Numerous non-motor changes or symptoms due to autonomic dysfunction are frequent in patients with PD and have been reported by many investigators [4–6]. Among autonomic abnormalities, orthostatic hypotension or prandial hypotension is often observed in patients with PD, probably resulting from the progressive impairment of preganglionic and postganglionic sympathetic neurons [7, 8]. However, clear recordings of MSNA are often hard to obtain because of advanced autonomic impairment or numerous artifacts due to involuntary tremor. Thus, only a few studies have investigated whether MSNA is actually decreased or not in patients with PD [2, 9]. The characteristic features of MSNA in patients with PD showing mild autonomic symptoms and in age-matched healthy control were reported in 2003 by our colleagues [2].

A summary of their findings is as follows:

Recent microneurographic studies have confirmed that resting MSNA gradually increases with age in healthy subjects because of reduced sensitivity of the baroreceptors or reduction of parasympathetic tone with advancing age [10, 11]. In contrast, resting MSNA gradually decreases with age and also with the duration of disease in PD patients. Thus, older PD patients have lower MSNA than normal subjects, reflecting their generally longer duration of disease. The reason why the frequency of MSNA bursts in younger PD patients is similar to control values remains unclear, but it is speculated that the progression of autonomic impairment may be slower in younger patients than older patients. In the abovementioned study, none of the patients had severe manifestations of autonomic failure such as frequent syncope due to orthostatic hypotension. Symptomatic autonomic deficits would not occur as long as the MSNA response to tilting is preserved, even if resting MSNA is low. It is speculated that since peripheral nerves are impaired at the early stage and central nerves are impaired at the later stage in autonomic nerves of PD, MSNA could be elicited even because of preserved central pathway in baroreflex arc.

Many investigators have studied the association between PD and orthostatic intolerance or orthostatic hypotension. It was reported that 70 % of patients with PD exhibited a mild to severe orthostatic decline of blood pressure [5] and that all PD patients have the symptom of postural dizziness, with obvious postural hypotension being observed in 27 % of them [4]. Moreover, a significant decrease of the systolic blood pressure was observed in PD patients even before initiation of antiparkinsonian treatment [12]. Although a few investigators found no difference in the response of BP to head-up tilt between PD patients and healthy controls [13, 14], most recent studies have demonstrated that mild to severe orthostatic hypotension is frequent in PD, being related to both the disease duration and severity. The abovementioned MSNA findings are consistent with previous observations of sympathetic vasomotor impairment in PD, because this study confirmed that orthostatic intolerance or hypotension may reflect an age and duration-dependent reduction in sympathetic outflow to muscles and not a diminution in the vasoconstrictive response of peripheral arteries.

Measurement of myocardial ¹²³I-metaiodobenzylguanidine (MIBG) uptake is useful in the assessment of cardiac sympathetic nerve function in patients with neurodegenerative disorders and diabetes mellitus [15, 16]. Recent investigations have shown that patients with PD frequently have an obvious decrease of MIBG uptake, and a relationship between MIBG findings and clinical features or disease specificity has been reported [17, 18]. However, it has not been clear whether MIBG findings reflect organic or functional changes of cardiac sympathetic nerves. To resolve this issue, the relationship between abnormal cardiac MIBG uptake and quantitative MSNA data was analyzed in PD patients by our colleagues in 2005 [19].

The results they obtained were as follows:

There may be no significant relationship between MSNA and the H/M ratio or WR because some patients with reduced MSNA have a normal H/M ratio or WR. Since the sympathetic nervous system displays characteristic regional differentiation [20], it is possible that these correlations are not observed because MSNA regulating the sympathetic tone of vessels in the leg muscles is compared with MIBG uptake that reflects cardiac sympathetic function. Another possible explanation for the missing correlation is that MIBG uptake is already very low at an early stage of PD and therefore does not decrease much further over time. Therefore, recording the MSNA of peripheral nerves is considered to be more sensitive than cardiac MIBG scintigraphy for estimating progressive changes of autonomic function in PD patients. It is speculated that cardiac MIBG scintigraphy may reflect not only organic changes of postganglionic sympathetic neurons but also other factors contributing to the metabolism of noradrenaline or MIBG at sympathetic nerve endings.

In 1994, Takeuchi et al. reported that the response of MSNA to head-up tilt was weaker after administration of levodopa than before administration, while there were no significant differences of resting MSNA and the response of MSNA to head-up tilt between PD patients and healthy controls [9]. They concluded that these findings suggested the existence of potential impairment of the medullary vasomotor center in PD. In 2014, Sverrisdottir et al. reported on recording of MSNA during ON and OFF of deep brain stimulation to the midbrain and subthalamic nuclei. During stimulation, they noted a decreased burst frequency and decreased blood pressure, along with an unchanged burst amplitude and increased vasomotor baroreflex sensitivity [21]. However, cardiac MIBG scintigraphy findings and the relationship between MSNA and age or disease duration were not described in these reports.

ALS is a fatal neurodegenerative disorder that mainly causes motor symptoms due to progressive generalized muscular weakness and muscle atrophy because of gradual impairment of the cranial and spinal motor neurons. Formerly, autonomic symptoms such as neurogenic bladder and constipation were considered to be negative features. However, various abnormalities of autonomic function, especially related to the cardiovascular system, have been identified in ALS by physiological and pharmacological studies [22, 23]. To assess autonomic function, quantitative analysis of MSNA along with BP and HR at rest and during head-up tilt was performed in ALS patients, and the results were compared with those obtained in healthy subjects by our colleagues in 1993 [24].

The results that they reported were as follows:

MSNA was reported to be markedly elevated in younger ALS patients, while MSNA is similar in elderly ALS patients and age-matched controls, suggesting that the lack of a difference in older subjects may be related to the increase of MSNA that normally occurs with aging [10, 11]. The changes of MSNA in ALS patients were reported to be smaller than in controls when they are placed in the head-up tilt position. Because ALS patients do not show postural hypotension, the muted response may result from increased baseline MSNA. The reason why MSNA is elevated is that since nerve conduction studies such as F-wave amplitudes suggest a marked increase in discharge from anterior horn cells secondary to reinnervation, the pathogenic agents responsible for ALS easily affect motor neurons, while sympathetic neurons are comparatively resistant to the same agents but are very excitable.

Most previous investigations have found that BP and HR are slightly increased in patients with ALS [22, 23]. Nogues et al. reported resting sinus tachycardia in ambulant ALS patients with normal breathing [25]. In the abovementioned study, resting MSNA was found to be increased in ALS patients, despite the absence of known cardiovascular abnormalities or significant respiratory impairment. Although a decreased PaO₂ or increased PaCO₂ is known to elevate MSNA [26], respiratory impairment is unlikely to account for the increase of MSNA in ALS patients.

It could not be ruled out that the increase of MSNA in ALS patients was influenced by a reduction of daily activities, bulbar symptoms, or subclinical respiratory distress. Furthermore, it was not clear whether this increase was specific to patients with ALS. To further clarify the influence of muscle wasting and limitation of daily activities on sympathetic outflow to the muscles, MSNA was compared between patients with ALS and patients with a similar level of disability due to other neuromuscular disorders by our colleagues in 1995 [1].

The results they obtained were as follows: