In this study, DLB patients clearly had more severe cognitive decline compared with PD patients. Olfaction was more impaired in DLB than PD. Olfactory dysfunction has recognized in PD and has been associated with cognitive dysfunction in PD [20, 32]. De novo PD with mild cognitive decline shows olfactory impairment compared with patients without cognitive dysfunction [33]. This is consistent with DLB patients with impaired cognition having more severe olfactory dysfunction than that in PD patients. Our study has also found that DLB patients were commonly male in contrast with that PD patients were frequently female, and that patients with diffuse or limbic Lewy body pathologies tended to be found in male has been already reported [34].
MIBG uptake in scintigraphy indicating cardiac sympathetic denervation was lower in patients with DLB than in those with PD. BP fall on standing was significantly larger, NE at rest was lower, and the BP fall in PPH and SH were larger in DLB. Neurogenic SH differed significantly between PD and DLB cases, but not the prevalence of SH. The prevalence of constipation in DLB was higher than in PD, which suggests that intestinal autonomic dysfunction might be severer in DLB. Overall, our findings suggest that DLB involves wider spread severer sympathetic and parasympathetic autonomic dysfunction in peripheral and central nervous system compared with PD [14].
The nocturnal fall in BP in ABPM, which was found in healthy persons, was reduced more in DLB than PD. Abnormal daily BP fluctuation in PD [35, 36] has been associated with cardiovascular dysautonomia [36], but has rarely been reported in DLB. PD patients with this condition, including reduced or reverse nocturnal BP fall on ABPM, have also been found to have a higher prevalence of OH [35]. More profound impairment of the nocturnal fall in BP might be found in DLB with severe cardiovascular autonomic dysfunction. It was previously reported that cognitive function has been linked to abnormal BP fluctuation in PD [11, 13], including an abnormality in nocturnal BP fall in ABPM. The novel finding in our study is that nocturnal BP abnormality was associated with cognitive and executive dysfunction in early stage and de novo PD patients after adjustment for other dysautonomia of cardiovascular autonomic factors, including OH, PPH, SH and cardiac sympathetic impairment indicated by MIBG uptake insufficiency.
Del Pino [37] has already mentioned that cardiovascular autonomic dysfunction was associated with cognitive and neuropsychiatric impairment in Lewy body disease, using a number of tests to assess autonomic function such as hemodynamic parameters during deep breathing, the Valsalva maneuver, and head up tilt test. Several pathogeneses have been suggested for the association of cognitive dysfunction and BP abnormality, but the underlying mechanism is still unclear. The Braak hypothesis [38] suggests that Lewy body (LB) pathology initially occurs in the olfactory nucleus and dorsal motor nucleus and progressively ascends through the brain stem to the cortex, causing noradrenergic and dopaminergic neuronal degeneration that results in progression of motor, cognitive, and autonomic impairment. Cognitive decline in PD has been associated with specific patterns of LB density in the entorhinal cortex and anterior cingulate cortex [39], which plays a role in autonomic nervous system (ANS) control, including the higher centers of autonomic regulations [40]. 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 due to the LB pathology in PD [41]. Involvement of the noradrenergic neurons of the LC is increasingly recognized as a potential major contributor to cognitive manifestations in early PD, particularly for impaired attention [42]. The LC also projects to the parasympathetic neurons of the dorsal motor nucleus of the vagus (the nucleus ambiguous), while the descending pathway projects to sympathetic preganglionic neurons in the spinal cord [42] in autonomic nervous system. 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 [43]. Therefore, spoiling of the LC may cause abnormal daily BP fluctuation such as reduced nocturnal fall in BP, in addition to cardiac parasympathetic and 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 [44, 45]. Cognitive scores and WMH volumes on MRI are severely reduced in PD patients with both OH and SH, and lability of BP circulation may be related to cognitive function and WMH volume on MRI [11]. Our study revealed that abnormal BP fluctuation, and especially a reduced nocturnal fall in BP, was associated with cognitive and executive function in PD, after adjustment for other autonomic characteristics, including cardiovascular sympathetic function reflected by cardiac MIBG uptake, OH, PPH, circulatory NE concentration, 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, were correlated with SH and aging in our PD patients. This may indicate executive dysfunction occurred due to damage of prefrontal areas, which is readily attributable to cerebrovascular circulatory insufficiency of the cortex, white matter or age-related changes in the brain in PD [23].
In contrast to PD, we found that cognitive and executive impairments in DLB patients were not correlated with lability of BP and nocturnal BP. Dysautonomia in DLB seems to be severer than that in PD from our results and previous reports [14, 15]. It is uncertain whether PD and DLB including 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, 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 [38] suggests that α synucleinopathy initially involves the intestinal organ 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 occur due to white matter damage from BP dysregulation and noradrenergic decline of the LC [41]. Some papers suggested that cognition dysfunction should be associated with cardiovascular autonomic failure if LB pathology involves the ACC or insular cortex. Cognitive decline has already progressed due to involvement of LB pathology in brain cortex, so that cognitive impairment in DLB should not be strongly influenced by BP dysregulation. Alzheimer disease (AD) pathology with hyperphosphorylated tau and amyloid-β (Aβ) may also contribute to cognitive decline in DLB and PD. Aβ plaques are significantly more common in cortical and subcortical regions in DLB compared to PDD [46, 47], and DLB displays concurrent AD-related pathology compared to PDD [48]. Cardiovascular dysautonomia including reduced cardiac MIBG uptake and OH is not as impaired in AD compared to DLB [49]. Thus, AD pathology in DLB may be not correlated with ANS effects, and the increased AD pathology may induce dissociation between cognitive and BP dysregulation in DLB compared to PD.