Cardiovascular dysautonomia in de novo Parkinson’s disease without orthostatic hypotension

Background: Clinical symptoms of Parkinson’s disease (PD) include not only motor distress, but also autonomic dysfunction. Objective: To study the characteristics of subclinical autonomic nervous dysfunction in de novo PD without orthostatic hypotension (OH). Methods: Autonomic nervous function including cardiac sympathetic gain was evaluated on the basis of cardiac radioiodinated metaiodobenzylguanidine (MIBG) uptake, the response to the Valsalva maneuver, and spectral analyses of the RR interval and blood pressure in 20 patients with de novo PD without OH. Results: Decreased cardiac MIBG uptake was found even in patients with PD without OH. Hemodynamic studies using the Valsalva maneuver revealed that patients with PD without OH had preserved baroreceptor reflex sensitivity in phase II and phase IV. Blood pressures normally responded in early and late phase II, but not in phase IV. Blood pressure recovery time was slightly reduced in patients with PD without OH when compared with the value in controls. The low frequency component of the RR interval and systolic blood pressure and the ratio of RR‐LF to RR‐HF in de novo PD without OH were significantly reduced when compared with the control values, whereas the high frequency component of the RR interval did not differ significantly. Conclusion: These results show that latent cardiac and vasomotor sympathetic dysfunction but not parasympathetic dysfunction is already present in early stage de novo PD, even without orthostatic hypotension.     

Cardiovascular dysautonomia in de novo Parkinson's disease

BACKGROUND: Clinical symptoms of Parkinson's disease (PD) include not only motor distress, but also autonomic dysfunction. OBJECTIVE: To clarify the progression of autonomic nervous dysfunction in PD. METHODS: The subjects were 44 patients with de novo PD. Autonomic nervous function, including cardiac sympathetic gain, was evaluated on the basis of cardiac radioiodinated metaiodobenzylguanidine (MIBG) uptake, the response to the Valsalva maneuver, and spectral analyses of the RR interval and blood pressure. RESULTS: Decreased cardiac MIBG uptake was found even in patients with early stage PD. MIBG uptake gradually decreased with increased disease severity. Hemodynamic studies using the Valsalva maneuver revealed that patients with early stage PD had reduced baroreceptor reflex sensitivity (BRS) in phase II, but not phase IV. Blood pressures normally rose in phases II and IV, but the increments decreased with disease progression. In early stage PD, the low frequency power of the RR interval (RR-LF) and the ratio (LF/HF) of RR-LF to the high frequency component of the RR interval (RR-HF) were significantly lower than the respective control values, despite no significant difference in RR-HF; these variables decreased with disease progression. CONCLUSION: Our results show that latent sympathetic nervous dysfunction without parasympathetic dysfunction, especially that involving the sinus node, is already present in early stage de novo PD. It is unclear whether the responsible lesion is central or peripheral.     

Autonomic involvement in Parkinson's disease: pathology, pathophysiology, clinical features and possible peripheral biomarkers

Autonomic nervous system involvement occurs at early stages in both Parkinson's disease (PD) and incidental Lewy body disease (ILBD), and affects the sympathetic, parasympathetic, and enteric nervous systems (ENS). It has been proposed that alpha-synuclein (α-SYN) pathology in PD has a distal to proximal progression along autonomic pathways. The ENS is affected before the dorsal motor nucleus of the vagus (DMV), and distal axons of cardiac sympathetic nerves degenerate before there is loss of paravertebral sympathetic ganglion neurons. Consistent with neuropathological findings, some autonomic manifestations such as constipation or impaired cardiac uptake of norepinephrine precursors, occur at early stages of the disease even before the onset of motor symptoms. Biopsy of peripheral tissues may constitute a promising approach to detect α-SYN neuropathology in autonomic nerves and a useful early biomarker of PD.     

Impaired cardiovascular autonomic function in Parkinson's disease with visual hallucinations.

We assessed the relations of visual hallucinations (VH) to cardiovascular autonomic dysfunction in patients with Parkinson's disease (PD). The subjects were 37 patients without VH (VH(-)) and 31 with VH (VH(+)). Autonomic function was evaluated on the basis of cardiac 123-radioiodinated metaiodobenzylguanidine (123I-MIBG) uptake and hemodynamic testing with Valsalva maneuver. Systolic blood pressure (SBP) and plasma norepinephrine concentrations (NE) were measured by tilt-table testing. 123I-MIBG uptake was lower in VH(+) than VH(-). Hemodynamic studies showed that VH(-) had only cardiac sympathetic and parasympathetic dysfunction, while VH(+) additionally had reduced vasomotor sympathetic functions. The fall in SBP during tilt-table testing was greater in VH(+) than VH(-). NE and its difference in the supine and upright positions were decreased in VH(+). We conclude that cardiac and vasomotor sympathetic dysfunction is more severe in VH(+) than in VH(-). Severe dysfunction in PD with VH is probably attributed to Lewy-body lesions or neuronal loss in sympathetic ganglia, the central autonomic system, or both.     

帕金森病患者自主神经功能障碍相关研究

目的 评估交感神经皮肤反应(sympathetic skin response,SSR)和PD自主神经症状量表(the scale for outcomes in PD for autonomic symptoms,SCOPA-AUT)对帕金森病(Parkinson disease,PD)患者自主神经功能损害的诊断价值及自主神经功能障碍影响因素.方法 应用SSR、SCOPA-AUT和统一帕金森病评分量表(unified Parkinson disease rating scale,UPDRS)对50例PD患者进行评估;应用SSR及SCOPA-AUT量表对33例对照组进行评估.结果 PD组四肢SSR的潜伏期及波幅与对照组相比差异有显著统计学意义(P<0.01或0.05).SCOPA-AUT总分(23.54±12.48)、消化系统症状(8.00±3.77)及泌尿系统症状评分(6.28±3.51)均高于对照组,差异有统计学意义(P<0.01).SCOPA.AUT总分与UPDRS评分、H&Y分级、Schwab和England日常生活得分显著相关,差异有统计学意义(P<0.01或0.05),与病程、年龄无明显的相关性(P>0.05).结论 PD患者自主神经功能障碍随着病情进展而加重,PD患者SCOPA-AUT评分与上、下肢SSR波幅呈负相关,SSR和SCOPA-AUT可作为评价PD患者自主神经功能障碍的客观量化临床指标.

Abstract：

Objective To investigate the diagnostic value of sympathetic skin response(SSR)and the scale for outcomes in PD for autonomic symptoms(SCOPA-AUT)in autonomic dysfunction and influencing factors of autonomic dysfunction in patients with parkinson's disease(PD).Methods SSR,SCOPA-AUT and unified Parkinson's disease rating scale(UPDRS)were used to evaluate 50 patients with PD.The results were taken from patients with PD and compared with those of 33 control subjects.Results It was significantly different to compare the SSR latency and amplitude of PD patients limbs with those of the normal controls.PD patients had more total SCOPA-AUT score(23.54 4±12.48)and domain scores in gastrointestinal(8.00 4±3.77)and urinary symptoms(6.28±3.51)compared to control subjects(P<0.01).There were significant correlations between the total score with UPDRS.Hoehn-Yabr scale or score of Schwab and England disability scale(P<0.01 or 0.05),and no correlation with duration or age(P>0.05).Conclusions Autonomic dysfunction of PD increased significantly with disease severity.There were significantly negative correlation between the total score of SCOPA-AUT with the limb SSR amplitude(P<0.05)in PD patients.SSR and SCOPA-AUT can act as an objective index to assess autonomic dysfunctions in patients with PD quantitatively.     

Olfactory dysfunction and cardiovascular dysautonomia in Parkinson’s disease

Several studies have reported that olfactory dysfunction is an early neuropathological manifestation of Parkinson’s disease (PD). Reduced cardiac meta-iodobenzylguanidine (¹²³I-MIBG) uptake may be one of the earliest signs of PD. We studied the relation of olfactory dysfunction to cardiovascular dysautonomia in patients with PD. The study group comprised 66 patients with PD (70.5 years) and 26 controls (70.3 years) for olfactory assessment, 21 controls (72.1 years) for cardiac ¹²³I-MIBG scintigraphy and heart rate variability (HRV), assessed using the coefficient of variation for RR intervals (HRV), and 23 controls (69.2 years) for orthostatic blood pressure response. Olfactory function was assessed by the odor stick identification test Japan (OSIT-J), and cardiovascular autonomic function was evaluated by ¹²³I-MIBG scintigraphy of the heart, the fall in orthostatic blood pressure, and HRV. Patients with PD had a significantly lower OSIT-J score than did the controls (4.1 ± 3.0 vs. 9.9 ± 1.7, p = 0.001). The OSIT-J score was unrelated to variables other than gender, including age, disease duration, motor score on the unified Parkinson’s disease rating scale, score on the mini-mental state examination, motor phenotype, visual hallucinations, and dopaminergic medication on multiple regression and logistic regression analyses. The OSIT-J score was related to the heart/mediastinum ratio of cardiac ¹²³I-MIBG uptake, the fall in orthostatic blood pressure, and HRV, after adjustment for other clinical variables. Olfactory dysfunction in PD was, thus, significantly related to both cardiac sympathetic and parasympathetic dysfunction, as well as vascular sympathetic dysfunction. As non-motor symptoms of PD, olfactory dysfunction and autonomic network failure appear to be closely related in PD.     

Autonomic dysfunction in movement disorders

Dysfunction of the autonomic nervous system is an under-recognised but important aspect of the aetiological and clinical manifestation of primary degenerative dysautonomias such as multiple system atrophy (MSA) and Parkinson's disease (PD). Although the clinical presentation of dysautonomia in these two disorders may overlap, yet pathological and in vivo imaging studies suggest considerable differences. Functional imaging studies suggest that selective cardiac sympathetic denervation may occur early in PD but not in other parkinsonian syndromes. The clinical implication of this apparently disease specific peripheral dysautonomia is unknown and would be the subject of much interest in future years. Dysautonomia in degenerative disorders also affect respiration, genitourinary function and sleep. Sleep related disorders such as rapid eye movement behaviour disorder and urinary voiding dysfunction appear to precede the development of PD related symptoms while patients with sporadic ataxia have been shown to progress to develop MSA. Dysautonomia has also been recognised in other movement disorders, examples being the combination of dystonia and complex regional pain syndrome with elevated HLA-DR13 and late onset Huntington's disease presenting with dominant parkinsonism and minimal chorea. These studies have helped progress in various diagnostic and management parameters in relation to autonomic dysfunction and movement disorders.     

Autonomic symptoms in idiopathic REM behavior disorder: a multicentre case–control study

Patients with idiopathic REM sleep behavior disorder (iRBD) are at very high risk of developing neurodegenerative synucleinopathies, which are disorders with prominent autonomic dysfunction. Several studies have documented autonomic dysfunction in iRBD, but large-scale assessment of autonomic symptoms has never been systematically performed. Patients with polysomnography-confirmed iRBD (318 cases) and controls (137 healthy volunteers and 181 sleep center controls with sleep diagnoses other than RBD) were recruited from 13 neurological centers in 10 countries from 2008 to 2011. A validated scale to study the disorders of the autonomic nervous system in Parkinson's disease (PD) patients, the SCOPA-AUT, was administered to all the patients and controls. The SCOPA-AUT consists of 25 items assessing the following domains: gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual dysfunction. Our results show that compared to control subjects with a similar overall age and sex distribution, patients with iRBD experience significantly more problems with gastrointestinal, urinary, and cardiovascular functioning. The most prominent differences in severity of autonomic symptoms between our iRBD patients and controls emerged in the gastrointestinal domain. Interestingly, it has been reported that an altered gastrointestinal motility can predate the motor phase of PD. The cardiovascular domain SCOPA-AUT score in our study in iRBD patients was intermediate with respect to the scores reported in PD patients by other authors. Our findings underline the importance of collecting data on autonomic symptoms in iRBD. These data may be used in prospective studies for evaluating the risk of developing neurodegenerative disorders.     

I-123 MIBG cardiac scintigraphy and autonomic test evaluation in multiple sclerosis patients

Autonomic symptoms are common in multiple sclerosis (MS) patients and may cause significant disability. The purpose of this study was to evaluate direct cardiac sympathetic denervation in MS patients with I-123 MIBG cardiac scintigraphy compared with other parasympathetic electrophysiological examinations of autonomic dysfunction. Ten patients with MS and 7 age- and sex-matched control subjects were prospectively evaluated. The neurological deficit and disability stages of the patients were rated according to the Kurtzke Expanded Disability Status Scale (EDSS). Autonomic tests included the R-R interval, Valsalva ratio and standup test. All patients and control subjects had planar and SPECT cardiac scintigraphy with I-123 MIBG injection. Seven MS patients had relapsing-remitting (R-R) type and three had secondary progressive type (SP). A pathological MIBG cardiac washout rate was found in 3/10 MS patients, all of them with SP-MS. The other seven had normal washout rates. No correlation was found between the scan and the individual parasympathetic autonomic test results. I-123 MIBG myocardial scintigraphy may detect direct disturbances of the sympathetic cardiac function in patients with MS in addition to parasympathetic dysfunction tests and can be an important additional means of assessing autonomic pathways. Determination in MS of the co-existence of autonomic dysfunction, especially the cardiac sympathetic involvement in the SP type, may aid in evaluation of disease severity and cardiac function follow-up. All departments are affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Israel.     

Pupillography refines the diagnosis of diabetic autonomic neuropathy

Although diabetic autonomic neuropathy involves most organs, diagnosis is largely based on cardiovascular tests. Light reflex pupillography (LRP) non-invasively evaluates pupillary autonomic function. We tested whether LRP demonstrates autonomic pupillary dysfunction in diabetics independently from cardiac autonomic neuropathy (CAN) or peripheral neuropathy (PN). In 36 type-II diabetics (39-84 years) and 36 controls (35-78 years), we performed LRP. We determined diameter (PD), early and late re-dilation velocities (DV) as sympathetic parameters and reflex amplitude (RA) and constriction velocity (CV) as parasympathetic pupillary indices. We assessed the frequency of CAN using heart rate variability tests and evaluated the frequency of PN using neurological examination, nerve conduction studies, thermal and vibratory threshold determination. Twenty-eight (77.8%) patients had abnormal pupillography results, but only 20 patients (56%) had signs of PN or CAN. In nine patients with PN, only pupillography identified autonomic neuropathy. Four patients had pupillary dysfunction but no CAN or PN. In comparison to controls, patients had reduced PD, late DV, RA and CV indicating sympathetic and parasympathetic dysfunction. The incidence and severity of pupillary abnormalities did not differ between patients with and without CAN or PN. LRP demonstrates sympathetic and parasympathetic pupillary dysfunction independently from PN or CAN and thus refines the diagnosis of autonomic neuropathy in type-II diabetics.     

Assessment of autonomic nerve function in myotonic dystrophy

The function of the autonomic nervous system was studied in 23 patients with myotonic dystrophy, from a defined population in northern Sweden with an extremely high prevalence of this disease. Heart rate variability tests showed only minor signs of parasympathetic dysfunction. Blood pressure and plasma noradrenaline measurements in recumbent and upright positions showed no signs of sympathetic neuropathy. Increased plasma levels of noradrenaline was an unexpected finding. Our study does not support the hypothesis that cardiac arrhythmias, orthostatic hypotension, gastrointestinal motility disturbances and urinary bladder dysfunction in myotonic dystrophy are caused by autonomic neuropathy, and we believe that these symptoms should rather be ascribed to a defective function of the target organs.     

Synuclein deposition and non-motor symptoms in Parkinson disease

Parkinson disease (PD) is a multisystem neurodegenerative disorder clinically characterized by motor and non-motor (NM) symptoms. The causes of NM symptoms in PD, many of which antedating motor dysfunction, are multifocal and unlikely explained by single lesions. They include olfactory, autonomic, sensory, skin, sleep, visual, neuropsychiatric, and other manifestations. Most NM features in PD are related to α-synuclein pathology which, in addition to the dopaminergic striatonigral system, involves non-nigral brainstem nuclei, sympathetic, parasympathetic, enteric and pelvic plexuses, cardiac systems, submandibular gland, adrenal medulla, skin, retina, and other visceral organs. This suggests a topographical and chronological spread of lesions, particularly in the prodromal stages of the disease, which, however, awaits further confirmation. A few animal models are available that recapitulate NM symptoms in human PD, but their validity is under discussion. More studies are warranted to refine the exact correlations between presymptomatic and late-developing NM features of PD and α-synuclein pathology as a basis for more effective preventive and therapeutic options of this devastating disease.     

Autonomic dysfunction in PD: a window to early detection?

It has been suggested that autonomic dysfunction constitutes a biomarker for early detection of the disease process in Parkinson disease (PD). Recent findings based on cardiac sympathetic and striatal dopaminergic imaging in the same patients indicate that this view is overly simple. Although evidence of cardiac sympathetic denervation is associated with other non-motor manifestations such as anosmia, REM behavior disorder, dementia, baroreflex failure, and orthostatic hypotension (OH), across individual patients the severities of OH and of the cardiac sympathetic lesion (indicated by thoracic 6-[(18)F]fluorodopamine PET scanning) are unrelated to the severity of the putamen dopaminergic lesion (indicated by brain 6-[(18)F]fluorodopa PET scanning). Moreover, whereas cases have been reported with neuroimaging evidence of cardiac sympathetic denervation several years before motor onset of PD, in other cases loss of cardiac sympathetic innervation progresses approximately concurrently with the movement disorder or can even occur as a late finding. Bases for independent sympathetic noradrenergic and striatal dopaminergic lesions in Lewy body diseases remain poorly understood. In elderly patients with unexplained OH or other evidence of autonomic failure, it is reasonable for clinicians to look for subtle signs of parkinsonism, such as masked facies, cogwheel rigidity, and shuffling gate.     

Reduced cardiac <Superscript>123</Superscript>I-MIBG uptake reflects cardiac sympathetic dysfunction in de novo Parkinson’s disease

It remains unclear whether cardiac iodine-123-labeled metaiodobenzylguanidine (¹²³I-MIBG) uptake is clinically related to autonomic dysfunction on conventional autonomic function testing in de novo Parkinson’s disease (PD). We therefore studied the relation between cardiac ¹²³I-MIBG uptake and cardiovascular autonomic dysfunction in patients with de novo PD. The subjects were 26 patients with de novo PD. The ratio of the average pixel count in the heart to that in the mediastinum was calculated to derive the cardiac ¹²³I-MIBG uptake. Cardiovascular autonomic function was evaluated on the basis of cardiovascular autonomic response on the Valsalva maneuver (VM), and systolic blood pressure response (SBP) on head-up tilt-table testing (HUT). Patients with de novo PD had significantly reduced cardiac ¹²³I-MIBG uptake as compared with controls (1.58 ± 0.43 vs. 2.25 ± 0.34, p = 0.0001) and cardiovascular autonomic response on the VM. No significant difference in the fall in SBP on HUT was found between patients with de novo PD and the controls. Cardiac ¹²³I-MIBG uptake in de novo PD was not significantly related to vasomotor sympathetic function, baroreceptor reflex gain, cardiac parasympathetic function, or the changes in SBP on HUT. Cardiac ¹²³I-MIBG uptake was, however, significantly related to the blood pressure overshoot in phase IV of the VM (r = 0.648, p = 0.0003). Cardiac ¹²³I-MIBG uptake began to decrease in association with the reduction in the overshoot of phase IV on the VM. Cardiac ¹²³I-MIBG uptake clinically reflects cardiac sympathetic dysfunction in de novo PD.     

Imaging the Autonomic Nervous System in Parkinson’s Disease

Purpose of Review

Patients with Parkinson’s disease (PD) often display gastrointestinal and genitourinary autonomic symptoms years or even decades prior to diagnosis. These symptoms are thought to be caused in part by pathological α-synuclein inclusions in the peripheral autonomic and enteric nervous systems. It has been proposed that the initial α-synuclein aggregation may in some PD patients originate in peripheral nerve terminals and then spread centripetally to the spinal cord and brainstem. In vivo imaging methods can directly quantify the degeneration of the autonomic nervous system as well as the functional consequences such as perturbed motility. Here, we review the methodological principles of these imaging techniques and the major findings in patients with PD and atypical parkinsonism.

Recent Findings

Loss of sympathetic and parasympathetic nerve terminals in PD can be visualized using radiotracer imaging, including ¹²³I-MIBG scintigraphy, and ¹⁸F-dopamine and ¹¹C-donepezil PET. Recently, ultrasonographical studies disclosed reduced diameter of the vagal nerves in PD patients. Radiological and radioisotope techniques have demonstrated dysmotility and prolonged transit time throughout all subdivisions of the gastrointestinal tract in PD. The prevalence of objective dysfunction as measured with these imaging methods is often considerably higher compared to the prevalence of subjective symptoms experienced by the patients.

Summary

Degeneration of the autonomic nervous system may play a key role in the pathogenesis of PD. In vivo imaging techniques provide powerful and noninvasive tools to quantify the degree and extent of this degeneration and its functional consequences.

     

Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson's disease.

[(123)I]Metaiodobenzylguanidine ([(123)I]MIBG) cardiac scintigraphy could be helpful to differentiate Parkinson's disease (PD) from multiple system atrophy (MSA), demonstrating that, in PD with autonomic failure but not in MSA, there is a myocardial postganglionic sympathetic dysfunction. To investigate whether this method is more sensitive than standard autonomic testing to detect early involvement of sympathetic cardiac efferent, we analyse MIBG myocardial uptake in 8 PD patients with normal autonomic testing (nondysautonomia PD group, NDPD) in comparison with 10 PD patients with abnormal autonomic testing (dysautonomia PD group, DPD) and 10 MSA patients. Global MIBG uptake was assessed using the ratio of [(123)I]MIBG uptake in the heart to the upper mediastinum (H/M) on planar scintigraphic data. Regional MIBG uptake was determined on two single photon emission tomography scans in regions of the left ventricle. The mean H/M ratios were significantly different among the three groups (P < 0.0001). H/M ratios of both NDPD and DPD patients groups (H/M = 1.83 +/- 0.50 and 1.24 +/- 0.40, respectively) were significantly lower than in MSA patients (H/M = 2.52 +/- 0.60). However, in NDPD patients, H/M was significantly higher than in DPD patients. When compared to MSA patients, NDPD patients showed a regional reduction in MIBG uptake in all left ventricle regions markedly in the apex and the inferior wall. Our results suggest that MIBG myocardial scintigraphy (analysis of both H/M ratio and regional MIBG uptake) may be more sensitive than standard autonomic testing for the early detection of silent autonomic dysfunction in PD.     

Cardiovascular dysautonomia in Parkinson disease: from pathophysiology to pathogenesis

Signs or symptoms of impaired autonomic regulation of circulation often attend Parkinson disease (PD). This review covers biomarkers and mechanisms of autonomic cardiovascular abnormalities in PD and related alpha-synucleinopathies. The clearest clinical laboratory correlate of dysautonomia in PD is loss of myocardial noradrenergic innervation, detected by cardiac sympathetic neuroimaging. About 30-40% of PD patients have orthostatic hypotension (OH), defined as a persistent, consistent fall in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 min of change in position from supine to standing. Neuroimaging evidence of cardiac sympathetic denervation is universal in PD with OH (PD+OH). In PD without OH about half the patients have diffuse left ventricular myocardial sympathetic denervation, a substantial minority have partial denervation confined to the inferolateral or apical walls, and a small number have normal innervation. Among patients with partial denervation the neuronal loss invariably progresses over time, and in those with normal innervation at least some loss eventually becomes evident. Thus, cardiac sympathetic denervation in PD occurs independently of the movement disorder. PD+OH also entails extra-cardiac noradrenergic denervation, but this is not as severe as in pure autonomic failure. PD+OH patients have failure of both the parasympathetic and sympathetic components of the arterial baroreflex. OH in PD therefore seems to reflect a "triple whammy" of cardiac and extra-cardiac noradrenergic denervation and baroreflex failure. In contrast, most patients with multiple system atrophy, which can resemble PD+OH clinically, do not have evidence for cardiac or extra-cardiac noradrenergic denervation. Catecholamines in the neuronal cytoplasm are potentially toxic, via spontaneous and enzyme-catalyzed oxidation. Normally cytoplasmic catecholamines are efficiently taken up into vesicles via the vesicular monoamine transporter. The recent finding of decreased vesicular uptake in Lewy body diseases therefore suggests a pathogenetic mechanism for loss of catecholaminergic neurons in the periphery and brain. Parkinson disease (PD) is one of the most common chronic neurodegenerative diseases of the elderly, and it is likely that as populations age PD will become even more prevalent and more of a public health burden. Severe depletion of dopaminergic neurons of the nigrostriatal system characterizes and likely produces the movement disorder (rest tremor, slowness of movement, rigid muscle tone, and postural instability) in PD. Over the past two decades, compelling evidence has accrued that PD also involves loss of noradrenergic neurons in the heart. This finding supports the view that loss of catecholaminergic neurons, both in the nigrostriatal system and the heart, is fundamental in PD. By the time PD manifests clinically, most of the nigrostriatal dopaminergic neurons are already lost. Identifying laboratory measures-biomarkers-of the disease process is therefore crucial for advances in treatment and prevention. Deposition of the protein, alpha-synuclein, in the form of Lewy bodies in catecholaminergic neurons is a pathologic hallmark of PD. Alpha-synucleinopathy in autonomic neurons may occur early in the pathogenetic process. The timing of cardiac noradrenergic denervation in PD is therefore a key issue. This review updates the field of autonomic cardiovascular abnormalities in PD and related disorders, with emphasis on relationships among striatal dopamine depletion, sympathetic noradrenergic denervation, and alpha-synucleinopathy.     

Assessment of autonomic dysfunction in Parkinson's disease: the SCOPA-AUT.

We developed a questionnaire to assess autonomic symptoms in patients with Parkinson's disease (PD) and evaluated its reliability and validity. Based on the results of a postal survey in 46 PD patients, 21 multiple system atrophy patients, and 8 movement disorders specialists, items were included according to their frequency, burden, and clinical relevance. The questionnaire was evaluated in 140 PD patients and 100 controls, and test-retest reliability was established in a sample of 55 PD patients. The SCOPA-AUT consists of 25 items assessing the following regions: gastrointestinal (7), urinary (6), cardiovascular (3), thermoregulatory (4), pupillomotor (1), and sexual (2 items for men and 2 items for women) dysfunction. Test-retest reliability was good. Autonomic problems increased significantly with increasing disease severity for all autonomic regions, except sexual dysfunction. We conclude that SCOPA-AUT is a reliable and valid questionnaire that evaluates autonomic dysfunction in PD.     

Autonomic dysfunction in Parkinson's disease: a comprehensive symptom survey

BACKGROUND: Autonomic dysfunction occurs in Parkinson's disease (PD), but few studies have addressed it in a comprehensive manner. METHODS: Autonomic symptoms were evaluated by a questionnaire in sixty-eight subjects (44 patients and 24 controls). RESULTS: PD patients experienced higher frequency and severity of autonomic dysfunction. When all autonomic symptoms were pooled into an aggregate score, differences between patients and controls were highly statistically significant (p<0.0001). 'Increased salivation', 'frequency of dysphagia', decreased 'BM (bowel movement) frequency', i.e. constipation, and 'orthostatic dizziness' were more frequent in PD patients (p<0.05). A prediction model to determine the predictors of autonomic dysfunction was unsuccessful. CONCLUSION: Differences in the prevalence of autonomic symptoms in PD and non-parkinsonian controls are apparent from this study.     

Autonomic dysfunction in genetic forms of synucleinopathies

The discovery of genetic links between alpha‐synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia. By contrast, in familial cases of parkinsonism without Lewy bodies, such as in PARK2, the autonomic profile remains normal throughout the course of the disease. The degeneration of the central and peripheral autonomic systems in genetic as well as sporadic forms of neurodegenerative synucleinopathies correlates with the accumulation of alpha‐synuclein immunoreactive‐containing inclusions. Given that dysautonomia has a significant impact on the quality of life of sufferers and autonomic symptoms are generally treatable, a prompt diagnostic testing and treatment should be provided. Moreover, new evidence suggests that autonomic dysfunction can be used as an outcome prediction factor in some forms of synucleinopathies or premotor diagnostic markers that could be used in the future to define further research avenues. In this review, we describe the autonomic dysfunction of genetic synucleinopathies in comparison to the dysautonomia of sporadic forms of alpha‐synuclein accumulation and provide the reader with an up‐to‐date overview of the current understanding in this fast‐growing field. © 2018 International Parkinson and Movement Disorder Society