Successful Aging and Frailty

Cognitive Impairment Clinical Trial

— SAFe  

Official title:

Molecular and Functional Basis of Successful Aging and Frailty

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03963050
• Other study ID #: 27111
• Status: Recruiting
• Phase: N/A
• Start date: September 1, 2019
• Est. completion date: December 31, 2023

Study information

• Verified date: November 2020
• Source: Universita di Verona
• Contact: Manuela Calderara
• Phone: +39 0458124287
• Email: manuela.calderara[@]univr.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Frailty is the term commonly utilized to describe the geriatric syndrome that exposes the elderly to increased risk of negative health-related events. The frailty phenotypes (PF: physical or CF: cognitive) have demonstrated to predict the major negative health-related outcomes in the old population and show extensive similarities with sarcopenia (for PF) or dementia (for CF). However, the role of neurophysiological and biological factors contributing to the physical and cognitive frail condition, and in particular in which way mitochondrial dysfunction, as well as the hypertrophic and atrophic pathways assessed by genes expression, metabolomics and microbiota composition are contributing to these frail conditions, are still under debate. Therefore, the aim of this trial will be to make evidence based on the behaviors and the strategies that promote healthy lifestyle and successful human aging.

Description:

In the majority of the world, the population is living to a greater age. However, older age is usually associated with elevated risk of several pathologies, as well as age-related organ dysfunctions, which in turn can accelerate functional impairments, disability, or death. To identify this geriatric syndrome the term frailty phenotype has been commonly utilized. In particular, the frailty phenotype can be distinguished in physical frailty (PF) phenotype or cognitive frailty (CF) phenotype.

Despite several groups of researchers tried to develop preventive interventions to counteract the physical and cognitive frail condition of elderly, the success of this task has been tempered by the lack of standardized, and universally agreed protocols. Moreover, the limited knowledge of the neurophysiological, and biological determinants of these conditions has precluded important advances in the research of this domain.

Many factors combine to achieve a successful aging: genetics, health care and healty lifestile. Therefore, the aim of the current trial will be to understand the behaviors and the strategies that promote healthy lifestyle and successful human aging.

Oldest old participants with CF and PF will be selected from the neurorehabilitation unit of the University Hospital of Verona (Italy). Healthy oldest old and young participants will be recruited from the section of Movement Sciences of the University of Verona.

After a first phase of neurophysiological and biological examinations that will involve all the 4 groups, only CF and PF participants will be randomly assigned to an intervention program (physical exercise, physical+cognitive exercise or control). Frail participants assigned to exercise groups will then perform 1 year of intervention, 3 days per week, 1 hour per day. Afterwards, the three groups of intervention will undergo the same neurophysiological and biological examinations of the beginning of the study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 180
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 80 Years to 90 Years

Eligibility

Inclusion Criteria:

• YH: 30 healthy young (20-25 years old) participants. They must be free of any disease.

• OH: 30 healthy oldest old (80-90 years old) participants. They must be free of any neural or physical disease and any severe chronic disease (CODP, Heart Failure) that can compromise exercise.

• PF: 30 oldest old (80-90 years old) participants. They must be characterized by functional deficits (sarcopenia, osteoporosis and muscle weakness) without cognitive impairment. Additionally, participants cannot be affected by any severe chronic disease that compromise exercise.

• CF: 30 oldest old (80-90 years old) participants. They must be characterized by mild cognitive impairment (MCI) and subjective cognitive decline without functional deficits. Additionally, participants cannot be affected by any severe chronic disease that compromise exercise.

Exclusion Criteria YH

• Any medication

• Any disease

• General: pregnancy, addictive or previous addictive behavior defined as the abuse of cannabis, opioids or other drugs, carrier of infectious diseases.

• For TMS: Epilepsy, metallic prosthesis, malignant tumor

Exclusion Criteria OH

• Heart failure, angina, pulmonary disease.

• Cognitive frailty (MCI, Alzheimer) or physical frailty (musculoskeletal diseases)

• General: coagulation disorders, pregnancy, addictive or previous addictive behavior defined as the abuse of cannabis, opioids or other drugs, carrier of infectious diseases, suffering from musculoskeletal diseases, suffering from mental illness, inability to cooperate, subjects suffering from known cardiac conditions (e.g., pacemakers, arrhythmias, and cardiac conduction disturbances) or peripheral neuropathy. Moreover, subjects suffering from diabetes, arthritis and under medication will be scored according to specific criteria.

• Assumption of any anticoagulant medication

• Assumption of antiplatelet medications in high dose (es: acetylsalicylic acid >200mg x day)

• For TMS: Epilepsy, metallic prosthesis, malignant tumor

• For MRI: pacemaker, internal defibrillator or other ferromagnetic implants

Exclusion Criteria PF

• Simultaneous presence of physical frailty and cognitive impairment (CDR=0.5)

• For exercise testing and training: heart failure, angina, pulmonary disease.

• General: coagulation disorders, pregnancy, addictive or previous addictive behavior defined as the abuse of cannabis, opioids or other drugs, carrier of infectious diseases, suffering from musculoskeletal diseases, suffering from mental illness, inability to cooperate, subjects suffering from known cardiac conditions (e.g., pacemakers, arrhythmias, and cardiac conduction disturbances) or peripheral neuropathy. Moreover, subjects suffering from diabetes, arthritis and under medication will be scored according to specific criteria.

• The T-scores for the whole body and PA-projection total spine parameters: According to the World Health Organization (WHO) recommendation, participants will be diagnosed as having osteoporosis when the minimum T-score, measured at any site, will be less than -2.5, osteopenia if T-score between -1 and -2.5 and normal if T-score will be greater than -1 according to the World Health Organization guideline. Diagnosis will be made on basis of lowest T score at any measured site (T score =-1 SD = Normal; T score between -1 and -2.5 SD = Low bone mass, and T Score =-2.5 SD = Osteoporosis). T-score reference values are provided by the DXA scanner manufacturer.

• Assumption of any anticoagulant medication

• Assumption of antiplatelet medications in high dose (es: acetylsalicylic acid >200mg x day)

• For TMS: Epilepsy, metallic prosthesis, malignant tumor

• For MRI: pacemaker, internal defibrillator or other ferromagnetic implants

• Decline a priori to participate in the intervention Phase 2 of the study

• Cut-off exclusion criteria of PF:

• Fried's Frailty Phenotype: < 3 positive characteristics

• Timed-up-and-go test: <10 sec

• The Multidimensional Prognostic Instrument (MPI): < 0.66 score

• The GAITRite system: > 0.9 m/s

• Groningen Frailty Indicator: <4

Exclusion Criteria CF

• Simultaneous presence of physical frailty and cognitive impairment (CDR=0.5)

• For exercise testing and training: heart failure, angina, pulmonary disease.

• General: coagulation disorders, pregnancy, addictive or previous addictive behavior defined as the abuse of cannabis, opioids or other drugs, carrier of infectious diseases, suffering from musculoskeletal diseases, suffering from mental illness, inability to cooperate, subjects suffering from known cardiac conditions (e.g., pacemakers, arrhythmias, and cardiac conduction disturbances) or peripheral neuropathy. Moreover, subjects suffering from diabetes, arthritis and under medication will be scored according to specific criteria.

• The T-scores for the whole body and PA-projection total spine parameters: According to the World Health Organization (WHO) recommendation, participants will be diagnosed as having osteoporosis when the minimum T-score, measured at any site, will be less than -2.5, osteopenia if T-score between -1 and -2.5 and normal if T-score will be greater than -1 according to the World Health Organization guideline. Diagnosis will be made on basis of lowest T score at any measured site (T score =-1 SD = Normal; T score between -1 and -2.5 SD = Low bone mass, and T Score =-2.5 SD = Osteoporosis). T-score reference values are provided by the DXA scanner manufacturer.

• Assumption of any anticoagulant medication

• Assumption of antiplatelet medications in high dose (es: acetylsalicylic acid >200mg x day)

• For TMS: Epilepsy, metallic prosthesis, malignant tumor

• For MRI: pacemaker, internal defibrillator or other ferromagnetic implants

• Decline a priori to participate in the intervention Phase 2 of the study

• Cut-off exclusion criteria of CF:

• Mini Mental State (MMSE): cut-off 23.8

• FCSRT: IFR (immediate free recall) cut off <19.59; ITR (immediate total recall) cut off<35; DFR (delayed free recall) cut off <6.31; DTR (delayed total recall) cut off<11; index of sensitivity of cueing cut off<0.9; Number of intrusions cut off>0

• Digit Span: cut off 3.75

• Digit Span Reversal (WAIS): cut off 2.65

• Rey-Osterrieth Complex Figure Test: cut off copy 28.88 - cut off

• deferred reproduction 9.47

• Trial Making Test A(ENB2): cut off >93 sec; TMT B (ENB2): cut off >282 sec; TMT B-A (ENB2): cut off>186 sec

• Frontal Assessment Battery (FAB): cut off <13.4

• Phonemic Fluency (ENB2): cut off 3

• Clock Test: cut off <6.25

• Time up and Go TUG-COG: cut off >15sec

• Cognitive Function Instrument (partly for the caregiver): no cut-off

• Neuropsychiatric Inventory (for the caregiver): cut-off >0

• Geriatric Depression Scale: cut-off>10

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Cognitive Impairment
• Frailty
• Frailty Syndrome
• Sarcopenia

Intervention

Other:
• Exercise Training
The ET program will consist of endurance exercises at 70% of maximal Heart Rate and resistance exercises at 85% of 1 repetition maximum.
• Exercise Training + Cognitive Training
ET: The intervention program will consist of endurance exercises at 70% of maximal Heart Rate and resistance exercises at 85% of 1 repetition maximum. CT: The intervention program will be configured as a cognitive rehabilitation and mainly memory rehabilitation: the participants will be trained in practicing restorative and compensatory mnemonic techniques, such as visual imagery, face-name association, calendar, notes and prompts.
• Control
NO changes in lifestyle

Locations

Country	Name	City	State
Italy	University of Verona	Verona

Sponsors (1)

Lead Sponsor	Collaborator
Universita di Verona

Country where clinical trial is conducted

Italy, 

References & Publications (12)

Alsop DC, Detre JA, Golay X, Günther M, Hendrikse J, Hernandez-Garcia L, Lu H, MacIntosh BJ, Parkes LM, Smits M, van Osch MJ, Wang DJ, Wong EC, Zaharchuk G. Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A con — View Citation

Buxton RB, Frank LR, Wong EC, Siewert B, Warach S, Edelman RR. A general kinetic model for quantitative perfusion imaging with arterial spin labeling. Magn Reson Med. 1998 Sep;40(3):383-96. — View Citation

Detre JA, Leigh JS, Williams DS, Koretsky AP. Perfusion imaging. Magn Reson Med. 1992 Jan;23(1):37-45. — View Citation

Du AT, Jahng GH, Hayasaka S, Kramer JH, Rosen HJ, Gorno-Tempini ML, Rankin KP, Miller BL, Weiner MW, Schuff N. Hypoperfusion in frontotemporal dementia and Alzheimer disease by arterial spin labeling MRI. Neurology. 2006 Oct 10;67(7):1215-20. — View Citation

Hatse S, Brouwers B, Dalmasso B, Laenen A, Kenis C, Schöffski P, Wildiers H. Circulating MicroRNAs as easy-to-measure aging biomarkers in older breast cancer patients: correlation with chronological age but not with fitness/frailty status. PLoS One. 2014 — View Citation

Mayeux R, Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med. 2012 Aug 1;2(8). pii: a006239. doi: 10.1101/cshperspect.a006239. Review. — View Citation

Pedrinolla A, Schena F, Venturelli M. Resilience to Alzheimer's Disease: The Role of Physical Activity. Curr Alzheimer Res. 2017 Apr 3;14(5):546 - 553. — View Citation

Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001 May 1;29(9):e45. — View Citation

Popa-Wagner A, Mitran S, Sivanesan S, Chang E, Buga AM. ROS and brain diseases: the good, the bad, and the ugly. Oxid Med Cell Longev. 2013;2013:963520. doi: 10.1155/2013/963520. Epub 2013 Dec 5. Review. — View Citation

Princivalle A, Monasta L, Butturini G, Bassi C, Perbellini L. Pancreatic ductal adenocarcinoma can be detected by analysis of volatile organic compounds (VOCs) in alveolar air. BMC Cancer. 2018 May 4;18(1):529. doi: 10.1186/s12885-018-4452-0. — View Citation

Rusanova I, Diaz-Casado ME, Fernández-Ortiz M, Aranda-Martínez P, Guerra-Librero A, García-García FJ, Escames G, Mañas L, Acuña-Castroviejo D. Analysis of Plasma MicroRNAs as Predictors and Biomarkers of Aging and Frailty in Humans. Oxid Med Cell Longev. — View Citation

Tan L, Yu JT, Tan MS, Liu QY, Wang HF, Zhang W, Jiang T, Tan L. Genome-wide serum microRNA expression profiling identifies serum biomarkers for Alzheimer's disease. J Alzheimers Dis. 2014;40(4):1017-27. doi: 10.3233/JAD-132144. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Expression of potential biomarkers (circulating miRNA)	Noncoding RNAs, in particular, microRNAs (miRNAs), are a new regulatory system which plays a pivotal role in skeletal muscle adaptation and repairing.	3 years
Primary	Structural cerebral cortex adaptations (TMS)	Single-pulse TMS will be used to map the brain area representing the vastus lateralis (VL).	3 years
Primary	Functional cerebral cortex adaptations (TMS)	Single-pulse TMS will be used to investigate the excitability of the corticospinal system. A double-cone coil will be used to stimulate the leg area of the primary motor cortex (M1).	3 years
Primary	Modifications in the metabolism of cerebral areas (ASL-MRI)	To assess non-invasively cerebral blood flow (CBF)	3 years
Primary	Muscle mass alterations (DXA)	Muscle mass will be assessed with DXA	3 years
Primary	Alveolar profiles	Changes in biogenic volatile organic compound concentrations can be used to mirror metabolic or pathophysiological processes in the whole body	3 years
Secondary	Changes in muscular fiber type	Outcome of the changes in fiber typing on the components of the muscle mechanics in each group and Pre-Post intervention in CF and PF groups will be evaluated.	3 years
Secondary	Changes in neuromuscular control 1	The force rate of development during a maximum voluntary contraction and a tetanic stimulation will be compared in order to estimate the role of central command flow to the muscle in changing the efficiency of the tension development at the tendon.	3 years
Secondary	Changes in neuromuscular control 2	The EMG envelope rate of development during a maximum voluntary contraction and a tetanic stimulation will be compared in order to estimate the role of central command flow to the muscle in changing the efficiency of the tension development at the tendon.	3 years
Secondary	Mitochondrial Respiration	Changes in mitochondrial respiration function will be measured to asses the level of mitochondrial dysfunction.	3 years