Cognition and transcranial sonography in Parkinson's disease patients with or without orthostatic hypotension

Abstract Background Orthostatic hypotension (OH) is a common nonmotor symptom in patients with Parkinson's disease (PD), with an incidence ranging from 14% to 54%. Aims This study explored changes in cognition and transcranial sonography (TCS) findings in patients with PD and OH. Methods We enrolled PD patients who visited the outpatient or inpatient department from 2017 to 2020. Blood pressure was measured in different positions, and demographic data were collected. Motor and nonmotor symptoms were evaluated using standard scales. A subset of 107 patients underwent TCS. Results We enrolled 66 PD‐OH patients and 92 PD‐no orthostatic hypotension (NOH) patients. There were no significant differences in gender, age, disease duration, or Hoehn and Yahr stage between groups. Binary logistic regression revealed age as an independent risk factor for OH in PD patients. There were statistically significant group differences in visuospatial and executive function and Unified Parkinson's Disease Rating Scale (UPDRS) I and II scores (p < .05). Among PD‐OH patients, there was a statistically significant difference in UPDRS II and III scores between patients with or without clinical symptoms (p < .05). The substantia nigra (SN) area was significantly larger in PD‐NOH patients (0.45 ± 0.18 cm2) than PD‐OH patients (0.34 ± 0.16 cm2) (p < .05). Conclusions PD‐OH patients had poorer visuospatial and executive function and lower UPDRS I and II scores compared with PD‐NOH patients. Within the PD‐OH group, there was no significant difference in cognition between patients with or without clinical symptoms. The difference in the SN area may indicate different subtypes of PD or a tendency to develop parkinsonism syndrome.


INTRODUCTION
Orthostatic hypotension (OH) is a nonmotor symptom in Parkinson's disease (PD) that is more common in advanced stages of the disease.
OH reflects autonomic nervous system dysfunction, and the prevalence in PD is about 53% (Zhang et al., 2019). This condition is associated with many other nonmotor symptoms such as lightheadedness and fatigue (Xin et al., 2016). Lewy bodies are a pathologic biomarker of PD, and alpha-synuclein is an important component of these proteinaceous aggregates. Alpha-synuclein is deposited in both the central nervous system and peripheral autonomic nervous system. Central and peripheral baroreflex mechanisms are damaged in PD-OH patients (Freeman et al., 2018;Goldstein et al., 2005). Levodopa, dopamine receptor agonists, and other PD treatments may cause or aggravate OH (Kujawa et al., 2000). This nonmotor symptom is burdensome to PD patients and their family because it can cause repeated falls, and current interventions are inadequate. According to a population-based, prospective, longitudinal cohort study, only 0.5% of PD patients use antihypertensive drugs (Hiorth et al., 2019). There is an urgent need for research focused on the incidence, clinical features, and interventions for OH in PD patients.
Cognitive dysfunction is another common nonmotor symptom in PD. A systematic review reported that the point prevalence of dementia in PD was 24%-31% (Aarsland et al., 2005). Executive, attentional, and visuospatial dysfunction and memory impairment are common in patients with PD dementia (Aarsland et al., 2017). Long disease duration and atypical neurological features such as early autonomic failure are risk factors for cognitive dysfunction in PD (Hanagasi et al., 2017).
OH is also associated with cognitive impairment (McDonald et al., 2016). A previous study reported that patients with PD-OH exhibit transient deficits in executive function, memory, and visuospatial function in an upright position, but performance improves in the supine position (Zhang et al., 2019). Dementia in PD decreases the quality of life of both patients and their caregivers and increases healthcarerelated costs (Svenningsson et al., 2012). Investigating OH may help clarify the mechanisms underlying PD dementia and identify novel targets to improve cognition in PD patients.
Transcranial sonography (TCS) is a noninvasive method for PD diagnosis. Patients with PD show significant lager substantia nigra (SN) area in TCS compared to normal controls (Tao et al., 2019). An echogenic area between 0.20 and 0.25 cm 2 occurs in the SN of 90% of PD patients (Berg et al., 2013). This may be associated with abnormal deposition of iron-containing protein. OH is directly associated with atrophy of subcortical structures, particularly the caudate. The striatum is also affected by blood pressure (BP) variabilities (Yoo et al., 2020). Study show that in healthy individuals, hyper echogenicity SN has been associated with slight deficits in specific cognitive functions (Yilmaz et al., 2016). We would like to explore the difference of TCS image between patients with and without OH.
In our study, we explored the clinical characters, motor symptoms, and nonsymptoms in PD patients with or without OH. Furthermore, we evaluated TCS image characteristics to find the probable mechanisms of OH.

Participants
A total of 158 PD patients treated at the Second Affiliated Hospital of Soochow University from 2017 to 2020 were included in the study. All patients were diagnosed with PD according to the diagnostic criteria of the UK Parkinson's Disease Society Brain Bank by at least two neurologists (Hughes et al., 1992). Of these, 107 patients underwent TCS.
We excluded PD patients who were taking the other chronic medications. This study was approved by the ethics committee of the Second Affiliated Hospital of Soochow University.

Study design
This was a cross-sectional study. We used a corrected electronic sphyg- TCS was performed as previously described (Sheng et al., 2017 Abbreviations: B, unstandardized beta reported from regression analysis; CI, confidence interval; OR, odds ratio; SE, standard error. *p < .05 was considered statistically significant.
was no correlation between the extent of BP difference and cognitive function.
There were no differences in age, gender, duration, or H-Y stage between subjects with asymptomatic and symptomatic OH (p > .05).
However, patients with symptomatic OH tended to have higher lower SDP, OSP, ODP, and MBP measurements. Symptomatic OH was also associated with higher scores for UPDRS II (p = .003) and UPDRS III (p = .016). The groups did not differ in the other assessments of motor and nonmotor symptoms (Table 3).
Only 73 (33 PD-OH, 40 PD-NOH) patients completed TCS. Those who could not schedule the examination or had poor temporal windows were excluded. The side with larger SN area and the lower velocity middle cerebral artery were used for comparisons between groups. The level of SN was adjusted as previously described (Sheng et al., 2017).
The larger area of these patients belonged to the third level. The area of SN was both ≥0.20 cm 2 , which is a cut-off value to detect PD. We found that PD-NOH had a larger mean SN area (p = .009). There were no significant differences in middle cerebral velocity or resistance or third ventricle width (Table 4).

DISCUSSION
Our results showed that older age was associated with an increased prevalence of OH, which is consistent with previous studies (Palma et al., 2015;Szewczyk-Krolikowski et al., 2014 ). There were no significant differences in gender, severity, or duration between the PD-OH and PD-NOH groups, although others have reported that disease duration is associated with OH in this population (Pilleri et al., 2013).

PD-OH patients tend have lower scores in activities of daily living
(ADL) than those with PD-NOH (Mol et al., 2018). In PD-OH patients, those with symptomatic OH tend to have lower ADL scores compared to those with asymptomatic OH group. This may be because symptomatic OH can cause dizziness and fainting (Kotagal et al., 2016).
There was no difference in cognitive function between the symptomatic and asymptomatic PD-OH groups.
We found that executive and visuospatial functions were statistically impaired in PD-OH with OH compared with PD-NOH. A previous study found that subjects with PD-OH had impairments of specific functions, namely attention, visuospatial working memory, and verbal memory (Pilleri et al., 2013). This result partially overlaps with our con-clusion. Another study found that executive function was reduced in the upright position (Sforza et al., 2018), which is consistent with our results.
The reasons underlying cognitive decline in PD-OH patients is currently unclear. One hypothesis is that central and peripheral noradrenergic dysfunction may lead to cognitive deficits. Hypothalamus damage has been reported in PD patients (Langston & Forno, 1978). This structure is the integration center of the autonomic nervous system and is under the influence of the limbic system (Blessing, 1997). This may explain why executive functions were impaired in PD-OH patients.
Hemodynamics may play an important role in contributing to cognitive dysfunction. One study showed that hyperperfusion and hypotension may cause ischemic damage to subcortical structures (McDonald et al., 2016). Another group reported that cognitive impairment is associated with more white matter hyperintensities on magnetic resonance imaging (Kim et al., 2012). This is consistent with our findings; PD-OH patients had higher SSP and lower OSP and ODP, and ischemic damage may affect executive function.
SN hyperechogenicity ≥0.20 cm 2 is considered as a cut-off point to detect PD (Chitsaz et al., 2013), but we found higher values in both groups in our study (PD-OH: 0.34 cm 2 , PD-NOH: 0.45 cm 2 ). PD-OH patients showed smaller SN hyperechogenic areas. It may indicate that different clinical subtypes of PD are associated with different SN patterns (Walter, Dressler, et al., 2007). Patients with postural instability and gait difficulty have larger SN hyperechogenicity areas on TCS (Sheng et al., 2017), so it is possible that PD patients with OH have smaller SN hyperechogenicity areas. TCS can also be used to diagnose parkinsonism. It is reported that the frequency of SN hyperechogenicity in nontremor dominant PD patients was significantly higher than in patients with multiple system atrophy (MSA) with predominant parkinsonism (Zhou et al., 2018). PD-OH may be more likely to convert to MSA. The early presence of OH is a Movement Disorder Society clinical diagnostic criterion for PD (Postuma et al., 2015). Measuring the SN area may help us distinguish parkinsonism syndrome (PDS) from PD. However, it is not clear why the SN becomes hyperechogenic. Two studies reported that increased cellular iron and neuromelanin contents and microglia are associated with SN hyperechogenecity (Berg et al., 2010;Tribl et al., 2009 ). This may suggest different mechanisms underlying PD and PDS.
Our results should be considered in the context of its limitations.
First, this was a cross-sectional study, so when OH develops in patients with PD is not clear. Since we did not follow up for patient outcomes, TA B L E 3 Basic statistics and motor and non-motor symptoms evaluation of symptomatic orthostatic hypotension (OH) and asymptomatic OH Level of the substantia nigra 3.00 ± 0.00 3.00 ± 0.00 -Area of the substantia nigra (cm 2 ) 0.34 ± 0.16 0.45 ± 0.18 .009* Values are reported as the mean ± standard deviation (SD). *p < .05 was considered statistically significant. the long-term evolution of OH in PD remains unknown. Second, we