Faculty Bibliography

BACKGROUND:Sleep disturbances and nocturnal hypokinesia are common in Parkinson's disease (PD). Recent work using wearable technologies showed fewer nocturnal movements in PD when compared with controls. However, it is unclear how these manifest across the disease spectrum. OBJECTIVES:We assessed the prevalence of sleep disturbances and nocturnal hypokinesia in early and advanced PD and their relation to nonmotor symptoms and dopaminergic medication. METHODS:A total of 305 patients with PD with diverse disease severity (Hoehn and Yahr [H&Y] stage 1 = 47, H&Y stage 2 = 181, H&Y stage 3 = 77) and 205 healthy controls continuously wore a tri-axial accelerometer on the lower back for at least 2 days. Lying, turning, and upright -time at night were extracted from the acceleration signals. Percent upright time and nighttime walking were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed were used to evaluate nocturnal movements. RESULTS:Nocturnal lying time was similar among all groups (healthy controls, 7.5 ± 1.2 hours; H&Y stage 1, 7.3 ± 0.9 hours; H&Y stage 2, 7.2 ± 1.3 hours; H&Y stage 3, 7.4 ± 1.6 hours; P = 0.501). However, patients with advanced PD had more upright periods, whereas the number and velocity of their turns were reduced (P ≤ 0.021). Recently diagnosed patients (<1 year from diagnosis) were similar to controls in the number of nocturnal turns (P = 0.148), but showed longer turning time (P = 0.001) and reduced turn magnitude (P = 0.002). Reduced nocturnal movements were associated with increased PD motor severity and worse dysautonomia and cognition and with dopaminergic medication. CONCLUSIONS:Using wearable sensors for continuous monitoring of movement at night may offer an unbiased measure of disease severity that could enhance optimal nighttime dopaminergic treatment and utilization of turning strategies. © 2020 International Parkinson and Movement Disorder Society.

BACKGROUND:Pathological and genetic evidence implicates toxic effects of aggregated α-synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α-synuclein is a promising strategy for delaying disease progression. OBJECTIVE:This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human-derived monoclonal antibody that preferentially binds to aggregated α-synuclein, in healthy volunteers and participants with Parkinson's disease. METHODS:A total of 48 healthy volunteers (age 40-65, 19 women) and 18 Parkinson's disease participants (age 47-75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single-dose cohorts of BIIB054 (range 1-135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α-synuclein complexes were measured in plasma. RESULTS:Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half-life of BIIB054 was 28 to 35 days; the cerebrospinal fluid-to-serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α-synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α-synuclein complex formation. CONCLUSIONS:BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Cognitive impairment in Parkinson's disease (PD) is related to the reorganization of brain topology. Although drug challenge studies have proven how levodopa treatment can modulate functional connectivity in brain circuits, the role of chronic dopaminergic therapy on cognitive status and functional connectivity has never been investigated. We sought to characterize brain functional topology in mid-stage PD patients under chronic antiparkinson treatment and explore the presence of correlation between reorganization of brain architecture and specific cognitive deficits. We explored networks topology and functional connectivity in 16 patients with PD and 16 matched controls through a graph theoretical analysis of resting state-functional MRI data, and evaluated the relationships between network metrics and cognitive performance. PD patients showed a preserved small-world network topology but a lower clustering coefficient in comparison with healthy controls. Locally, PD patients showed lower degree of connectivity and local efficiency in many hubs corresponding to functionally relevant areas. Four disconnected subnetworks were also identified in regions responsible for executive control, sensory-motor control and planning, motor coordination and visual elaboration. Executive functions and information processing speed were directly correlated with degree of connectivity and local efficiency in frontal, parietal and occipital areas. While functional reorganization appears in both motor and cognitive areas, the clinical expression of network imbalance seems to be partially compensated by the chronic levodopa treatment with regards to the motor but not to the cognitive performance. In a context of reduced network segregation, the presence of higher local efficiency in hubs regions correlates with a better cognitive performance.

OBJECTIVE: To assess whether multifocal, high-frequency repetitive transcranial magnetic stimulation (rTMS) of motor and prefrontal cortex benefits motor and mood symptoms in patients with Parkinson disease (PD). METHODS: Patients with PD and depression were enrolled in this multicenter, double-blind, sham-controlled, parallel-group study of real or realistic (electric) sham rTMS. Patients were randomized to 1 of 4 groups: bilateral M1 ( + sham dorsolateral prefrontal cortex [DLPFC]), DLPFC ( + sham M1), M1 + DLPFC, or double sham. The TMS course consisted of 10 daily sessions of 2,000 stimuli for the left DLPFC and 1,000 stimuli for each M1 (50 x 4-second trains of 40 stimuli at 10 Hz). Patients were evaluated at baseline, at 1 week, and at 1, 3, and 6 months after treatment. Primary endpoints were changes in motor function assessed with the Unified Parkinson's Disease Rating Scale-III and in mood with the Hamilton Depression Rating Scale at 1 month. RESULTS: Of the 160 patients planned for recruitment, 85 were screened, 61 were randomized, and 50 completed all study visits. Real M1 rTMS resulted in greater improvement in motor function than sham at the primary endpoint (p < 0.05). There was no improvement in mood in the DLPFC group compared to the double-sham group, as well as no benefit to combining M1 and DLPFC stimulation for either motor or mood symptoms. CONCLUSIONS: In patients with PD with depression, M1 rTMS is an effective treatment of motor symptoms, while mood benefit after 2 weeks of DLPFC rTMS is not better than sham. Targeting both M1 and DLPFC in each rTMS session showed no evidence of synergistic effects. CLINICALTRIALSGOV IDENTIFIER: NCT01080794. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with PD with depression, M1 rTMS leads to improvement in motor function while DLPFC rTMS does not lead to improvement in depression compared to sham rTMS.

Freezing of gait (FOG) is 'an episodic inability to generate effective stepping in the absence of any known cause other than parkinsonism or high level gait disorders'. FOG is one of the most disabling symptoms in Parkinson's disease, especially in its more advanced stages. Early recognition is important as FOG is related to higher fall risk and poorer prognosis. Although specific treatments are still elusive, there have been recent advances in the development of new therapeutic approaches. The aim of this review is to present the latest knowledge regarding the phenomenology, pathogenesis, diagnostic assessment and conventional treatment of FOG in Parkinson's disease. A review of the evidence supporting noninvasive brain stimulation will follow to highlight the potential of these strategies.

Objective: To evaluate structural volumetric changes in basal gangliathalamocortical (BGTC) regions related to cognitive function in Parkinson's disease (PD) patients with and without cognitive impairment. Methods: In a cohort of 35 PD patients (24 males, 11 females) and 31 controls (11males, 20 females), we evaluated the volumes of the following BGTC structures: lateral and medial orbitofrontal cortex, anterior cingulate cortex, and caudate nuclei based on automated segmentation of T1- weighted 3T brain MRI images with FreeSurfer 5.3. All images were manually inspected for accuracy of segmentation. SPM12 was used to generate intracranial volumes (ICV) for normalization of all measured structures. All subjects underwent clinical and neuropsychological assessments to determine cognitive status. Results: Based on a battery of neuropsychological tests and a clinicians' multidisciplinary consensus conference, we classified 15 PD subjects as cognitively impaired (PD-impaired; 11 males, 4 females; MOCA 22.9 +/- 3.63) and 20 as cognitively normal (PD-NC; 13 males, 7 females; MOCA 27 +/- 1.86). PD-impaired had smaller left caudate (0.22 +/- 0.02 vs. 0.25 +/- 0.03, p<0.05) and smaller right lateral orbitofrontal cortex than controls (0.45 +/- 0.04 vs. 0.50 +/- 0.05, p<0.05). PD-NC showed a trend towards smaller left caudate as compared to controls (0.23 +/- 0.02 vs. 0.25 +/- 0.03, p=0.05). Compared to PD-NC, PD-impaired had smaller right lateral orbitofrontal volumes (0.45 +/- 0.04 vs. 0.50 +/- 0.06, p<0.05). Conclusion: PD patients with cognitive impairment have more widespread structural changes in basal ganglia-thalamocortical circuits than PD without cognitive impairment. Automated volumetric measures of such cortical volumes may serve as a potential biomarker of cognitive status of PD patients

Objective: Progressive ataxia with palatal tremor (PAPT) is a rare clinical syndrome characterized by progressive imbalance, dysarthria and visual disturbances. Neuroimaging typically demonstrates hypertrophy and T2 hyperintensity of the olivary complexes. To date, only a few cases of sporadic PAPT have been reported in the literature. Here, we present a patient with idiopathic, degenerative progressive cerebellar ataxia with palatal tremor. Methods: An 80-year-old male presented with two-year history of slowly progressive truncal ataxia, incoordination, dysarthria, dysphagia and visual disturbances. The patient had no history of stroke, demyelinating disease, autonomic dysfunction or other movement disorders. There was no significant family history. Results: Neurological examination was significant for dysarthric speech, dysmetria on finger-nose-finer test, dysdiadochokinesis, axial ataxia, mild bradykinesia, subtle hypermetric saccades and palatal myoclonus 2 Hz, (without an audible click). There was no nystagmus. Paraneoplastic antibodies, including GAD-65, were not present. MRI showed bilateral, symmetric hypertrophy and T2/FLAIR hyperintensity in the inferior olivary nuclei. Conclusion: Sporadic PAPT may be more common than previously thought. Careful clinical examination (including observation of the soft palate for myoclonic movements) may help to reveal the diagnosis. This presentation should be included in the differential diagnosis of hypertrophic olivary degeneration secondary to vascular or demyelinating lesion within the triangle of Guillain-Mollaret

Objectives: Classic radiological presentation of Wilson's disease (WD) with face of the "giant panda" is typically used to distinguish WD from other extrapyramidal disorders. Central pontine myelinolysis like (CPMlike) changes in WD are rarely reported and are distinct from the classic commonly known osmotic demyelination. Although CPM-like changes on MRI in young WD patients are common, there are no published reports of such radiological picture in the exceptional cases of late onset WD. We report on a late onset WD with sequential MRI changes with response to de-coppering therapy. Methods: A 64 year-old male with pulmonary sarcoidosis presented with a two-year history of worsening axial ataxia, postural, kinetic and rest tremors and cognitive decline. His examination was also significant for generalized hyperreflexia, Babinski sign and the presence of Kayser-Fleischer rings. WD diagnosis was confirmed with low ceruloplasmin and with the presence of homozygous mutation in the ATP7B gene. Results: MRI at symptom onset showed diffuse T2/FLAIR hyperintensity in the pons which was contiguous with hyperintensity of the midbrain, as well as focal hyperintensity in left thalamus and generalized cortical atrophy. Following nine months of chelation with trientine, partial resolution of the T2 hyperintensity in the pons was observed, while thalamus hyperintensity became less conspicuous. Conclusions: WD must be considered in all patients that present with hepatic or neurological symptoms without definitive diagnosis, regardless of age. WD and CPM-like radiological changes in older adult WD patients may be under-recognized, but genetic confirmation and clinical exam findings should guide treatment

Objectives: Exploratory study comparing potential therapeutic effects of two different repetitive transcranial magnetic stimulation (rTMS) interventions on pre-motor cortex areas in Parkinson's disease (PD) patients. Cortical pre-motor areas are known to be involved in movement coordination, processing of complex multi-segmental movements and axial muscle adjustments during movement. Methods: Fifteen PD patients with H&Y scores 2-3 participated in a parallel double-blind randomized pilot study of four weekly low-frequency rTMS sessions and were assessed at 4 weeks post-treatment. Stimulation arms were rTMS over dorsal pre-motor cortex and supplementary motor area (PMd+SMA) or sham over PMd and rTMS over SMA (SMA alone). The UPDRS-III and a subset of combined axial items were the primary outcomes. Results: At 4 weeks post-treatment, rANOVA analysis over 6 study timepoints revealed a significant difference between groups for total UPDRS (p=0.027); magnitude of decrease in total UPDRS was greater in PMd+SMA group. UPDRS-III significantly decreased in both groups: 6.85(SD3.5) points in PMd+SMA, 6.33(SD2.25) in SMA alone. Analysis of a subset of axial item scores obtained from UPDRS-III showed improvement only in the PMd+SMA group (23.71% reduction) but couldn't reach statistical significance (z=-1.903, p=0.057). Our major limitation is our sample size. Conclusions: Both rTMS interventions were well tolerated and significantly improved UPDRS motor scores. Combined rTMS over PMd+SMA might be a promising therapy for axial related symptoms; larger studies need to be conducted to corroborate its real potential