In Parkinson disease (PD), by the time the movement disorder develops, most of the nigrostriatal dopamine terminals have been lost. Identification of biomarkers of PD should improve early diagnosis and spur development of effective treatments.
Braak has proposed a pathogenetic sequence beginning outside the brain, with invasion of peripheral, vulnerable autonomic neurons, followed by alpha-synucleinopathy in lower brainstem nuclei and then by alpha-synucleinopathy in the midbrain substantia nigra and then finally in the cerebral cortex.3,4 Consistent with early involvement of peripheral autonomic or lower brainstem centers, several studies of de novo PD have reported evidence of cardiac noradrenergic denervation5,8,14,22 or of decreased baroreflex-cardiovagal function.1,2,6,14,18
Whether these abnormalities can actually precede symptomatic PD has been unknown. Here we report the case of a patient who had cardiac noradrenergic denervation, detected by 6-[18F]fluorodopamine positron emission tomography, and decreased baroreflex-cardiovagal gain, detected by abnormal beat-to-beat blood pressure and heart rate responses to the Valsalva maneuver, 4 years before the clinical onset of PD.
A 56-year-old man was referred for possible pheochromocytoma, based on episodic hypertensive episodes and symptoms suggesting excessive catecholamine effects.
He had no serious health problems until about 1998, when he began to experience malaise and exercise intolerance and episodes of hypertension or hypotension, palpitations, and chest tightness. He also had a long history of constipation and dyspepsia, a tendency to urinary retention, and complained of a sense of fullness in the left neck. The patient’s career was in marketing and business development, until he quit work due to his symptoms. His mother had died of PD. Cardiac catheterization showed normal coronary arteries. Gastrointestinal endoscopy was unrevealing. Biochemical testing showed elevated plasma levels and urinary excretion of epinephrine. Thyroid function was normal.
Over several months in 2005 the patient noted progressive slowing of movement and inability to relax the arms, small handwriting, decreased facial expression, and decreased voice volume. The patient returned to the NIH in November 2005, to participate in a protocol on pseudopheochromocytoma, the evaluation again including 6-[18F]fluorodopamine positron emission tomographic scanning and beat-to-beat blood pressure and heart rate associated with the Valsalva maneuver. 6-[18F]fluorodopamine PET again revealed severely decreased 6-[18F]fluorodopaminederived radioactivity throughout the left ventricular myocardium (Figure 1). In the interventricular septum, radioactivity at the midpoint of the scanning frame between 5 and 10 minutes after initiation of injection of 6-[18F]fluorodopamine was 1,286 nCi-kg/cc-mCi, more than 2 standard deviations below the normal mean and one of the lowest values we have recorded so far (Figure 3). Blood pressure decreased progressively in Phase II of the Valsalva maneuver, to a greater extent than in 2001, there was no overshoot of pressure after release of the maneuver, and the return of pressure toward baseline was prolonged, findings pointing to failure of sympathetically mediated reflexive vasoconstriction.12,23 Baroreflex-cardiovagal gain was also lower than in 2001 (1.2 msec/mm Hg from the results in Phase II, 2.6 msec/mm Hg from those in Phase IV), both because the range of heart was smaller and the extent of change in systolic pressure larger in 2005 than in 2001.
Neurological consultation in November 2005 noted stooped posture and axial instability, cogwheel rigidity in all four extremities, paucity of spontaneous movements, masked face with infrequent blinking, and monotone voice, but with normal speed of gait and no resting tremor. The patient was diagnosed with mild PD.