Timing of Orthostatic Hypotension, Not Symptom Severity, Increases Dementia Risk in Parkinson Disease, Multiple System Atrophy


The increased risk of dementia in patients showing early orthostatic hypotension was independent of the presence of concomitant supine hypertension and other factors associated with cognitive impairment.

Eduardo de Pablo-Fernandez, MD, clinical research association, UCL Institute of Neurology

Eduardo de Pablo-Fernandez, MD

Findings from a retrospective study published in Neurology showed an association between early development of orthostatic hypotension (OH)—but not severity of OH symptoms—and future dementia in Parkinson disease (PD) and cognitive impairment in multiple system atrophy (MSA). OH was not found to be associated with more extensive Lewy, amyloid-ß, tau, Alzheimer disease or cerebrovascular pathologies.

In a cohort of 132 patients with PD and 137 with MSA, presence of early OH resulted in an increased dementia risk in patients with PD by 14% per year (hazard ratio [HR], 0.86; 95% CI, 0.80-0.93) and cognitive impairment risk in patients with MSA by 41% per year (HR, 0.59; 95% CI, 0.42-0.83). Additionally, the presence of concomitant supine hypertension (SH) was associated with an increased risk of dementia in patients with PD in the univariate analysis although it did not remain significant after adjusting for other relevant factors in the multivariate analysis.

"Taking our results and evidence from previous clinical studies together, it is likely that repeated cerebral hypoperfusion events secondary to OH may induce non-specific hypoxia-related neurodegeneration contributing to cognitive impairment," senior investigator Eduardo de Pablo-Fernandez, MD, clinical research association, UCL Institute of Neurology, and colleagues concluded, "Further research is required to evaluate whether interventions aimed at improving circulatory abnormalities and brain hypoperfusion associated to OH are able to reduce dementia risk in PD and MSA."

The retrospective study included consecutive pathology-confirmed patients with brain donation to the Queen Square Brain Bank in London, United Kingdom, between 2009 and 2019 for patients with PD, and between 2002 and 2018 for patients with MSA. OH was defined by a documented decrease of more than 20 mmHg in systolic or more than 10 mmHg in diastolic blood pressure on standing or presence of orthostatic symptoms suggesting OH persistence over at least 6 months and after therapeutic measures to address non-neurogenic OH had been implemented based on the clinical impression of the treating physician.

Patients with MSA developed OH earlier in the disease course and with more severe symptoms than those with PD. The cumulative prevalence for dementia in patients with PD was 57.6% whilst only 10 patients with MSA out of 134 (7.3%) developed frank dementia (chi2 = 39.043; P <.001) with 10 more additional patients with MSA with mild cognitive impairment. Dementia tended to occur late in patients with PD and in earlier stages for patients with MSA.

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A distinctive clinical phenotype was found in patients with PD and early OH, with older age at diagnosis, postural-instability and gait-difficulty motor subtype, poorer response to levodopa and poorer cognitive performance at diagnosis. Once again, no association was found with severity of motor symptoms. In the MSA group, the development of OH was associated with older age. Although not statistically significant, investigators did observe a trend towards a posterior cortical pattern of cognitive impairment in PD cases with early OH.

Additional findings on univariate analysis showed that the severity of tau pathology and AD pathologies increased dementia risk in patients with PD; however, only the latter remained statistically significant in the multivariate analysis. The multivariate model also showed independently associated variables such as older age, poor cognitive performance at diagnosis, and poor response to levodopa, in addition to early OH, that were associated with dementia in PD.

"Our findings have important clinical implications and raise questions about the current management of OH in patients with PD and MSA,” Pablo-Fernandez et al wrote. "Current treatment recommendations are guided by symptom severity and aimed at reducing the symptomatic burden and improving functional capacity. Due to the chronicity of OH in patients with PD and MSA, cerebral blood flow regulatory mechanisms in these patients develop adaptive changes. Therefore, OH symptoms may not be an accurate indicator of cerebral hypoperfusion and some authors propose the incorporation of vasodynamic parameters (standing mean blood pressure) in therapeutic decision making."1

1. Barrio IR, Miki Y, Juanmuktane ZT, Warner T, Pablo-Fernandez ED. Association between orthostatic hypotension and dementia in patients with Parkinson disease and multiple system atrophy. Neurology. Published online December 16, 2022. doi:10.1212/WNL.000000000000201659
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