White matter microstructure in Parkinson's disease with and without elevated rapid eye movement sleep muscle tone.

People with Parkinson's disease who have elevated muscle activity during rapid eye movement sleep (REM sleep without atonia) typically have a worse motor and cognitive impairment compared with those with normal muscle atonia during rapid eye movement sleep. This study used tract-based spatial statistics to compare diffusion MRI measures of fractional anisotropy, radial, mean and axial diffusivity (measures of axonal microstructure based on the directionality of water diffusion) in white matter tracts between people with Parkinson's disease with and without rapid eye movement sleep without atonia and controls and their relationship to measures of motor and cognitive function. Thirty-eight individuals with mild-to-moderate Parkinson's disease and 21 matched control subjects underwent ultra-high field MRI (7 T), quantitative motor assessments of gait and bradykinesia and neuropsychological testing. The Parkinson's disease cohort was separated post hoc into those with and without elevated chin or leg muscle activity during rapid eye movement sleep based on polysomnography findings. Fractional anisotropy was significantly higher, and diffusivity significantly lower, in regions of the corpus callosum, projection and association white matter pathways in the Parkinson's group with normal rapid eye movement sleep muscle tone compared with controls, and in a subset of pathways relative to the Parkinson's disease group with rapid eye movement sleep without atonia. The Parkinson's disease group with elevated rapid eye movement sleep muscle tone showed significant impairments in the gait and upper arm speed compared with controls and significantly worse scores in specific cognitive domains (executive function, visuospatial memory) compared with the Parkinson's disease group with normal rapid eye movement sleep muscle tone. Regression analyses showed that gait speed and step length in the Parkinson's disease cohort were predicted by measures of fractional anisotropy of the anterior corona radiata, whereas elbow flexion velocity was predicted by fractional anisotropy of the superior corona radiata. Visuospatial memory task performance was predicted by the radial diffusivity of the posterior corona radiata. These findings show that people with mild-to-moderate severity of Parkinson's disease who have normal muscle tone during rapid eye movement sleep demonstrate compensatory-like adaptations in axonal microstructure that are associated with preserved motor and cognitive function, but these adaptations are reduced or absent in those with increased rapid eye movement sleep motor tone.

Best Practices in the Clinical Management of Progressive Supranuclear Palsy and Corticobasal Syndrome: A Consensus Statement of the CurePSP Centers of Care.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.

Semi-automated approaches to optimize deep brain stimulation parameters in Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) is a treatment option for Parkinson's disease patients when medication does not sufficiently manage their symptoms. DBS can be a highly effect therapy, but only after a time-consuming trial-and-error stimulation parameter adjustment process that is susceptible to clinician bias. This trial-and-error process will be further prolonged with the introduction of segmented electrodes that are now commercially available. New approaches to optimizing a patient's stimulation parameters, that can also handle the increasing complexity of new electrode and stimulator designs, is needed. METHODS: To improve DBS parameter programming, we explored two semi-automated optimization approaches: a Bayesian optimization (BayesOpt) algorithm to efficiently determine a patient's optimal stimulation parameter for minimizing rigidity, and a probit Gaussian process (pGP) to assess patient's preference. Quantified rigidity measurements were obtained using a robotic manipulandum in two participants over two visits. Rigidity was measured, in 5Hz increments, between 10-185Hz (total 30-36 frequencies) on the first visit and at eight BayesOpt algorithm-selected frequencies on the second visit. The participant was also asked their preference between the current and previous stimulation frequency. First, we compared the optimal frequency between visits with the participant's preferred frequency. Next, we evaluated the efficiency of the BayesOpt algorithm, comparing it to random and equal interval selection of frequency. RESULTS: The BayesOpt algorithm estimated the optimal frequency to be the highest tolerable frequency, matching the optimal frequency found during the first visit. However, the participants' pGP models indicate a preference at frequencies between 70-110 Hz. Here the stimulation frequency is lowest that achieves nearly maximal suppression of rigidity. BayesOpt was efficient, estimating the rigidity response curve to stimulation that was almost indistinguishable when compared to the longer brute force method. CONCLUSIONS: These results provide preliminary evidence of the feasibility to use BayesOpt for determining the optimal frequency, while pGP patient's preferences include more difficult to measure outcomes. Both novel approaches can shorten DBS programming and can be expanded to include multiple symptoms and parameters.

Quantitative Assessment of Occipital Metabolic and Energetic Changes in Parkinson's Patients, Using In Vivo 31P MRS-Based Metabolic Imaging at 7T.

Abnormal energy metabolism associated with mitochondrial dysfunction is thought to be a major contributor to the progression of neurodegenerative diseases such as Parkinson's disease (PD). Recent advancements in the field of magnetic resonance (MR) based metabolic imaging provide state-of-the-art technologies for non-invasively probing cerebral energy metabolism under various brain conditions. In this proof-of-principle clinical study, we employed quantitative 31P MR spectroscopy (MRS) imaging techniques to determine a constellation of metabolic and bioenergetic parameters, including cerebral adenosine triphosphate (ATP) and other phosphorous metabolite concentrations, intracellular pH and nicotinamide adenine dinucleotide (NAD) redox ratio, and ATP production rates in the occipital lobe of cognitive-normal PD patients, and then we compared them with age-sex matched healthy controls. Small but statistically significant differences in intracellular pH, NAD and ATP contents and ATPase enzyme activity between the two groups were detected, suggesting that subtle defects in energy metabolism and mitochondrial function are quantifiable before regional neurological deficits or pathogenesis begin to occur in these patients. Pilot data aiming to evaluate the bioenergetic effect of mitochondrial-protective bile acid, ursodeoxycholic acid (UDCA) were also obtained. These results collectively demonstrated that in vivo 31P MRS-based neuroimaging can non-invasively and quantitatively assess key metabolic-energetic metrics in the human brain. This provides an exciting opportunity to better understand neurodegenerative diseases, their progression and response to treatment.

REM Sleep Without Atonia and Gait Impairment in People with Mild-to-Moderate Parkinson's Disease.

BACKGROUND: Subtle gait deficits can be seen in people with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD), a prodromal stage of Parkinson's disease (PD) and related alpha-synucleinopathies. It is unknown if the presence and level of REM sleep without atonia (RSWA, the electromyographic hallmark of RBD) is related to the severity of gait disturbances in people with PD. OBJECTIVE: We hypothesized that gait disturbances in people with mild-to-moderate PD would be greater in participants with RSWA compared to those without RSWA and matched controls, and that gait impairment would correlate with measures of RSWA. METHODS: Spatiotemporal characteristics of gait were obtained from 41 people with PD and 21 age-matched controls. Overnight sleep studies were used to quantify muscle activity during REM sleep and group participants with PD into those with RSWA (PD-RSWA+, n = 22) and normal REM sleep muscle tone (PD-RSWA-, n = 19). Gait characteristics were compared between groups and correlated to RSWA. RESULTS: The PD-RSWA+ group demonstrated significantly reduced gait speed and step lengths and increased stance and double support times compared to controls, and decreased speed and cadence and increased stride velocity variability compared to PD-RSWA- group. Larger RSWA scores were correlated with worse gait impairment in the PD group. CONCLUSION: The presence and level of muscle tone during REM sleep is associated with the severity of gait disturbances in PD. Pathophysiological processes contributing to disordered gait may occur earlier and/or progress more rapidly in people with PD and RBD.

REM sleep without atonia is associated with increased rigidity in patients with mild to moderate Parkinson's disease.

OBJECTIVE: Increased muscle activity during rapid eye movement (REM) sleep (i.e. REM sleep without atonia) is common in people with Parkinson's disease (PD). This study tested the hypotheses that people with PD and REM sleep without atonia (RSWA) would present with more severe and symmetric rigidity compared to individuals with PD without RSWA and age-matched controls. METHODS: Sixty-one individuals participated in this study (41 PD, 20 controls). An overnight sleep study was used to classify participants with PD as having either elevated (PD-RSWA+) or normal muscle activity (PD-RSWA-) during REM sleep. Quantitative measures of rigidity were obtained using a robotic manipulandum that passively pronated and supinated the forearm. RESULTS: Quantitative measures of forearm rigidity were significantly higher in the PD-RSWA+ group compared to the control group. Rigidity was significantly more asymmetric between limbs in the PD-RSWA- group compared with controls, while there was no significant difference in symmetry between the control and PD-RSWA+ groups. CONCLUSION: In people with mild to moderate PD, RSWA is associated with an increased and more symmetric presentation of upper limb rigidity. SIGNIFICANCE: Dysfunction of brainstem systems that control muscle tone during REM sleep may contribute to increased rigidity during wakefulness in people with PD.

Pharmacokinetics, Safety, and Tolerability of Orally Administered Ursodeoxycholic Acid in Patients With Parkinson's Disease-A Pilot Study.

Mitochondrial dysfunction is implicated in the pathogenesis of Parkinson's disease. Preliminary data have shown lower brain adenosine triphosphate (ATP) levels in Parkinson's disease versus age-matched healthy controls. Ursodeoxycholic acid (UDCA) may improve impaired mitochondrial function. Our objective was to evaluate UDCA tolerability, pharmacokinetics, and its effect on brain bioenergetics in individuals with Parkinson's disease. An open-label, prospective, multiple-ascending-dose study of oral UDCA in 5 individuals with Parkinson's disease was completed. A blood safety panel, plasma concentrations of UDCA and UDCA conjugates, and brain ATP levels were measured before and after therapy (week 1: 15 mg/kg/day; week 2: 30 mg/kg/day; and weeks 3-6: 50 mg/kg/day). UDCA and conjugates were measured using liquid chromatography-mass spectrometry. ATP levels and ATPase activity were measured using 7-Tesla 31 P magnetic resonance spectroscopy. Secondary measures included the Unified Parkinson's Disease Rating Scale and Montreal Cognitive Assessment. UDCA was generally well tolerated. The most frequent adverse event was gastrointestinal discomfort, rated by subjects as mild to moderate. Noncompartmental pharmacokinetic analysis resulted in (mean ± standard deviation) a maximum concentration of 8749 ± 2840 ng/mL and half-life of 2.1 ± 0.71 hr. Magnetic resonance spectroscopy data were obtained in 3 individuals with Parkinson's disease and showed modest increases in ATP and decreases in ATPase activity. Changes in Unified Parkinson's Disease Rating Scale (parts I-IV) and Montreal Cognitive Assessment scores (mean ± standard deviation) were -4.6 ± 6.4 and 2 ± 1.7, respectively. This is the first report of UDCA use in individuals with Parkinson's disease. Its pharmacokinetics are variable, and at high doses it appears reasonably well tolerated. Our findings warrant additional studies of its effect on brain bioenergetics.

Hatha yoga training improves standing balance but not gait in Parkinson's disease.

Background and purpose: Complementary therapies, such as yoga, have been proposed to address gait and balance problems in Parkinson's disease (PD). However, the effects of yoga on gait and static balance have not been studied systematically in people with PD (PWP). Here we evaluated the effects of a 12-week long Hatha yoga intervention on biomechanical parameters of gait and posture in PWP. Methods: We employed a pilot randomized controlled trial design with two groups of mild-to-moderate PWP (immediate treatment, waitlist control; N  = 10 each; Mean Hoehn and Yahr score = 2 for each group). Baseline Unified Parkinson's Disease Rating Scale (UPDRS) motor scores, and gait and postural kinematics including postural sway path length, cadence, walking speed, and turning time were obtained. The immediate treatment group received a 60-min Hatha yoga training twice a week for 12 weeks, while the waitlisted control group received no training. After 12 weeks, gait and postural kinematics were assessed (post-test for treatment group and second-baseline for waitlist group). Then, the waitlist group received the same yoga training and was evaluated post-training. Results: After Hatha yoga training, UPDRS motor scores improved with an 8-point mean decrease which is considered as a moderate clinically important change for mild-moderate PD. Sway path length during stance decreased significantly (mean reduction: -34.4%). No significant between-group differences or improvements in gait kinematics were observed. Conclusion: This study showed that a 12-week Hatha yoga training can improve static balance in PWP. We found no evidence that it systematically improves gait performance in PWP.

The Transition from Standing to Walking Is Affected in People with Parkinson's Disease and Freezing of Gait.

BACKGROUND: It has been hypothesized that freezing of gait (FOG) in people with Parkinson's disease (PD) is due to abnormal coupling between posture and gait. OBJECTIVE: In this study, we examined the relationship between anticipatory postural adjustments (APAs) preceding gait initiation and the kinematics of the first two steps between people with FOG and without FOG. METHODS: The kinetics and kinematics of self-initiated gait were recorded in 25 people with PD (11 with FOG, 14 without FOG). Outcome variables included the amplitude and timing of the ground reaction forces (GRFs), center of pressure (CoP) shifts and the spatial and temporal characteristics of the first and second steps. RESULTS: The magnitude and timing of the APA phase of gait initiation were not significantly different between participants with and without FOG, yet the first step in the FOG group was distinguished by a significantly wider and less variable first step width, followed by a subsequent wider and shortened second step with reduced toe clearance. Multiple linear regression showed that the relationship between the initial conditions (stance width), APAs (posterior shift of the CoP) and the kinematics of the first step were different between groups with a significantly increased slope in the FOG group. CONCLUSION: These findings demonstrate that the transition from standing to walking is different between those with and without FOG and that alterations in the initial conditions or APAs are more likely to impact the execution of the two steps in people with FOG.

GBA1 mutations: Prospects for exosomal biomarkers in α-synuclein pathologies.

The discovery that patients with Gaucher Disease (GD), a rare lysosomal storage disorder, were developing symptoms similar to Parkinson's disease (PD) led to investigation of the relationship between the two seemingly unrelated pathologies. GD, an autosomal recessive disorder, is the result of a biallelic mutation in the gene GBA1, which encodes for the enzyme glucocerebrosidase (GCase). Since the observation of its relation to PD, GBA1 mutations have become recognized as the most common genetic risk factor for development of synucleinopathies such as PD and dementia with Lewy bodies. Although the exact mechanism by which GBA1 mutations promote PD is unknown, current understanding suggests that impaired GCase inhibits lysosomal activity and decreases the overall ability of the cell to degrade proteins, specifically the neuronal protein α-synuclein. Decreased elimination of α-synuclein can lead to its abnormal accumulation and aggregation, an important component of PD development. Further understanding of how decreased GCase activity increases risk for α-synuclein pathology can assist with the development of clinical biomarkers for early detection of synucleinopathies, as well as promote novel treatments tailored for people with a GBA1 mutation. Historically, α-synuclein has not been a reliable biomarker for PD. However, recent research on α-synuclein content within exosomes, which are small vesicles released by cells that carry specific cellular cargo, has yielded encouraging results. Moreover, decreased GCase activity has been shown to influence exosomal contents. Exosomes have emerged as a promising new avenue for the identification of novel biomarkers and therapeutic targets aimed at improving neuronal GCase function and limiting the development of synucleinopathies.

Neurochemical abnormalities in patients with type 1 Gaucher disease on standard of care therapy.

Type 1 Gaucher disease (GD1), a glycosphingolipid storage disorder caused by deficient activity of lysosomal glucocerebrosidase, is classically considered non-neuronopathic. However, current evidence challenges this view. Multiple studies show that mutations in GBA1 gene and decreased glucocerebrosidase activity are associated with increased risk for Parkinson disease. We tested the hypothesis that subjects with GD1 will show neurochemical abnormalities consistent with cerebral involvement. We performed Magnetic Resonance Spectroscopy at 7 T to quantify neurochemical profiles in participants with GD1 (n = 12) who are on stable therapy. Age and gender matched healthy participants served as controls (n = 13). Neurochemical profiles were obtained from parietal white matter (PWM), posterior cingulate cortex (PCC), and putamen. Further, in the GD1 group, the neurochemical profiles were compared between individuals with and without a single L444P allele. We observed significantly lower levels of key neuronal markers, N-acetylaspartate, γ-aminobutyric acid, glutamate and glutamate-to-glutamine ratio in PCC of participants with GD1 compared to healthy controls (P < .015). Glutamate concentration was also lower in the putamen in GD1 (P = .01). Glucose + taurine concentration was significantly higher in PWM (P = .04). Interestingly, individuals without L444P had significantly lower aspartate and N-acetylaspartylglutamate in PCC (both P < .001), although this group was 7 years younger than those with an L444P allele. This study demonstrates neurochemical abnormalities in individuals with GD1, for which clinical and prognostic significance remains to be determined. Further studies in a larger cohort are required to confirm an association of neurochemical levels with mutation status and glucocerebrosidase structure and function. SYNOPSIS: Ultrahigh field magnetic resonance spectroscopy reveals abnormalities in neurochemical profiles in patients with GD1 compared to matched healthy controls.

Motor phenotype classification in moderate to advanced PD in BioFIND study.

BACKGROUND: Three motor phenotypes have been described in PD: postural instability and gait difficulty (PIGD) dominant, tremor-dominant (TD), and indeterminate (IND) subtype. These phenotypes have been associated with different cognitive trajectories, motor outcomes, and biomarkers profiles. However, whether motor subtype classifications change with treatment and disease progression is not well established. METHODS: To evaluate motor subtype ratio changes, we used the chi-square test for the off and on state motor subtypes for 115 PD participants in the BioFIND study and used repeated-measures analyses to evaluate longitudinal changes in 162 PD participants with five-year follow-up in the PPMI study. RESULTS: PIGD and TD subtypes in moderate to advanced PD participants change with dopaminergic agents. For those who shifted subtypes, improvement in tremor accounted for the transition of 15 (25.4%) TD participants, while the lack of tremor improvement along with minimal changes in PIGD score resulted in changes for eight (19.0%) PIGD individuals. Analyses of PPMI data revealed that all three subgroups had a significant decrease in subtype ratio with disease progression and a significant decline in subtype ratio occurred only in the TD subgroup with dopaminergic agents. The impact of dopaminergic medication effect on subtype shift for each visit was also more notable with disease advancement. CONCLUSIONS: Motor subtypes are not fixed but change with progression of the disease and with treatment. Improvement in tremor was the main contributor to motor phenotype transitions in the BioFIND cohort. A more stable classification system for subtypes based on underlying biological differences is desirable.

Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial.

BACKGROUND: Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy. METHODS: This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41-86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094. FINDINGS: Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17%] of 12 patients and in ten [28%] of 36 patients), urinary tract infections (in one [8%] of 12 and in six [17%] of 36), contusions (in one [8%] of 12 and in five [14%] of 36), and headaches (in none and in five [14%] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported. INTERPRETATION: Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092. FUNDING: Bristol-Myers Squibb, Biogen.

Effects of yoga on oxidative stress, motor function, and non-motor symptoms in Parkinson's disease: a pilot randomized controlled trial.

OBJECTIVE: To examine the feasibility, acceptability, and preliminary effects of Hatha yoga on oxidative stress, motor function, and non-motor symptoms among individuals with Parkinson's disease (PD). METHODS: The study has a pilot randomized controlled trial design with two arms: an immediate treatment group and a wait-list control group. The yoga-for-PD program was implemented via twice weekly 60-min group-based classes for 12 weeks. Participants were assessed at baseline, 12 weeks, and 6 months post-intervention. Outcome measures included oxidative stress, motor function, physical activity, cognitive function, sleep quality, and quality of life. Data on program acceptability and yoga adherence were collected during the intervention and at 6 months post-intervention. RESULTS: Participants (n = 20) had a mean age of 63 years (SD 8, range 49-75) and disease duration 4.8 years (SD 2.9, range 1-13). All participants had mild-moderate disease severity; 18 (90%) were on dopaminergic medications. Seventeen participants (85%) attended at least 75% of the classes and 4 (20%) attended all classes. Most participants (n = 17) reported they "definitely enjoyed" the intervention program. No adverse events were reported. At 12 weeks, there were no major differences in blood oxidative stress markers between the two groups. Motor function based on the Unified Parkinson's Disease Rating Scale was better in the treatment group, but their scores on sleep and outlook in Parkinson's Disease Quality of Life (PDQUALIF) Scale and the physical activity levels based on the Longitudinal Aging Study Amsterdam Physical Activity Questionnaire were worse than those of the control group. In within-group comparisons, motor function, cognitive function, and catalase improved but three PDQUALIF domains (social and role function, sleep, and outlook) and physical activity level worsened by the end of the yoga intervention program compared to baseline. The response rate for the 6-month follow-up survey was 74% (n = 14) with six participants (43%) who signed up for a yoga class and four (29%) who practiced it independently. Health problems were the main barrier to yoga practice. CONCLUSION: Yoga is feasible and acceptable and may serve as a complementary method for improving motor function in PD. Further research using a larger sample size is needed to determine its impact on oxidative stress and non-motor symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Registration Number: NCT02509610031.

Corrigendum: Multi-modal Brain MRI in Subjects with PD and iRBD.

[This corrects the article on p. 709 in vol. 11, PMID: 29311789.].

White matter measures correlate with essential tremor severity-A pilot diffusion tensor imaging study.

BACKGROUND: An evolving pathophysiological concept of essential tremor (ET) points to diffuse brain network involvement, which emphasizes the need to investigate white matter (WM) changes associated with motor symptoms of ET. OBJECTIVES: To investigate ET-related WM changes and WM correlates of tremor severity using tremor clinical rating scales and accelerometry. METHODS: Tract-based spatial statistics (TBSS) approach was utilized to compare 3 Tesla diffusion tensor imaging (DTI) data from 12 ET patients and 10 age- and gender-matched healthy individuals. Clinical scales, tremor frequency and amplitude as measured by accelerometry were correlated with DTI data. RESULTS: ET patients demonstrated mean (MD) and radial diffusivity (RD) abnormalities in tracts involved in primary and associative motor functions such as bilateral corticospinal tracts, the superior longitudinal fascicles, and the corpus callosum but also in nonmotor regions including the inferior fronto-occipital and longitudinal fascicles, cingulum bundles, anterior thalamic radiations, and uncinate fascicles. A combined tremor frequency and amplitude score correlated with RD and MD in extensive WM areas, which partially overlapped the regions that were associated with tremor frequency. No significant relationship was found between DTI measures and clinical rating scales scores. CONCLUSIONS: The results show that ET-related diffusion WM changes and their correlates with tremor severity are preferentially located in the primary and associative motor areas. In contrast, a relationship between WM was not detected with clinical rating scales. Accelerometry parameters may, therefore, serve as a potentially useful clinical measures that relate to WM deficits in ET.

The effects of anodal tDCS over the supplementary motor area on gait initiation in Parkinson's disease with freezing of gait: a pilot study.

OBJECTIVE: We investigated if anodal transcranial direct current stimulation (A-tDCS), applied over the supplementary motor areas (SMAs), could improve gait initiation in Parkinson's disease (PD) with freezing of gait (FOG). METHODS: In this double-blinded cross-over pilot study, ten PD with FOG underwent two stimulation sessions: A-tDCS (1 mA, 10 min) and sham stimulation. Eight blocks of gait initiation were collected per session: (1) pre-tDCS, with acoustic cueing; (2) pre-tDCS, self-initiated (no cue); and (3-8) post-tDCS, self-initiated. Gait initiation kinetics were analyzed with two-way repeated measures ANOVAs for the effects of A-tDCS. RESULTS: A-tDCS did not significantly improve the magnitude or timing of anticipatory postural adjustments or the execution of the first step during self-initiated gait compared with baseline measures (p > .13). The lack of significant change was not due to an inability to generate functional APAs since external cueing markedly improved gait initiation (p < .01). CONCLUSIONS: A single dose of A-tDCS over the SMAs did not improve self-initiated gait in PD and FOG. Alternative approaches using a different dose or cortical target are worthy of exploration since individuals demonstrated the capacity to improve. SIGNIFICANCE: Neuromodulation strategies tailored to facilitate SMA activity may be ineffective for the treatment of gait initiation impairment in people with PD and FOG.

Somatosensory Training Improves Proprioception and Untrained Motor Function in Parkinson's Disease.

Background: Proprioceptive impairment is a common feature of Parkinson's disease (PD). Proprioceptive function is only partially restored with anti-parkinsonian medication or deep brain stimulation. Behavioral exercises focusing on somatosensation have been promoted to overcome this therapeutic gap. However, conclusive evidence on the effectiveness of such somatosensory-focused behavioral training for improving somatosensory function is lacking. Moreover, it is unclear, if such training has any effect on motor performance in PD. Objective: To investigate, whether proprioception improves with a somatosensory focused, robot-aided training in people with PD (PWPs), and whether enhanced proprioception translates to improved motor performance. Method: Thirteen PWPs of mild-moderate clinical severity were assessed and trained ON medication using a robotic wrist exoskeleton. Thirteen healthy elderly participants served as controls. Training involved making increasingly accurate, continuous, precise small amplitude wrist flexion/extension movements. Wrist position sense acuity, as a marker of proprioception function, and spatial error during wrist pointing, as a marker of untrained motor performance, were recorded twice before and once after training. Functional hand writing kinematics exhibited during training were evaluated in the PD group for determining training-induced changes. Results: Training improved position sense acuity in all PWPs (mean change: 28%; p < 0.001) and healthy controls (mean change: 23%; p < 0.01). Second, 10/13 PD participants and 10/13 healthy control participants had reduced spatial movement error in the untrained wrist pointing task after training. Third, spatial error for the functional handwriting tasks (line tracing and tracking) did not improve with training in the PD group. Conclusion: Proprioceptive function in mild to moderate PD is trainable and improves with a somatosensory-focused motor training. Learning showed a local transfer within the trained joint degree-of-freedom as improved spatial accuracy in an unpracticed motor task. No learning gains were observed for the untrained functional handwriting task, indicating that training may be specific to the trained joint degree-of-freedom.

Repeated-Dose Oral N-Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress.

Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using 1 H-MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations and the reduced-to-oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration-time profiles were described by a first-order absorption, 1-compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4-HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.

Cerebrospinal fluid, plasma, and saliva in the BioFIND study: Relationships among biomarkers and Parkinson's disease Features.

OBJECTIVE: Examine relationships among neurodegenerative biomarkers and PD motor and nonmotor symptoms. BACKGROUND: CSF alpha-synuclein is decreased in PD versus healthy controls, but whether plasma and saliva alpha-synuclein differentiate these groups is controversial. Correlations of alpha-synuclein among biofluids (CSF, plasma, saliva) or biomarkers (eg, beta-amyloid, tau [total, phosphorylated]) are not fully understood. The relationships of these biomarkers with PD clinical features remain unclear. METHODS: BioFIND, a cross-sectional, observational study, examines clinical and biomarker characteristics in moderate-advanced PD and matched healthy controls. We compared alpha-synuclein concentrations across diagnosis, biofluids, and CSF biomarkers. Correlations of CSF biomarkers and MDS-UPDRS, motor phenotype, MoCA, and rapid eye movement sleep behavior disorder questionnaire scores in PD were examined. RESULTS: CSF alpha-synuclein was lower in PD versus controls (P = .01), controlling for age, gender, and education. Plasma and saliva alpha-synuclein did not differ between PD and controls, and alpha-synuclein did not significantly correlate among biofluids. CSF beta-amyloid1-42 was lower in PD versus controls (P < .01), and correlated weakly with MoCA recall scores (r = 0.23, P = .02). CSF alpha-synuclein was lower in the postural instability/gait difficulty phenotype than other motor phenotypes (P < .01). No CSF biomarkers predicted or correlated with total motor or rapid eye movement sleep behavior disorder scores. CSF alpha-synuclein correlated with beta-amyloid1-42 , total-tau, and phosphorylated-tau (r = 0.41, 0.81, 0.43, respectively; Ps < .001). CONCLUSION: Lower CSF alpha-synuclein is associated with diagnosis and motor phenotype in moderate-advanced PD. Plasma and saliva alpha-synuclein neither correlate with CSF alpha-synuclein, nor distinguish PD from controls. CSF beta-amyloid1-42 remains a potential biomarker for cognitive impairment in PD. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.