Therapeutic potential of iron modulating drugs in a mouse model of multiple system atrophy.

Multiple System Atrophy (MSA) is a rare neurodegenerative synucleinopathy which leads to severe disability followed by death within 6-9 years of symptom onset. There is compelling evidence suggesting that biological trace metals like iron and copper play an important role in synucleinopathies like Parkinson's disease and removing excess brain iron using chelators could slow down the disease progression. In human MSA, there is evidence of increased iron in affected brain regions, but role of iron and therapeutic efficacy of iron-lowering drugs in pre-clinical models of MSA have not been studied. We studied age-related changes in iron metabolism in different brain regions of the PLP-αsyn mice and tested whether iron-lowering drugs could alleviate disease phenotype in aged PLP-αsyn mice. Iron content, iron-ferritin association, ferritin protein levels and copper-ceruloplasmin association were measured in prefrontal cortex, putamen, substantia nigra and cerebellum of 3, 8, and 20-month-old PLP-αsyn and age-matched non-transgenic mice. Moreover, 12-month-old PLP-αsyn mice were administered deferiprone or ceruloplasmin or vehicle for 2 months. At the end of treatment period, motor testing and stereological analyses were performed. We found iron accumulation and perturbed iron-ferritin interaction in substantia nigra, putamen and cerebellum of aged PLP-αsyn mice. Furthermore, we found significant reduction in ceruloplasmin-bound copper in substantia nigra and cerebellum of the PLP-αsyn mice. Both deferiprone and ceruloplasmin prevented decline in motor performance in aged PLP-αsyn mice and were associated with higher neuronal survival and reduced density of α-synuclein aggregates in substantia nigra. This is the first study to report brain iron accumulation in a mouse model of MSA. Our results indicate that elevated iron in MSA mice may result from ceruloplasmin dysfunction and provide evidence that targeting iron in MSA could be a viable therapeutic option.

A Life-threatening Complication of Multiple System Atrophy.

CASE PRESENTATION: A 50-year-old woman was initially seen in 2016 for sleep disorders consultation, referred by Neurology because of progressive cerebellar ataxia syndrome with possible autonomic involvement and sleep-disordered breathing described as having stridorous sounds during her sleep. She had initially presented to Neurology because of issues with balance, and she had frequent falls at home. In 2016, her speech was clear, and she was able to ambulate steadily with a cane. She underwent a diagnostic polysomnogram that did not demonstrate clinically significant sleep apnea. However, the study demonstrated rapid eye movement (REM) sleep without atonia in 62% of REM epochs (normal, up to 27%) and a soft inspiratory stridor during non-REM and REM sleep. The patient was lost to follow-up until she presented to us for reevaluation 3 years later. In the interim, she had been diagnosed with multiple system atrophy-cerebellar type (MSA-C) at another health-care institution.

Differential value of external anal- and urethral-sphincter electromyography in multiple system atrophy cerebellar type and spinocerebellar ataxias.

OBJECTIVE: Clinically differentiating multiple system atrophy cerebellar type (MSA-C) and spinocerebellar ataxias (SCAs) is challenging, especially at early disease stages, because of their similarities in clinical manifestation and imaging results. The purpose of this study was to explore the value of external anal-sphincter electromyography (EAS-EMG) and urethral-sphincter electromyography (US-EMG) for distinguishing between MSA-C and SCAs. METHODS: A total of 51 subjects, including 33 MSA-C and 18 SCAs, were recruited. Average duration and amplitude of motor unit potentials (MUPs), percentage of polyphasic MUPs, amplitude during strong contraction and recruitment pattern during maximal voluntary contraction were recorded and analyzed to identify differential diagnostic results of EAS-EMG and US-EMG for MSA-C and SCAs. RESULTS: Significant differences in average MUP duration, percentage of polyphasic MUPs, and ratio of simple phase and simple-mix phase using EAS-EMG were noted between patients with MSA-C and SCAs. These same parameters also differed significantly between MSA-C and SCAs male patients using US-EMG. CONCLUSIONS: EAS-EMG may serve as a potential method for early differential diagnosis between patients with MSA-C and SCAs. Furthermore, US-EMG could be a supplementary method for males when EAS-EMG is not available.

Altered resting-state voxel-level whole-brain functional connectivity in multiple system atrophy patients with cognitive impairment.

OBJECTIVE: There is increasing evidence of cognitive impairment (CI) frequently occurring in patients with multiple system atrophy (MSA); however, the neurobiological mechanisms underlying CI in patients with MSA remain unclear. METHODS: We enrolled 61 patients with probable MSA and 33 healthy controls (HC). We used degree centrality (DC) analysis to assess changes in the centrality level of MSA-CI related brain nodes. We conducted a secondary seed-based functional connectivity (FC) analysis to investigate dysfunctions in cognitive networks related to MSA. Further, we analysed the correlation between clinical symptoms and acquired connectivity measures. RESULTS: Compared with HC, patients with MSA-CI and those with MSA with normal cognition (MSA-NCI) exhibited lower DC values in the left calcarine and right postcentral regions and higher DC values in the bilateral caudate and left precuneus. There were significant differences in the DC values in the right middle prefrontal gyrus between the MSA-CI and MSA-NCI groups. The mean DC values in the right middle prefrontal gyrus (RMPFG) were correlated with clinical cognitive severity. Consequently, we used this brain region as a seed in secondary seed-based FC analysis and observed FC changes within the right precuneus, inferior parietal lobe, and right insula. CONCLUSIONS: Decreased middle prefrontal cortex activity and its altered functional connectivity with the precuneus, inferior parietal lobe, and insula are possible biomarkers of cognitive dysfunction in patients with MSA-CI. SIGNIFICANCE: Cognitive impairment in MSA is associated with alterations in the dorsolateral prefrontal cortex network.

Urodynamic study for distinguishing multiple system atrophy from Parkinson disease.

OBJECTIVE: To evaluate the differences in urodynamic findings between multiple system atrophy (MSA) and Parkinson disease (PD) and to identify the differential diagnostic ability of urodynamic study. METHODS: We reviewed patients with MSA or PD who underwent urodynamic studies between January 2011 and August 2018. Patients with probable MSA and PD determined by movement disorder specialists at our center were included. Patients with alleged MSA or PD from outside hospitals, atypical or secondary parkinsonism, and any history of pelvic operation or radiation therapy were excluded. RESULTS: A total of 219 patients, 107 with MSA (male:female 50:57) and 112 with PD (male:female 57:55), were included. Patients with MSA had shorter disease duration and were referred for urologic evaluation earlier (p < 0.001). Detrusor overactivity and associated urine leakage were prominent in PD (p < 0.001). Patients with MSA showed lower maximal flow rate (4.0 ± 5.8 vs 9.1 ± 8.3 mL/s, p < 0.001) and larger postvoid residual (290.8 ± 196.7 vs 134.0 ± 188.1 mL, p < 0.001) with decreased compliance (44.9% vs 10.7%, p < 0.001) and impaired contractility (24.9 ± 33.8 vs 65.7 ± 51.1, p < 0.001). Postvoid residual from a pressure-flow study had the highest sensitivity and specificity (74.8% and 75.9%), followed by detrusor pressure at maximal uroflow (72.6% and 70.5%), bladder contractility index, and postvoid residual from uroflowmetry (71.0% and 70.5%, respectively). CONCLUSIONS: Patients with MSA showed lower maximal flow rate, larger postvoid residual with decreased compliance, and impaired contractility, whereas patients with PD had higher incidence of detrusor overactivity and associated leakage. For differential diagnosis, postvoid residual from a pressure-flow study provided the best sensitivity and specificity. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that urodynamic measures can distinguish patients with MSA from those with PD.

The Relevance of Iron in the Pathogenesis of Multiple System Atrophy: A Viewpoint.

Iron is essential for cellular development and maintenance of multiple physiological processes in the central nervous system. The disturbance of its homeostasis leads to abnormal iron deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Iron toxicity has been established in the pathogenesis of Parkinson's disease; however, its contribution to multiple system atrophy (MSA) remains elusive. MSA is characterized by cytoplasmic inclusions of misfolded α-synuclein (α-SYN) in oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs). Remarkably, the oligodendrocytes possess high amounts of iron, which together with GCI pathology make a contribution toward MSA pathogenesis likely. Consistent with this observation, the GCI density is associated with neurodegeneration in central autonomic networks as well as olivopontocerebellar and striatonigral pathways. Iron converts native α-SYN into a ß-sheet conformation and promotes its aggregation either directly or via increasing levels of oxidative stress. Interestingly, α-SYN possesses ferrireductase activity and α-SYN expression underlies iron mediated translational control via RNA stem loop structures. Despite a correlation between progressive putaminal atrophy and iron accumulation as well as clinical decline, it remains unclear whether pathologic iron accumulation in MSA is a secondary event in the cascade of neuronal degeneration rather than a primary cause. This review summarizes the current knowledge of iron in MSA and gives evidence for perturbed iron homeostasis as a potential pathogenic factor in MSA-associated neurodegeneration.

Does sympathetic dysfunction occur before denervation in pure autonomic failure?

Pure autonomic failure (PAF) is a rare sporadic disorder characterized by autonomic failure in the absence of a movement disorder or dementia and is associated with very low plasma norepinephrine (NE) levels-suggesting widespread sympathetic denervation, however due to its rarity the pathology remains poorly elucidated. We sought to correlate clinical and neurochemical findings with sympathetic nerve protein abundances, accessed by way of a forearm vein biopsy, in patients with PAF and in healthy controls and patients with multiple systems atrophy (MSA) in whom sympathetic nerves are considered intact. The abundance of sympathetic nerve proteins, extracted from forearm vein biopsy specimens, in 11 patients with PAF, 8 patients with MSA and 9 age-matched healthy control participants was performed following a clinical evaluation and detailed evaluation of sympathetic nervous system function, which included head-up tilt (HUT) testing with measurement of plasma catecholamines and muscle sympathetic nerve activity (MSNA) in addition to haemodynamic assessment to confirm the clinical phenotype. PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) (P<0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) (P<0.05) protein expression compared with control and MSA participants. These findings were associated with a significantly higher ratio of plasma 3,4-dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls (P<0.05). The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis. The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves and suggests that sympathetic dysfunction may occur ahead of denervation.

Case of possible multiple system atrophy with a characteristic imaging finding of open bladder neck during storage phase as an initial sign.

Multiple system atrophy is a neurodegenerative disease that affects autonomic and motor systems. Patients with multiple system atrophy usually experience lower urinary tract symptoms, which sometimes appear as an initial symptom before the emergence of the generalized symptoms. An open bladder neck during the filling phase on video urodynamic study is one characteristic imaging finding after the diagnosis of multiple system atrophy, but has not previously been reported at an early phase of the disease. We report a case in which an open bladder neck was observed on several imaging modalities before generalized symptoms emerged. Because occult neurogenic bladder might exist in patients whose lower urinary tract symptoms are resistant to pharmacotherapy, we report this case to raise awareness of the importance of sufficient imaging evaluations. An open bladder neck might be an important imaging finding for diagnosing multiple system atrophy, irrespective of the presence of generalized symptoms. This finding could help avoid false diagnosis and unnecessary treatment.

Role of the microtubule-associated TPPP/p25 in Parkinson's and related diseases and its therapeutic potential.

INTRODUCTION: The discovery and development of therapeutic strategies for the treatments of Parkinson's disease (PD) and other synucleinopathies are limited by a lack of understanding of the pathomechanisms and their connection with different diseases such as cancers. Areas covered: The hallmarks of these diseases are frequently multifunctional disordered proteins displaying moonlighting and/or chameleon features, which are challenging drug targets. A representative of these proteins is the disordered Tubulin Polymerization Promoting Protein (TPPP/p25) expressed specifically in oligodendrocytes (OLGs) in normal brain. Its non-physiological level is tightly related to the etiology of PD and Multiple System Atrophy (TPPP/p25 enrichment in inclusions of neurons and OLGs, respectively), multiple sclerosis (TPPP/p25-positive OLG destruction), as well as glioma (loss of TPPP/p25 expression). The established anti-proliferative potency of TPPP/p25 may raise its influence in cancer development. The recognition that whereas too much TPPP/p25 could kill neurons in PD, but its loss keeps cells alive in cancer could contribute to our understanding of the interrelationship of 'TPPP/p25 diseases'. Expert commentary: The knowledge accumulated so far underlines the key roles of the multifunctional TPPP/p25 in both physiological and diverse pathological processes, consequently its validation as drug target sorely needs a new innovative strategy that is briefly reviewed here.

Palliative Care Discussions in Multiple System Atrophy: A Retrospective Review.

OBJECTIVE: Multiple system atrophy (MSA) is an incurable neurodegenerative illness in which progressive symptoms, including stridor and acute laryngeal obstruction, occur. Advanced care planning and palliative care discussions in people living with MSA are not well defined. The aim of the present study is to evaluate advanced care planning and current practices in palliative care in MSA to identify opportunities for improving quality of care. METHODS: The study is a retrospective chart review assessing the focus and timing of palliative care discussions in people living with MSA. Some 22 charts were reviewed. RESULTS: A total of 22 patients were included. The most common symptoms were parkinsonism, orthostatic hypotension, GI/GU dysfunction, ataxia and gait impairment. Six patients had stridor. Of the palliative care discussions that took place, the most common topics were diagnosis, symptoms or symptom management, and prognosis. In the majority of patients who died and who had a do-not-attempt-resuscitation order, discussions surrounding resuscitation and goals of care took place only hours before death. CONCLUSIONS: There is no standard approach to advanced care planning and palliative care discussions in people living with MSA. We propose a framework to guide advanced care planning and palliative care discussions in MSA.

Oxidative Stress and Environmental Exposures are Associated with Multiple System Atrophy in Chinese Patients.

OBJECTIVE: Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). The aim of this study is to examine oxidant biomarkers including homocysteine (Hcys), bilirubin, uric acid, lipids, and potential environmental risk factors and to ascertain whether these data correlate with MSA in a Chinese population. METHODS: In this study, serum levels of Hcys, bilirubin, uric acid, and lipids were studied in 55 MSA patients and 76 healthy controls (HCs). Education, anti-parkinsonian agent usage, smoking, drinking, farming, and living area of the subjects also were analyzed. The Unified MSA Rating Scale (UMSARS), Hoehn & Yahr stage, International Cooperative Ataxia Rating Scale, and Mini-Mental State Examination were used to assess the disease severity, the parkinsonism, ataxia, and the cognitive ability of MSA, respectively. RESULTS: The levels of Hcys were higher (p<0.001) and those of total bilirubin (p=0.007), indirect bilirubin (p=0.011), and total cholesterol (p=0.046) were lower in MSA patients than in healthy controls, whereas uric acid levels did not differ significantly between MSA and healthy controls. Moreover, Hcys levels in MSA patients had positive correlations with illness duration (r s =0.422, p=0.001) and UMSARS-I (r s =0.555, p<0.001), respectively. High-density lipoprotein cholesterol levels were negatively correlated with UMSARS-I (r s =-0.325, p=0.015). Farming was more frequent in MSA patients (1-20 years: odds ratio, 6.36; p20 years: odds ratio, 10.26; p=0.001), whereas current smoking was less frequent (odds ratio, 0.13, p=0.002). CONCLUSIONS: Elevated Hcys and decreased high-density lipoprotein cholesterol may be associated with the disease severity of MSA. Environmental exposures such as farming and smoking may contribute to the occurrence but not the progression of MSA.

Altered bulbocavernosus reflex in patients with multiple system atrophy.

OBJECTIVES: Multiple system atrophy (MSA) is characterized by a combination of symptoms including autonomic dysfunction, parkinsonism, cerebellar ataxia, and cortico-spinal disorders. The disease can have either predominant parkinsonism or cerebellar features (MSA-P and MSA-C, respectively). The measurement of the bulbocavernosus reflex (BCR) and pudendal nerve somatosensory-evoked potentials (PSEPs) was originally developed to diagnose diabetic cystopathy and other neuropathologic diseases that share similar symptoms with MSA. We investigated the relationship between abnormalities of neurophysiological parameters and MSA, and estimated the potential value of BCR. METHODS: Fifty-one MSA patients (28 and 23 MSA-P and 23 MSA-C patients, respectively) and 30 healthy controls who were seen at the Department of Neurology were included in the study. A Keypoint EMG/EP system was used to test BCR and PSEPs, and the latencies and amplitudes were recorded for statistical analyses. RESULTS: The BCR was elicited in 78.4% patients with MSA (22/28 MSA-P, 18/23 MSA-C). Prolonged BCR latencies were found in patients with MSA compared with healthy controls (p < 0.001). BCR amplitudes were significantly lower in the MSA group than the control group (p < 0.001). PSEP P41 amplitudes were not significantly different between the MSA and control groups in males (p = 0.608) or females (p = 0.897). There were no significant differences in PSEP latencies among the MSA-P, MSA-C, and control groups (p = 1.0, p = 0.263, and p = 0.060, respectively). DISCUSSION: MSA patients exhibit prolonged BCR latencies and lower amplitudes, which provides a rough anatomical localization of nervous system lesions in MSA patients.

Mutation Analysis of COQ2 in Chinese Patients with Cerebellar Subtype of Multiple System Atrophy.

AIMS: Recently, mutations in COQ2 encoding para-hydroxybenzoate-polyprenyl transferase have been identified to increase the risk of multiple system atrophy (MSA) in multiplex families and sporadic cases. The prevalence of COQ2 mutations was showed to be higher in cerebellar subtype (MSA-C) than parkinsonism subtype (MSA-P). The aim of this study was to investigate the association between COQ2 mutations and MSA-C in Chinese patients. METHODS: A Chinese cohort of 116 patients with MSA-C and 192 healthy control individuals were recruited. Sanger sequencing of COQ2 was performed in all these subjects. RESULTS: Two missense mutations (p.L402F and p.R173H) and one synonymous mutation (p.A32A) were detected in 3 patients, respectively. They were not found in the 192 controls as well as the 1000 Genomes Database. The p.L402F and p.A32A were novel. CONCLUSION: Our results indicated that COQ2 tended to play a population-specific and subtype-depended role in conferring susceptibility to MSA.

Update on novel familial forms of Parkinson's disease and multiple system atrophy.

Parkinson's disease (PD) and multiple system atrophy (MSA) are progressive neurodegenerative disorders classified as synucleinopathies, which are defined by the presence of α-synuclein protein pathology. Genetic studies have identified a total of 18 PARK loci that are associated with PD. The SNCA gene encodes the α-synuclein protein. The first pathogenic α-synuclein p.A53T substitution was discovered in 1997; this was followed by the identification of p.A30P and p.E46K pathogenic substitutions in 1998 and 2004, respectively. In the last year, two possible α-synuclein pathogenic substitutions, p.A18T and p.A29S, and two probable pathogenic substitutions, p.H50Q and p.G51D have been nominated. Next-generation sequencing approaches in familial PD have identified mutations in the VPS35 gene. A VPS35 p.D620N substitution remains the only confirmed pathogenic substitution. A second synucleinopathy, MSA, originally was considered a sporadic condition with little or no familial aggregation. However, recessive COQ2 mutations recently were nominated to be the genetic cause in a subset of familial and sporadic MSA cases. Further studies on the clinicogenetics and pathology of parkinsonian disorders will facilitate clarification of the molecular characteristics and pathomechanisms underlying these disorders.

[Comparative study on diagnostic significance of urethral sphincter versus external anal sphincter electromyography in patients with multiple system atrophy].

OBJECTIVE: To evaluate the diagnostic value of external anal sphincter electromyography (EAS-EMG) versus urethral sphincter electromyography (US-EMG) in patients with multiple system atrophy (MSA). METHODS: A total of 27 MSA patients were examined with EAS and US-EMG as treatment group while 28 non-MSA subjects as control group. Spontaneous activities during relaxation, mean duration & amplitude of motor unit potential (MUP), percentage of polyphasic and variations during strong contraction were recorded and analyzed statistically. RESULTS: There was significant difference in light contraction between MSA and non-MSA cases on both EAS-EMG and US-EMG (EAS-EMG, P < 0.001; US-EMG, P = 0.002) . Meanwhile, strong contraction and percentage of polyphasic showed significant differences between MSA and non-MSA cases on EAS-EMG only (strong contraction, P = 0.016; percentage of polyphasic, P = 0.004) . EAS-EMG showed more significant changes in neurogenic injury than US-EMG. CONCLUSIONS: US-EMG and EAS-EMG are valuable for the diagnosis of MSA. The differences of multiple parameters of EAS-EMG were more significant than those of US-EMG for MSA cases. US-EMG may serve as a supplement of EAS-EMG in case of restriction.

[The diagnostic value of urethral sphincter electromyography in patients with multiple system atrophy].

OBJECTIVE: To analyze diagnostic evaluation of urethral sphincter electromyography (US-EMGs) for patients with multiple system atrophy (MSA). METHODS: Totally 15 patients who were diagnosed as MSA were examined as treatment group while 17 non-MSA patients were examined as controls. US-EMGs were performed in the both groups. Spontaneous activities when relax, parameters of motor unit potentials (MUPs) mean duration and amplitude, percentage of polyphasic ware, satellite potential, recruitment potentials and amplitude when strong contraction were recorded and analyzed. RESULTS: US-EMGs changes of various abnormalities were found in 13 cases (86.7%) in MSA group. There were significant differences of electromyographic findings between the MSA group and control group including MUPs mean duration [(12.79 ± 3.18) ms vs (9.49 ± 1.51) ms] and amplitude [(828.53 ± 459.89) µV vs (378.76 ± 152.26) µV] as well as recruitment potentials [(11.47 ± 21.55)% vs (8.23 ± 10.74)%] and amplitude [(2.19 ± 1.24) mV vs (0.75 ± 0.42) mV] when strong contraction (all P values < 0.05). CONCLUSIONS: There is certain value of US-EMGs for the diagnosis of MSA. It could be used as a routine electrophysiological method for the patients who are suspected of MSA. It could be a supplement of external anal sphincter electromyography.

Erythropoietin is neuroprotective in a transgenic mouse model of multiple system atrophy.

Multiple system atrophy is a rapidly progressive neurodegenerative disorder with a markedly reduced life expectancy. Failure of symptomatic treatment raises an urgent need for disease-modifying strategies. We have investigated the neuroprotective potential of erythropoietin in (proteolipid protein)-α-synuclein transgenic mice exposed to 3-nitropropionic acid featuring multiple system atrophy-like pathology including oligodendroglial α-synuclein inclusions and selective neuronal degeneration. Mice were treated with erythropoietin starting before (early erythropoietin) and after (late erythropoietin) intoxication with 3-nitropropionic acid. Nonintoxicated animals receiving erythropoietin and intoxicated animals treated with saline served as control groups. Behavioral tests included pole test, open field activity, and motor behavior scale. Immunohistochemistry for tyrosine hydroxylase and dopamine and cyclic adenosine monophosphate-regulated phosphoprotein (DARPP-32) was analyzed stereologically. Animals receiving erythropoietin before and after 3-nitropropionic acid intoxication scored significantly lower on the motor behavior scale and they performed better in the pole test than controls with no significant difference between early and late erythropoietin administration. Similarly, rearing scores were worse in 3-nitropropionic acid-treated animals with no difference between the erythropoietin subgroups. Immunohistochemistry revealed significant attenuation of 3-nitropropionic acid-induced loss of tyrosine hydroxylase and DARPP-32 positive neurons in substantia nigra pars compacta and striatum, respectively, in both erythropoietin-treated groups without significant group difference in the substantia nigra. However, at striatal level, a significant difference between early and late erythropoietin administration was observed. In the combined (proteolipid protein)-α-synuclein 3-nitropropionic acid multiple system atrophy mouse model, erythropoietin appears to rescue dopaminergic and striatal gabaergic projection neurons. This effect is associated with improved motor function. Further studies are warranted to develop erythropoietin as a potential interventional therapy in multiple system atrophy.

Multi-organ autonomic dysfunction in Parkinson disease.

Both pathologic and clinical studies of autonomic pathways have expanded the concept of Parkinson disease (PD) from a movement disorder to a multi-level widespread neurodegenerative process with non-motor features spanning several organ systems. This review integrates neuropathologic findings and autonomic physiology in PD as it relates to end organ autonomic function. Symptoms, pathology and physiology of the cardiovascular, skin/sweat gland, urinary, gastrointestinal, pupillary and neuroendocrine systems can be probed by autopsy, biopsy and non-invasive electrophysiological techniques in vivo which assess autonomic anatomy and function. There is mounting evidence that PD affects a chain of neurons in autonomic pathways. Consequently, autonomic physiology may serve as a window into non-motor PD progression and allow the development of mechanistically based treatment strategies for several non-motor features of PD. End-organ physiologic markers may be used to inform a model of PD pathophysiology and non-motor progression.