subtypes. Since enrollment, 22 had DBS, 48 developed dementia, and 46 have died. Although there were no subtype differences in rate of DBS, dementia occurred at a higher rate in the "cognitive & motor" subtype. Surprisingly, mortality risk was similarly elevated for both "cognitive & motor" and "psychiatric & motor" subtypes compared to the "motor only" subtype (relative risk = 3.15, 2.60). INTERPRETATION: Psychiatric and cognitive features, rather than motor deficits, distinguish clinical PD subtypes and predict greater risk of subsequent dementia and mortality. These results emphasize the value of multi-domain assessments to better characterize clinical variability in PD. Further, differences in dementia and mortality rates demonstrate the prognostic utility of PD subtypes.

Dual-task costs of texting while walking forward and backward are greater for older adults than younger adults.

Cognitive-motor dual-tasking involves concurrent performance of two tasks with distinct cognitive and motor demands and is associated with increased fall risk. In this hypothesis-driven study, younger (18-30 years, n = 24) and older (60-75 years, n = 26) adults completed six walking tasks in triplicate. Participants walked forward and backward along a GAITRite mat, in isolation or while performing a verbal fluency task. Verbal fluency tasks involved verbally listing or typing on a smartphone as many words as possible within a given category (e.g., clothes). Using repeated measures MANOVA models, we examined how age, method of fluency task (verbal or texting), and direction of walking altered dual-task performance. Given that tasks like texting and backward walking require greater cognitive resources than verbal and forward walking tasks, respectively, we hypothesized older adults would show higher dual-task costs (DTCs) than younger adults across different task types and walking directions, with degree of impairment more apparent in texting dual-task trials compared to verbal dual-task trials. We also hypothesized that both age groups would have greater DTCs while walking backward than while walking forward, regardless of task. Independent of age group, velocity and stride length were reduced for texting compared to the verbal task during both forward and backward walking; cadence and velocity were reduced while walking forward compared to walking backward for the texting task; and stride length was reduced for forward walking compared to backward walking during the verbal task. Younger adults performed better than older adults on all tasks with the most pronounced differences seen in velocity and stride length during forward-texting and backward-texting. Interaction effects for velocity and stride length while walking forward indicated younger adults performed better than older adults for the texting task but similarly during the verbal task. An interaction for cadence during the verbal task indicated younger adults performed better than older adults while walking backward but similarly while walking forward. In summary, older adults experienced greater gait decrement for all dual-task conditions. The greater declines in velocity and stride length in combination with cadence being stable suggest reductions in velocity during texting were due to shorter strides rather than a reduced rate of stepping. Contrary to our hypotheses, we found greater DTCs while walking forward rather than backward, which may be due to reduced gait performance during single-task backward walking; thus, further decrements with dual-tasking are unlikely. These findings underscore the need for further research investigating fall risk potential associated with texting and walking among aging populations and how interventions targeting stride length during dual-task circumstances may improve performance.

Cross-Sectional Analysis of Backward, Forward, and Dual Task Gait Kinematics in People With Parkinson Disease With and Without Freezing of Gait.

People with Parkinson disease demonstrate increased gait variability, but the primary variability sources are poorly understood. People with Parkinson disease and freezing of gait (freezers) have greater gait impairments than people with Parkinson disease without freezing of gait (nonfreezers), which may relate to cerebellar dysfunction. Thirteen freezers and 31 nonfreezers completed backward, forward, and forward with dual task gait trials. Sagittal joint angle waveforms were extracted for the hip, knee, and ankle using 3D motion capture. Decomposition indices were calculated for the 3 joint combinations. Principal component analysis extracted variance sources from the joint waveforms. Freezers had significantly greater decomposition between hip-ankle (F1,42 = 5.1, P = .03) and hip-knee (F1,42 = 5.3, P = .03) movements. The principal component analysis did not differentiate freezers and nonfreezers; however, primary variance sources differed between conditions. Primary variance during forward and forward with dual task gait came from joint angle magnitude and peak angle timing. Backward gait showed primary variance from joint angle magnitude and range of motion. The results show that freezers decompose movement more than nonfreezers, implicating cerebellar involvement in freezing of gait. Primary variance differs between gait conditions, and tailoring gait interventions to address variability sources may improve intervention efficacy.

Changes in Parkinsonian gait kinematics with self-generated and externally-generated cues: a comparison of responders and non-responders.

Purpose: Rhythmic auditory stimulation such as listening to music can alleviate gait bradykinesia in people with Parkinson disease (PD) by increasing spatiotemporal gait features. However, evidence about what specific kinematic alterations lead to these improvements is limited, and differences in responsiveness to cueing likely affect individual motor strategies. Self-generated cueing techniques, such as singing or mental singing, provide similar benefits but no evidence exists about how these techniques affect lower limb joint movement. In this study, we assessed immediate effects of external and self-generated cueing on lower limb movement trajectories during gait.Methods: Using 3D motion capture, we assessed sagittal plane joint angles at the hip, knee, and ankle across 35 participants with PD, divided into responders (n = 23) and non-responders (n = 12) based on a clinically meaningful change in gait speed. Joint motion was assessed as overall range of motion as well as at two key time points during the gait cycle: initial contact and toe-off.Results: Responders used both cue types to increase gait speed and induce increases in overall joint ROM at the hip while only self-generated cues also increased ROM at the ankle. Increased joint excursions for responders were also evident at initial contact and toe-off.Conclusions: Our results indicate that self-generated rhythmic cues can induce similar increases in joint excursions as externally-generated cues and that some people may respond more positively than others. These results provide important insight into how self-generated cueing techniques may be tailored to meet the varied individual needs of people with PD.

Yoga Improves Balance and Low-Back Pain, but Not Anxiety, in People with Parkinson's Disease.

Individuals with Parkinson's disease (PD) experience postural instability, low-back pain (LBP), and anxiety. These symptoms increase the risk of falls and decrease quality of life. Research shows yoga improves balance and decreases LBP and anxiety in healthy adults, but its effects in PD are poorly understood. All participants were part of a larger intervention study. Participants received pretest and posttest evaluations, including the Balance Evaluation Systems Test (BESTest), Beck Anxiety Inventory (BAI), and Revised Oswestry Disability Index (ROSW). Total scores for each measure, as well as individual balance system section scores from the BESTest (biomechanical constraints, stability limits/verticality, transitions/anticipatory, reactive, sensory orientation, and stability in gait) were compared within groups pre- to posttest. Participants in the yoga group (n = 13) completed a twice-weekly 12-week yoga interve n t i o n , whereas controls (n = 13) continued their usual routines for 12 weeks. Both the yoga (Z = -3.20, p = 0.001) and control (Z = -2.10, p = 0.040) groups improved on the BESTest total score. The control group showed no changes in individual balance systems, whereas the yoga group improved in stability limits/verticality (Z = -2.3, p = 0.020), transitions/ anticipatory (Z = -2.50, p = 0.010), reactive (Z = -2.70, p = 0.008), and sensory orientation (Z = -2.30, p = 0.020). ROSW decreased in the yoga group only (Z = -2.10, p = 0.030). BAI did not change in either group. Yoga is a nonpharmacological intervention that can improve balance and LBP in people with PD. This study demonstrated that yoga is feasible for people with PD, and participants reported high levels of enjoyment and intent to practice yoga after the study.

The impact of age, surface characteristics, and dual-tasking on postural sway.

Postural control integrates somatosensory, vestibular, and visual input to maintain balance. Age, dual-tasking (DT), and varying surfaces may impact postural control and lead to falls. Research suggests smartphone use is a growing safety hazard, as it reduces situational awareness while increasing dual-task costs (DTCs). Therefore, we examined postural control using a modern, motor-cognitive, dual-task paradigm and examined DTCs associated with age, surface characteristic, and type of DT. Younger (n=24) and older (n=26) participants completed three 30- second trials of six different task conditions. Participants either stood quietly (single-task) or performed a secondary, word generation task (dual-task) that included verbally listing words (verbal) or typing words (texting) on a smartphone within a given category (e.g., vegetables) while on a firm, stable surface (level floor) or compliant, unstable surface (foam pad). Repeated-measures MANOVAs tested differences in postural sway (measured by sway angle, velocity, and acceleration) between age groups and task conditions. Results indicated poorer performance on the verbal DT than texting DT while standing on the level floor; performance was similar between the two DTs when standing on the foam pad. We also found poorer performance on the foam pad compared to level floor while texting; performance was similar between surfaces for the verbal DT. Younger adults generally had better performance than older adults within each task, particularly for texting on the level floor. In summary, older age, verbal tasks, and compliant, unstable surfaces have greater impact on postural control parameters compared to younger age, texting, and firm, stable surfaces.

Usability of a daily mHealth application designed to address mobility, speech and dexterity in Parkinson's disease.

Aim: This study investigated the usability of a mobile health (mHealth) smartphone application to treat gait, speech and dexterity in people with Parkinson's disease. Methods: Participants either used an mHealth application (intervention) or maintained their normal routine (control) for 12 weeks and were evaluated at baseline and post-test time points for primary outcome measures of adherence, gait, speech and dexterity. mHealth application adherence was compared with percent change scores on gait, speech and dexterity measures. Results: Adherence was moderate and there were no significant group, time or interaction effects for any outcome measures. Correlations between adherence and outcomes were weak and negative. Conclusion: These data suggest that usability of this mHealth application was limited as indicated by low adherence. The application alone in its present form was not adequate to treat symptoms of gait, speech or dexterity in people with Parkinson's disease.

Effects of exercise on gait and motor imagery in people with Parkinson disease and freezing of gait.

INTRODUCTION: Exercise improves gait in Parkinson disease (PD), but whether exercise differentially affects people with PD with (freezers) and without freezing of gait (non-freezers) remains unclear. This study examines exercise's effects on gait performance, neural correlates related to these effects, and potential neural activation differences between freezers and non-freezers during motor imagery (MI) of gait. METHODS: Thirty-seven participants from a larger exercise intervention completed behavioral assessments and functional magnetic resonance imaging (fMRI) scans before and after a 12-week exercise intervention. Gait performance was characterized using gait velocity and stride length, and a region of interest (ROI) fMRI analysis examined task-based blood oxygen-level dependent (BOLD) signal changes of the somatomotor network (SMN) during MI of forward (IMG-FWD) and backward (IMG-BWD) gait. RESULTS: Velocity (F(1,34) = 55.04, p < 0.001) and stride length (F(1,34) = 77.58, p < 0.001) were significantly lower for backward versus forward walking in all participants. The ROI analysis showed freezers had lower BOLD signal compared to non-freezers in the cerebellum (F(1,32) = 7.01, p = 0.01), primary motor (left: F(1,32) = 7.09, p = 0.01; right: F(1,32) = 7.45, p = 0.01), and primary sensory (left: F(1,32) = 9.59, p = 0.004; right: F(1,32) = 8.18, p = 0.007) cortices during IMG-BWD only. The evidence suggests the exercise intervention did not affect gait or BOLD signal during MI. CONCLUSION: While all participants had significantly slower and shorter backward velocity and stride length, respectively, the exercise intervention had no effect. Similarly, BOLD signal during MI did not change with exercise; however, freezers had significantly lower BOLD signal during IMG-BWD compared to non-freezers. This suggests potential decreased recruitment of the SMN during MI of gait in freezers.

Cerebellar Volume and Executive Function in Parkinson Disease with and without Freezing of Gait.

BACKGROUND: Freezing of gait (FOG) affects approximately 50% of people with Parkinson Disease (PD), impacting quality of life and placing financial and emotional strain on the individual and caregivers. People with PD and FOG have similar deficits in motor adaptation and cognition as individuals with cerebellar lesions, indicating the cerebellum may play a role in FOG. OBJECTIVE: To examine potential differences in cerebellar volumes and their relationships with cognition between PD with (FOG+) and without FOG (FOG-). METHODS: Sixty-three participants were divided into two groups, FOG+ (n = 25) and FOG- (n = 38), based on the New Freezing of Gait Questionnaire. Cognitive assessment included Trail Making, Stroop, Verbal Fluency, and Go-NoGo executive function tasks. All participants completed structural T1- and T2-weighted MRI scans. Imaging data were processed with FreeSurfer and the Spatially Unbiased Infratentorial toolbox to segment the cerebellum into individual lobules. RESULTS: FOG+ performed significantly worse on phonemic verbal fluency (F(1, 22)  =  7.06, p = 0.01) as well as the Go-NoGo task (F(1, 22)  =  9.00, p = 0.004). We found no differences in cerebellar volumes between groups (F(4, 55)  = 1.42, p = 0.24), but there were significant relationships between verbal fluency measures and lobule volumes in FOG-. CONCLUSIONS: These findings underscore the need for longitudinal studies to better characterize potential changes in cerebellar volume, cognitive function, and functional connectivity between people with PD with and without FOG.