Sustained chemogenetic activation of locus coeruleus norepinephrine neurons promotes dopaminergic neuron survival in synucleinopathy.

Dopaminergic neuron degeneration in the midbrain plays a pivotal role in motor symptoms associated with Parkinson's disease. However, non-motor symptoms of Parkinson's disease and post-mortem histopathology confirm dysfunction in other brain areas, including the locus coeruleus and its associated neurotransmitter norepinephrine. Here, we investigate the role of central norepinephrine-producing neurons in Parkinson's disease by chronically stimulating catecholaminergic neurons in the locus coeruleus using chemogenetic manipulation. We show that norepinephrine neurons send complex axonal projections to the dopaminergic neurons in the substantia nigra, confirming physical communication between these regions. Furthermore, we demonstrate that increased activity of norepinephrine neurons is protective against dopaminergic neuronal depletion in human α-syn A53T missense mutation over-expressing mice and prevents motor dysfunction in these mice. Remarkably, elevated norepinephrine neurons action fails to alleviate α-synuclein aggregation and microgliosis in the substantia nigra suggesting the presence of an alternate neuroprotective mechanism. The beneficial effects of high norepinephrine neuron activity might be attributed to the action of norepinephrine on dopaminergic neurons, as recombinant norepinephrine treatment increased primary dopaminergic neuron cultures survival and neurite sprouting. Collectively, our results suggest a neuroprotective mechanism where noradrenergic neurons activity preserves the integrity of dopaminergic neurons, which prevents synucleinopathy-dependent loss of these cells.

Urinary Tract Infection in Parkinson's Disease.

Urinary tract infection (UTI) is a common precipitant of acute neurological deterioration in patients with Parkinson's disease (PD) and a leading cause of delirium, functional decline, falls, and hospitalization. Various clinical features of PD including autonomic dysfunction and altered urodynamics, frailty and cognitive impairment, and the need for bladder catheterization contribute to an increased risk of UTI. Sepsis due to UTI is a feared consequence of untreated or undertreated UTI and a leading cause of morbidity in PD. Emerging research suggests that immune-mediated brain injury may underlie the pathogenesis of UTI-induced deterioration of PD symptoms. Existing strategies to prevent UTI in patients with PD include use of topical estrogen, prophylactic supplements, antibiotic bladder irrigation, clean catheterization techniques, and prophylactic oral antibiotics, while bacterial interference and vaccines/immunostimulants directed against common UTI pathogens are potentially emerging strategies that are currently under investigation. Future research is needed to mitigate the deleterious effects of UTI in PD.

Three-dimensional simultaneous brain mapping of T1, T2, T2∗ and magnetic susceptibility with MR Multitasking.

PURPOSE: To develop a new technique that enables simultaneous quantification of whole-brain T1 , T2 , T2∗ , as well as susceptibility and synthesis of six contrast-weighted images in a single 9.1-minute scan. METHODS: The technique uses hybrid T2 -prepared inversion-recovery pulse modules and multi-echo gradient-echo readouts to collect k-space data with various T1, T2, and T2∗ weightings. The underlying image is represented as a six-dimensional low-rank tensor consisting of three spatial dimensions and three temporal dimensions corresponding to T1 recovery, T2 decay, and multi-echo behaviors, respectively. Multiparametric maps were fitted from reconstructed image series. The proposed method was validated on phantoms and healthy volunteers, by comparing quantitative measurements against corresponding reference methods. The feasibility of generating six contrast-weighted images was also examined. RESULTS: High quality, co-registered T1 , T2 , and T2∗ susceptibility maps were generated that closely resembled the reference maps. Phantom measurements showed substantial consistency (R2 > 0.98) with the reference measurements. Despite the significant differences of T1 (p < .001), T2 (p = .002), and T2∗ (p = 0.008) between our method and the references for in vivo studies, excellent agreement was achieved with all intraclass correlation coefficients greater than 0.75. No significant difference was found for susceptibility (p = .900). The framework is also capable of synthesizing six contrast-weighted images. CONCLUSION: The MR Multitasking-based 3D brain mapping of T1 , T2 , T2∗ , and susceptibility agrees well with the reference and is a promising technique for multicontrast and quantitative imaging.

Sustained quality-of-life improvements over 10 years after deep brain stimulation for dystonia.

BACKGROUND: Little is known about the quality of life of people with dystonia and DBS beyond 5 years. The objectives of this study were (1) to examine the long-term quality-of-life outcomes in a large cohort of people with dystonia and DBS, (2) to determine the incidence of stimulation-induced parkinsonism, and (3) to elucidate the potential long-term cognitive impact of DBS in this cohort. METHODS: Fifty-four subjects with dystonia and DBS for more than 5 years were contacted via social media and were offered to complete a quality-of-life survey comparing current-day life and life prior to DBS. The primary study outcomes were the Short Form survey, a parkinsonian symptoms questionnaire, the Telephone Montreal Cognitive Assessment, and the Measurement of Every Day Cognition. RESULTS: Thirty-seven of 54 subjects consented to the study. Average age was 39.7 ± 16.6 years, 16 were female, and 23 were DYT1+. Average time from implantation was 10.5 years. Average total Short Form survey scores improved, from 43.7 pre-DBS to 69.5 current day (P < 0.0005). Mean total self-reported parkinsonian symptom score was 13.8 ± 14.7, with worsening balance and hypophonia the most common. Average Telephone Montreal Cognitive Assessment was 20.1 ± 1.6, with 3 of 29 scores (10.3%) in the impaired range (score of 18 or less). Average total Every Day Cognition score was 1.25 ± 0.35, with 3 subjects (10.3%) scoring in the range of impaired cognition (>1.81). CONCLUSIONS: DBS for dystonia results in long-term quality-of-life improvements that persist on average 10 years or more after surgery. The prevalence of stimulation-induced parkinsonism and cognitive impairment is low. © 2018 International Parkinson and Movement Disorder Society.

High Prevalence of Undiagnosed Insulin Resistance in Non-Diabetic Subjects with Parkinson's Disease.

BACKGROUND: Reduced glucose tolerance has been long recognized as a potential risk factor for Parkinson's disease (PD), and increasing scrutiny is currently being placed on insulin resistance (IR) as a pathologic driver of neurodegeneration. However, the prevalence of IR in PD is unknown. OBJECTIVE: To determine IR prevalence in non-diabetic patients with PD and to correlate IR with other metabolic indicators, motor and non-motor symptoms (NMS) of PD, and quality of life (QoL). METHODS: Non-diabetic patients with a diagnosis of PD were identified and tested for fasting insulin, fasting glucose, and HbA1c. Patients were also offered to take a battery of clinical tests (MoCA, NMSQ, and PDQ-39) and had their PD medications, height, weight, and other demographic features recorded. IR was defined as HOMA-IR≥2.0 and/or HbA1c≥5.7. IR abnormalities were correlated with BMI and demographic features, in addition to motor and NMS. RESULTS: 154 subjects (109 M, 45F, mean age 67.7±10.5) were included in this study. Mean HOMA-IR was 2.3±1.8. Ninety out of 154 (58.4%) subjects had abnormal IR. IR was more frequent in overweight and obese subjects (61.1% and 82.8% respectively) than normal weight subjects (41.5%). Multivariate analysis showed that BMI was the only significant predictor of IR (p < 0.0001). There was no significant correlation between HOMA-IR and MoCA, PDQ-39, and NMSQ scores. CONCLUSIONS: IR is prevalent in PD and it correlates with BMI. A correlation between IR with cognitive and QoL measures cannot be determined on the basis of this sample.

Deep Brain Stimulation and Nonmotor Symptoms.

Deep brain stimulation (DBS) is currently the treatment of choice for advanced Parkinson's disease (PD). Several brain targets, including the subthalamic nucleus and the globus pallidus internus, have been successfully employed, with excellent motor outcomes. Despite less established knowledge, DBS may be a powerful tool for managing a wide variety of nonmotor symptoms (NMS) in PD patients, either directly or indirectly due to motor benefit or reduction of dopaminergic drug load. After an assessment of global nonmotor outcomes of DBS, as measured by currently available clinical scales and questionnaires, this chapter will address DBS effects on four main NMS categories: neurobehavioral, including cognitive and neuropsychiatric symptoms, autonomic dysfunction, including orthostatic hypotension, constipation, and urinary dysfunction, sleep disturbances, including insomnia, REM sleep behavior disorder, and restless leg syndrome, to conclude with sensory symptoms, mainly focusing on pain. An overall positive impact of DBS on most NMS emerges from the reviewed studies. However, current opinion on the effect of DBS on NMS in PD needs to be tempered by the relatively low number of cases and the lack of large, controlled, specifically designed studies for most NMS categories.

Overuse Cervical Dystonia: A Case Report and Literature Review.

BACKGROUND: Overuse or task-specific dystonia has been described in a number of professions characterized by repetitive actions, typically affecting the upper extremities. Cervical dystonia (CD), however, has rarely been associated with overuse. CASE REPORT: We present a case report of typical CD that developed in the context of chronic repetitive movements associated with the patient's professional occupation as an office manager who spent many hours per day holding a phone to his ear. DISCUSSION: Overuse CD should be suspected when typical symptoms and signs of CD develop in the context of chronic repetitive use or overuse of cervical muscles, especially where exacerbating tasks involve asymmetric postures.