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

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

Carbon Dioxide Partial Pressure Oscillations During Exercise: Relation to Cerebral Blood Flow Regulation and and to the Prevalence of 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).

COPD, Carbon dioxide partial pressure (pCO2), Cerebral blood flow (CBF), Cognitive dysfunction, Mild/Moderate Cognitive Impairment (MCI), Pulmonary Rehabilitation (PR), Standardized Mini Mental State Examination (SMMSE), Addenbrooke's Cognitive Examination (ACE-R), Montreal Cognitive Assessment (MoCA), Telephone Interview for Cognitive Status (TICS), Stroop test (Reaction Time)

Evaluation of the acute effect of a 3-week Pulmonary Rehabilitation (PR) program in cognitive function of MCI-Group using SMMSE, ACE-R, MoCA, TICS and Stroop test clinical instruments in reference to potential changes in pCO2 oscillation patterns (post-PR). Intervention: Pulmonary Rehabilitation program; 12 sessions of exercise training/breathing techniques.

Evaluation of the acute effect of a 3-week Pulmonary Rehabilitation (PR) program in cognitive function of control-group using SMMSE, ACE-R, MoCA, TICS and Stroop test clinical instruments in reference to potential changes in pCO2 oscillation patterns (post-PR). Intervention: Pulmonary Rehabilitation program; 12 sessions of exercise training/breathing techniques.

Patients will attend a comprehensive 3-week PR program (12sessions/ 60min·day) including high intensive interval exercise equivalent to 100% of peak work rate (WRpeak) with 30sec work periods interspersed with 30sec rest periods for 30min and light resistance training (3muscle groups/ 4sets each/10repetitions; ~30min).

Changes in transcutaneous pCO2 (ΔpCO2, mmHg from baseline values) during Cycle-Endurance Test (CET) at 75% of peak Work Rate (WRpeak). The pCO2 oscillations will be transcutaneous monitored and continuously recorded by the use of "SenTec" Digital Monitoring System (pre/post measurements): 1st measurement during a CET prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement during a CET at the end of PR program (post-PR).

Screening of Cognitive Dysfunction according to Petersen's criteria: Consistent memory complaints preferably corroborated by a close-informant. Objective characterization of specific deficits in memory and/or other cognitive domains, as indicated by a poor performance on MoCA (<26 points), MMSE (<25 points), ACE-R (<88 points) and TICS (<33 points). Preserved ability to perform activities of daily living (ADLs), or minimal impairment if considering instrumental ADLs. Normal global cognitive function. Absence of dementia (Clinical Dementia Rating Scale (CDR ≤1 point)).

Evaluation of Cognitive Impairment (CI) by the use of clinical instrument of the Standardized Mini-Mental State Examination (SMMSE, scores); 1st measurement prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement at the end of PR program (post-PR).

Evaluation of Cognitive Impairment (CI) by the use of clinical instrument of the Addenbrooke's Cognitive Examination (ACE-R scores); 1st measurement prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement at the end of PR program (post-PR).

Evaluation of Cognitive Impairment (CI) by the use of clinical instrument of the Montreal-Cognitive Assessment (MoCa scores); 1st measurement prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement at the end of PR program (post-PR).

Evaluation of Cognitive Impairment (CI) by the use of clinical instrument of the Telephone Interview for Cognitive Status (TICS scores); 1st measurement prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement at the end of PR program (post-PR).

Assessment of cognitive performance (Stroop test - reaction-time, seconds) before and immediately after Cycle-Endurance Test (CET) at 75% of WRpeak. Cognitive performance will be measured by the use of Stroop-test (pre/post measurements): 1st measurement during a CET prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement during a CET at the end of PR program (post-PR).

Measurement of Cerebral Blood Flow velocity (CBFv, cm/sec) as surrogate of Cerebral Blood Flow (CBF) before and immediately after Cycle-Endurance Test (CET) at 75% of WRpeak. Cerebral Blood Flow velocity (CBFv) will be measured by the use of transcranial Doppler ultrasonography (pre/post measurements): 1st measurement during a CET prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement during a CET at the end of PR program (post-PR).

Measurement Tissue Oxygen Saturation (TOI, %) as an index of frontal cortex cerebrovascular oxygen saturation during Cycle-Endurance Test (CET) at 75% of WRpeak. Tissue oxygen saturation (TOI, %) will be continuously measured by the use of Near-Infrared Spectroscopy (NIRS-method; pre/post measurement): 1st measurement during a CET prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement during a CET at the end of PR program (post-PR).

Measurement of the changes in Deoxygenated Haemoglobin (ΔHHb) in micrometer per centimeter (μM/cm) as an index of frontal cortex cerebrovascular oxygen saturation during Cycle-Endurance Test (CET) at 75% of WRpeak. Changes in Deoxygenated Haemoglobin (ΔHHb, μM/cm) will be continuously measured by the use of Near-Infrared Spectroscopy (NIRS-method; pre/post measurement): 1st measurement during a CET prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement during a CET at the end of PR program (post-PR).

Measurement of exercise capacity by a cardiopulmonary exercise test (CPET) on cycle ergometer using an incremental protocol to the limit of tolerance (peak Work Rate, watts)) for establishing the work rate corresponding to 75% of peak (maximum working capacity) according to the international guidelines.

Psychological factors will be assessed by the use of the Hospital Anxiety and Depression Scale (HADS).

Psychological factors will be assessed by the use of the St. George Respiratory Questionnaire (SGRQ).

Perception of dyspnoea will be assessed by the use of the Medical Research Council (MRC) dyspnoea scale.

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

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