Comparison of Two Non-invasive Neuromodulation Techniques as Synergistic Therapy to Cognitive Stimulation in Amnestic Mild Cognitive Impairment (aMCI): Genetic Characterization, Proteins Associated With Neurogenesis, Clinical, Neuroimaging and Electrophysiological Markers

Mild Cognitive Impairment can be described as an intermediate stage between intact cognition and dementia, this study has become a global priority due to alarming changes in the population pyramid that place the world population at a higher risk of developing dementia. The global prevalence of MCI is between 15-20% in people over 60 years old. In 2012, a prevalence of MCI of 3.2% was found in Mexico City, which encourages the researchers to study this phenomenon to achieve early detection and create interventions that could delay the onset of dementia and even prevent it. Symptomatology is distinguished by deficits in one or more cognitive domains through formal tests applied repeatedly; the individual can manifest symptoms directly by identifying as different from a previous state and/or being corroborated by an informant. The amnestic cognitive impairment (aMCI) occurs when the cognitive failure is limited only to the domain of episodic memory. Generally, there is a slight functional impairment for complex tasks, but the basic and instrumental activities of daily life must be preserved. Behavioral and psychological symptoms (BPSD) can occur. Apathy, anxiety, and depression present in patients with mild cognitive impairment may represent an increased risk of dementia and in many cases, can be the first symptoms to appear. The evaluation is essential because BPSD are often controllable with treatment and appears in up to 77% of patients with MCI.

Despite the need to stop the progression to dementia, a MCI treatment is currently nonspecific, focused on associated events, with pharmacological and non-pharmacological measures aimed to reduce cognitive and neuropsychiatric symptoms. Therapeutic methods that promote neuroplasticity, for instance, cognitive stimulation (CS) and non-invasive neuromodulatory techniques such as Repetitive Transcranial Magnetic Stimulation (rTMS) and Transcranial Direct Current Stimulation (tDCS), optimize performance by stimulating the neural network distributed around a dysfunctional circuit, interacting with brain plasticity, and inducing or increasing compensatory mechanisms. This phenomenon could add to the cognitive reserve and interfere with the temporal evolution of the symptoms. Thereby, the rTMS and tDCS have been suggested as a possible treatment in aMCI. These non-invasive alternatives (rTMS and tDCS) have shown efficacy as a treatment in other disorders, but evidence is required on the efficacy, tolerability, and viability of the application in patients with amnesic MCI as well as the time that the effect of its application remains, which creates the need of further studies with maintenance phases.

In this project, the researchers propose a clinical trial for participants with risk of developing dementia using rTMS and tDCS added to CS in an effectiveness comparison using strict placebo control methods which will only be used with rTMS and tDCS, not with CS. The non-invasive neuromodulating techniques will be applied as a treatment alternative to be able to compare the techniques with CS alone, taking into account clinical and neuropsychological evaluations in addition to: 1) the known clinical risk factors (physical activity, comorbidities treatment, etc.) that allow to characterize patients; 2) characterize the participants with genetic biomarkers using the APOE4, CR1, COMT, TREM2 and ABCA7 genotype; 3) document the biological effects related to neurogenesis from olfactory epithelial neural progenitor cells isolated before and after treatment. In addition to the documentation of soluble factors secreted by olfactory epithelial neural progenitor cells, what is relevant to the knowledge of the influence of peripheral serum on microglia. This is crucial role in inflammation. The evaluations will be performed at different time points such as: Baseline (T0), after first phase of treatment (T1=15 sessions/week of tDCS+CS), after maintenance (T2=12 sessions/week of tDCS+CS), and follow-up phase (T3=1 year after treatment); 4) use hippocampal volume, cortical thickness of the medial temporal cortex and parietal cortex using structural magnetic resonance imaging and the default mode network using functional magnetic resonance imaging at rest as a biomarker of response to treatment and 5) associate the response to treatment with changes in Motor Evoked Potential (MEP) amplitude to generate a response-to-treatment biomarker with neuromodulators in MCI and changes in electroencephalogram (EEG).

Among the current limitations on knowledge of this disease, many studies use biomarkers to predict MCI or progression to dementia, and although most biomarkers are reported to be valuable in this setting, few are compared with each other, so this is currently difficult to understand the relative importance of the different biomarkers when used together. For this reason, the present project could be a contribution in the short and long term to detect changes that may or may not be related to each other and generate multiple lines of research.

Population aging will continue to increase and therefore there will be a greater number of people with aMCI. Currently, there is no treatment that prevents the progression of aMCI to AD, so the trend is to make earlier interventions. aMCI is a condition of opportunity because the cognitive reserve of the patients has not been exhausted, so developing studies with innovative treatments and few side effects that can change the evolution over time is important. To that end, understanding the etiology of this progression and designig treatments that delay or definitively stop aMCI are of importance to preserve the functionality of individuals with this condition.