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KEY PAPERS

ABSTRACT

There is substantial interest in identifying bio-markers to detect early Parkinson disease (PD).

Cardiac noradrenergic denervation and attenuatedbaroreflex-cardiovagal function occur in de novo PD,but whether these abnormalities can precede PD hasbeen unknown. Here we report the case of a patientwho had profoundly decreased left ventricular myo-cardial 6-[18F]fluorodopamine-derived radioactivityand low baroreflex-cardiovagal gain, 4 years beforethe onset of symptoms and signs of PD. The resultslead us to hypothesize that cardiac noradrenergicdenervation and decreased baroreflex-cardiovagalfunction may occur early in the pathogenesis of PD.

In Parkinson disease (PD), by the time the move-ment disorder develops, most o the nigrostriataldopamine terminals have been lost. Identifcationo biomarkers o PD should improve early diagno-

sis and spur development o eective treatments.Braak has proposed a pathogenetic sequence begin-

ning outside the brain, with invasion o peripheral,vulnerable autonomic neurons, ollowed by alpha-synucleinopathy in lower brainstem nuclei and thenby alpha-synucleinopathy in the midbrain substantianigra and then fnally in the cerebral cortex.3,4 Consis-tent with early involvement o peripheral autonomicor lower brainstem centers, several studies o de novoPD have reported evidence o cardiac noradrenergicdenervation5,8,14,22 or o decreased baroreex-cardio-vagal unction.1,2,6,14,18

Whether these abnormalities can actually precede

symptomatic PD has been unknown. Here we reportthe case o a patient who had cardiac noradrenergicdenervation, detected by 6-[18F]uorodopamine posi-tron emission tomography, and decreased baroreex-cardiovagal gain, detected by abnormal beat-to-beatblood pressure and heart rate responses to the Valsalvamaneuver, 4 years beore the clinical onset o PD.

CASE REPORT

A 56-year-old man was reerred or possible pheochro-mocytoma, based on episodic hypertensive episodes andsymptoms suggesting excessive catecholamine eects.

He had no serious health problems until about 1998,when he began to experience malaise and exercise intol-erance and episodes o hypertension or hypotension,palpitations, and chest tightness. He also had a long

history o constipation and dyspepsia, a tendency tourinary retention, and complained o a sense o ullnessin the let neck. The patients career was in marketingand business development, until he quit work due to hissymptoms. His mother had died o PD. Cardiac cath-eterization showed normal coronary arteries. Gastro-intestinal endoscopy was unrevealing. Biochemical test-ing showed elevated plasma levels and urinary excretiono epinephrine. Thyroid unction was normal.

Because o the hypertensive paroxysms, pheo-chromocytoma was suspected. In April 2000, thepatient had a plasma epinephrine level about twicethe upper limit o normal and a plasma metanephrinelevel about 50% above normal. In July 2001, he wasevaluated at the National Institutes o Health (NIH).Normal ollow-up plasma metanephrine, and ailureo 6-[18F]uorodopamine PET to detect an adrenal orextra-adrenal ocus o radioactivity, excluded pheo-chromocytoma.17 At that time the concentrationo 6-[18F]uorodopamine-derived radioactivity wasound to be markedly decreased in the let ventricularmyocardium (Figure 1).

Autonomic unction testing included measure-

DAVID S. GOLDSTEIN, MD, PhDClinical Neurocardiology Section, National Institute

of Neurological Disorders and Stroke (NINDS),

National Institutes of Health (NIH), Bethesda, MD

Cardiac sympathetic denervation precedingmotor signs in Parkinson disease*

* This article is reprinted, with permission, from Clinical Autonomic Research(Goldstein DS, et al. Clin Auton Res 2007; 17:118121). The original publica-tion is available at www.springerlink.com.

No author conflicts of interest were reported in the original publication of this article.

doi:10.3949/ccjm.76.s2.10

YEHONATAN SHARABI, MDClinical Neurocardiology Section, NINDS,

NIH, Bethesda, MD

BARBARA I. KARP, MDClinical Neurosciences Program, NINDS,

NIH, Bethesda, MD

OLADI BENTHOClinical Neurocardiology Section,

NINDS, NIH, Bethesda, MD

AHMED SALEEM, MDClinical Neurocardiology Section, NINDS,

NIH, Bethesda, MD

KAREL PACAK, MD, PhDReproductive Biology and Medicine Branch,

National Institute of Child Health andDevelopment, NIH, Bethesda, MD

GRAEME EISENHOFER, PhDClinical Neurocardiology Section, NINDS,

NIH, Bethesda, MD

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CARDIAC SYMPATHETIC DENERVATION IN PARKINSON DISEASE

ments o beat-to-beat blood pressure and heart rateduring and ater perormance o the Valsalva maneu-ver. Blood pressure decreased early in Phase II andthen leveled o, and there was an overshoot in pres-sure during Phase IV (dashed line inFigure 2), whichare normal fndings. Baroreex-cardiovagal gain,calculated rom the slope o the relationship betweencardiac interbeat interval (with one beat delay) andsystolic blood pressure during Phase II o the maneu-ver, was decreased at 3.2 msec/mm Hg; baroreex-cardiovagal gain calculated rom the data in Phase IV

ater release o the maneuver was also decreased at 3.1msec/mm Hg).11,14,15

Over several months in 2005 the patient notedprogressive slowing o movement and inability torelax the arms, small handwriting, decreased acialexpression, and decreased voice volume. The patientreturned to the NIH in November 2005, to partici-pate in a protocol on pseudopheochromocytoma, theevaluation again including 6-[18F]uorodopaminepositron emission tomographic scanning and beat-to-beat blood pressure and heart rate associated with theValsalva maneuver. 6-[18F]uorodopamine PET againrevealed severely decreased 6-[18F]uorodopamine-

derived radioactivity throughout the let ventricularmyocardium (Figure 1). In the interventricular sep-tum, radioactivity at the midpoint o the scanningrame between 5 and 10 minutes ater initiation oinjection o 6-[18F]uorodopamine was 1,286 nCi-kg/cc-mCi, more than 2 standard deviations below thenormal mean and one o the lowest values we haverecorded so ar (Figure 3). Blood pressure decreasedprogressively in Phase II o the Valsalva maneuver,to a greater extent than in 2001, there was no over-

shoot o pressure ater release o the maneuver, andthe return o pressure toward baseline was prolonged,fndings pointing to ailure o sympathetically medi-ated reexive vasoconstriction.12,23 Baroreex-cardio-vagal gain was also lower than in 2001 (1.2 msec/mmHg rom the results in Phase II, 2.6 msec/mm Hg romthose in Phase IV), both because the range o heartwas smaller and the extent o change in systolic pres-sure larger in 2005 than in 2001.

As a test o the status o the adrenomedullary hor-monal system, blood was obtained via an indwelling

arm catheter during supine rest and ater bolus i.v.injection o 1 mg o glucagon and assayed or plasmacatecholamines in our laboratory. Both in July 2001and November 2005, the ratio o plasma epinephrine(in pg/mL) to norepinephrine (in pg/mL) was relativelyhigh during supine rest (76:99 and 101:234), and thepatient had large increases o plasma epinephrine lev-els in response to glucagon (peak values more than 250pg/mL, more than six times the normal peak value).

Neurological consultation in November 2005noted stooped posture and axial instability, cogwheelrigidity in all our extremities, paucity o spontaneousmovements, masked ace with inrequent blinking,

and monotone voice, but with normal speed o gaitand no resting tremor. The patient was diagnosedwith mild PD.

DISCUSSION

In this patient, results o 6-[18F]uorodopamine PETscanning indicated cardiac sympathetic denervation4 years beore the clinical onset o PD. Consideringthat in PD loss o cardiac noradrenergic innervationprogresses slowly over years,13 and that the patient

FIGURE 1. Thoracic 6-[18F]fluorodopamine (18FDA) and 13N-ammonia (13NH3) images in July 2001 and November 2005. Note absence of left ven-

tricular myocardial 6-[18F]fluorodopamine-derived radioactivity at both times, indicating cardiac sympathetic denervation. Myocardial perfusion,as indicated by 13NH

3-derived radioactivity, was normal.

July 2001 November 2005 November 2005

18FDA 18FDA 13NH3

LiverLiver

Liver

Heart Heart Heart

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GOLDSTEIN AND COLLEAGUES

already had evidence or markedly decreased cardiac

noradrenergic innervation at the time o initial evalu-ation, loss o cardiac sympathetic nerves probably pre-ceded the movement disorder by many more than the4 years between initial testing and the onset o PD.

The fndings in this case ft with previous reportso cardiac noradrenergic denervation in de novo PDand with the concept o a peripheral-to-central andcaudal-to-rostral pathogenetic sequence. Orimo andco-workers have noted loss o noradrenergic terminalinnervation o the myocardium beore loss o cellbodies in sympathetic ganglia in PD.16

Our patient also had evidence or decreasedbaroreex-cardiovagal unction 4 years beore the

movement disorder. The baroreex is a homeostaticarc, and abnormalities o aerent neurotransmission,central integration by brainstem centers, or vagaleerent pre-ganglionic or post-ganglionic fbers couldresult in the same clinical laboratory fnding o lowbaroreex-cardiovagal gain. In particular, the extentto which baroreex-cardiovagal ailure in PD reectsa brainstem lesion, as opposed to an aerent lesion orloss o parasympathetic cholinergic eerents, remainsunknown. The results in our patient are consistent

with the view that baroreex-cardiovagal unctionworsens over years beore the onset o PD.

Chronic constipation, which also preceded par-

kinsonism in our case, would be consistent with earlydysregulation o gastrointestinal autonomic unction.Accumulations o alpha-synuclein in enteric neuronsand in the dorsal motor nucleus o the vagus nerve,the central neural site o origin o parasympatheticinnervation o much o the gastrointestinal tract, hasbeen reported to be an early pathological fnding.3 Asnoted above, however, the occurrence o central neu-ral pathology would not exclude a concurrent aerentor eerent lesion, and studies have ound Lewy bodiesin the myenteric plexus o both the esophagus andcolon,9 as well as loss o enteric dopaminergic neu-rons in PD with chronic constipation.19

Evidence or abnormalities o the sympatheticnoradrenergic and parasympathetic cholinergic com-ponents o the autonomic nervous system in our patientoccurred without evidence or compromised adreno-medullary unction. On the contrary, the patient hadaugmented plasma epinephrine responses to glucagoninjection, both upon initial evaluation and at ollow-up. The patient thereore did not appear to have di-use loss o catecholaminergic cells. Although studieshave noted decreased adrenomedullary catecholamine

Normal PD no SNF PD + SNF0

5,000

10,000

15,000

Group

Radioactivity(nCi-kg/cc-mCi)

FIGURE 3. Individual values for septal myocardial 6-[18F]fluorodop-amine-derived radioactivity, in normal control subjects (white circles),patients with Parkinson disease without sympathetic neurocircula-tory failure (PD no SNF, green circles), patients with Parkinsondisease and sympathetic neurocirculatory failure (PD + SNF, bluecircles), and the case reported here (large green circle). Dashed lineshows the normal mean value and light green shaded area 2 stan-dard deviations from the normal mean. Note markedly decreased6-[18F]fluorodopamine-derived radioactivity in the current case.

FIGURE 2. Beat-to-beat heart rate and blood pressure responses tothe Valsalva maneuver (12-second duration, 30 mm Hg) in July 2001and November 2005. In the latter recording, note progressive declinein blood pressure during Phase II, smaller pressure overshoot, anddelayed return of pressure toward baseline in Phase IV, consistentwith worsening baroreflex-sympathoneural function. Heart rateresponses during and after the maneuver were also smaller in 2005than in 2001, despite larger changes in blood pressure, consistentwith worsening baroreflex-cardiovagal function.

Valsalva

I II IVIII

0

20

60

40

0

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40

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g)

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2001

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