A novel conceptual framework for the functionality of the glymphatic system.

The glymphatic system is responsible for the clearance of the potentially harmful metabolic waste of the central nervous system. The prevalent theory is that the cerebrospinal fluid (CSF) circulates in the perivascular space (PVS) and through the astrocytes' aquaporin-4 channels (AQ-4), and it is then drained by the lymphatic vessels after mixing with interstitial fluid (ISF). However, there is little evidence supporting this hypothesis. A deeper understanding of the physiology of the glymphatic system could transform the way we understand neuropathology and our approach to treating neurological and neuropsychiatric disorders. In this review, we introduce a new conceptual framework for the functionality of the glymphatic system, offering new directions for future research. We propose that CSF and ISF exchange flow depends on arterial pulsation, respiration, posture, and sleep. PVS changes due to disrupted cerebral autoregulation, alternations of intrathoracic pressure, venous flow, and body position can also influence the glymphatic flow. The role of respiration remains controversial due to the variety of parameters that interfere with glymphatic functionality. Slow-wave sleep is important for glymphatic clearance due to neuronal electromagnetic synchronization and expansion of the interstitial space. Therefore, sleep and vascular disorders, as well as aging, may hinder glymphatic flow and induce a noxious milieu of susceptibility to neurodegenerative disorders because of metabolic waste accumulation. We lastly introduce a new idea postulating that electromagnetic induction may constitute one of the propelling forces for the convectional current and mixing of CSF and ISF.

Research Evidence of the Role of the Glymphatic System and Its Potential Pharmacological Modulation in Neurodegenerative Diseases.

The glymphatic system is a unique pathway that utilises end-feet Aquaporin 4 (AQP4) channels within perivascular astrocytes, which is believed to cause cerebrospinal fluid (CSF) inflow into perivascular space (PVS), providing nutrients and waste disposal of the brain parenchyma. It is theorised that the bulk flow of CSF within the PVS removes waste products, soluble proteins, and products of metabolic activity, such as amyloid-ß (Aß). In the experimental model, the glymphatic system is selectively active during slow-wave sleep, and its activity is affected by both sleep dysfunction and deprivation. Dysfunction of the glymphatic system has been proposed as a potential key driver of neurodegeneration. This hypothesis is indirectly supported by the close relationship between neurodegenerative diseases and sleep alterations, frequently occurring years before the clinical diagnosis. Therefore, a detailed characterisation of the function of the glymphatic system in human physiology and disease would shed light on its early stage pathophysiology. The study of the glymphatic system is also critical to identifying means for its pharmacological modulation, which may have the potential for disease modification. This review will critically outline the primary evidence from literature about the dysfunction of the glymphatic system in neurodegeneration and discuss the rationale and current knowledge about pharmacological modulation of the glymphatic system in the animal model and its potential clinical applications in human clinical trials.

Recent Advances in Neuroimaging Techniques to Assist Clinical Trials on Cell-Based Therapies in Neurodegenerative Diseases.

Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are progressive disorders for which curative therapy is still lacking. Cell-based therapy aims at replacing dysfunctional cellular populations by repairing damaged tissue and by enriching the microenvironment of selective brain areas, and thus constitutes a promising disease-modifying treatment of neurodegenerative diseases. Scientific research has engineered a wide range of human-derived cellular populations to help overcome some of the logistical, safety, and ethical issues associated with this approach. Open-label studies and clinical trials in human participants have used neuroimaging techniques, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), to assess the success of the transplantation, to evaluate the functional integration of the implanted tissue into the host environment and to understand the pathophysiological changes associated with the therapy. Neuroimaging has constituted an outcome measure of large, randomized clinical trials, and has given answers to clarify the pathophysiology underlying some of the complications linked with this therapy. Novel PET radiotracers and MRI sequences for the staging of neurodegenerative diseases and to study alterations at the molecular level significantly expands the translational potential of neuroimaging to assist pre-clinical and clinical research on cell-based therapy in these disorders. This concise review summarizes the current use of neuroimaging in human studies of cell-based replacement therapy and focuses on the future applications of PET and MRI techniques to evaluate the pathophysiology and treatment efficacy, as well as to aid patient selection and as an outcome measure to improve treatment success.

Predictors of RBD progression and conversion to synucleinopathies.

PURPOSE OF REVIEW: Rapid eye movement (REM) sleep behaviour disorder (RBD) is considered the expression of the initial neurodegenerative process underlying synucleinopathies and constitutes the most important marker of their prodromal phase. This article reviews recent research from longitudinal research studies in isolated RBD (iRBD) aiming to describe the most promising progression biomarkers of iRBD and to delineate the current knowledge on the level of prediction of future outcome in iRBD patients at diagnosis. RECENT FINDINGS: Longitudinal studies revealed the potential value of a variety of biomarkers, including clinical markers of motor, autonomic, cognitive, and olfactory symptoms, neurophysiological markers such as REM sleep without atonia and electroencephalography, genetic and epigenetic markers, cerebrospinal fluid and serum markers, and neuroimaging markers to track the progression and predict phenoconversion. To-date the most promising neuroimaging biomarker in iRBD to aid the prediction of phenoconversion is striatal presynaptic striatal dopaminergic dysfunction. There is a variety of potential biomarkers for monitoring disease progression and predicting iRBD conversion into synucleinopathies. A combined multimodal biomarker model could offer a more sensitive and specific tool. Further longitudinal studies are warranted to iRBD as a high-risk population for early neuroprotective interventions and disease-modifying therapies.

Nucleus basalis of Meynert degeneration predicts cognitive impairment in Parkinson's disease.

Cognitive impairment affects approximately 20%-50% of patients with Parkinson's disease (PD), with a higher prevalence as the disease advances. The nucleus basalis of Meynert (NBM) provides the majority of cholinergic innervations to the cerebral cortex. Dysfunction of the cholinergic system and degeneration of the NBM have been implicated in the pathophysiology of cognitive impairment in neurodegenerative disorders including PD. Several studies have aimed to identify risk factors associated with cognitive decline in order to construct models to predict future cognitive impairment in PD. Given the link between cholinergic dysfunction and the pathogenesis of cognitive decline in PD, a number of studies have focused on the role of the NBM underlying cognitive performance. Recently, microstructural alterations within the NBM, detected using diffusion tensor imaging, have been identified as a strong predictor for the development of cognitive impairment in patients with PD. These microstructural changes in NBM have been shown to precede structural gray matter volumetric loss and may present with an early marker to predict cognitive decline in patients with PD. Longitudinal studies are warranted to provide insights into the potential utility of cholinergic positron emission tomography imaging to predict the development of cognitive impairment in PD and other neurodegenerative disorders. Provided the urgent need for disease modifying therapies aiming to slow and ultimately halt the progression of cognitive impairment, neuromodulation of NBM, and treatments targeting the cholinergic system may hold a promising potential. In this review, we discuss the link between NBM pathology and clinical symptomatology of cognitive impairment in PD with a focus on the use of in vivo imaging techniques and potential therapeutic interventions.

Serotonergic imaging in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of monoaminergic central pathways such as the serotonergic. The degeneration of serotonergic signaling in striatal and extrastriatal brain regions is an early feature of PD and is associated with several motor and non-motor complications of the disease. Molecular imaging techniques with Positron Emission Tomography (PET) have greatly contributed to the investigation of biological changes in vivo and to the understanding of the extent of serotonergic pathology in patients or individuals at risk for PD. Such discoveries provide with opportunities for the identification of new targets that can be used for the development of novel disease-modifying drugs or symptomatic treatments. Future studies of imaging serotonergic molecular targets will better clarify the importance of serotonergic pathology in PD, including progression of pathology, target-identification for pharmacotherapy, and relevance to endogenous synaptic serotonin levels. In this article, we review the current status and understanding of serotonergic imaging in PD.

Aquaporin-4 polymorphisms predict amyloid burden and clinical outcome in the Alzheimer's disease spectrum.

Clearance of amyloid-ß (Aß) from the brain is hypothesized to be mediated by the glymphatic system through aquaporin-4 (AQP4) water channels. Genetic variation of AQP4 may impact water channel function, Aß clearance, and clinical outcomes. We examined whether single-nucleotide polymorphisms (SNPs) of the AQP4 gene were related to Aß neuropathology on [18F]Florbetapir PET in 100 Aß positive late mild cognitive impairment (LMCI) or Alzheimer's disease (AD) patients and were predictive of clinical outcome in prodromal AD patients. AQP4 SNP rs72878794 was associated with decreased Aß uptake, whereas rs151244 was associated with increased Aß uptake, increased risk of conversion from MCI and LMCI to AD, and an increased 4-year rate of cognitive decline in LMCI. AQP4 genetic variation was associated with Aß accumulation, disease stage progression, and cognitive decline. This variation may correspond to changes in glymphatic system functioning and brain Aß clearance and could be a useful biomarker in predicting disease burden for those on the dementia spectrum.

Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease.

BACKGROUND: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients. METHODS: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [11 C]UCB-J, [11 C]SA-4503, and [18 F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments. RESULTS: Reduced [11 C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [11 C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11 C]SA-4503 and [18 F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [11 C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline. CONCLUSIONS: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

REM Sleep without atonia correlates with abnormal vestibular-evoked myogenic potentials in isolated REM sleep behavior disorder.

STUDY OBJECTIVES: The neurophysiological hallmark of REM sleep behavior disorder (RBD) is loss of atonia during REM sleep. Indeed, signs and symptoms of neurodegeneration can occur after years, even decades, from its beginning. This study aimed to measure neurophysiological alterations of the brainstem that potentially correlate with the severity of atonia loss, and determining whether a prodromal neurodegenerative disorder underlines this condition when it occurs as an isolated condition (iRBD). METHODS: Subjects with iRBD and matched healthy controls were recruited. The study included the recording of one-night polysomnography, vestibular-evoked myogenic potentials (VEMPs), and a [123I]-FP-CIT dopamine transporter (DAT) scan. The quantification of REM sleep without atonia (RSWA) was made according to two previously published manual methods and one automated method. RESULTS: The rate of alteration of VEMPs and VEMP score were significantly higher in iRBD patients than controls. Moreover, VEMP score was negatively correlated with the automated REM atonia index; a marginal statistical significance was also reached for the positive correlation with the visual tonic electromyographic parameter, while the other correlations, including that with DAT-scan score were not statistically significant. CONCLUSIONS: Brainstem neurophysiology in iRBD can be assessed by VEMPs and their alterations may possibly indicate an early expression of the neurodegenerative process underlying this disorder at the brainstem level, which awaits future longitudinal confirmation. The correlation between RSWA and VEMP alteration might also represent a prodromal aspect anticipating the possible evolution from iRBD to neurodegeneration, whereas DAT-scan abnormalities might represent a later step in this evolution.

Vestibular Evoked Myogenic Potentials Are Abnormal in Idiopathic REM Sleep Behavior Disorder.

Objectives: To investigate brainstem function in idiopathic REM sleep Behavior Disorder (iRBD), a condition occurring as a result of a derangement of connections within brainstem structures, with a battery of Vestibular Evoked Myogenic Potentials (VEMPs), neurophysiological tools suited for the functional investigation of the brainstem. Neurophysiological data were correlated with clinical characteristics of patients. Methods: Twenty patients with iRBD and 22 healthy controls underwent cervical (cVEMP), masseter (mVEMP) and ocular (oVEMP) VEMP recording. Patients were assessed clinically according to presence of motor as well as non-motor symptoms such as constipation, depression, and hyposmia. Also, they were screened for postural instability through the Berg Balance Scale (BBS). VEMPs were categorized as for increasing degrees of abnormalities, namely latency delay, amplitude reduction and absence; a VEMP score was built accordingly. Results: Compared with controls, iRBD had higher rates of abnormalities both in the VEMP battery (iRBD 75%, Controls 23%; p < 0.01) as well as in each single VEMP (cVEMP: 45 vs. 5%; mVEMP: 65 vs. 13.6%; oVEMP: 50 vs. 5%; p < 0.01), which exhibited significantly lower amplitudes (cVEMP and oVEMP: p < 0.0001; mVEMP: p = 0.001) in iRBD. Within altered reflexes, absence was predominant in oVEMP (81%), amplitude reduction in mVEMP (50%) and cVEMP (70%). Severity of VEMP alterations was significantly higher in iRBD compared with controls (p < 0.05 for all VEMPs), as indicated by the larger VEMP scores in the former. The oVEMP score correlated inversely with poor performances on the BBS. Conclusion: VEMPs unveil consistent and extensive brainstem abnormalities in iRBD patients. Further studies are warranted for testing the potential of VEMPs in the monitoring of the evolution of iRBD over time.

Imaging Transplantation in Movement Disorders.

Cell replacement therapy with graft transplantation has been tested as a disease-modifying treatment in neurodegenerative diseases characterized by the damage of a predominant cell type, such as substantia nigra dopaminergic neurons in Parkinson's disease (PD) or striatal medium spiny projection neurons in Huntington's disease (HD). The results of these trials are mixed with success in preclinical and pilot open-label trials, which were not consistently reproduced in randomized controlled trials. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) molecular imaging and functional magnetic resonance imaging allow the graft survival, and its relationship with the host tissues to be studied in vivo. In PD, PET with [18F]DOPA showed that graft survival does not necessarily correlate with the clinical improvement and PD patients with worse outcome had lower binding in the ventral striatum and a high serotonin ([11C]DASB PET) to dopamine ([18F]DOPA PET) ratio in the grafted neurons. In HD, PET with [11C]PK11195 showed the graft survival and the clinical responses may be related to the reactive activation of the host inflammatory/immune system. Findings from these studies have been used to refine study protocols and patient selection in current clinical trials, which includes identifying suitable candidates for transplantation using imaging markers and employing multiple and/or novel PET tracers to better assess graft functions and inflammatory responses to grafts.

Resistance Training for Muscle Weakness in Multiple Sclerosis: Direct Versus Contralateral Approach in Individuals With Ankle Dorsiflexors' Disparity in Strength.

OBJECTIVE: To compare effects of contralateral strength training (CST) and direct strength training of the more affected ankle dorsiflexors on muscle performance and clinical functional outcomes in people with multiple sclerosis (MS) exhibiting interlimb strength asymmetry. DESIGN: Randomized controlled trial. SETTING: University hospital. PARTICIPANTS: Individuals with relapsing-remitting MS (N=30) and mild-to-moderate disability (Expanded Disability Status Scale score ≤6) presenting with ankle dorsiflexors' strength disparity. INTERVENTIONS: Participants were randomly assigned to a CST (n=15) or direct strength training (n=15) group performing 6 weeks of maximal intensity strength training of the less or more affected dorsiflexors, respectively. MAIN OUTCOME MEASURES: Maximal strength, endurance to fatigue, and mobility outcomes were assessed before, at the intervention end, and at 12-week follow-up. Strength and fatigue parameters were measured after 3 weeks of training (midintervention). RESULTS: In the more affected limb of both groups, pre- to postintervention significant increases in maximal strength (P≤.006) and fatigue endurance (P≤.04) were detected along with consistent retention of these improvements at follow-up (P≤.04). At midintervention, the direct strength training group showed significant improvements (P≤.002), with no further increase at postintervention, despite training continuation. Conversely, the CST group showed nonsignificant strength gains, increasing to significance at postintervention (P≤.003). In both groups, significant pre- to postintervention improvements in mobility outcomes (P≤.03), not retained at follow-up, were observed. CONCLUSIONS: After 6 weeks of training, CST proved as effective as direct strength training in enhancing performance of the more affected limb with a different time course, which may have practical implications in management of severely weakened limbs where direct strength training is not initially possible.

Dance therapy improves motor and cognitive functions in patients with Parkinson's disease.

OBJECTIVE: To explore the effects of Dance Therapy (DT) and Traditional Rehabilitation (TR) on both motor and cognitive domains in Parkinson's Disease patients (PD) with postural instability. METHODS: Sixteen PD patients with recent history of falls were divided in two groups (Dance Therapy, DT and Traditional Rehabilitation, TR); nine patients received 1-hour DT classes twice per week, completing 20 lessons within 10 weeks; seven patients received a similar cycle of 20 group sessions of 60 minutes TR. Motor (Berg Balance Scale - BBS, Gait Dynamic Index - GDI, Timed Up and Go Test - TUG, 4 Square-Step Test - 4SST, 6-Minute Walking Test - 6MWT) and cognitive measures (Frontal Assessment Battery - FAB, Trail Making Test A & B - TMT A&B, Stroop Test) were tested at baseline, after the treatment completion and after 8-week follow-up. RESULTS: In the DT group, but not in the TR group, motor and cognitive outcomes significantly improved after treatment and retained after follow-up. Significant changes were found for 6MWT (p = 0.028), TUG (p = 0.007), TMT-A (p = 0.014) and TMT-B (p = 0.036). CONCLUSIONS: DT is an unconventional physical therapy for PD patients which effectively impacts on motor (endurance and risk of falls) and non-motor functions (executive functions).

Effect of Contralateral Strength Training on Muscle Weakness in People With Multiple Sclerosis: Proof-of-Concept Case Series.

BACKGROUND: The contralateral strength training (CST) effect is a transfer of muscle performance to the untrained limb following training of the contralateral side. OBJECTIVE: The aim of this study was to explore, in individuals with multiple sclerosis (MS) presenting marked lower limb strength asymmetry, the effectiveness of CST on management of muscle weakness of the more-affected limb following training of the less-affected limb. DESIGN: A single-subject research design was used. METHODS: Eight individuals with MS underwent 16 to 18 high-intensity training sessions of the less-affected ankle dorsiflexor muscles. The primary outcome measure of this single-system case series was maximal strength expressed as peak moment and maximal work. Secondary outcome measures were: Six-Minute-Walk Test, Timed "Up & Go" Test, 10-Meter Timed Walk Test, and Multiple Sclerosis Quality of Life-54 questionnaire. RESULTS: After the 6-week intervention, the contralateral more affected (untrained) limb showed a 22% to 24% increase in maximal strength. From pretest-posttest measurements, participants also performed significantly better on the clinical and functional secondary outcome measures. At the 12-week follow-up, the strength levels of the weaker untrained limb remained significantly superior to baseline levels in the majority (5 out of 8) of the outcome parameters. LIMITATIONS: Considering the design used, the absence of a control group, and the sample size, these findings should be cautiously generalized and will need confirmation in a properly planned randomized controlled trial. CONCLUSIONS: The present proof-of-concept study shows, for the first time, the occurrence of the CST effect on muscle performance of ankle dorsiflexor muscles in people with MS. These preliminary findings reveal new potential implications for CST as a promising rehabilitation approach to those conditions where unilateral muscle weakness does not allow or makes difficult performing conventional strength training of the weaker limb.

A comprehensive assessment of the cross-training effect in ankle dorsiflexors of healthy subjects: A randomized controlled study.

PURPOSE: To investigate the cross-training effect, induced on ankle dorsiflexors (AD) by unilateral strength-training of the contralateral muscles, as transfer of peak torque (PT) and muscle work (MW) and their relative contributions to muscle performance. METHODS: Thirty healthy volunteers were randomly assigned to a training or control group. The trained group sustained a 4-week maximal isokinetic training of the stronger AD at 90 and 45°/s. At both angular velocities, PT, MW and MW/PT ratio were measured from both legs at baseline and after intervention (trained group) or no-intervention (controls). The familiarization/learning-effect was calculated and subtracted by PT and MW measures to obtain their net changes. RESULTS: Net PT increased in both legs (untrained: +27.5% at 90°/s and +17.9% at 45°/s; trained: +15% at 90°/s and +16.3% at 45°/s). Similarly, net MW increased in both the untrained (90°/s: +29.6%; 45°/s: +37%) and trained (90°/s: +23.4%; 45°/s: +18.3%) legs. PT and MW gains were larger in the untrained than trained AD (p<0.0005), with MW improving more than PT at 45°/s (p=0.04). The MW/PT ratio increased bilaterally only in the trained group (p<0.05), depending on the angular velocity. CONCLUSIONS: The cross-training effect occurred in AD muscles in terms of both PT and MW, with MW adding valuable information to PT-analysis in describing muscle performance. Moreover, the MW/PT ratio allowed estimating the contributions of these parameters to muscle capability and may represent a novel index in isokinetic testing. The greater improvements in the untrained than trained limb raises interesting clinical implications in asymmetric conditions.