4.1. Cardiovascular autonomic system in PD
PD and ET are the most common movement disorders in the elderly. Both ET patients and the elderly can display subtle parkinsonian signs [54]. Furthermore, a recent study demonstrated that one in five patients with ET have a tremor at rest [55]. In patients with PD, postural tremors occur as frequently as tremors at rest, and may be the presenting symptom [56]. Accordingly, differentiating between ET and PD is often challenging [4,5]. To improve the early diagnosis of ET and PD, positron emission tomography (PET), cardiac MIBG scanning, and olfaction studies have been proposed [57,58].
However, simple markers are also needed to allow the accurate identification of PD during the early stages. Our results showed that almost all parameters of HRV were significantly lower in patients with PD compared to those with ET, whereas differences between the ET and control groups were not significant. This suggests that HRV may be helpful in differentiating PD from ET at the early stage of PD. Although PD and ET differ in their pathogenesis, their clinical features are similar.
Patients with TDPD usually respond poorly to levodopa treatment, and their prognosis is favorable.
In addition, some patients with definite signs of PD have normal 18F-dopamine PET scans, and those with isolated resting or action tremors have consistently abnormal striatal dopamine transporter (DAT) uptake [59]. As such, early TDPD is commonly misdiagnosed as ET, emphasizing the need for an additional simple diagnostic tool capable of distinguishing between the two conditions. The distinction is important in determining prognosis, treatment planning, and identifying eligible patients for clinical studies.
TP and SDNN represent overall cardiac autonomic dysfunction, and RMSSD represents parasympathetic function. While LF predominantly represents the sympathetic nervous system, the HF component is generally a marker of the vagal nervous system. In our study, most HRV parameters were significantly lower in the PD group compared to the ET and control groups. Among HRV components, overall cardiac autonomic dysfunction (TP, SDNN) and cardiac sympathetic dysfunction (LF) was more prominent than parasympathetic dysfunction (HF, RMSSD). Our findings suggest that cardiac sympathetic dysfunction is prominent, but cardiac parasympathetic dysfunction is also present in early PD. This is consistent with previous studies reporting prominent peripheral sympathetic denervation combined with significant central autonomic dysfunction in the brainstem including the
３７
dorsal vagal nucleus in PD. However, an understanding of the pathological role played by HRV is needed to validate its usefulness as an early non-invasive imaging marker in PD.
Dementia is one of the most disabling non-motor symptoms that occurs in PD. Our findings show that decreased cardiac MIBG uptake increases the risk for the development of dementia.
Several studies have indicated that cognition, olfaction, visual hallucination and RBD are associated with decreased cardiac MIBG uptake in PD [25-27]. By contrast, striatal dopamine depletion is not well correlated with non-motor symptoms [60,61] but rather is correlated with motor severity and predicts the motor progression [62]. This suggests that the cardiac MIBG uptake might provide information regarding the presence of an extranigral alpha-synuclein pathology. Our results are in agreement with those of a previous Japanese follow up study, which showed a significant difference in the motor progression and the occurrence of dementia between the two groups that were divided according to delayed H/M ratio [63].
The clinical significance of HRV on cognition remains unclear. Some cross-sectional studies found that HRV in patients with MCI was similar to that of healthy controls [64], but others showed that HRV was slightly impaired compared to controls when subjects were standing [65,66]. Our findings demonstrate that in early PD, visuospatial and frontal function are correlated with some HRV parameters. There are several explanations for these observed associations. First, low HRV as a reflection of autonomic dysfunction might directly underlie cognitive impairment by causing dysregulation of cerebral perfusion [67,68]. Furthermore, it is possible that low HRV might reflect established cerebral lesions and neurodegenerative processes present in the brain [69]. Secondly, that low HRV is associated with increased blood pressure variability, which is associated with cognitive decline and structural brain changes [70]. Executive function is mainly controlled by the prefrontal cortex of the brain. Reduced HRV is associated with hypoactivity of the prefrontal cortex, which is likely to affect executive function [71]. Furthermore, the frontal cortex is able to adjust HRV via subcortical structures such as the amygdala. This cortico-subcortical inhibitory circuit represents the structural connection between neuropsychological processes (such as cognitive function) and physiologic processes (such as HRV). Abnormalities in the cortico-subcortical circuit can be reflected in HRV. Future brain imaging studies could provide new insight into the biology of these associations [72].
３８
4.2. Vascular endothelial system in PD
Levodopa treatment is the gold standard therapy in PD patients. However, this therapy increases serum levels of homocysteine, due to its metabolism via catechol-O-methyltransferase [73]. Several reports have shown that hyperhomocysteinemia might be associated with increased prevalence of coronary artery disease, carotid intima media thickness, peripheral neuropathy, and cognitive impairment in patients with PD [74-77], although there have been conflicting results concerning the risk of stroke in PD [78].
It is generally accepted that endothelial dysfunction is part of the early pathogenesis of atherosclerosis [46]. Along with traditional vascular risk factors, hyperhomocysteinemia is known to decrease FMD [79]. In this study, FMD was significantly lower in the levodopa treatment group compared to those in the levodopa/entacapone treatment group and controls. In addition, homocysteine level was negatively correlated with FMD, and was an independent predictor of the lowest tertile, indicating that endothelial dysfunction as assessed by the FMD is associated with chronic levodopa treatment in PD patients.
In our prospective follow-up study in de novo PD, FMD decreased after 1 year of levodopa treatment.
However, there was no correlation between the changes in homocysteine levels and FMD. In addition, STN DBS surgery could decrease levodopa dosage by almost 50%, and improve motor and endothelial function but had no direct effect on cardiac autonomic function.
Decreased FMD has been found in patients with cerebrovascular risk factors [80] and has been shown to have prognostic significance in the development of cardiovascular events [81]. In addition to traditional vascular risk factors, hyperhomocysteinemia is known to decrease FMD [79]. However, it is unclear whether hyperhomocysteinemia is a direct cause of decreased FMD or a marker of atherosclerosis. Several studies demonstrated that acute changes in homocysteine by methionine loading can cause decreased FMD in healthy elderly patients [82]. In this regard, the results of the present study provide evidence of a possible association between FMD and homocysteine levels in patients with PD. In line with our findings, Yong et al. demonstrated that changes in homocysteine levels after treatment with levodopa affect cerebral hemodynamics, such as pulsatility index. This may reflect systemic vascular resistance and increased vascular stiffness associated with endothelial dysfunction [83]. Similarly, in patients with ischemic stroke, hyperhomocysteinemia was independently associated with an increased pulsatility index in the cerebral arteries [84]. In addition,
３９
several reports have demonstrated that homocysteine-lowering therapy (using folic acid or vitamin B) can improve endothelial dysfunction as assessed by FMD [85] and reduce progression of carotid intima media thickness (a marker of early atherosclerosis) in asymptomatic subjects with hyperhomocysteinemia [86]. However, our prospective study shows that changes in homocysteine levels after levodopa treatment or DBS surgery did not correlate with FMD changes. It is possible levodopa may generate more oxidative stress, which may affect endothelial function [87].
Several recent studies report evidence of vascular involvement in PD, supporting our findings. For example, CSF biomarkers of angiogenesis are increased in PD, and are associated with gait impairments, increased blood brain barrier permeability, white matter lesions and cerebral microbleeds, indicating that abnormal angiogenesis may be present in PD pathogenesis and contribute to dopa-resistant symptoms [88]. Other lines of evidence include a human pathological study of PD cases showing endothelial degeneration and preservation of basement membrane, leading to an increase in string vessel formation in PD. String vessels have no function in circulation, suggesting cerebral hypoperfusion may contribute to the neuronal degeneration characteristic of PD [45].