Autonomic dysfunction in Parkinson's disease and its correlates to medication and dopamine transporter binding

Abstract Patients with idiopathic Parkinson's disease (PD) may suffer from autonomic nervous system dysfunction even in the early phase of the disease. We assessed the autonomic cardiovascular and sudomotor regulation in de novo PD patients with and without medication. We also measured the dopamine (DAT) and serotonin transporter (SERT) uptake in the PD patients using 2β-carboxymethoxy-3β-(4-iodophenyl)tropane (β-CIT) SPECT and studied the clinical correlates of the uptake. Sixty PD patients were included in the study and randomised to receive levodopa, bromocriptine or selegiline (n=20 in each) as their treatment. Thirty patients were examined with β-CIT SPECT. The results of the patients were compared with those of healthy controls and within the subgroups at different time points. Cardiovascular autonomic regulation was assessed using standard cardiovascular reflex tests at baseline, after six months' medication and following a 6-week washout period. The heart rate (HR) and blood pressure (BP) regulation was impaired in PD patients at baseline, and PD medications modified the responses further. Bromocriptine and selegiline, in contrast to levodopa, increased the orthostatic BP fall and suppressed the BP response to isometric exercise. The long-term cardiovascular autonomic function was evaluated from ambulatory ECG recordings by analysis of traditional spectral and non-spectral components of HR fluctuation together with two-dimensional vector analysis and power-law relationship analysis of the HR dynamics. All spectral measures and the slope of the power-law relationship demonstrated impaired tonic cardiovascular regulation in the PD patients. Sympathetic sudomotor activity was evaluated using the sympathetic skin response (SSR). The major finding was suppression of the SSR amplitudes with an inverse correlation to clinical disability, whereas PD medication seemed to have only minor effects. The changes in amplitude and repetitiveness of the SSRs with normal adaptation suggest deficits at several levels of the SSR reflex arc. DAT uptake, assessed by β-CIT SPECT, was diminished in the striatum and especially the putamen of the PD patients, and correlated with the results of the cardiovascular reflex tests and ambulatory ECG recordings. Simultaneous measurement of SERT binding demonstrated decreased SERT availability in the thalamic and frontal areas. The results demonstrate disturbances of the reflectory and tonic cardiovascular autonomic regulation caused by PD itself. PD medications further modify the reflectory responses. The degenerative process in PD also involves the sympathetic sudomotor pathway. β-CIT SPECT provides a useful method for simultaneous assessment of DAT and SERT binding, demonstrating the deficit of serotonin metabolism in PD

A comparison of indirect and direct targeted STN DBS in the treatment of Parkinson’s disease:surgical method and clinical outcome over 15-year timespan

Abstract Background: Deep brain stimulation (DBS) in the subthalamic nucleus (STN) is used in advanced Parkinson’s disease (PD) for reducing motor fluctuations and the side effects of antiparkinsonian medication (APM). The development of neuroimaging has enabled the direct targeting of the STN. The aim of this study is to evaluate the outcome in patients with PD using STN DBS when changing from atlas-based indirect targeting method (iTM) to direct MRI-based targeting (dTM) assuming dTM is superior. Methods: Twenty-five consecutive PD patients underwent dTM STN DBS surgery from 2014 to 2017 with follow-up for 1 year. The neuroimaging, surgical method, outcome in Unified Parkinson’s Disease Rating Scale (UPDRS) scores, and reduction of APM are described and compared with the results of an earlier iTM STN DBS study. Results: Twelve months after a dTM STN DBS, significant improvement (p < 0.001) was seen in six out of seven parameters of UPDRS when patients had medication (medON) and stimulation (stimON). The activities of daily living (UPDRSII) and motor scores (UPDRSIII) improved by 41% and 62%, respectively. Dyskinesias and fluctuations were both reduced by 81%. In dTM STN DBS group, the levodopa equivalent dose (LED) and the total daily levodopa equivalent dose (LEDD) were significantly decreased by 62% and 55%, respectively, compared with the baseline (p < 0.001). Five patients (20%) were without levodopa medication 12 months after the operation. Conclusions: The development of surgical technique based on advanced neuroimaging has improved the outcome of PD STN DBS

Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.

Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.This article is freely available via PubMed Central. Click on the 'Additional Link' above to access the full-text

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome

Monogenic Early-Onset Lymphoproliferation and Autoimmunity: The Natural History of STAT3 GOF Syndrome.

Background In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Objective This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. Methods We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Results Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. Conclusion : STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome. Key word