Cognitive Alterations in Pulmonary Arterial Hypertension (PAH): an Exploratory Cross- Sectional Study

Pulmonary Arterial Hypertension (PAH) is a rare chronic disease marked by a pathological and sustained increase in pulmonary artery pressure as a result of structural and functional changes within the pulmonary vasculature. Beyond its cardiopulmonary manifestations, a growing body of evidence suggests that PAH may also affect cerebral hemodynamics and cognitive functioning as a consequence of prolonged reductions in cerebrovascular oxygenation potentially underlying the frontal-executive, attentional, and mnestic impairments reported in this population. Despite these preliminary findings, the few studies currently available have significant methodological limitations, such as the lack of appropriate control groups or the inclusion of other pulmonary hypertension subtypes in the cohort. In addition, they tend to rely on global cognitive screening tests that are unsuitable for the precise characterization of domain-specific alterations, such as those observed in PAH.

This study aims to address these limitations by employing a battery of computerized neuropsychological tests to detect the presence of selective cognitive alterations in individuals diagnosed with PAH, through comparison with a control group matched for age, sex, handedness and schooling.

The project is designed as a cross-sectional observational study conducted at a single center, with the primary aim to assess the presence of selective cognitive alterations in patients diagnosed with PAH, comparing their performance with that of a healthy control group matched for age, sex, handedness, and level of education.

The secondary objective is to explore the relationship between cognitive variables and clinical variables in patients with PAH, such as disease duration, age at diagnosis, oxygen therapy, and reported comorbidities.

Participants will be assessed in a single in-person session at the IRCCS Maugeri Milano, using a computerised battery of tests that will last approximately 50 minutes.

Recruitment will take place consecutively among patients hospitalised at the U.O. Rehabilitative Cardiology of the IRCCS Maugeri- Milano Via Camaldoli. Healthy controls will be identified on a voluntary basis among IRCCS Maugeri staff, healthy family members of patients, or through other authorised internal channels.The total duration of the study is expected to be 24 months, with an estimated start date of 15/11/2025 and end date of 31/07/2027.

Participants will undergo an initial collection of medical history data to verify their eligibility for the study. The information collected will include sociodemographic data (sex, age, marital status, number of children, employment status, level of education, years of schooling) and clinical data (past and recent medical history, current drug therapies, behavioural habits such as smoking and/or alcohol consumption, handedness). Data relating to performance in neuropsychological tests will be collected using the Inquisit 7.0 by Millisecond platform (https://www.millisecond.com/). Cognitive tasks will be performed individually and in person on an HP Envy x360 PC running Windows 11.

Assessment tools Neuropsychological tests were chosen to investigate selective alterations in cognitive functions related to brain areas whose activation was found to be altered in PAH patients in the aforementioned studies, such as the selective and sustained attention, working memory, processing speed and cognitive flexibility, inhibitory control, interference contrast, categorical abstraction, as well as learning and long-term verbal memory.

Selected test are listed below:

• Iowa Gambling Task (IGT): developed by Bechara and colleagues (1994);
• Emotional Stroop Task (EST): a variant of the classic Stroop Test, developed by Smith and Waterman (2003);
• The Rey Auditory Verbal Learning Test (RAVLT): validated in the Italian version by Carlesimo et al., (1995); The Visual Simon Task (VST): a variant of the Simon Task (2004); The Wisconsin Card Sorting Test (WCST): by Heaton et al., (1993);