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Autonomic disorders predicting Parkinson's disease
Parkinsonism and Related Disorders 20S1 (2014) S94–S98
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Autonomic disorders predicting Parkinson’s disease Jose-Alberto Palma, Horacio Kaufmann * Dysautonomia Center, Department of Neurology, New York University Medical Center, New York, USA
article info
summary
Keywords: Predictive biomarker Premotor phase Early detection Autonomic nervous system Chronotropic insufficiency Orthostatic hypotension Lewy body disease
It is now well recognized that there is a premotor phase of Parkinson’s disease (PD) with hyposmia and REM sleep behavior disorder caused by degeneration of specific CNS neurons. Most patients with PD describe autonomic symptoms at the time of diagnosis suggesting that these features may have potential sensitivity as clinical biomarkers of the premotor phase. The recognition that damage to peripheral autonomic neurons is present in the early stages of PD has led to a search for specific abnormalities in autonomic function that could serve as predictive biomarkers. There is evidence that constipation, urinary and sexual dysfunction and more recently decreased cardiac chronotropic response during exercise, are part of the premotor parkinsonian phenotype. The sensitivity and specificity of these features has yet to be accurately assessed. We briefly review the evidence for autonomic dysfunction as biomarker of premotor PD. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction Hallmark characteristics of Parkinson’s disease (PD) include motor signs and symptoms, such as resting tremor, rigidity, bradykinesia, and gait disturbance. In addition, PD patients frequently exhibit non-motor features, such as sleep disturbances, impaired sense of smell (hyposmia), visual changes, neuropsychiatric, and autonomic abnormalities. Among these non-motor features, autonomic abnormalities are now recognized as a cardinal feature of PD, with characteristic deficits in cardiovascular, gastrointestinal (GI), genitourinary, and thermoregulatory functions. Non-motor manifestations of PD are receiving increased attention, in part because they may be present at very early stages of the disease, sometimes years before the classic motor signs and symptoms become apparent [1]. Therefore, non-motor features may potentially predict the future development of PD years or even decades earlier than a motor-based diagnosis. Detecting this prodromal, premotor threshold by clinical examination, symptoms screening, or other tests is an important goal of research. The presence of rapid eye movement (REM) sleep behavior disorder (RBD), and olfactory dysfunction, are already recognized to markedly increase the future risk of developing PD. In this review we will focus on the autonomic abnormalities that may occur in the premotor phase of PD, as a result of involvement of the peripheral autonomic nervous system, with emphasis on their potential relevance as putative clinical predictors of the disease (Table 1). * Corresponding author. Prof. Horacio Kaufmann, Dysautonomia Center – New York University Medical Center, 530 First Avenue, Suite 9Q, New York 10016, USA. Tel.: +1 212 263 7225; fax: +1 212 263 7041. E-mail address: [email protected] (H. Kaufmann). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
Table 1 Clinical biomarkers of premotor Parkinson’s disease Central nervous system
Peripheral and enteric nervous systems
Olfactory loss
Cardiovascular dysfunction
REM sleep behavior disorder
Gastrointestinal disturbances, constipation
Depression and mood disorders
Urinary dysfunction Sexual impairment, erectile dysfunction
2. Pathophysiological basis of using autonomic dysfunction as predictor of PD Involvement of the dopaminergic nigrostriatal neurons underlies the motor deficits of PD. However, as shown by the staging system proposed by Braak and colleagues [2], the first stage of PD in the central nervous system (CNS) involves deposition of a-synuclein in the anterior olfactory nucleus and dorsal motor nucleus of the vagus. Peripheral autonomic ganglia may also be involved in this early Stage 1. Stage 2 is characterized by involvement of the medulla oblongata and the pons. Stage 3 affects midbrain (including the substantia nigra), and at Stages 4–6 cortical structures are affected. Additional studies suggest that peripheral postganglionic sympathetic denervation may occur even earlier [3,4], thus constituting the earliest stage of the disease, at least in certain patients [1,5]. The fact that incidental LB may be present in peripheral autonomic neurons before a diagnosis of PD is made [6] suggests that screening for specific autonomic abnormalities may detect the earliest stages of PD before it spreads to the CNS (Fig. 1). This raises the possibility that tests of peripheral autonomic function may be used as clinical predictive biomarkers for PD.
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cardiac MIBG, with normal plasma catecholamines, suggesting a cardiac-specific involvement in these patients. 3.2. Chronotropic insufficiency The clinical phenotype of cardiac sympathetic denervation in patients with PD has not been fully defined. It is likely to include chronotropic insufficiency, a finding that has been documented during treadmill exercise stress testing in patients with an established diagnosis of PD [12]. In a recent cohort study of 2,539 patients without a history of neurological disease who had undergone cardiac stress testing [13], 18 patients developed PD after a mean of 4 years. Retrospective analysis of the cohort revealed that patients who subsequently developed PD had a blunted heart rate response during stress testing (i.e., their maximum heart rate was significantly lower than expected for age and gender) when compared to those who did not develop motor symptoms. These findings suggest that chronotropic insufficiency may be an early sign of premotor PD, which might serve as potential biomarker.
Fig. 1. Distribution of incidental Lewy bodies in elderly subjects without clinical evidence of parkinsonism or dementia. Data are those reported by Bloch and colleagues [6]. Interestingly, the localization of Lewy bodies in this group was strikingly similar to those reported in PAF patients [7]. Information regarding nonmotor symptoms (orthostatic hypotension, erectile dysfunction or urinary problems) was not collected by Bloch et al.
3. Cardiovascular dysfunction Changes in cardiovascular physiology are virtually universal in PD, and they may precede the development of motor features and the diagnosis of PD. Post-mortem studies of patients with incidental Lewy body (LB) disease, i.e., patients with LB in the CNS but no clinical features of PD during life, which is thought to be a presymptomatic stage of PD, showed a-synucleincontaining neuronal inclusions (Lewy pathology) in epicardial nerve fascicles [8]. In addition, LB restricted to the heart and stellate ganglia have been reported in post-mortem studies of patients without LB in the CNS or in neuronal somata of the paravertebral sympathetic ganglia [9], supporting the notion that a-synuclein deposits in cardiac postganglionic sympathetic nerve can precede involvement of other structures. 3.1. Cardiac sympathetic neuroimaging The sympathetic innervation of the heart can be visualized in vivo using radiolabeled molecules that are substrates for the neuronal membrane norepinephrine transporter and for the vesicular monoamine transporter. 123 I-metaiodobenzylguanidine (MIBG) is widely available and combined with scintigraphy (single-photon emission computed tomography, SPECT) has been used in a large number of studies of patients with PD. 6-[18 F]fluorodopamine with positron emission tomography (PET) has also been used. 6-[18 F]fluorodopamine and MIBG uptake are consistently reduced in most PD patients, even at early stages, suggesting either functional abnormalities of the neuronal reuptake system or degeneration of cardiac sympathetic nerves. No large studies have specifically evaluated whether impaired cardiac MIBG uptake can identify premotor PD. A recent study of asymptomatic carriers of a point mutation resulting in glutamic acid substitution by lysine in position 46 (E46K) of the a-synuclein gene (SNCA) disclosed reduced cardiac MIBG uptake with normal plasma norepinephrine levels and normal BP values [10]. Previous reports showed that patients with SNCA gene duplication and triplication [11] develop cardiac denervation, as measured by
3.3. Orthostatic hypotension Orthostatic hypotension (OH) (i.e., fall in blood pressure of ≥20 mmHg systolic or 10 mmHg diastolic when moving from supine to standing) is present in up to 52% of PD patients [14]. OH in PD is likely a consequence of sympathetic denervation of the vasculature, as cardiac sympathetic denervation does not impair orthostatic tolerance. Normally, baroreflex-mediated sympathetic activation causing vasoconstriction maintains blood pressure in the standing posture. This compensatory vasoconstriction is absent or attenuated in patients with PD, resulting in OH. Interestingly, OH can occasionally precede the development of the disease. In a retrospective evaluation of the clinical data of 35 patients with PD and OH, 21 (60%) had documented early-onset OH (i.e., OH before, concurrent with, or starting within 1 year after the onset of motor symptoms). In 4 of these patients (i.e., 11% from the total of 35), OH had preceded the onset of parkinsonism [15]. However, a large prospective cohort study with a 14-year follow-up period involving more than 5,000 adults aged 65 years and older failed to show OH as a predictor of PD. Of 214 cases of incident PD that were identified during the follow-up period, OH was documented in 27 (18%) before the onset of motor symptoms while OH was documented in a similar percentage of patients who did not develop PD (970 patients, 17.9%) [16]. On the other hand, a recent study by Postuma and colleagues that prospectively assessed the autonomic symptoms in 91 patients with idiopathic RBD without parkinsonism or dementia showed that, after a mean follow-up period of 3.3 years, 32 developed a neurodegenerative disease [17]. 66% of patients with parkinsonism or dementia had OH at disease diagnosis compared with 0% of patients with “still idiopathic” RBD. The systolic blood pressure drop from lying to standing predicted the conversion to a defined neurodegenerative disorder with a sensitivity of around 60% up to 3 years before diagnosis. However, the severity of orthostatic symptoms, as measured by the Unified Multiple System Atrophy Rating Scale (UMSARS), was not a predictable biomarker. 3.4. Heart rate variability Heart rate variability (HRV) is also being explored as a potential tool to screen for individuals at risk for PD. Some HRV variables, namely the standard deviation of the R–R intervals (SDNN), the very-low frequency (VLF) and low frequency (LF) spectral components, and the LF/HF ratio, are consistently decreased in patients with PD [18]. In patients with RBD, many of whom will develop PD, HRV is also
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decreased [19], which raises the possibility that HRV may be decreased in the premotor phase of PD. Three prospective studies, however, have failed to prove that decreased HRV is an accurate predictor of PD. In the first study, a prospective cohort of patients with RBD without motor symptoms or dementia, decreased SDNN, VLF, LF or LF/HF ratio did not predict the development of a neurodegenerative disease [20]. Also, in two large cohort studies, a lower HRV (i.e., SDNN, LF or LF/HF ratio) was not associated with increased risk for incident PD, suggesting that reduced HRV may not predate the diagnosis of PD [16,18]. In these cohorts, however, the number of incident PD cases was probably too small to detect an association, and no non-linear HRV measures were used. Further research is needed to ascertain whether HRV measurements may have predictive value. 4. Gastrointestinal dysfunction Abnormally low GI motility is arguably the most common autonomic symptom in patients with PD, with constipation reported by 80% of PD patients [21]. Regurgitation, nausea, and epigastric discomfort, all symptoms of gastroparesis, are not infrequent in patients with PD. This is not surprising as autopsy findings in PD patients showed LB pathology in enteric neurons along the entire gastrointestinal tract, from the esophagus to the colon, particularly in neurons of Auerbach’s plexus in the lower esophagus, mostly in VIP-containing neurons [22]. Anecdotal reports suggest that gastroparesis may predate motor abnormalities in some patients with PD. Constipation, however, is now recognized as the most reliable autonomic disturbance in premotor PD. The strongest evidence that constipation can precede PD comes from the Honolulu Heart Program [23], a large population-based prospective study. This study found a 2.7-fold risk of PD among men with less than 1 bowel movement/day vs. men with 1 or more bowel movements/ day and a 4.1-fold risk of PD when compared with men with more than 2 bowel movements/day. The same investigators reported that patients with incidental LB, i.e., individuals found to have LB in postmortem neuropathology studies but who did not develop clinically evident PD during life, also had a high incidence of constipation. More recently, a large prospective study with a cohort of more than 100,000 people confirmed these results by showing that the multivariate-adjusted relative risk of developing PD in 6 years in subjects with one bowel movement every 3 days or less was 4.98 for men and 2.15 for women [24]. Supporting constipation as a premotor symptom in PD, recent evidence proves that a-synuclein pathology is already present in the colon of PD patients before they develop motor symptoms [25]. These studies strongly support the notion that constipation is an early, premotor sign of PD. Given that information on bowel movement frequency and constipation is easy to collect, it must be included as a screening tool for early PD identification. 5. Sexual dysfunction It is possible that dopaminergic mechanisms have a role in libido and arousal-related vasodilatation of penile erectile structures. Up to 79% of men with PD acknowledge sexual function impairment, namely erectile dysfunction, ejaculation problems, and difficulties achieving orgasm. The cause of erectile dysfunction in male PD patients is largely unknown, but may be related to dopamine deficiency. Similarly, up to 75% of women with PD report sexual problems including decreased libido and difficulties reaching orgasm. A retrospective analysis of a large cohort of men followed between the years 1986 and 2002, showed a 3.8-fold increase in the likelihood of developing PD among subjects with erectile dysfunction at baseline [26]. The risk was even higher for younger
men, which supports that erectile dysfunction is part of the constellation of premotor autonomic markers of PD. A recent prospective evaluation of subjects with idiopathic RBD seems to confirm this, as the sensitivity of erectile dysfunction to predict conversion to a neurodegenerative disorder in this group of patients was around 68% up to 5 years before the diagnosis [17]. 6. Urinary dysfunction Urinary symptoms have been described in the premotor phase of PD. Onuf’s nucleus, which is located in the ventral part of the anterior horn of the first three segments of the sacral spinal cord, plays a key role in urinary continence and the micturition reflex as it innervates the external urethral sphincter via the pudendal nerve. Degeneration of cells in this nucleus is one of the classical hallmarks of multiple system atrophy (MSA). This is in contrast to PD patients, in whom Onuf’s nucleus is usually spared. Urinary symptoms in patients with PD are attributed to loss of the D1 receptor-mediated tonic inhibition of the micturition reflex [27]. A recent case report of a patient with PD suggests that this assumption might not be completely accurate. This patient presented with symptoms of urinary dysfunction at the age of 52, developed parkinsonism two years later, and died at age 59. Autopsy confirmed the diagnosis of PD and showed a-synuclein aggregates in neurons of the Onuf’s nucleus as the presumed substrate of this presentation [28]. Supporting the notion that urinary symptoms may antedate motor abnormalities in patients with PD, a small cohort study showed that, from a sample of 100 oncologic patients aged 44 to 84 years without a clinical history of neurological disease who had undergone major abdominopelvic resection, 26% had a-synuclein aggregates in the vesicoprostatic plexus [4]. Subsequently, six patients with a-synuclein aggregates and 10 patients without aggregates underwent yearly double-blind neurologic assessments. At 16 months after the biopsy, none of these patients had developed PD, dementia or autonomic failure. Patients with aggregates, however, exhibited a longer blood pressure recovery time during phase IV of Valsalva maneuver, reduced cardiac MIBG uptake, and reduced brain dopamine transporter SPECT. At 30 months after the biopsy, the lower MIBG uptake and dopamine transporter values tended to correlate in a non-significant way with higher UPDRS-III scores. Although this study lacked a long-term follow-up and no incident cases of PD were identified, their findings suggest that a-synuclein aggregates in peripheral autonomic neurons may be an early event in the development of PD. 7. Is pure autonomic failure premotor PD? Pure autonomic failure (PAF) is a neurodegenerative disease that affects peripheral autonomic neurons with neuropathology almost identical to incidental LB disease, i.e., widespread synucleincontaing intraneuronal LB in sympathetic ganglia and distal sympathetic axons and a few in the substantia nigra and locus ceruleus [7]. Patients typically present with symptomatic orthostatic hypotension and syncope, reduced sweating, erectile dysfunction, and constipation; some patients have hyposmia and RBD as well. Whether PAF is a distinct entity or part of the premotor spectrum of other synucleinopathies, such as PD, is intriguing. After 15–20 years of documented follow-up, some patients with typical PAF develop parkinsonism or dementia [1]. An ongoing multicenter, natural history observational study by the Autonomic Disorder Consortium should provide further insight into this question. 8. Differentiating premotor PD from premotor MSA In up to 50% of patients with MSA severe autonomic abnormalities, most frequently OH and erectile dysfunction, precede the
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development of the movement disorder. This premotor, autonomic phase lasts on average 3 years followed by the insidious onset of parkinsonism, cerebellar ataxia or both. Only rarely this is the case in patients with PD, but when it occurs, premotor features of autonomic dysfunction are similar in PD to those preceding MSA. In contrast to PD, cardiac sympathetic innervation remains frequently intact in MSA, which can be ascertained by cardiac neuroimaging. Vocal cord palsy is frequent in patients with MSA and may lead to aspiration. Olfaction is usually preserved in MSA while it is frequently decreased early on, even in the premotor phase, in patients with PD.
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Acknowledgements HK receives research support from the National Institutes of Health (NIH) U54NS065736. The Autonomic Disorders Consortium (U54NS065736) is a part of the NIH Rare Diseases Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), and the NINDS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Conflict of interests
9. Future perspective and concluding remarks There is considerable evidence that autonomic dysfunction is an early feature of PD but no single autonomic abnormality predicts the disease with good reliability and sensitivity. With the exception of constipation, the identification of autonomic symptoms as predictive biomarkers of PD is still insufficiently developed. Other autonomic symptoms, such as swallowing dysfunction, sweating abnormalities, or pupillary dysfunction have not been systematically studied yet in the premotor phase, and may be areas for future research. Some important limitations must be noted when assessing autonomic symptoms as potential biomarkers of the premotor phase of PD. First, signs and symptoms of significant autonomic dysfunction are not always present in the early stages of PD and only appear later in the disease process, which may indicate a low sensitivity as early predictors. Also, the specificity of some autonomic symptoms is probably low: for example, in the elderly, the prevalence of constipation is around 30%, compared with a prevalence of PD of around 1–2%. Moreover, autonomic dysfunction frequently occurs in common conditions such as diabetes, or as a side effect of medications, and this can markedly reduce their specificity as predictive biomarkers. In studies of clinical predictive biomarkers, it may be best to design a score that includes some well-defined premotor symptoms (e.g., hyposmia, RBD, constipation), which can be applied to the general population. In those subjects with a high score, more specific tests (e.g., neurological examination and functional neuroimaging) could be applied. Such a methodology is currently being used in several, ongoing population-based studies to define subjects at-risk for PD. For example, the PREDICT-PD study [29] uses an internet-based survey with demographic questions and items related to early non-motor features and risk factors for PD (including constipation, erectile dysfunction, depression, RBD, and family history of PD). Participants also undergo a keyboardtapping task to quantify bradykinesia, and are mailed the UPSIT (University of Pennsylvania Smell Identification Test) to quantify olfactory dysfunction. Subjects are then classified as high-risk or low-risk individuals. The conversion of individuals in the higher-risk group to clinically established PD would offer strong evidence of the predictive value of this algorithm. Additional similar studies include the Honolulu-Asia Aging Study (HAAS) which evaluates constipation, daytime sleepiness, and olfaction; the Parkinson Associated Risk Study (PARS) which assesses olfaction, cognitive function, autonomic dysfunction, and DAT scan; and the T¨ ubingen evaluation of Risk factors for Early detection of NeuroDegeneration (TREND) study which evaluates RBD, depression, hyposmia, autonomic dysfunction, visual dysfunction, carotid ultrasound, and neuropsychological function [30]. Accurate recognition of predictive biomarkers of PD will allow the study of potential neuroprotective drugs at a stage when they may actually prevent the development of the motor features of PD.
The authors have no conflicts of interest to declare. References [1] Kaufmann H, Nahm K, Purohit D, Wolfe D. Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 2004;63:1093–5. [2] Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24:197–211. [3] Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K. Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 2007;113:421–9. [4] Minguez-Castellanos A, Chamorro CE, Escamilla-Sevilla F, Ortega-Moreno A, Rebollo AC, Gomez-Rio M, et al. Do alpha-synuclein aggregates in autonomic plexuses predate Lewy body disorders? A cohort study. Neurology 2007;68: 2012–8. [5] Orimo S, Takahashi A, Uchihara T, Mori F, Kakita A, Wakabayashi K, et al. Degeneration of cardiac sympathetic nerve begins in the early disease process of Parkinson’s disease. Brain Pathol 2007;17:24–30. [6] Bloch A, Probst A, Bissig H, Adams H, Tolnay M. Alpha-synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Appl Neurobiol 2006;32:284–95. [7] Hague K, Lento P, Morgello S, Caro S, Kaufmann H. The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature. Acta Neuropathol 1997;94:192–6. [8] Dickson DW, Fujishiro H, DelleDonne A, Menke J, Ahmed Z, Klos KJ, et al. Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease. Acta Neuropathol 2008;115:437–44. [9] Miki Y, Mori F, Wakabayashi K, Kuroda N, Orimo S. Incidental Lewy body disease restricted to the heart and stellate ganglia. Mov Disord 2009;24:2299–301. [10] Tijero B, Gomez-Esteban JC, Lezcano E, Fernandez-Gonzalez C, Somme J, Llorens V, et al. Cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K mutation in the alpha synuclein gene. Parkinsonism Relat Disord 2013;19:95–100. [11] Orimo S, Uchihara T, Nakamura A, Mori F, Ikeuchi T, Onodera O, et al. Cardiac sympathetic denervation in Parkinson’s disease linked to SNCA duplication. Acta Neuropathol 2008;116:575–7. [12] DiFrancisco-Donoghue J, Elokda A, Lamberg EM, Bono N, Werner WG. Norepinephrine and cardiovascular responses to maximal exercise in Parkinson’s disease on and off medication. Mov Disord 2009;24:1773–8. [13] Palma JA, Carmona-Abellan MM, Barriobero N, Trevino-Peinado C, GarciaLopez M, Fernandez-Jarne E, et al. Is cardiac function impaired in premotor Parkinson’s disease? A retrospective cohort study. Mov Disord 2013;28:591–6. [14] Low PA. Prevalence of orthostatic hypotension. Clin Auton Res 2008; 18(Suppl 1):8–13. [15] Goldstein DS. Orthostatic hypotension as an early finding in Parkinson’s disease. Clin Auton Res 2006;16:46–54. [16] Jain S, Ton TG, Perera S, Zheng Y, Stein PK, Thacker E, et al. Cardiovascular physiology in premotor Parkinson’s disease: A neuroepidemiologic study. Mov Disord 2012;27:988–95. [17] Postuma RB, Gagnon J-F, Pelletier A, Montplaisir J. Prodromal autonomic symptoms and signs in Parkinson’s disease and dementia with Lewy bodies. Mov Disord 2013;28:597–604. [18] Palma JA, Urrestarazu E, Alegre M, Pastor MA, Valencia M, Artieda J, et al. Cardiac autonomic impairment during sleep is linked with disease severity in Parkinson’s disease. Clin Neurophysiol 2013;124:1163–8. [19] Valappil RA, Black JE, Broderick MJ, Carrillo O, Frenette E, Sullivan SS, et al. Exploring the electrocardiogram as a potential tool to screen for premotor Parkinson’s disease. Mov Disord 2010;25:2296–303. [20] Postuma RB, Lanfranchi PA, Blais H, Gagnon JF, Montplaisir JY. Cardiac autonomic dysfunction in idiopathic REM sleep behavior disorder. Mov Disord 2010;25:2304–10.
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[21] Verbaan D, Marinus J, Visser M, van Rooden SM, Stiggelbout AM, van Hilten JJ. Patient-reported autonomic symptoms in Parkinson disease. Neurology 2007; 69:333–41. [22] Derkinderen P, Rouaud T, Lebouvier T, Bruley des Varannes S, Neunlist M, De Giorgio R. Parkinson disease: The enteric nervous system spills its guts. Neurology 2011;77:1761–7. [23] Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, et al. Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology 2001;57:456–62. [24] Gao X, Chen H, Schwarzschild MA, Ascherio A. A prospective study of bowel movement frequency and risk of Parkinson’s disease. Am J Epidemiol 2011;174: 546–51. [25] Shannon KM, Keshavarzian A, Dodiya HB, Jakate S, Kordower JH. Is alphasynuclein in the colon a biomarker for premotor Parkinson’s Disease? Evidence from 3 cases. Mov Disord 2012;27:716–9.
[26] Gao X, Chen H, Schwarzschild MA, Glasser DB, Logroscino G, Rimm EB, et al. Erectile function and risk of Parkinson’s disease. Am J Epidemiol 2007;166: 1446–50. [27] Winge K, Fowler CJ. Bladder dysfunction in Parkinsonism: mechanisms, prevalence, symptoms, and management. Mov Disord 2006;21:737–45. [28] O’Sullivan SS, Holton JL, Massey LA, Williams DR, Revesz T, Lees AJ. Parkinson’s disease with Onuf’s nucleus involvement mimicking multiple system atrophy. J Neurol Neurosurg Psychiatry 2008;79:232–4. [29] Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Knowles CH, Hardy J, et al. PREDICT-PD: Identifying risk of Parkinson’s disease in the community: methods and baseline results. J Neurol Neurosurg Psychiatry 2013 Aug 18 [Epub ahead of print]. [30] Berg D, Marek K, Ross GW, Poewe W. Defining at-risk populations for Parkinson’s disease: Lessons from ongoing studies. Mov Disord 2012;27: 656–65.
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Autonomic disorders predicting Parkinson’s disease Jose-Alberto Palma, Horacio Kaufmann * Dysautonomia Center, Department of Neurology, New York University Medical Center, New York, USA
article info
summary
Keywords: Predictive biomarker Premotor phase Early detection Autonomic nervous system Chronotropic insufficiency Orthostatic hypotension Lewy body disease
It is now well recognized that there is a premotor phase of Parkinson’s disease (PD) with hyposmia and REM sleep behavior disorder caused by degeneration of specific CNS neurons. Most patients with PD describe autonomic symptoms at the time of diagnosis suggesting that these features may have potential sensitivity as clinical biomarkers of the premotor phase. The recognition that damage to peripheral autonomic neurons is present in the early stages of PD has led to a search for specific abnormalities in autonomic function that could serve as predictive biomarkers. There is evidence that constipation, urinary and sexual dysfunction and more recently decreased cardiac chronotropic response during exercise, are part of the premotor parkinsonian phenotype. The sensitivity and specificity of these features has yet to be accurately assessed. We briefly review the evidence for autonomic dysfunction as biomarker of premotor PD. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction Hallmark characteristics of Parkinson’s disease (PD) include motor signs and symptoms, such as resting tremor, rigidity, bradykinesia, and gait disturbance. In addition, PD patients frequently exhibit non-motor features, such as sleep disturbances, impaired sense of smell (hyposmia), visual changes, neuropsychiatric, and autonomic abnormalities. Among these non-motor features, autonomic abnormalities are now recognized as a cardinal feature of PD, with characteristic deficits in cardiovascular, gastrointestinal (GI), genitourinary, and thermoregulatory functions. Non-motor manifestations of PD are receiving increased attention, in part because they may be present at very early stages of the disease, sometimes years before the classic motor signs and symptoms become apparent [1]. Therefore, non-motor features may potentially predict the future development of PD years or even decades earlier than a motor-based diagnosis. Detecting this prodromal, premotor threshold by clinical examination, symptoms screening, or other tests is an important goal of research. The presence of rapid eye movement (REM) sleep behavior disorder (RBD), and olfactory dysfunction, are already recognized to markedly increase the future risk of developing PD. In this review we will focus on the autonomic abnormalities that may occur in the premotor phase of PD, as a result of involvement of the peripheral autonomic nervous system, with emphasis on their potential relevance as putative clinical predictors of the disease (Table 1). * Corresponding author. Prof. Horacio Kaufmann, Dysautonomia Center – New York University Medical Center, 530 First Avenue, Suite 9Q, New York 10016, USA. Tel.: +1 212 263 7225; fax: +1 212 263 7041. E-mail address: [email protected] (H. Kaufmann). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
Table 1 Clinical biomarkers of premotor Parkinson’s disease Central nervous system
Peripheral and enteric nervous systems
Olfactory loss
Cardiovascular dysfunction
REM sleep behavior disorder
Gastrointestinal disturbances, constipation
Depression and mood disorders
Urinary dysfunction Sexual impairment, erectile dysfunction
2. Pathophysiological basis of using autonomic dysfunction as predictor of PD Involvement of the dopaminergic nigrostriatal neurons underlies the motor deficits of PD. However, as shown by the staging system proposed by Braak and colleagues [2], the first stage of PD in the central nervous system (CNS) involves deposition of a-synuclein in the anterior olfactory nucleus and dorsal motor nucleus of the vagus. Peripheral autonomic ganglia may also be involved in this early Stage 1. Stage 2 is characterized by involvement of the medulla oblongata and the pons. Stage 3 affects midbrain (including the substantia nigra), and at Stages 4–6 cortical structures are affected. Additional studies suggest that peripheral postganglionic sympathetic denervation may occur even earlier [3,4], thus constituting the earliest stage of the disease, at least in certain patients [1,5]. The fact that incidental LB may be present in peripheral autonomic neurons before a diagnosis of PD is made [6] suggests that screening for specific autonomic abnormalities may detect the earliest stages of PD before it spreads to the CNS (Fig. 1). This raises the possibility that tests of peripheral autonomic function may be used as clinical predictive biomarkers for PD.
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cardiac MIBG, with normal plasma catecholamines, suggesting a cardiac-specific involvement in these patients. 3.2. Chronotropic insufficiency The clinical phenotype of cardiac sympathetic denervation in patients with PD has not been fully defined. It is likely to include chronotropic insufficiency, a finding that has been documented during treadmill exercise stress testing in patients with an established diagnosis of PD [12]. In a recent cohort study of 2,539 patients without a history of neurological disease who had undergone cardiac stress testing [13], 18 patients developed PD after a mean of 4 years. Retrospective analysis of the cohort revealed that patients who subsequently developed PD had a blunted heart rate response during stress testing (i.e., their maximum heart rate was significantly lower than expected for age and gender) when compared to those who did not develop motor symptoms. These findings suggest that chronotropic insufficiency may be an early sign of premotor PD, which might serve as potential biomarker.
Fig. 1. Distribution of incidental Lewy bodies in elderly subjects without clinical evidence of parkinsonism or dementia. Data are those reported by Bloch and colleagues [6]. Interestingly, the localization of Lewy bodies in this group was strikingly similar to those reported in PAF patients [7]. Information regarding nonmotor symptoms (orthostatic hypotension, erectile dysfunction or urinary problems) was not collected by Bloch et al.
3. Cardiovascular dysfunction Changes in cardiovascular physiology are virtually universal in PD, and they may precede the development of motor features and the diagnosis of PD. Post-mortem studies of patients with incidental Lewy body (LB) disease, i.e., patients with LB in the CNS but no clinical features of PD during life, which is thought to be a presymptomatic stage of PD, showed a-synucleincontaining neuronal inclusions (Lewy pathology) in epicardial nerve fascicles [8]. In addition, LB restricted to the heart and stellate ganglia have been reported in post-mortem studies of patients without LB in the CNS or in neuronal somata of the paravertebral sympathetic ganglia [9], supporting the notion that a-synuclein deposits in cardiac postganglionic sympathetic nerve can precede involvement of other structures. 3.1. Cardiac sympathetic neuroimaging The sympathetic innervation of the heart can be visualized in vivo using radiolabeled molecules that are substrates for the neuronal membrane norepinephrine transporter and for the vesicular monoamine transporter. 123 I-metaiodobenzylguanidine (MIBG) is widely available and combined with scintigraphy (single-photon emission computed tomography, SPECT) has been used in a large number of studies of patients with PD. 6-[18 F]fluorodopamine with positron emission tomography (PET) has also been used. 6-[18 F]fluorodopamine and MIBG uptake are consistently reduced in most PD patients, even at early stages, suggesting either functional abnormalities of the neuronal reuptake system or degeneration of cardiac sympathetic nerves. No large studies have specifically evaluated whether impaired cardiac MIBG uptake can identify premotor PD. A recent study of asymptomatic carriers of a point mutation resulting in glutamic acid substitution by lysine in position 46 (E46K) of the a-synuclein gene (SNCA) disclosed reduced cardiac MIBG uptake with normal plasma norepinephrine levels and normal BP values [10]. Previous reports showed that patients with SNCA gene duplication and triplication [11] develop cardiac denervation, as measured by
3.3. Orthostatic hypotension Orthostatic hypotension (OH) (i.e., fall in blood pressure of ≥20 mmHg systolic or 10 mmHg diastolic when moving from supine to standing) is present in up to 52% of PD patients [14]. OH in PD is likely a consequence of sympathetic denervation of the vasculature, as cardiac sympathetic denervation does not impair orthostatic tolerance. Normally, baroreflex-mediated sympathetic activation causing vasoconstriction maintains blood pressure in the standing posture. This compensatory vasoconstriction is absent or attenuated in patients with PD, resulting in OH. Interestingly, OH can occasionally precede the development of the disease. In a retrospective evaluation of the clinical data of 35 patients with PD and OH, 21 (60%) had documented early-onset OH (i.e., OH before, concurrent with, or starting within 1 year after the onset of motor symptoms). In 4 of these patients (i.e., 11% from the total of 35), OH had preceded the onset of parkinsonism [15]. However, a large prospective cohort study with a 14-year follow-up period involving more than 5,000 adults aged 65 years and older failed to show OH as a predictor of PD. Of 214 cases of incident PD that were identified during the follow-up period, OH was documented in 27 (18%) before the onset of motor symptoms while OH was documented in a similar percentage of patients who did not develop PD (970 patients, 17.9%) [16]. On the other hand, a recent study by Postuma and colleagues that prospectively assessed the autonomic symptoms in 91 patients with idiopathic RBD without parkinsonism or dementia showed that, after a mean follow-up period of 3.3 years, 32 developed a neurodegenerative disease [17]. 66% of patients with parkinsonism or dementia had OH at disease diagnosis compared with 0% of patients with “still idiopathic” RBD. The systolic blood pressure drop from lying to standing predicted the conversion to a defined neurodegenerative disorder with a sensitivity of around 60% up to 3 years before diagnosis. However, the severity of orthostatic symptoms, as measured by the Unified Multiple System Atrophy Rating Scale (UMSARS), was not a predictable biomarker. 3.4. Heart rate variability Heart rate variability (HRV) is also being explored as a potential tool to screen for individuals at risk for PD. Some HRV variables, namely the standard deviation of the R–R intervals (SDNN), the very-low frequency (VLF) and low frequency (LF) spectral components, and the LF/HF ratio, are consistently decreased in patients with PD [18]. In patients with RBD, many of whom will develop PD, HRV is also
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decreased [19], which raises the possibility that HRV may be decreased in the premotor phase of PD. Three prospective studies, however, have failed to prove that decreased HRV is an accurate predictor of PD. In the first study, a prospective cohort of patients with RBD without motor symptoms or dementia, decreased SDNN, VLF, LF or LF/HF ratio did not predict the development of a neurodegenerative disease [20]. Also, in two large cohort studies, a lower HRV (i.e., SDNN, LF or LF/HF ratio) was not associated with increased risk for incident PD, suggesting that reduced HRV may not predate the diagnosis of PD [16,18]. In these cohorts, however, the number of incident PD cases was probably too small to detect an association, and no non-linear HRV measures were used. Further research is needed to ascertain whether HRV measurements may have predictive value. 4. Gastrointestinal dysfunction Abnormally low GI motility is arguably the most common autonomic symptom in patients with PD, with constipation reported by 80% of PD patients [21]. Regurgitation, nausea, and epigastric discomfort, all symptoms of gastroparesis, are not infrequent in patients with PD. This is not surprising as autopsy findings in PD patients showed LB pathology in enteric neurons along the entire gastrointestinal tract, from the esophagus to the colon, particularly in neurons of Auerbach’s plexus in the lower esophagus, mostly in VIP-containing neurons [22]. Anecdotal reports suggest that gastroparesis may predate motor abnormalities in some patients with PD. Constipation, however, is now recognized as the most reliable autonomic disturbance in premotor PD. The strongest evidence that constipation can precede PD comes from the Honolulu Heart Program [23], a large population-based prospective study. This study found a 2.7-fold risk of PD among men with less than 1 bowel movement/day vs. men with 1 or more bowel movements/ day and a 4.1-fold risk of PD when compared with men with more than 2 bowel movements/day. The same investigators reported that patients with incidental LB, i.e., individuals found to have LB in postmortem neuropathology studies but who did not develop clinically evident PD during life, also had a high incidence of constipation. More recently, a large prospective study with a cohort of more than 100,000 people confirmed these results by showing that the multivariate-adjusted relative risk of developing PD in 6 years in subjects with one bowel movement every 3 days or less was 4.98 for men and 2.15 for women [24]. Supporting constipation as a premotor symptom in PD, recent evidence proves that a-synuclein pathology is already present in the colon of PD patients before they develop motor symptoms [25]. These studies strongly support the notion that constipation is an early, premotor sign of PD. Given that information on bowel movement frequency and constipation is easy to collect, it must be included as a screening tool for early PD identification. 5. Sexual dysfunction It is possible that dopaminergic mechanisms have a role in libido and arousal-related vasodilatation of penile erectile structures. Up to 79% of men with PD acknowledge sexual function impairment, namely erectile dysfunction, ejaculation problems, and difficulties achieving orgasm. The cause of erectile dysfunction in male PD patients is largely unknown, but may be related to dopamine deficiency. Similarly, up to 75% of women with PD report sexual problems including decreased libido and difficulties reaching orgasm. A retrospective analysis of a large cohort of men followed between the years 1986 and 2002, showed a 3.8-fold increase in the likelihood of developing PD among subjects with erectile dysfunction at baseline [26]. The risk was even higher for younger
men, which supports that erectile dysfunction is part of the constellation of premotor autonomic markers of PD. A recent prospective evaluation of subjects with idiopathic RBD seems to confirm this, as the sensitivity of erectile dysfunction to predict conversion to a neurodegenerative disorder in this group of patients was around 68% up to 5 years before the diagnosis [17]. 6. Urinary dysfunction Urinary symptoms have been described in the premotor phase of PD. Onuf’s nucleus, which is located in the ventral part of the anterior horn of the first three segments of the sacral spinal cord, plays a key role in urinary continence and the micturition reflex as it innervates the external urethral sphincter via the pudendal nerve. Degeneration of cells in this nucleus is one of the classical hallmarks of multiple system atrophy (MSA). This is in contrast to PD patients, in whom Onuf’s nucleus is usually spared. Urinary symptoms in patients with PD are attributed to loss of the D1 receptor-mediated tonic inhibition of the micturition reflex [27]. A recent case report of a patient with PD suggests that this assumption might not be completely accurate. This patient presented with symptoms of urinary dysfunction at the age of 52, developed parkinsonism two years later, and died at age 59. Autopsy confirmed the diagnosis of PD and showed a-synuclein aggregates in neurons of the Onuf’s nucleus as the presumed substrate of this presentation [28]. Supporting the notion that urinary symptoms may antedate motor abnormalities in patients with PD, a small cohort study showed that, from a sample of 100 oncologic patients aged 44 to 84 years without a clinical history of neurological disease who had undergone major abdominopelvic resection, 26% had a-synuclein aggregates in the vesicoprostatic plexus [4]. Subsequently, six patients with a-synuclein aggregates and 10 patients without aggregates underwent yearly double-blind neurologic assessments. At 16 months after the biopsy, none of these patients had developed PD, dementia or autonomic failure. Patients with aggregates, however, exhibited a longer blood pressure recovery time during phase IV of Valsalva maneuver, reduced cardiac MIBG uptake, and reduced brain dopamine transporter SPECT. At 30 months after the biopsy, the lower MIBG uptake and dopamine transporter values tended to correlate in a non-significant way with higher UPDRS-III scores. Although this study lacked a long-term follow-up and no incident cases of PD were identified, their findings suggest that a-synuclein aggregates in peripheral autonomic neurons may be an early event in the development of PD. 7. Is pure autonomic failure premotor PD? Pure autonomic failure (PAF) is a neurodegenerative disease that affects peripheral autonomic neurons with neuropathology almost identical to incidental LB disease, i.e., widespread synucleincontaing intraneuronal LB in sympathetic ganglia and distal sympathetic axons and a few in the substantia nigra and locus ceruleus [7]. Patients typically present with symptomatic orthostatic hypotension and syncope, reduced sweating, erectile dysfunction, and constipation; some patients have hyposmia and RBD as well. Whether PAF is a distinct entity or part of the premotor spectrum of other synucleinopathies, such as PD, is intriguing. After 15–20 years of documented follow-up, some patients with typical PAF develop parkinsonism or dementia [1]. An ongoing multicenter, natural history observational study by the Autonomic Disorder Consortium should provide further insight into this question. 8. Differentiating premotor PD from premotor MSA In up to 50% of patients with MSA severe autonomic abnormalities, most frequently OH and erectile dysfunction, precede the
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development of the movement disorder. This premotor, autonomic phase lasts on average 3 years followed by the insidious onset of parkinsonism, cerebellar ataxia or both. Only rarely this is the case in patients with PD, but when it occurs, premotor features of autonomic dysfunction are similar in PD to those preceding MSA. In contrast to PD, cardiac sympathetic innervation remains frequently intact in MSA, which can be ascertained by cardiac neuroimaging. Vocal cord palsy is frequent in patients with MSA and may lead to aspiration. Olfaction is usually preserved in MSA while it is frequently decreased early on, even in the premotor phase, in patients with PD.
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Acknowledgements HK receives research support from the National Institutes of Health (NIH) U54NS065736. The Autonomic Disorders Consortium (U54NS065736) is a part of the NIH Rare Diseases Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), and the NINDS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Conflict of interests
9. Future perspective and concluding remarks There is considerable evidence that autonomic dysfunction is an early feature of PD but no single autonomic abnormality predicts the disease with good reliability and sensitivity. With the exception of constipation, the identification of autonomic symptoms as predictive biomarkers of PD is still insufficiently developed. Other autonomic symptoms, such as swallowing dysfunction, sweating abnormalities, or pupillary dysfunction have not been systematically studied yet in the premotor phase, and may be areas for future research. Some important limitations must be noted when assessing autonomic symptoms as potential biomarkers of the premotor phase of PD. First, signs and symptoms of significant autonomic dysfunction are not always present in the early stages of PD and only appear later in the disease process, which may indicate a low sensitivity as early predictors. Also, the specificity of some autonomic symptoms is probably low: for example, in the elderly, the prevalence of constipation is around 30%, compared with a prevalence of PD of around 1–2%. Moreover, autonomic dysfunction frequently occurs in common conditions such as diabetes, or as a side effect of medications, and this can markedly reduce their specificity as predictive biomarkers. In studies of clinical predictive biomarkers, it may be best to design a score that includes some well-defined premotor symptoms (e.g., hyposmia, RBD, constipation), which can be applied to the general population. In those subjects with a high score, more specific tests (e.g., neurological examination and functional neuroimaging) could be applied. Such a methodology is currently being used in several, ongoing population-based studies to define subjects at-risk for PD. For example, the PREDICT-PD study [29] uses an internet-based survey with demographic questions and items related to early non-motor features and risk factors for PD (including constipation, erectile dysfunction, depression, RBD, and family history of PD). Participants also undergo a keyboardtapping task to quantify bradykinesia, and are mailed the UPSIT (University of Pennsylvania Smell Identification Test) to quantify olfactory dysfunction. Subjects are then classified as high-risk or low-risk individuals. The conversion of individuals in the higher-risk group to clinically established PD would offer strong evidence of the predictive value of this algorithm. Additional similar studies include the Honolulu-Asia Aging Study (HAAS) which evaluates constipation, daytime sleepiness, and olfaction; the Parkinson Associated Risk Study (PARS) which assesses olfaction, cognitive function, autonomic dysfunction, and DAT scan; and the T¨ ubingen evaluation of Risk factors for Early detection of NeuroDegeneration (TREND) study which evaluates RBD, depression, hyposmia, autonomic dysfunction, visual dysfunction, carotid ultrasound, and neuropsychological function [30]. Accurate recognition of predictive biomarkers of PD will allow the study of potential neuroprotective drugs at a stage when they may actually prevent the development of the motor features of PD.
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