Introduction

Cardiovascular autonomic failure is often found in older populations, and in the general population, the prevalence of orthostatic hypotension (OH) is estimated to be approximately 18% in those aged >65 years; however, only 2% of cases are symptomatic [1]. The prevalence of OH increases to as high as 50% among nursing home residents and 67.9% in acute geriatric wards [2, 3]. OH is associated with morbidity and mortality [4], as well as the incidence of coronary heart disease, heart failure, stroke, and all-cause death [5]. Neurogenic OH (NOH) is a consequence of inadequate release of norepinephrine from sympathetic vasomotor neurons, leading to vasoconstrictor failure followed by a variety of symptoms, including syncope and falls; it is frequently observed in neurodegenerative disorders such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) [6]. The clinical features of these disorders involve progressive motor dysfunction, such as tremor, rigidity, bradykinesia, gait disturbance, cerebellar ataxia, and cognitive decline [7,8,9]. The pathological features include abnormal intracellular aggregation of misfolded α-synuclein in neurons and glial cells, which are referred to as α-synucleinopathies [10, 11]. In addition to these progressive motor symptoms, cardiovascular autotomic failure, such as OH and alterations in blood pressure (BP), is frequently observed from the early stage of the disease course [12]. This type of cardiovascular autonomic failure is known to play a critical role not only in patient quality of life (QOL) but also in cognitive impairment. Furthermore, NOH is associated with supine hypertension (SH), a hemodynamically opposite form of BP dysregulation, and with loss of nocturnal BP fall, as detected by ambulatory blood pressure monitoring (ABPM). In this review, we introduce the characteristics of BP dysregulation in α-synucleinopathies and its association with cognitive impairment.

OH in α-synucleinopathies

NOH is defined as a drop in orthostatic systolic blood pressure (SBP) or diastolic blood pressure (DBP) of ≥20 and/or ≥10 mmHg, respectively, with absence of a heart rate (HR) increase. The ratio of HR to SBP changes at 3 min of tilt (ΔHR/ΔSBP) < 0.5 has also been proposed to discriminate NOH from non-NOH [13]. NOH is found in approximately 30% of cases of PD (range 9.6%–64.9%) [14], and its prevalence depends on age, levodopa dose, duration, and disease severity [15, 16]. A similar or higher prevalence of NOH (30–50%) is found in DLB [17, 18] and MSA (55–81%) [19, 20], but the diagnostic criteria for NOH in MSA are much stricter (orthostatic SBP and DBP drops of 30 or 15 mmHg, respectively). The mechanisms underlying OH differ between PD/DLB and MSA. In PD/DLB, both central and peripheral nerves are involved in NOH, and release of the neurotransmitter norepinephrine from sympathetic postganglionic neurons is impaired. In MSA, postganglionic sympathetic fibers are usually preserved, with degeneration of the central nervous system (CNS) being the main cause of NOH [21, 22]. OH typically manifests with a variety of symptoms, including syncope, falls, and orthostatic intolerance (e.g., lightheadedness, fatigue, blurred vision, neck and shoulder pain in the upright position). Even the transient form of OH, which resolves within 30 s, is associated with falls and syncope, as in the classical type of OH in PD [23]. The presence of early-onset autonomic dysfunction, including OH, is also associated with the risk of disease progression (hazard ratio: 0.86, 95% confidence interval [CI]: 0.83–0.89; P < 0.001) and a reduced survival rate (hazard ratio: 0.92, 95%CI: 0.88–0.96; P < 0.01) [24].

Supine hypertension (SH)

NOH in α-synucleinopathies is often associated with SH. SH is usually defined as SBP > 140–150 mmHg and DBP > 90 mmHg after over 5 min in the supine position [25]. The frequency of SH has been reported to be 21–46% in PD [26,27,28], and it is similar in MSA [19, 26]. Factors proposed to contribute to SH include baroreceptor impairment, disruption of the renin-angiotensin-aldosterone axis with paradoxical elevation of angiotensin II, low renin, and normal aldosterone levels, and denervation supersensitivity at the level of vascular adrenoreceptors due to impaired sympathetic transmission [25]. Although SH is usually asymptomatic, it often exacerbates NOH through nocturnal pressure natriuresis with frequent nocturia, sleep disruption, and overnight volume depletion [25]. The presence of SH is considered to increase the risk of end-organ damage (e.g., heart, kidney, brain) and cardiovascular disease, which is observed in essential hypertension. Indeed, SH is associated with left ventricular hypertrophy [29, 30] and impaired renal function [31] in patients with autonomic failure (e.g., MSA, PD, pure autonomic failure (PAF); peripheral autonomic neurodegenerative disease caused by α-synuclein deposition). Furthermore, coexisting NOH and SH is not only associated with renal impairment, left ventricular hypertrophy, and severity of white matter hyperintensity (WMH) on magnetic resonance imaging (MRI) but is also independently associated with an earlier incidence of cardiovascular events and death during longitudinal follow-up among patients with α-synucleinopathies [32].

Characteristics of ABPM in α-synucleinopathies

ABPM can measure 24-hour ambulatory BP, nocturnal BP fall, morning surge, and BP variability. It is also a useful tool for screening cardiovascular autonomic function. Abnormal ABPM values are frequently observed in α-synucleinopathies (Fig. 1). Schmidt et al [33]. compared the ABPM profiles of neurodegenerative disorders of α-synucleinopathies (MSA, PD) and tauopathies (progressive supranuclear palsy: PSP) with those of healthy controls and found no significant differences regarding mean BP or HR in the daytime among the groups. However, they did observe a significant increase in nighttime BP in patients with PD and MSA, and the reduced nocturnal blood pressure fall (NBPF) was significantly higher in those with PD (48%), MSA (68%), or PSP (40%) than in controls (8%). Among the subjects with reduced NBPF, significantly higher percentages of patients with PD (22%) and MSA (48%) showed the reverse-dipper (riser) pattern than patients with PSP (8%) and healthy controls (4%). Moreover, the frequent pathological BP increase at night correlated closely with OH in those with PD and MSA. Similarly, many studies have reported high proportions of patients showing nondipper (22–37%) and riser (6–56%) patterns in PD [27, 33,34,35,36,37,38] and of those showing nondipper (20–39%) and riser (38–57%) patterns in MSA [33,34,35,36], regardless of disease duration and severity. Reverse dipping and nocturnal hypertension are also associated with end-organ damage, such as left ventricular hypertrophy and dysfunction, in PD [39].

Fig. 1
figure 1

Daytime blood pressure fluctuation and reverse dipping (riser) in α-synucleinopathies. SBP systolic blood pressure, PD Parkinson’s disease, MSA multiple system atrophy

In addition to the classic head-up tilt test, ABPM is also useful for assessing OH [36, 40], and reverse-dipping exhibits higher diagnostic accuracy for NOH and SH to discriminate cardiovascular dysautonomia than bedside blood pressure ascertainment [38]. Furthermore, alterations in circadian BP rhythms are frequently observed in α-synucleinopathies [41], and BP variability, especially daytime SBP, which may reflect orthostatic changes in BP coupled with postprandial hypotension, is useful for detecting autonomic failure (Fig. 1) [42]. Therefore, recent studies have proposed utilizing these parameters from ABPM to diagnose autonomic failure in α-synucleinopathies [43, 44].

OH and cognitive impairment

Cognitive impairment is an important factor for a poor prognosis and caregiver burden in PD [45, 46]. The prevalence of dementia in PD is close to 30%, and the cumulative prevalence is at least 75% in patients with PD who survive for more than 10 years after the initial diagnosis [47]. The cumulative incidence of PD with mild cognitive impairment (PD-MCI) has been reported to be 9.9% and 28.9% after 1 and 5 years of follow-up, respectively, and early PD-MCI has prognostic value for predicting dementia [48].

In PD, the presence of OH has been shown to be able to predict cognitive decline and dementia based on longitudinal analysis [49, 50], and a recent meta-analysis of prospective cohort studies also found OH to be a significant predictor of cognitive impairment in PD (relative risk: 2.98, 95%CI: 1.41–6.28) [51]. Although dementia is considered a nonsupportive feature for the diagnosis of MSA, a previous study reported reduced Mini-Mental State Examination (MMSE) scores in 26% of patients with MSA [52]. Neuropsychological assessments have also recognized executive dysfunction as a prominent cognitive disturbance, affecting up to 49% of patients with MSA [52]. One longitudinal study found OH to be associated with worsening global cognitive status in patients with MSA [53].

OH is typically classified into NOH, with decreased orthostatic BP without a compensatory HR increase, and non-NOH, with an HR increase, subtypes. Interestingly, NOH is associated with a risk of dementia (hazard ratio: 7.3, 95%CI: 2.2–24.6), whereas no such association is seen in non-NOH (hazard ratio: 2.9, 95%CI: 0.8–10.9) compared with patients without OH in PD [54]. Cognitive assessment by MMSE and Montreal Cognitive Assessment (MoCA) has revealed significantly lower scores in NOH, but not in non-NOH, than in patients without OH in PD [54]. Therefore, not only OH but also the absence of an orthostatic HR may be an important predictor of cognitive impairment in PD (Fig. 2).

Fig. 2
figure 2

Rate of dementia with or without OH in Parkinson’s disease. Modified from Ref. [54]. OH orthostatic hypotension

Pathophysiological association between cardiovascular dysautonomia and cognitive impairment in α-synucleinopathies

Several possible mechanisms between OH and cognitive impairment have been postulated for PD and DLB. The severity of autonomic dysfunction has been shown to be associated with not only cognitive impairment but also more severe motor symptoms, depressive symptoms, psychiatric complications, and sleep disturbance [55]. Therefore, OH and cognitive impairment may reflect α-synuclein-mediated neurodegeneration in diffuse areas of both the central and peripheral nervous systems, as well as its severity in PD [56].

Another hypothesis is that repeated transient cerebral hypoperfusion by OH affects cognitive function (Fig. 3). Indeed, one study reported that regional cerebral hypoperfusion detected by single-photon emission computed tomography was significantly pronounced in the passive head-up tilt test in cases with cardiovascular vasodepressor syncope [57]. Upright posture has been reported to exacerbate cognitive function in patients with PD compared with controls, and PD with OH shows greater changes in posture-mediated cognitive deficits than PD without OH [58]. These findings indicate that cerebral hypoperfusion is an important pathology aggravating cognitive function and that OH itself is a possible therapeutic target for cognitive impairment in α-synucleinopathies.

Fig. 3
figure 3

Proposed pathological link between abnormal blood pressure profiles and dementia in Lewy body disorders. BBB blood brain barrier, BP blood pressure, CMBs cerebral microbleeds, WML white matter lesion

In PD pathology, α-synuclein is the main factor related to dementia. In an experimental model, a brief reduction in cerebral blood flow promoted aggregation of α-synuclein, which was associated with extensive neuronal cell death and large infarctions [59]. Transient focal cerebral ischemia increased aggregation of α-synuclein and induced loss of dopaminergic neurons in the substantia nigra over a long-term observation in mice overexpressing human α-synuclein with the familial A53T mutation, which does not naturally lead to PD neuropathology [60]. Furthermore, chronic brain hypoperfusion induced significant loss of dopaminergic neurons and striatal dopaminergic terminals [61]. These findings suggest that OH-induced recurrent episodic brain hypoperfusion may increase the risk of extensive aggregation of α-synuclein and promote neurodegeneration, resulting in cognitive impairment in PD and DLB (Fig. 3).

Coexistence of Alzheimer’s pathologies, such as amyloid-β and tau pathologies, is closely related to dementia in PD [62]. OH is associated with an increased risk of dementia in the general population and correlates with the conversion from cognitive impairment to dementia and Alzheimer’s disease [63, 64]. Neural-derived exosome levels of Aβ42, total tau, and phosphorylated tau are significantly elevated in cases with OH and correlate with a decrease in mean cerebral blood flow velocity from the supine to upright position [65]. In an experimental model, chronic hypoperfusion was found to accelerate Alzheimer’s pathology [66, 67]. Several human epidemiological studies have reported increasing evidence of a close relationship between atrial fibrillation (AF) and Alzheimer’s disease [68]. Chronic cerebral hypoperfusion from persistent AF is proposed to aggravate Alzheimer’s pathology, leading to dementia [68]. These reports suggest that OH may increase the risk of cognitive impairment through repeated cerebral hypoperfusion and result in progression of Alzheimer’s pathology in PD (Fig. 3).

Cerebrovascular pathology and cerebral atrophy

OH and SH are also associated with increases in cerebrovascular pathologies such as white matter lesions (WMLs) and cerebral microbleeds (CMBs) and may contribute to cognitive impairment in α-synucleinopathies (Fig. 3) [69,70,71,72]. Both OH and SH may synergistically contribute to small vessel disease [27, 73]. The presence of SH is associated with higher WMH in α-synucleinopathies with NOH, and nighttime SBP is independently associated with WMH volume [32]. Furthermore, the presence of both OH and SH is associated with a significantly higher number of CMBs compared with OH alone in PD [74]. Because the burden of WMH and CMBs is reported to increase the risk of cognitive impairment in PD, SH in addition to OH increases the cerebrovascular pathologies that may contribute to cognitive impairment in PD [71, 75].

Because of the pathophysiological impact of OH and SH on the CNS mentioned above, it would be of great interest to investigate the association between OH, SH, and cerebral atrophy. Despite few such links to date, a recent report showed that OH is associated with cerebral atrophy with prominent temporal region involvement in PD and DLB [76]. Further studies are warranted to clarify associations among OH, SH, changes in brain structures, and their contribution to cognitive impairment.

Reverse-dipping and cognitive impairment in PD

As few studies have investigated the association between abnormal 24-hour ABPM profiles and cognitive impairment, an association remains unclear. Early reports demonstrated that cognitive impairment is associated with OH, SH, and WML but not the non dipping pattern [27]. However, another study found that the reverse-dipper pattern was seen significantly more often in patients with PD than in those without OH and was significantly associated with lower MMSE and MoCA scores [77]. We previously reported the riser (reverse-dipping) pattern to be significantly more common in PD patients with dementia than in those without dementia (59.3% vs. 32.7%, respectively; P = 0.01), whereas the dipper pattern was found to be negatively associated with dementia (3.7% vs. 23.6%; P = 0.02) [37]. The riser pattern was also significantly associated with dementia (odds ratio [OR]: 11.6, 95%CI: 2.14–215.0; P < 0.01), and the same trend was observed after adjusting for associated factors except OH. Furthermore, when the risk of dementia was evaluated for each nocturnal ABPM pattern with or without OH, dementia was not related to the dipper or nondipper pattern in patients without OH (Fig. 4). The rate of dementia was higher with the riser pattern and coexisting OH than without OH (10.2% vs. 1.5%), and a coexisting riser pattern and OH was significantly associated with dementia compared with the riser pattern alone (OR: 7.82, 95%CI: 1.83–54.6; P < 0.01). These results indicate that the riser pattern may be an important factor in cognitive impairment in PD coexisting with OH (Fig. 4). Although the pathophysiological association between 24-hour ABPM profiles and cognitive impairment is unclear in α-synucleinopathies, there are several clues. Daytime BP variability and higher nocturnal SBP levels have been shown to be associated with cognitive impairment in the older population with hypertension [78, 79], and elevated SBP, especially sleep SBP, has been shown to be significantly associated with total brain atrophy and cognitive decline [80].

Fig. 4
figure 4

Rate of dementia for each nocturnal blood pressure profile with or without OH in Parkinson’s disease. Modified from Ref. [37]. OH orthostatic hypotension

Management of OH in α-synucleinopathies

As described above, abnormal circadian blood pressure regulation has the potential to damage the CNS, which would aggravate neurodegeneration in daily life in α-synucleinopathies (Fig. 5). Because the symptoms of OH are variable, not all patients are symptomatic; furthermore, pharmacological treatment often exacerbates SH, and the management of OH should be considered carefully for each patient. First, if the patient is taking medication that aggravates OH, such as diuretics, or vasodilation medication, dose reduction or cessation should be considered. Because dopaminergic drugs can also lower BP through both peripheral and central mechanisms [81], dopaminergic medications such as levodopa and dopamine receptor agonists should be properly adjusted if the motor symptoms are permissible.

Fig. 5
figure 5

Images of daily blood pressure dysregulation and potential damage to the central nervous system in α-synucleinopathies. BP blood pressure, OH orthostatic hypotension

Nonpharmacological measures, such as (i) avoiding environmental or behavioral stimuli that exacerbate symptoms, (ii) adequate hydration and salt intake, (iii) regular physical exercise, (iv) physical maneuvers to raise BP, and (v) use of compressive garments, are useful [82]. Furthermore, sleeping in the head-up position to reduce SH-related nocturnal diuresis may also be helpful [82].

Pharmacological treatment is recommended for patients with symptomatic OH. The purpose of pharmacotherapy is to not only restore normotension but to also ameliorate all symptoms. One study found that a mean standing BP < 75 mmHg was useful for deciding whether the benefits of initiating pharmacological treatment for OH outweigh the risk of exacerbating SH in PD [83]. American and European guidelines recommend several drugs for the treatment of OH [84]. Midodrine, a peripherally selective α-1-adrenergic agonist with a rapid effect and short duration, has led to improvements in standing SBP and symptoms related to NOH [85]. Because of the risk of aggravating SH, midodrine should not be taken within several hours before bedtime. Droxidopa, a synthetic amino acid metabolized by DOPA decarboxylase to yield norepinephrine, enhances the effects of peripheral vasoconstriction. Droxidopa significantly increases standing SBP and improves the symptoms of NOH [86]; it has also been reported to have potential beneficial effects on motor symptoms in PD [87]. Fludrocortisone, a synthetic steroid with mineralocorticoid activity, enhances renal sodium reabsorption, resulting in volume expansion [82]. In general, risks of hypokalemia and edema should be monitored as well as SH. Midodrine and fludrocortisone are recommended by both American and European guidelines, but there is no special recommendation of droxidopa in the European guidelines [84].

Management of SH and reverse dipping in α-synucleinopathies

No antihypertensive treatment has been approved for SH because of a lack of evidence of long-term efficacy and because such treatment may worsen OH. Nevertheless, a consensus panel recommends considering individualized treatment and balancing the negative consequences of SH if patients with SH and NOH show SBP 160–180 mmHg or DBP 90–100 mmHg [88]. They also recommend treating SH with short-acting antihypertensive agents in the evening if patients have SBP > 180 mmHg or DBP > 110 mmHg. The short-term efficacy of several pharmacological treatments, such as losartan (an angiotensin II receptor blocker), eplerenone (an aldosterone receptor antagonist), transdermal nitroglycerin, nifedipine (a calcium-channel blocker), and nebivolol (a selective β1-adorenoreceptor blocker), have been studied in small clinical trials [89]. Nonpharmacological measures, such as sleeping in the head-up tilt or semirecumbent position, which reduces nighttime pressure natriuresis and improves morning OH, eating small snacks at bedtime, which induces postprandial hypotension, and reducing water consumption in the evening, should also be considered [89].

There are scarce data evaluating treatment of elevated nocturnal BP in α-synucleinopathies. Similar mechanisms are considered between SH and increased nocturnal BP; however, as baseline BP levels are low in most patients with α-synucleinopathies, aggressive treatment targeting nocturnal BP may lower daytime BP and worsen NOH. Further studies are warranted to explore this issue.

Conclusion

Abnormal circadian BP regulation is frequently observed in α-synucleinopathies. These variations in BP are usually asymptomatic, but the condition has the potential to be related to QOL, cognitive impairment, and poor prognosis. Although further studies are warranted to investigate whether early management of these BP abnormalities is associated with reduction in cognitive impairment and with better outcomes, regular BP monitoring at home or in the office and 24-hour ambulatory monitoring are considered to be important in the daily care of α-synucleinopathies.