In this study, DLB patients clearly had more severe cognitive decline than did PD patients. Olfaction was more impaired in DLB patients, and olfactory dysfunction has been associated with cognitive dysfunction [20, 31]. De novo PD with mild cognitive decline is associated with more olfactory impairment than that found in patients without cognitive dysfunction . This is consistent with the fact that DLB patients with impaired cognition have more severe olfactory dysfunction than that found in PD patients.
MIBG uptake on scintigraphy, indicating cardiac sympathetic denervation, was lower in patients with DLB than in those with PD. Falls in BP on standing were significantly greater, NE at rest was lower, and the BP falls in PPH and SH were greater in patients with DLB. Neurogenic SH differed significantly between patients with PD and those with DLB, but was not related to the prevalence of SH. The prevalence of constipation in DLB was higher than that in PD, suggesting that intestinal autonomic dysfunction might be severer in DLB. Overall, our findings suggest that DLB involves wider spread and severer sympathetic and parasympathetic autonomic dysfunction than PD, which might be caused by peripheral and CNS impairments .
Abnormal daily BP fluctuations in PD [33, 34] have been associated with cardiovascular dysautonomia , but have rarely been reported in DLB. PD patients with this condition, including reduced or reverse nocturnal BP falls on ABPM, have also been found to have a higher prevalence of OH .
Thus, severe cardiovascular autonomic dysfunction in DLB might be linked to more profound impairment of the nocturnal fall in BP. Cognitive function has previously been linked to abnormal BP fluctuations in PD [11, 13], including an abnormality in the nocturnal BP fall on ABPM. A novel finding in our study was that nocturnal BP abnormality was associated with cognitive and executive dysfunction in early stage and de novo PD after adjusting for other cardiovascular dysautonomic factors, including OH, PPH, SH, and cardiac sympathetic impairment as indicated by MIBG uptake insufficiency.
Several pathogeneses have been suggested for the association of cognitive dysfunction with BP abnormality, but the underlying mechanisms remain unclear. The Braak hypothesis  suggests that Lewy body (LB) pathology initially occurs in the olfactory nucleus and dorsal motor nucleus and progressively ascends through the brainstem to the cortex, causing noradrenergic and dopaminergic neuronal degeneration, which results in progression of motor, cognitive, and autonomic impairment. Cognitive declines in PD have been associated with specific patterns of LB density in the entorhinal cortex and anterior cingulate cortex , which play a role in autonomic nervous system (ANS) control, including the higher centers of autonomic regulation . Involvement of the anterior cingulate cortex might simultaneously cause cognitive impairment and cardiovascular sympathetic failure.
Noradrenergic projection from the locus coeruleus (LC) spreads extensively in the whole brain cortex, including the hippocampus, entorhinal and mediotemporal cortex, cingulate gyrus, and neocortex. Tyrosine hydroxylase immunoreactivity is lost in neurons projecting from the LC owing to the LB pathology in PD . Involvement of the noradrenergic neurons in the LC is increasingly recognized as a potential major contributor to cognitive manifestations in early PD, particularly impaired attention . The LC projects to the parasympathetic neurons of the dorsal motor nucleus of the vagus nerves (the nucleus ambiguous), while the descending pathway projects to the sympathetic preganglionic neurons in the spinal cord . Therefore, the LC should influence cardiovascular modulation via insufficiency of cardiac parasympathetic and cardiovascular sympathetic function. The LC also regulates part of the wake-promoting circuit with the suprachiasmatic nucleus and dorsomedial hypothalamus . Therefore, spoiling of the LC may cause abnormal daily BP fluctuations in addition to cardiovascular sympathetic failure.
BP insufficiency such as OH, including circadian rhythm failure, is associated with increased white matter hyperintensities (WMHs) on MRI, even in older people [41, 42], and cognitive impairment and WMHs are associated with OH, SH and WMHs in PD. Cognitive impairment and WMHs are common in SH . Our study showed that abnormal BP fluctuation and especially a reduced nocturnal fall in BP were associated with cognitive and executive functions in PD, after adjusting for other autonomic characteristics, including cardiovascular sympathetic function as reflected by cardiac MIBG uptake, OH, PPH, circulatory NE concentrations, and constipation. This suggests that increased lability of daily BP and nocturnal BP is a risk factor for cognitive impairment, even in early de novo PD. Furthermore, FAB scores, but not MMSE scores, correlated with SH and aging in our PD patients. This may indicate that executive dysfunction is caused by prefrontal area damage, which is readily attributable to cerebrovascular circulatory insufficiency of the cortex white matter or age-related changes in the brain in PD .
In contrast to PD, we found that cognitive and executive impairments in patients with DLB did not correlate with lability of BP. Our results and those of previous studies suggest that dysautonomia in DLB is severer than that in PD [14, 15]. It remains uncertain whether PD and DLB including Parkinson’s disease with dementia (PDD) are separate disease entities or parts of the same disease spectrum. LB pathology in PD is restricted to the brainstem and limbic regions, while the pathology more quickly extends to the neocortex in DLB. LB pathology in PD is also not so widely distributed in autonomic nervous organs, as compared with that in DLB. The discrepancy between cardiovascular and cognitive dysfunction in DLB might suggest that regional invasion of LB pathology differs between the neocortex and sympathetic autonomic center. Braak’s hypothesis  suggests that α-synucleinopathy initially involves intestinal organs and ascends to the brainstem, including the dorsal motor nucleus of the vagus, LC, medullary reticular formation, raphe nuclei, and peripheral sympathetic nervous system. These organs are associated with modulation of cardiovascular autonomic regulation in early PD.
Cognitive dysfunction in PD might be caused by white matter damage resulting from BP dysregulation and noradrenergic decline of the LC . Cognition dysfunction should be associated with cardiovascular autonomic failure if LB pathology involves the ACC or insular cortex. Because cognitive decline has already progressed due to involvement of LB pathology in the brain cortex, cognitive impairment in DLB should not be strongly influenced by BP dysregulation. Alzheimer disease (AD) pathology associated with hyperphosphorylated tau and amyloid-β (Aβ) may also contribute to cognitive declines in DLB and PD. Aβ plaques are significantly more common in cortical and subcortical regions in DLB than in PDD [43, 44], and DLB displays concurrent AD-related pathology as compared with PDD . Cardiovascular dysautonomia including reduced cardiac MIBG uptake and OH is not as impaired in AD as compared with DLB . Thus, AD pathology may not correlate with ANS effects, and increased AD pathology may induce greater dissociation between cognitive and BP dysregulation in DLB than in PD.
In conclusion, BP dysregulation, especially a reduced nocturnal fall in BP, was associated with cognitive and executive decline in PD, and this may be driven by impaired microvascular circulation or infiltration of α-synuclein from the peripheral ANS to the CNS, such as the LC or ACC. The absence of a correlation between cognitive and BP dysregulation in DLB is due to earlier spread of LB pathology to the neocortex, while ascending LB invasion of the LC or ANS occurs in PD. The more severe AD pathology in the cortex in DLB as compared with that in PD might also contribute to dissociation of cognitive dysfunction and BP abnormality. Therefore, treatment for BP dysregulation may prevent progression of cognitive decline in PD, but not in DLB.