Leader: Carlo Ferrarese (UNIMIB); Other collaborator(s): All Spoke 8 Partners and possible participation of researchers from other Spokes
The WHO's guidelines prioritize universal care and maintaining the health of elderly patients as central goals of global healthcare systems. The rapid development of artificial intelligence, digitalization of healthcare systems, and implementation of computerized clinical monitoring systems promise a shift towards patient-centric treatment and a true healthcare revolution. Recent legislation supports active aging through prevention programs for cognitive and functional decline, with initiatives like the Age-It project aiming to make Italy a leader in promoting healthy aging.
Evidence increasingly favors multicomponent interventions (combining exercise, nutrition, cognitive training, and socialization) over single-component interventions for preventing cognitive and functional decline in the elderly. However, the overall quality of evidence remains low, and implementing such protocols in elderly community settings remains uncertain. Technologies like assistive devices, smart home systems, monitoring tools, and assistive robots offer promising solutions for managing elderly individuals at risk of decline.
We will design a randomised controlled trial, aligned with WHO guidelines and the WW-FINGERS framework, that will represents the first Italian study to evaluate the effects of multidomain interventions, supported by innovative technologies, in preventing functional and cognitive decline in the elderly community. It will last 18 months, include up to 3000 elderly at risk subjects and encompass two phases: 1) observational population based study; 2) RCT longitudinal study. This research may pave the way for future investigations into the long-term effects of personalized multidimensional interventions, including analyzing population samples over years to detect changes in lifestyle, risk factors, functional efficiency, and cognitive abilities. Moreover, we will analyse and explore new biomarkers that might deepen our understanding of the aging process.
Brief description of the activities and of the intermediate results
By June 2024, the IN-TeMPO study reached several critical milestones. First, the study protocol was fully completed and officially registered on ClinicalTrials.gov under the identifier NCT06248723. This registration ensures the transparency and visibility of the trial and allows international collaboration, particularly with the Worldwide-FINGERS group, where joint data analyses will enhance the study’s impact.
Seven participant clinical centers were identified and confirmed to partake in the study. The distribution includes two centers in Northern Italy, two in Central Italy, and three in Southern Italy, allowing for a geographically diverse sample of participants. This step is crucial for ensuring that the results of the study are generalizable across different regions.
A draft of the first protocol amendment was prepared to be submitted to the ethics committee for approval. This amendment will likely include updates on interventions, procedures, or ancillary studies that emerged during the project’s development.
Furthermore, the first phase of the study, which is population-based and observational, commenced in collaboration with general practitioners (GPs). This collaboration helps identify potential participants for future intervention phases and provides essential baseline data.
Finally, the recruitment plan for the randomized controlled trial (RCT) phase was set to begin in September 2024. This second phase will involve the actual implementation of the multidomain interventions aimed at preventing cognitive and functional decline. The preparatory activities included finalizing procedures for participant recruitment, which is vital for ensuring smooth execution when enrollment starts.
The project has thus moved from foundational planning stages to early execution, with key infrastructures in place to begin interventions and data collection in the coming months.
By the end of September 2024, the IN-TeMPO project made significant strides, particularly in the preparation for the randomized controlled trial (RCT) and the introduction of two key ancillary studies.
The first major achievement was the successful testing of the electronic Case Report Form (eCRF) on the RedCap platform. This system will serve as the central hub for collecting and managing study data across all participating centers, ensuring data integrity and accessibility. Testing confirmed the system’s readiness, and final adjustments are underway to ensure that it will be fully operational when participant data collection begins.
Simultaneously, the health-tracking wearable devices selected for monitoring participants' vital parameters—such as heart rate, physical activity, and sleep quality—were tested for accuracy and usability. A deployment plan is in progress, ensuring that all research centers and participants will receive the devices promptly and that their integration into the study workflow is seamless.
Beyond the core study, two approved ancillary studies are now shaping up to add valuable layers of analysis:
Gait and Motion Analysis: This study will assess gait alterations and their correlations with biomarkers of neurodegeneration, inflammaging, sarcopenia, and APO-E gene typing. Using a 3D Motion Capture System, force platforms, and surface electromyography, the study will evaluate spatiotemporal, kinetic, and kinematic data related to walking. Participants from UNIMIB (both in the experimental and control groups) will undergo gait analysis. The study’s goal is to identify early biomechanical indicators of neurodegenerative or musculoskeletal conditions, allowing for tailored interventions based on individual risks. Follow-up gait analyses will monitor the progression of these conditions and how they relate to changes in biomarkers.
Enterogermina Supplement Study: This ancillary study will assess the role of Enterogermina (a probiotic containing Bacillus clausii) in enhancing the effectiveness of the multidomain interventions. Forty participants per center (Bicocca, La Sapienza, Naples) will be split into active and control groups. Half of the active group will take Enterogermina for 30 days during month 17 (T17). Microbiome analyses at T0, T17, and T18 will investigate whether the supplement positively influences intervention outcomes by altering gut microbiota.
These studies will enrich the understanding of both biomechanical and microbiological factors affecting cognitive and functional decline in older adults. With protocol amendments for both studies being prepared for ethics committee submission, the project is expanding its scope while maintaining focus on its core objectives.
During this trimester, the IN-TeMPO study officially entered its recruitment phase, following the submission of a protocol amendment for ethical approval, anticipated in January 2025. This amendment introduces two additional recruiting centers in Sicily and incorporates three ancillary studies focusing on MRI, hypoacusia evaluation and treatment, and sleep evaluation, which will be conducted at selected centers. To align with project deadlines, the intervention phase has been reduced to 12 months after consulting the WorldWideFINGERS network on statistical power and sample size considerations. This adjustment allows for the concentration of available resources within a shorter timeframe, albeit with an increased target sample size. Additionally, a 6-month extended support phase has been planned to sustain the lifestyle changes promoted by the intervention.
Recruitment for the randomized controlled trial (RCT) began at the coordinating clinical center at IRCCS San Gerardo dei Tintori in Monza, under the auspices of the University of Milano-Bicocca (UNIMIB). Recruitment will expand to other clinical centers as dedicated professionals are hired for the trial. Strategies for identifying eligible participants include collaboration with general practitioners and leveraging patient pools from memory clinics and Brain Health Services. However, the relatively strict inclusion and exclusion criteria have resulted in a lower-than-anticipated enrollment rate. To address this, the study team is exploring new outreach methods, such as newspaper advertisements and distribution of flyers, to attract potentially eligible participants. A study coordinator has been appointed at the coordinating center to streamline participant management and improve recruitment efficiency.
Eligible participants are being randomized into active or control groups using a custom-built online dashboard developed by study staff at UNIMIB. Participants in the active group have commenced nutritional and physical evaluations, with cognitive stimulation via BrainHQ slated to begin in January 2025, following two educational sessions led by neuropsychologists.
The website for the control group has been finalized and is ready for launch. It features a structured, week-by-week educational program that spans the entire 12-month study period, offering participants a robust support system.
Meanwhile, other recruiting centers are still in their screening phases, actively hiring key personnel and preparing for the RCT phase, pending approval of the protocol amendment.
Detailed operative protocols for collection, preparation and storage of biological samples, previously written by the laboratory of the coordinating unit (UNIMIB) in agreement with all laboratories involved in the analysis of blood biomarkers planned for this study (UNIMIB, UNIBA, CNR Lecce, UNIFI, UPO), were sent and discussed with all clinical centers before starting of the recruitment. At the end of December 2024, biological samples from 57 subjects enrolled in the clinical unit of Monza (IRCCS San Gerardo dei Tintori) were prepared and stored in the laboratory of UNIMIB for the planned biomarker analyses.
Scientific publications:
Pozzi FE, Appollonio I, Ferrarese C, Tremolizzo L. Can Traditional Board Games Prevent or Slow Down Cognitive Impairment? A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2023;95(3):829-845. doi: 10.3233/JAD-230473. PMID: 37638443.
Pozzi FE, Calì L, Ferrarese C, Appollonio I, Tremolizzo L. Assessing behavioral and psychological symptoms of dementia: a comprehensive review of current options and future perspectives. Front Dement. 2023 Jul 25;2:1226060. doi: 10.3389/frdem.2023.1226060. PMID: 39082001; PMCID: PMC11285590.
Pegoraro S, Facchin A, Luchesa F, Rolandi E, Guaita A, Arduino LS, Daini R. The Complexity of Reading Revealed by a Study with Healthy Older Adults. Brain Sci. 2024 Feb 28;14(3):230. doi: 10.3390/brainsci14030230. PMID: 38539618; PMCID: PMC10968258.
Dibello V, Lobbezoo F, Solfrizzi V, Custodero C, Lozupone M, Pilotto A, Dibello A, Santarcangelo F, Grandini S, Daniele A, Lafornara D, Manfredini D, Panza F. Oral health indicators and bone mineral density disorders in older age: A systematic review. Ageing Res Rev. 2024 Sep;100:102412. doi: 10.1016/j.arr.2024.102412. Epub 2024 Jul 9. PMID: 38992442.
Dibello V, Custodero C, Cavalcanti R, Lafornara D, Dibello A, Lozupone M, Daniele A, Pilotto A, Panza F, Solfrizzi V. Impact of periodontal disease on cognitive disorders, dementia, and depression: a systematic review and meta-analysis. Geroscience. 2024 Oct;46(5):5133-5169. doi: 10.1007/s11357-024-01243-8. Epub 2024 Jun 28. PMID: 38943006; PMCID: PMC11336026.
Dibello V, Lobbezoo F, Panza F, Lozupone M, Pilotto A, Vitale V, Custodero C, Dibello A, Vertucci V, Daniele A, Manfredini D, Solfrizzi V. Oral frailty indicators and cardio- and cerebrovascular diseases in older age: A systematic review. Mech Ageing Dev. 2025 Feb;223:112010. doi: 10.1016/j.mad.2024.112010. Epub 2024 Nov 28. PMID: 39615857.
Ami D, Santambrogio C, Vertemara J, Bovio F, Santisteban-Veiga A, Sabín J, Zampella G, Grandori R, Cipolla L, Natalello A. The Landscape of Osteocalcin Proteoforms Reveals Distinct Structural and Functional Roles of Its Carboxylation Sites. J Am Chem Soc. 2024 Oct 9;146(40):27755-27769. doi: 10.1021/jacs.4c09732. Epub 2024 Sep 30. PMID: 39348444.
Dissemination event:
Organization of the international meeting of the Milan Center for Neuroscience: NeuroMI 2024 “Brain health and prevention of cognitive decline”, Milan, October 23-25, 2024, University of Milano-Bicocca.