Where is the brain in all of this?

Moving forward the in vivo diagnosis of the synucleinopathies

Dysautonomia in the synucleinopathies: not just orthostatic hypotension

Early bladder dysfunction in multiple system atrophy: who seek shall find

Multiple system atrophy: a disorder targeting the brainstem control of survival

Association of innervation-adjusted alpha-synuclein in arrector pili muscles with cardiac noradrenergic deficiency in autonomic synucleinopathies Abstract Background Autonomic synucleinopathies feature deposition of the protein alpha-synuclein (AS) in neurons [e.g., Lewy body neurogenic orthostatic hypotension (nOH)] or glial cells (multiple system atrophy, MSA). AS in skin biopsies might provide biomarkers of these diseases; however, this approach would be complicated or invalidated if there were substantial loss of AS-containing nerves. We report AS content in arrector pili muscles in skin biopsies after adjustment for local innervation in patients with Lewy body nOH or MSA. Cardiac sympathetic neuroimaging by myocardial 18F-dopamine positron emission tomography (PET) was done to examine pathophysiological correlates of innervation-adjusted AS. Methods Thirty-one patients (19 Lewy body nOH, 12 MSA) underwent thoracic 18F-dopamine PET and skin biopsies. AS signal intensity analyzed by immunofluorescence microscopy was adjusted for innervation by the ratio of AS to protein gene product (PGP) 9.5, a pan-axonal marker (Harvard lab site), or the ratio of AS to tyrosine hydroxylase (TH), an indicator of catecholaminergic neurons (NIH lab site). Results The Lewy body nOH group had higher ratios of AS/PGP 9.5 or log AS/TH than did the MSA group (0.89 ± 0.05 vs. 0.66 ± 0.04, −0.13 ± 0.05 vs. −1.60 ± 0.33; p < 0.00001 each). All 19 Lewy body patients had AS/PGP 9.5 > 0.8 or log AS/TH > 1.2 and had myocardial 18F-dopamine-derived radioactivity < 6000 nCi-kg/cc-mCi, the lower limit of normal. Two MSA patients (17%) had increased AS/PGP or log AS/TH, and two (17%) had low 18F-dopamine-derived radioactivity. Conclusions Lewy body forms of nOH are associated with increased innervation-adjusted AS in arrector pili muscles and neuroimaging evidence of myocardial noradrenergic deficiency.

Sensitivity and specificity of cardiac metaiodobenzylguanidine scintigraphy in the early diagnosis of Parkinson’s disease Abstract Purpose Metaiodobenylguanidine (MIBG) scintigraphy has been shown to enhance the probability of correct diagnosis in patients with parkinsonian syndromes (PS). Thus far, studies of the clinical usefulness of MIBG have been confined to cross-sectional assessments, which are inevitably associated with diagnostic uncertainty during the early stages of these syndromes. In this study, the initial clinical diagnosis was reevaluated longitudinally to assess the sensitivity and specificity of clinical and MIBG parameters in the early diagnosis of PS. Methods 167 patients with PS (age 67.03 ± 8.92 years (mean ± standard deviation), duration of symptoms 2.48 ± 5.27 years, median Hoehn and Yahr score 2) underwent an initial clinical assessment and MIBG scintigraphy. Eighty seven of those patients (56 with Parkinson’s disease (PD), 1 with multiple system atrophy (MSA), 23 with atypical PS, 7 with tremor syndrome) were clinically reevaluated a mean of 3 years later in order to verify their initial diagnosis. Results The use of a lower limit of normal value of 1.74 for the heart-to-mediastinum ratio (HMR) achieved the best discrimination between PD and other PS. The sensitivity of MIBG scintigraphy to PD was 94%; it also had a specificity of 65%, a positive predictive value of 88%, and a negative predictive value of 79%. MIBG scintigraphy was better than initial clinical diagnosis alone (sensitivity 83%, specificity 39%) or levodopa responsiveness (sensitivity 92%, specificity 10%). However, a combination of clinical diagnosis and MIBG scintigraphy was found to be especially clinically useful (specificity 95%, sensitivity 83%, positive predictive value 95%, negative predictive value 83%). Conclusion MIBG scintigraphy was demonstrated to be a reliable tool for the diagnosis of early PD. The best diagnostic accuracy was achieved by combining a clinical examination with MIBG scintigraphy.

Frequency and factors related to drooling in Chinese patients with multiple system atrophy: a cross-sectional study Abstract Purpose Drooling is a common symptom of neurodegenerative diseases. We aimed to explore the frequency of drooling and its relationship to clinical features in a relatively large cohort of Chinese patients with multiple system atrophy (MSA). Methods We conducted a cross-sectional survey of 143 patients with MSA. Patients with drooling were identified as those with a score ≥ 1 on item 6 of the Unified Parkinson’s Disease Rating Scale. Additional scales were used to rate daily functionality, neurologic and cognitive capabilities, levels of anxiety and depression, and sleep quality. These results were compared between patients with and without drooling. Results The frequency of drooling in this cohort was 59.4% (85/143). Drooling was associated with significantly poorer scores on the Unified MSA Rating Scale (subscore I, subscore II, subscore IV, total score), Pittsburgh Sleep Quality Index, Hamilton Depression Scale, Hamilton Anxiety Scale, and Mini-Mental State Examination. After adjusting for confounders, regression analysis identified two independent risk factors for drooling: parkinsonism-associated MSA (OR 2.54, 95% CI 1.15–5.65) and hypomimia (OR 3.18, 95% CI 1.32–7.68). Conclusions Drooling is relatively common among Chinese MSA patients, and parkinsonism-associated MSA and hypomimia appear to be independent risk factors for drooling. The severity of this symptom correlates with the presence of severe motor symptoms, anxiety, depression, and sleep disorders.

Skin nerve α-synuclein deposits in Parkinson’s disease and other synucleinopathies: a review Abstract Purpose The in vivo diagnosis of synucleinopathies is an important research aim since clinical diagnostic criteria show low accuracy. The skin innervation, especially the autonomic subdivision, is a useful region to search for abnormal α-syn aggregates in synucleinopathies since the peripheral sympathetic nerves can be the earliest-affected neural region and autonomic symptoms may precede the classical symptoms of these disorders. Methods The major advantages of skin biopsy as an in vivo diagnostic tool for synucleinopathies are that it is an inexpensive and easy-to-perform technique requiring only limited facilities, and that it is repeatable in long-term studies as it causes only minor discomfort to the patient. Results This review analyzes current progress in this area of research that may facilitate the standardization of this method, potentially eliminating differences among laboratories in the implementation of the method. Conclusions The most suitable and commonly used technique for identifying in vivo α-syn aggregates in skin nerves is indirect immunofluorescence, although several aspects of this approach need to be standardized, particularly when synucleinopathies without autonomic failure present a patchy distribution of abnormal α-syn aggregates in skin nerves. By contrast, synucleinopathies with autonomic failure may present widespread diffusion of abnormal aggregates in autonomic skin nerves.

Functional neuroimaging of the central autonomic network: recent developments and clinical implications Abstract Purpose The central autonomic network (CAN) is an intricate system of brainstem, subcortical, and cortical structures that play key roles in the function of the autonomic nervous system. Prior to the advent of functional neuroimaging, in vivo studies of the human CAN were limited. The purpose of this review is to highlight the contribution of functional neuroimaging, specifically functional magnetic resonance imaging (fMRI), to the study of the CAN, and to discuss recent advances in this area. Additionally, we aim to emphasize exciting areas for future research. Methods We reviewed the existing literature in functional neuroimaging of the CAN. Here, we focus on fMRI research conducted in healthy human subjects, as well as research that has been done in disease states, to understand CAN function. To minimize confounding, papers examining CAN function in the context of cognition, emotion, pain, and affective disorders were excluded. Results fMRI has led to significant advances in the understanding of human CAN function. The CAN is composed of widespread brainstem and forebrain structures that are intricately connected and play key roles in reflexive and modulatory control of autonomic function. Conclusions fMRI technology has contributed extensively to current knowledge of CAN function. It holds promise to serve as a biomarker in disease states. With ongoing advancements in fMRI technology, there is great opportunity and need for future research involving the CAN.