SYNERGIC TRIAL (SYNchronizing Exercises, Remedies in Gait and Cognition) a multi-Centre randomized controlled double blind trial to improve gait and cognition in mild cognitive impairment

This paper outlines the protocol for a study designed to test the effectiveness of a multimodal intervention on cognitive function and mobility in older adults with Mild Cognitive Impairment (MCI). The core intervention is a combination of aerobic exercise (AE) and progressive resistance training (RT), referred to as "combined exercise."

This combined exercise is then tested with additional components in a quasi-factorial design:

**Interventions:**

* **Combined Exercise:** Aerobic exercise and progressive resistance training. The specific details of the exercise program (frequency, intensity, duration, types of exercises) are not detailed in this abstract but would be in the full protocol.

* **Dual-Task Cognitive Training:** A type of cognitive training that involves performing two tasks simultaneously, designed to challenge cognitive resources.

* **Vitamin D Supplementation:** 3 x 10,000 IU per week (totaling 30,000 IU/week).

**Comparators:**

* **Balance and Toning (BAT) Control:** A control exercise intervention that focuses on balance and toning, rather than aerobic or progressive resistance training. This serves as a control for the general effects of physical activity.

* **Sham Cognitive Training:** A control for the dual-task cognitive training, designed to mimic the experience without providing the specific cognitive challenge.

* **Placebo Vitamin D:** A placebo pill identical in appearance to the vitamin D supplement, used to control for the psychological effects of taking a supplement.

**Outcome Measures:**

* **Primary Outcome:**

* **ADAS-Cog (13 and plus modalities):** The Alzheimer's Disease Assessment Scale-Cognitive Subscale, a widely used psychometric test to assess cognitive function, particularly in memory, language, and praxis. The "13 and plus modalities" refers to specific versions or additional components of this scale. The study aims to measure changes in this score from baseline to 6 months.

* **Secondary Outcomes:**

* **Neuroimaging:** Techniques to visualize brain structure and function (specifics not detailed in abstract).

* **Neuro-cognitive performance:** A broader range of tests assessing various cognitive domains beyond ADAS-Cog.

* **Gait and mobility performance:** Measures of how participants walk and move, which are often impaired in MCI.

* **Serum biomarkers:** Blood tests to measure:

* **Inflammation:** C-reactive protein (CRP) and Interleukin 6 (IL-6).

* **Neuroplasticity:** Brain-derived neurotrophic factor (BDNF).

* **Endothelial markers:** Vascular endothelial growth factor 1 (VEGF-1).

* **Vitamin D serum levels:** To confirm compliance and effectiveness of supplementation.

The SYNERGIC trial plans to study:

**Sample Size:** Two hundred (200) participants.

**Population:** Older adults diagnosed with Mild Cognitive Impairment (MCI).

**Age Range:** 60 to 85 years old.

**Setting:** A multi-site study, meaning participants will be recruited and assessed at multiple research centers. The specific locations are not detailed in the abstract.

The inclusion of individuals with MCI is crucial because this population is at an increased risk of progressing to dementia, making interventions in this "pre-dementia state" particularly relevant for potentially stabilizing or reversing decline.

The study plans to use a comprehensive set of measures to assess the impact of the interventions:

**Primary Outcome Measurement:**

* **ADAS-Cog (13 and plus modalities):** This is a clinician-administered scale that assesses various aspects of cognitive function, including memory (word recall, recognition), language (naming, comprehension), orientation, and praxis (ability to perform learned movements). Scores typically range from 0 to 75, with higher scores indicating greater cognitive impairment. The "13 and plus modalities" suggests the use of an extended version of the scale, providing a more detailed assessment. This will be measured at baseline (before interventions begin) and again after 6 months of intervention.

**Secondary Outcome Measurements:**

* **Neuroimaging:** While specific techniques are not detailed in the abstract, common neuroimaging methods used in MCI research include Magnetic Resonance Imaging (MRI) to assess brain volume and structure (e.g., hippocampal atrophy), functional MRI (fMRI) to look at brain activity, and Diffusion Tensor Imaging (DTI) to assess white matter integrity. These provide objective measures of brain changes.

* **Neuro-cognitive performance:** This likely refers to a battery of standardized neuropsychological tests designed to assess specific cognitive domains such as executive function, attention, processing speed, and other memory types, providing a more granular view than the ADAS-Cog alone.

* **Gait and mobility performance:** These measures typically involve timed tests (e.g., 10-meter walk test, Timed Up and Go test), quantitative gait analysis using sensors (e.g., measuring stride length, speed, variability), and balance tests. These provide objective data on physical function.

* **Serum biomarkers:** Blood samples will be collected to measure:

* **C-reactive protein (CRP) and Interleukin 6 (IL-6):** These are inflammatory markers. Elevated levels are often associated with cognitive decline and neurodegenerative diseases.

* **Brain-derived neurotrophic factor (BDNF):** A protein that supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. It plays a key role in neuroplasticity and memory.

* **Vascular endothelial growth factor 1 (VEGF-1):** A signaling protein involved in the formation of new blood vessels (angiogenesis) and maintaining endothelial health, which is important for brain blood supply.

* **Vitamin D serum levels:** Measured to confirm that participants receiving vitamin D supplementation achieve adequate levels and to ensure that the placebo group's levels remain unchanged (or reflect natural variation). This is crucial for verifying the biological impact of the supplementation.

All these measures are chosen to provide a comprehensive picture of cognitive, physical, and biological changes in response to the interventions.

The SYNERGIC trial is designed as a **multi-site, randomized controlled, double-blinded, five-arm trial** with a **quasi-factorial design**. This is a robust study design chosen to provide strong evidence for the efficacy of the interventions.

**Study Design (RCT):** It is a **Randomized Controlled Trial (RCT)**, which is considered the gold standard for evaluating the effectiveness of interventions. Participants are randomly assigned to different groups, minimizing bias and ensuring that, on average, the groups are comparable at the start of the study. This allows researchers to attribute any observed differences in outcomes directly to the interventions, rather than to pre-existing differences between participants.

**Randomization:** Two hundred participants with MCI will be randomly assigned to one of five different study arms. The abstract doesn't specify the randomization method (e.g., block randomization, stratified randomization), but typically, computer-generated sequences are used to ensure true randomness.

* **Why it matters:** Randomization is critical because it helps to balance both known and unknown confounding factors across the groups. For example, if one group accidentally had more participants with higher baseline cognitive function, any improvements might be due to that initial difference, not the intervention. Randomization aims to prevent such imbalances.

**Blinding:** The study is **double-blinded**.

* **Participant Blinding:** Participants will not know which specific intervention arm they are assigned to (e.g., whether they are receiving real vitamin D or placebo, or which type of cognitive training).

* **Researcher/Assessor Blinding:** The researchers and assessors who interact with participants and collect data will also not know which intervention arm each participant is in.

* **Why it matters:** Double-blinding is crucial for minimizing bias. If participants know they are receiving an active treatment, they might experience a placebo effect (improvement due to expectation). If researchers know, they might unconsciously influence participants' responses or interpret results in a biased way. Blinding helps ensure that any observed effects are due to the intervention itself, not psychological factors or observer bias.

**Five-Arm, Quasi-Factorial Design:** The study has five distinct groups:

1. **Combined Exercise + Dual-Task Cognitive Training + Vitamin D** (full multimodal intervention)

2. **Combined Exercise + Dual-Task Cognitive Training + Placebo Vitamin D**

3. **Combined Exercise + Sham Cognitive Training + Vitamin D**

4. **Combined Exercise + Sham Cognitive Training + Placebo Vitamin D**

5. **Balance and Toning (BAT) Control + Sham Cognitive Training + Placebo Vitamin D** (all control interventions)

* **Why it matters:** This quasi-factorial design allows the researchers to investigate not only the overall effect of the multimodal intervention but also the individual contributions and potential synergistic effects of cognitive training and vitamin D when added to combined exercise. By having a group receiving all control interventions, they can establish a baseline for natural progression or general activity effects.

**Duration:** Participants will be followed for **6 months** after baseline measurements. The interventions will be administered throughout this 6-month period.

* **Why it matters:** A 6-month duration is often considered sufficient to observe changes in cognitive and physical function in MCI populations, though longer studies might be needed to assess long-term effects or progression to dementia.

**Statistical Approach:** The abstract does not detail the specific statistical methods, but given the design, it would likely involve comparing changes in ADAS-Cog scores (and secondary outcomes) from baseline to 6 months between the different intervention arms using methods like analysis of variance (ANOVA) or mixed-effects models, accounting for the multi-site nature of the study.

**What this design can and cannot prove:**

* **Can prove:** If completed as planned, this RCT design, with its randomization and double-blinding, is capable of providing strong evidence for the *causal efficacy* of the multimodal intervention (or its components) in improving cognitive and mobility outcomes in older adults with MCI. It can determine if the interventions *cause* an improvement compared to control conditions. The quasi-factorial design allows for investigating potential synergistic effects between the components.

* **Cannot prove (based on the abstract alone):**

* **Long-term effects:** A 6-month study cannot definitively prove long-term benefits or prevention of dementia progression beyond this period