The mechanism underlying central contribution to OH in PD is unresolved. We hypothesized that LC is a strong candidate for a central substrate (23). To test this hypothesis, we derived LC volumes using NM-MRI and compared them between PD patients with and without OH; we subsequently assessed correlations between LC volume and OVS; correlations between LC volumes and cognitive testing (MoCA) was also explored to examine potential influence on cognition. Prior studies report cognitive decline occurs in PD-OH to greater degree than in those without OH, irrespective of OHSx (12,13,39); additionally a role for LC function has been proposed for occurrence of OHSx (40). We thus examined the relationship of OHSx with LC/SNc volume and OVS, with symptoms of depression, anxiety, and fatigue also included given similarity between these and atypical OHSx.
Our primary prediction, that LC volume would be reduced in the OH group, compared to the no-OH group, was confirmed; SNc volumes did not differ between groups. In line with our primary prediction, LC volumes were additionally correlated with OVS across subjects. We found a weaker correlation between LC volume and cognition. These findings provide further evidence that LC neurodegeneration is a substrate for autonomic dysfunction in PD. However, the weak LC-MoCA correlation suggests a need for more extensive testing in a larger cohort. Our main secondary prediction related to OHSx; namely that LC volume and OVS would be predictive of OHSx. This prediction was partly confirmed; while no relationship between structural measures (LC/SNc volume) and OHSx was found, OVS (namely DBP change, to a lesser extent SBP) were predictive of OHSx. However, compared to OVS, OHSx was better predicted by depressive and fatigue symptoms.
Neuropathologically, LC is affected very early in PD and to a greater extent than SNc (24,25), compromising the brain and spinal cord’s primary source of noradrenergic innervation. The LC has several ascending and descending outputs that generally inhibit central preganglionic parasympathetic nuclei and activate preganglionic sympathetic pathways to result in a net sympathetic increase: projections to the hypothalamic paraventricular nucleus promote behavioral arousal and suppression of the baroreflex; descending alpha2-receptor activation in the vagal dorsal motor nucleus and nucleus ambiguus reduces parasympathetic cardiovascular effects; LC also provides alpha1-mediated excitatory influence to spinal preganglionic sympathetic interomediolateral nuclei (60). One exception to the LC’s general role in increasing in sympathetic activation is its inhibitory (alpha2) effects on rostroventrolateral medulla (RVLM) (60), which is the main sympathetic nucleus in the baroreflex arc (61). Nevertheless, it is logical that LC pathology, by impairing its overall sympathetic cardiovascular effects, contributes to cardiovascular dysautonomia in PD.
Our findings complement recent neuroimaging studies suggesting central contributions to dysautonomia in PD via structural (20) and functional alterations of central autonomic regulators (19,21). Indeed, a prior study by Sommerauer and colleagues found reduced cerebral norepinephrine transporter availability (via 11C-MeNER PET) correlated with OVS changes in PD (21). Our results add to these findings, supporting the hypothesis that structural disruption of LC contributes to PD-OH; not only were LC volumes lower in OH patients, LC volumes also generally correlated with OVS across all PD subjects. Furthermore, our findings were specific to LC, as no such reduction was observed in the SNc for the OH group. One curious result was a negative correlation between LC volume and HR changes across all PD subjects; i.e, lower LC volume was associated with greater orthostatic HR increase, which could be inconsistent with role in neurogenic OH (6). However, this effect may relate to a ‘release’ of LC’s typical inhibitory effects on RVLM (60), which could then contribute to an orthostatic HR increase. Interestingly, OH groups differed with respect to supine HR (lower in the OH group) but not standing HR. It is thus possible that LC pathology in PD may primarily affect orthostatic pressor response, with the blunted orthostatic HR change typical of neurogenic OH perhaps resulting from an alternative autonomic lesion, such as post-ganglionic cardiac sympathetic denervation (62).
Of note, our findings do contrast somewhat with structural findings by Sommerauer and colleagues (21), whose NM-MRI LC measures did not correlate with OVS. These differences likely relate to study methodology. The prior NM-MRI study did not directly compare OH vs. no-OH, utilizing only correlational analyses. Their protocol also restricted analysis to the 10 highest intensity voxels after manual region of interest (ROI) placement; this approach is subject to impacts from noise and operator-dependent variability. In contrast, we utilized semi-automated ROI placement and volume measurement using methods with high scan-rescan reproducibility (63,64). Similarly, a brief pathological report found no relationship between LC pathology and charted presence vs. absence of OH (34), However, this study utilized a cohort with advanced disease duration (averaging more than a decade), and OH designation was based on chart diagnosis alone; both of these factors likely affected results.
The LC has a well-established role with respect to attention and learning/memory via modulation of cerebral blood flow, frontal attentional/cognitive control mechanisms, and effects on memory and related synaptic plasticity (29,30,33,57,65,66). Prior work examining LC-related effects on PD cognitive impairment is limited, but supportive of LC playing a role: LC-related neuronal loss occurs earlier and to a greater degree than Meyert’s nucleus in PD (25); pharmacologic increase in NE levels improve cognitive performance in PD (67); NM-MRI based LC structural integrity correlated with cognition in PD (38) and is lower in PD patients with mild cognitive impairment (MCI), in comparison to those without MCI and healthy controls (36). The correlation we observed between MoCA score and LC volume is consistent with these findings, but will require replication with more extensive cognitive testing and a larger cohort of patients with OH.
Establishing a role for the LC in the pathophysiology of OH, and potentially cognitive impairment, in PD has implications for treatment, as centrally acting, noradrenergic medications may benefit patients from both perspectives. Atomoxetine, a norepinephrine transport inhibitor, is one example of a centrally and peripherally acting noradrenergic agent that has been examined in PD for effects on OH and cognition, though separately; multiple studies have found atomoxetine safe and effective for OH treatment, with better performance than the peripherally acting standard of care, alpha1 agonist midodrine (68,69). Additionally, atomoxetine’s effects are greater in patients with central, rather than peripherally-based, autonomic failure (70). Atomoxetine has been experimentally used to improve measures of somnolence, impulsivity and frontal function, and global cognition in PD (67,71,72), and the response in this regard varies as a function of LC integrity (73). These cognitive effects have been posited to relate to greater noradrenergically mediated prefrontal top-down control and more effective coherence of cortico-coeruleal circuits particularly involving the subthalamic nucleus (74). Based on these observations in treatment trials of atomoxetine, our findings would suggest the need for further investigation of this or similar drugs as candidate treatments for OH and cognitive impairment in PD.
Accurate definition of OH is essential to establish mechanistic understanding of OH in PD. However, for unclear reasons, relatively few patients (~33%) with OH endorse typical OHSx (4,5). Interestingly, we observed a reciprocal pattern of typical OHSx in those with and without OH (Fig. 3A). The significant proportion of PD patients without OH that report putative OHSx, and vice versa, is clinically important; this is particularly the case given we found no relationship between LC volumes and OHSx (Fig. 3B), contrasting prior postulation on a role for the LC in this regard (40). Additionally, while OVS did significantly predict OHSx they did so less robustly than depressive and fatigue-related symptoms (Fig. 3B), which were not different in occurrence between OH groups (Table 1). Interpretation of these findings is challenging given a lack of mechanistic understanding of hypotension perception. However, results may relate to the frequent non-specificity of atypical OHSx, which can include several fatigue or depression scale symptoms (15). Our results may reflect some of this overlap, particularly given a significant number of no-OH patients endorsing OHSx. Our findings are additionally similar to those seen in orthostatic intolerance patients, in which OHSx correlates highly with those of depression and fatigue (75,76). It is possible that a more specific/in-depth questionnaire for OHSx would have led to findings more specific to OVS.
There are limitations to this study. First, though we have similar numbers of OH patients compared to prior work involving NM-MRI, our findings would be strengthened by greater numbers of OH patients. Future work would benefit from comparison of LC volumes in the PD population with those of healthy controls as well. Similarly, our cognition-related results may have been more robust with a wider range of cognitive performance or more in-depth testing. Patient OVS may have been influenced by measurement during the ON-medication state; comparison of OFF and ON-state measures would potentially provide assurance of PD-mediated OH. It is notable, though, that our OH group generally had lower LEDDs. We performed no formal autonomic testing to confirm neurogenic OH, using instead clinically relevant bedside measures. Nevertheless, it is notable that our OH group’s average orthostatic HR change, divided by SBP change (12bpm¸30mmHg), meets neurogenic OH criteria determined by Norcliffe-Kaufman and colleagues (77). We additionally included anti-hypertensive use in our models comparing groups. Measuring OVS by only one minute could have affected findings; however, one-minute measures are clinically relevant to OHSx and adverse OH events (78).