Peripheral Levels of Renin-Angiotensin System Components Are Associated With Cognitive Performance in Huntington’s Disease

Abstract

The renin-angiotensin system (RAS) has proven to be involved in the pathophysiology of neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), serving as a potential therapeutic target and a disease burden marker. Studies have associated negative clinical outcomes with the activation of the classical RAS arm composed of the angiotensin-converting enzyme (ACE) and angiotensin (Ang) II, while suggested positive outcomes with the activation of the counter-regulatory RAS arm involving ACE2 and Ang-(1–7). Huntington’s disease (HD) shares many pathological and clinical outcomes with AD and PD, but the evidence of direct involvement of RAS components in the pathophysiology of HD is still limited and needs further investigation. Herein, we investigated peripheral levels of the RAS components Ang II, Ang-(1–7), ACE, and ACE2 in controls, premanifest, and manifest HD gene carriers and their relationship with clinical outcomes. Peripheral blood samples were collected via phlebotomy, and plasma concentrations of RAS components were measured by Enzyme-Linked Immunosorbent Assay. Clinical evaluation included a questionnaire about socio-demographic characteristics, motor, and cognitive assessments. Results showed (1) no significant group differences in plasma concentrations of RAS components; (2) positive correlations between ACE2 and Verbal Fluency Test (VFT) scores; and (3) negative correlations between Ang II and Mini–Mental State Examination scores. These results corroborate the proposed balance between the classical (ACE/Ang II) and the counter-regulatory [ACE2/Ang-(1–7)] arms of the RAS, with the former associated with negative clinical outcomes and the latter with positive effects in HD.

The updated development of blood-based biomarkers for Huntington’s disease

“…Rocha et al first studied the peripheral changes in critical RAS components, including Ang II, Ang-(1–7), ACE, and ACE2, and their correlations with clinical measurements. They detected no significant group differences among healthy controls, premanifest HD patients and motor manifest patients but reported correlations between plasma ACE and Ang II level with cognitive performance [ 114 ]. The sample size of this cross-sectional study is relatively small, and further longitudinal research is warranted.…”

Impact of the Renin-Angiotensin System on the Pathogeny and Pharmacotherapeutics of Neurodegenerative Diseases

“…It is linked to NDG diseases, with Ang II being considered a key component; it is involved in neuronal death through oxidative stress, inflammatory responses, and apoptosis [ 9 ]. These effects were confirmed in animal models of different NDG diseases, such as PD [ 148 ]. Thus, studying RAS may shed light on other NDG diseases, such as HD, allowing for alternative management strategies.…”

“…Other findings included an attenuation of cognitive impairment following the administration of AT 1 R antagonists, sustaining the idea that antihypertensive drugs that target RAS may be beneficial in NDG diseases. However, further studies are required for evaluating their specific effects and mechanisms in HD patients [ 148 ].…”

Renin-Angiotensin System in Huntington′s Disease: Evidence from Animal Models and Human Patients

“…Thus, higher levels of ACE2 were associated with better verbal function. A negative correlation between Ang II levels and general cognition scores in the Mini-Mental State Examination was also found, indicating that higher concentrations of Ang II were associated with worse cognitive performance [ 45 ]. Taken together, these findings support a protective role of the counter-regulatory axis in HD.…”