Clinical trial NCT04612686: Characterising Frailty Using Magnetic Resonance Imaging
Official title: Physiological Phenotyping of Frailty Using Magnetic Resonance Imaging
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Frailty
Frailty Syndrome
Frail Elderly Syndrome
Keywords: Phenotype
Magnetic resonance imaging
MRI
Phenotyping
Elderly
Frail
Frailty
Fried
Physiological
Physiology
Female
Heart
Brain
Muscle
Strength
Power output
Fatigability
Cognition
Older persons
Pre-frail
Non-frail
Lead sponsor: University of Nottingham
Sponsor class: OTHER
Collaborators: name: Medical Research Council
name: National Institute for Health Research, United Kingdom
First posted: 2020-11-03
Enrollment: 51
Sex: FEMALE
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Participants will be identified from hospital clinics for older people, many of whom will be frail. Participants will be female, aged over 65 years and outpatients attending these clinics.

Brief summary: Ageing is associated with the development of various negative conditions, such as frailty. Defined as a decreased ability to combat negative stressors (e.g. injury and illness), frailty is highly prevalent in elderly adults and significantly increases an individual's risk of adverse events such as falls, illness and death. The underlying physical characteristics of frailty are currently incompletely understood, with many previous studies focusing on one tissue (e.g. the brain) in isolation. However, frailty is known to affect many tissues simultaneously, and to further our insight into the biological basis of frailty and how to treat it, we must determine how different organs are affected at the same time.

The study will look at the physical characteristics of non-frail and frail elderly females (aged 65 years and over), who are attending geriatric clinics across the Nottingham University Hospitals NHS Trust. We will aim to recruit 51 participants with this cohort broken down into non-frail (n=17), pre-frail (n=17) and frail (n=17) subgroups. Participants will be allocated to these groups based on their Electronic Frailty Index, Clinical Frailty Scale and Fried frailty phenotype scores. All participants will undergo basic muscle function tests (grip strength, leg strength and muscle activity) and questionnaires on their first visit to University of Nottingham laboratories. At a second visit, they will then undergo one Magnetic Resonance Imaging (MRI) scanning session, at the Sir Peter Mansfield Imaging Centre within the University, to gather information about the structure and function of their heart, brain and skeletal muscle. MRI scan protocols will take approximately 45-60 mins. Data gathered from MRI scanning will be compared across non-frail, pre-frail and frail groups to investigate differences across frailty states, with the aim of highlighting the defining physical characteristics of the frail state which may help to develop future treatment interventions to combat the condition.

We hypothesise that frail females will present with common physical characteristics, the clustering of which will be indicative of frailty severity. We also hypothesise that certain physical traits present in the frail will not be present in the non-frail.

Detailed description: The study will recruit females aged over 65 years (n=51), from those attending hospital clinics for older people at both campuses of Nottingham University Hospitals National Health Service (NHS) Trust. A member of the clinical care team working within the clinic will identify potential participants who are 'frail', 'mildly frail/vulnerable' and 'non-frail' using the Clinical Frailty Scale (measured as part of routine care), and the electronic Frailty Index. Clinic staff will make the initial approach to patients about the study and if the individual is interested in taking part, clinic staff will inform the research team. A researcher will then approach the interested individual and provide a study information sheet outlining study procedures. Potential participants will then be given a week to consider participating in the research.

If individuals wish to participate, they will be invited to the David Greenfield Human Physiology laboratories at the Queen's Medical Centre. Here, researchers will explain the study again to volunteers and answer any questions that they may have. Volunteers will be asked to sign an informed consent document prior to any other study procedures being undertaken. Participants will initially have their height and body mass recorded and will complete questionnaires assessing their suitability to have magnetic resonance imaging (MRI) scans, their cognitive ability and independence across activities of daily living.

Each participant's frailty status will be confirmed via the Fried Frailty phenotype assessment which will include a timed 15ft (4.57m) walk, hand grip strength, and questionnaires (Center for Epidemiologic Studies Depression Scale, Minnesota Leisure Time Activity Questionnaire). Participants who do not exhibit any frailty components will be classed as non-frail, those showing one or two frailty components will be classified as pre-frail, and those presenting three or more components will be classed as frail. These measures of frailty severity will take approximately 30 minutes to complete.

Knee extensor strength and power measurements will then be made. They will involve participants being seated in a chair and supported within the measuring apparatus (a padded chair with back support at 90°) using straps (similar to a seat belt) which go across their hips and shoulders. The participant's ankle will be positioned against a lever arm of the equipment and again held in place by a padded support. The isometric strength assessment will involve the participant pushing against the lever arm with maximum effort whilst it is fixed and unable to move. A total of 3 contractions lasting \~2 seconds will be performed with a 1 min rest between each. Muscle power and fatigue will be assessed on the same machine but this time the lever arm will move at a fixed rate. Participants will be asked to extend their leg (as if kicking a ball) 10 times with the lever arm speed at a slow speed (60 degrees per second) and 10 at a faster speed (180 degrees per second). These tests of muscle power output have been administered routinely to elderly volunteers in the literature and our laboratory. However, if these tests are not tolerable for participants, we will terminate the test. Knee extensor measurements will take approximately 30 minutes to complete.

Measurements of thigh muscle motor unit recruitment and motor control (a measure of the electrical activity within the muscle) will then be taken. Measurements will involve placing adhesive non-invasive ECG pads on to the participant's thigh, and a small (24-gauge) needle inserted into the thigh muscle to a depth of \~0.5-2.5cm (depending on amount of subcutaneous fat present). Participants will then be asked to gently contract their thigh muscle (the limb will not be in motion) and the electrical activity of the muscle will be measured. In total, this measure will take approximately 40 minutes to complete. Once completed, the electrodes will be removed and the needle insertion site covered with a small adhesive dressing. Muscle activity measures will take approximately 40 minutes to complete.

On a separate day, following the visit to the physiology laboratories, participants will be invited to the Sir Peter Mansfield Imaging Centre at the University of Nottingham. Here, they will undergo MRI scanning to gather images of the heart, brain, skeletal muscle and fat content within the body. Participants will be made comfortable on the scan table using pillows and pads to support their back, neck and joints. They will be asked to lie as still as possible during the scan protocol and occasionally perform some short breath holds (necessary to acquire certain scans). In total, the time spent in the scanner will be approximately 60 minutes. However, lying still within the MRI scanner for \~60 minutes may be burdensome for elderly participants. Therefore, we will offer short comfort breaks after 15 minutes and 40 minutes of scanning, during which participants may leave the scan room to use the bathroom and consume refreshments if needed. This will not affect the scan procedure or image collection.

Eligibility criteria: Inclusion Criteria:

* Females aged over 65 years of age attending Nottingham University Hospitals NHS Trust 'falls and bone health' and general geriatric clinics;
* Able to provide informed consent;
* Once 17 participants have been recruited to any of the three study groups (non-frail, pre-frail, frail) the study will be restricted to people in the remaining groups only;
* Good understanding of written and spoken English.

Exclusion Criteria:

* Metal within the body which could be affected by MRI;
* Any other contraindications for MRI scan (e.g. brain aneurysm clips, permanent pacemaker);
* Over 190.5 cm in height
* Inability to lie on back within the MRI scanner
* Mobility limitations which would prevent the individual transferring onto equipment
* Unable to speak or understand English;
* In receipt of end of life care;
* Lacking the mental capacity to understand the requirements of study participation and provide consent.

Primary outcomes:
measure: Hand grip strength
timeFrame: Baseline (During visit to University physiology laboratory)
Secondary outcomes:
measure: Whole body skeletal muscle volume
timeFrame: Baseline (During visit to Sir Peter Mansfield Imaging Centre - University of Nottingham)
measure: Volumes of individual muscles in the lower limbs
timeFrame: Baseline (During visit to Sir Peter Mansfield Imaging Centre - University of Nottingham)
measure: White/grey matter volumes of the brain
timeFrame: Baseline (During visit to Sir Peter Mansfield Imaging Centre - University of Nottingham)
measure: Cerebral perfusion
timeFrame: Baseline (During visit to Sir Peter Mansfield Imaging Centre - University of Nottingham)
measure: Motor unit size and recruitment in thigh muscle
timeFrame: Baseline (During visit to University physiology laboratory)
measure: Cardiac stroke volume, ejection fraction and aortic strain of the heart
timeFrame: Baseline (During visit to Sir Peter Mansfield Imaging Centre - University of Nottingham)
measure: Knee extension strength
timeFrame: Baseline (During visit to University physiology laboratory)
measure: Walking speed
timeFrame: Baseline (During visit to University physiology laboratory)
measure: Clinical Frailty Scale
timeFrame: Initial patient screening (within clinic of Nottingham University Hospitals)
measure: Electronic Frailty Index
timeFrame: Initial patient screening (within clinic of Nottingham University Hospitals)
measure: Nottingham Extended Activities of Daily Living Scale
timeFrame: Baseline (During visit to University physiology laboratory)
measure: Fried frailty phenotype
timeFrame: Baseline (During visit to University physiology laboratory)
measure: Minnesota Leisure Time Activity Questionnaire
timeFrame: Baseline (During visit to University physiology laboratory)
measure: Center for Epidemiologic Studies Depression Scale
timeFrame: Baseline (During visit to University physiology laboratory)
measure: Montreal Cognitive Assessment questionnaire
timeFrame: Baseline (During visit to University physiology laboratory)
measure: Knee extension power output
timeFrame: Baseline (During visit to University physiology laboratory)
measure: Knee extension fatigability
timeFrame: Baseline (During visit to University physiology laboratory)
Other outcomes:
Locations:
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
state: Nottinghamshire
Study officials:
affiliation: University of Nottingham
name: Joseph Taylor, PhD student
role: PRINCIPAL_INVESTIGATOR
affiliation: Nottingham University Hospitals NHS Trust
name: Tahir Masud, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Nottingham
name: Paul Greenhaff, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Nottingham
name: Susan Francis, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Nottingham
name: John Gladman, Professor
role: STUDY_CHAIR
References:
citation: Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA; Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001 Mar;56(3):M146-56. doi: 10.1093/gerona/56.3.m146.
citation: Fried LP, Xue QL, Cappola AR, Ferrucci L, Chaves P, Varadhan R, Guralnik JM, Leng SX, Semba RD, Walston JD, Blaum CS, Bandeen-Roche K. Nonlinear multisystem physiological dysregulation associated with frailty in older women: implications for etiology and treatment. J Gerontol A Biol Sci Med Sci. 2009 Oct;64(10):1049-57. doi: 10.1093/gerona/glp076. Epub 2009 Jun 30.