pCO2 Oscillations During Exercise: Relation to Cerebral Blood Flow and to Cognitive Dysfunction in COPD

Investigators wish to identify a relationship between substantial changes in carbon dioxide partial-pressure (pCO2), which frequently occur during the transitions from rest to exercise (ΔpCO2 \>4 millimeters of mercury \[mmHg\] from baseline), and the prevalence of cognitive dysfunction in COPD. In particular, it is anticipated to investigate the vascular effect of pCO2 oscillations in the regulation of cerebral blood flow (CBF) during exercise and its impact on cognitive function in Chronic Obstructive Pulmonary Disease (COPD). Furthermore, this study aims to examine whether major pCO2 oscillations have prognostic value in cognitive deterioration at 6, 12, and 18-month follow-up. In addition, the acute effect of 3-week pulmonary rehabilitation (PR) on cognitive function will be explored. The evaluation of cognitive function will be performed by the use of Standardized Mini Mental State Examination (SMMSE), Addenbrooke's Cognitive Examination (ACE-R), Montreal Cognitive Assessment (MoCA), and Telephone Interview for Cognitive Status (TICS) assessing several cognitive domains (cognitive scores) whereas Stroop test \[color reading interference\] will be used for measuring cognitive performance (Reaction-Time).

Cerebral Blood Flow (CBF) regulation is crucial for the adequate oxygen supply to the brain and the sustenance of cerebrovascular reserve capacity. A fundamental physiologic regulator of CBF is the carbon dioxide partial pressure (pCO2), which determines the dilatation or contraction of cerebral vasculature. CBF regulation response has been found to be strongly dependent upon pCO2 but much less so upon changes in arterial oxygen saturation. CBF is highly sensitive to pCO2 changes which cause pronounced-vasodilatation in increased pCO2 (CBF augmentation) or vasoconstriction in decreased pCO2 levels (CBF diminution). During cerebral activation and increased metabolism, cerebral arterioles dilate contributing to increase CBF but this process is often challenged during exercise and has a potential impact on cognitive function. CBF is linked to cognitive function while serum level of Brain Derived Neurotrophic Factor (BDNF) has been shown as a critical driving force behind neural plasticity with a potential utility as a biomarker of cognitive decline.

Investigators assume that major pCO2 oscillations during exercise (ΔpCO2 \>4 millimeters of mercury \[mmHg\] from baseline) as a reflection of the abnormality in ventilatory efficiency/drive, lead to overall and local disturbances of cerebral blood flow (CBF) and thus can be associated to increased prevalence of cognitive dysfunction in patients with Chronic Obstructive Pulmonary Disease (COPD). Moreover, investigators hypothesize that patients with major pCO2 oscillations during exercise may develop worse cognitive impairment in several cognitive domains and greater cognitive decline compared to "isocapnic" patients at 6, 12, and 18-month follow-up. Inpatient PR may benefit cognitive function by improving breathing (diminishing pCO2 oscillations), therefore improving CBF, and by increasing cerebral neural activation through exercise.

With regard to cognitive dysfunction, which is associated to increased all-cause mortality and disability, investigators wish:

(A) to detect a relationship between major pCO2 oscillations during exercise and increased prevalence of cognitive dysfunction in COPD; (B) to investigate the impact of different pCO2 transitory-patterns (1. pCO2: decline/ hypocapnic, 2. steady/ isocapnic, 3. increase/ hypercapnic) on CBF regulation and cognitive function; (C) to examine whether major pCO2 oscillations can be a determinant of greater cognitive deterioration in several cognitive domains at 6, 12, and18-month follow-up and (D) to explore the acute effect of 3-week PR on pCO2 oscillations and CBF in respect to cognitive function in COPD patients with cognitive impairment.

The evaluation of cognitive function will be performed by the use of Standardized Mini Mental State Examination (SMMSE), Addenbrooke's Cognitive Examination (ACE-R), Montreal Cognitive Assessment (MoCA) and Telephone Interview for Cognitive Status (TICS) assessing several cognitive domains (cognitive scores) whereas Stroop test will be used for measuring cognitive performance (Reaction-Time).

Eligibility Criteria:
Inclusion Criteria:

* Patients with Chronic Obstructive Pulmonary Disease (COPD) in Global Initiative on Obstructive Lung Disease (GOLD) stages II to IV
* COPD patients with mild to moderate cognitive impairment (MCI-group: n=100) and without cognitive impairment (Control-group: n=60)
* Normotensive (Blood Pressure range: 101-143/62-91 millimeters of mercury \[mmHg\])

Exclusion Criteria:

* Resting partial pressure of oxygen in arterial blood (paO2) \<55 millimeters of mercury \[mmHg\]
* Resting partial pressure of carbon dioxide in arterial blood (paCO2) \>45 millimeters of mercury \[mmHg\]
* last exacerbation ≤4weeks
* severe cognitive impairment/dementia
* other neuropsychiatric symptoms