•During sleep, glymphatic system (GS) activation clears toxins from the brain.•Striatal dopamine modulates clock gene expression and sleep-wake rhythm.•Dopaminergic dysfunction and alpha-synuclein ...aggregations characterize PD.•Disrupted sleep in PD may decrease metabolic clearance with alpha-synuclein buildup.•Non-invasive neuroimaging of the GS may improve diagnostic and interventional tools.
Recent evidence has advanced our understanding of the function of sleep to include removal of neurotoxic protein aggregates via the glymphatic system. However, most research on the glymphatic system utilizes animal models, and the function of waste clearance processes in humans remains unclear. Understanding glymphatic function offers new insight into the development of neurodegenerative diseases that result from toxic protein inclusions, particularly those characterized by neuropathological sleep dysfunction, like Parkinson’s disease (PD). In PD, we propose that glymphatic flow may be compromised due to the combined neurotoxic effects of alpha-synuclein protein aggregates and deteriorated dopaminergic neurons that are linked to altered REM sleep, circadian rhythms, and clock gene dysfunction. This review highlights the importance of understanding the functional role of glymphatic system disturbance in neurodegenerative disorders and the subsequent clinical and neuropathological effects on disease progression. Future research initiatives utilizing noninvasive brain imaging methods in human subjects with PD are warranted, as in vivo identification of functional biomarkers in glymphatic system functioning may improve clinical diagnosis and treatment of PD.
Approximately one third of recently diagnosed Parkinson's disease (PD) patients experience cognitive decline. The nucleus basalis of Meynert (NBM) degenerates early in PD and is crucial for cognitive ...function. The two main NBM white matter pathways include a lateral and medial trajectory. However, research is needed to determine which pathway, if any, are associated with PD-related cognitive decline.
Thirty-seven PD patients with no mild cognitive impairment (MCI) were included in this study. Participants either developed MCI at 1-year follow up (PD MCI-Converters; n = 16) or did not (PD no-MCI; n = 21). Mean diffusivity (MD) of the medial and lateral NBM tracts were extracted using probabilistic tractography. Between-group differences in MD for each tract was compared using ANCOVA, controlling for age, sex, and disease duration. Control comparisons of the internal capsule MD were also performed. Associations between baseline MD and cognitive outcomes (working memory, psychomotor speed, delayed recall, and visuospatial function) were assessed using linear mixed models.
PD MCI-Converters had significantly greater MD and lower FA (p < .001) of both NBM tracts compared to PD no-MCI. No difference was found in the MD (p = .06) or FA (p = .31) of the control region. Trends were identified between: 1) lateral tract MD and FA with working memory decline; and 2) medial tract MD and reduced psychomotor speed.
Reduced integrity of the NBM tracts is evident in PD patients up to one year prior to the development of MCI. Thus, deterioration of the NBM tracts in PD may be an early marker of those at risk of cognitive decline.
•Reduced integrity of cholinergic network up to 1 year prior to cognitive decline.•Cholinergic network deficits in Parkinson's disease-related cognitive impairment.•Tractography of the nucleus basalis of meynert in Parkinson's disease.
A space-borne remote sensing method was applied, validated, and demonstrated in a case study on the Samuel de Champlain Bridge in Montreal, Canada. High-resolution C-band radar satellite imagery was ...analyzed using the Persistent Scatterer Interferometric Synthetic Aperture Radar technique to derive bridge displacements and compare them against theoretical estimates. Multispectral and long-wave thermal infrared satellite imagery acquired during the InSAR observation period and historical environmental data were analyzed to provide context for the interpretation and understanding of InSAR results. Thermal deformation measurements compared well with their theoretical estimates based on known bridge geometry and ambient temperature data. Non-thermal deformation measurements gave no evidence of settlement during the 2-year monitoring period, as would normally be expected for a newly constructed bridge with its foundation on bedrock. The availability of environmental data obtained from multispectral and thermal infrared satellite imagery was found to be useful in providing context for the bridge stability assessment. Ambient temperature measurements from thermal infrared satellite imagery were found to be a suitable alternative in cases where data from in situ temperature sensors or nearby weather stations are not available or not fit for purpose. No strong correlation was found between the river conditions and bridge deformation results from the InSAR analysis; this is partly due to the fact that most of these effects act along the river flow in the north–south direction, to which the satellite sensor is not sensitive.
Freezing of gait (FOG) is a devastating axial motor symptom in Parkinson's disease (PD) leading to falls, institutionalization, and even death. The response of FOG to dopaminergic medication and deep ...brain stimulation (DBS) is complex, variable, and yet to be optimized. Fundamental gaps in the knowledge of the underlying neurobiomechanical mechanisms of FOG render this symptom one of the unsolved challenges in the treatment of PD. Subcortical neural mechanisms of gait impairment and FOG in PD are largely unknown due to the challenge of accessing deep brain circuitry and measuring neural signals in real time in freely-moving subjects. Additionally, there is a lack of gait tasks that reliably elicit FOG. Since FOG is episodic, we hypothesized that dynamic features of subthalamic (STN) beta oscillations, or beta bursts, may contribute to the Freezer phenotype in PD during gait tasks that elicit FOG. We also investigated whether STN DBS at 60 Hz or 140 Hz affected beta burst dynamics and gait impairment differently in Freezers and Non-Freezers. Synchronized STN local field potentials, from an implanted, sensing neurostimulator (Activa® PC + S, Medtronic, Inc.), and gait kinematics were recorded in 12 PD subjects, off-medication during forward walking and stepping-in-place tasks under the following randomly presented conditions: NO, 60 Hz, and 140 Hz DBS. Prolonged movement band beta burst durations differentiated Freezers from Non-Freezers, were a pathological neural feature of FOG and were shortened during DBS which improved gait. Normal gait parameters, accompanied by shorter bursts in Non-Freezers, were unchanged during DBS. The difference between the mean burst duration between hemispheres (STNs) of all individuals strongly correlated with the difference in stride time between their legs but there was no correlation between mean burst duration of each STN and stride time of the contralateral leg, suggesting an interaction between hemispheres influences gait. These results suggest that prolonged STN beta burst durations measured during gait is an important biomarker for FOG and that STN DBS modulated long not short burst durations, thereby acting to restore physiological sensorimotor information processing, while improving gait.
•First study to investigate STN beta bursts during gait in freely moving PD subjects•Prolonged movement beta band burst durations were a pathological feature of FOG•STN DBS shortened pathological burst durations and improved gait in Freezers•Normal gait parameters, accompanied by shorter bursts, were not modulated by DBS•Greater difference in burst duration between STNs correlated with more impaired gait
Objective
Bradykinesia is the major cardinal motor sign of Parkinson disease (PD), but its neural underpinnings are unclear. The goal of this study was to examine whether changes in bradykinesia ...following long‐term subthalamic nucleus (STN) deep brain stimulation (DBS) are linked to local STN beta (13–30 Hz) dynamics or a wider bilateral network dysfunction.
Methods
Twenty‐one individuals with PD implanted with sensing neurostimulators (Activa® PC + S, Medtronic, PLC) in the STN participated in a longitudinal ‘washout’ therapy study every three to 6 months for an average of 3 years. At each visit, participants were withdrawn from medication (12/24/48 hours) and had DBS turned off (>60 minutes) before completing a repetitive wrist‐flexion extension task, a validated quantitative assessment of bradykinesia, while local field potentials were recorded. Local STN beta dynamics were investigated via beta power and burst duration, while interhemispheric beta synchrony was assessed with STN‐STN beta coherence.
Results
Higher interhemispheric STN beta coherence, but not contralateral beta power or burst duration, was significantly associated with worse bradykinesia. Bradykinesia worsened off therapy over time. Interhemispheric STN‐STN beta coherence also increased over time, whereas beta power and burst duration remained stable. The observed change in bradykinesia was related to the change in interhemispheric beta coherence, with greater increases in synchrony associated with further worsening of bradykinesia.
Interpretation
Together, these findings implicate interhemispheric beta synchrony as a neural correlate of the progression of bradykinesia following chronic STN DBS. This could imply the existence of a pathological bilateral network contributing to bradykinesia in PD. ANN NEUROL 2023;93:1029–1039
No biomarker of Parkinson's disease exists that allows clinicians to adjust chronic therapy, either medication or deep brain stimulation, with real-time feedback. Consequently, clinicians rely on ...time-intensive, empirical, and subjective clinical assessments of motor behaviour and adverse events to adjust therapies. Accumulating evidence suggests that hypokinetic aspects of Parkinson's disease and their improvement with therapy are related to pathological neural activity in the beta band (beta oscillopathy) in the subthalamic nucleus. Additionally, effectiveness of deep brain stimulation may depend on modulation of the dorsolateral sensorimotor region of the subthalamic nucleus, which is the primary site of this beta oscillopathy. Despite the feasibility of utilizing this information to provide integrated, biomarker-driven precise deep brain stimulation, these measures have not been brought together in awake freely moving individuals. We sought to directly test whether stimulation-related improvements in bradykinesia were contingent on reduction of beta power and burst durations, and/or the volume of the sensorimotor subthalamic nucleus that was modulated. We recorded synchronized local field potentials and kinematic data in 16 subthalamic nuclei of individuals with Parkinson's disease chronically implanted with neurostimulators during a repetitive wrist-flexion extension task, while administering randomized different intensities of high frequency stimulation. Increased intensities of deep brain stimulation improved movement velocity and were associated with an intensity-dependent reduction in beta power and mean burst duration, measured during movement. The degree of reduction in this beta oscillopathy was associated with the improvement in movement velocity. Moreover, the reduction in beta power and beta burst durations was dependent on the theoretical degree of tissue modulated in the sensorimotor region of the subthalamic nucleus. Finally, the degree of attenuation of both beta power and beta burst durations, together with the degree of overlap of stimulation with the sensorimotor subthalamic nucleus significantly explained the stimulation-related improvement in movement velocity. The above results provide direct evidence that subthalamic nucleus deep brain stimulation-related improvements in bradykinesia are related to the reduction in beta oscillopathy within the sensorimotor region. With the advent of sensing neurostimulators, this beta oscillopathy combined with lead location could be used as a marker for real-time feedback to adjust clinical settings or to drive closed-loop deep brain stimulation in freely moving individuals with Parkinson's disease.
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