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.
Clinical trials with rTMS and tDCS carried out in aMCI have already shown favorable
results regarding episodic memory, semantic memory, and speed of information processing.
This trial will be able to contribute to the already reported findings that allow to
identify better therapeutic approaches that support the standardization of the
application of neuromodulatory techniques. Besides, the possible additive effect of
neuromodulatory techniques and CS is well known, but no studies are comparing between
diferent interventions with each other. The genetic characterization will be obtained, an
experimental biomarker of secretion proteins from olfactory epithelial neural progenitor
cells together with the analysis of the neurogenic process occurring in the olfactory
epithelium will be generated, an experimental biomarker of serum and the effects soluble
factors contained in serum on microglia will be generated, neuroimaging and produce
neurophysiological measures considered as possible neuroplasticity biomarkers (MEPs and
EEG) associated with the response to non-pharmacological treatment will be recorded and
evaluated if the parameters are related to clinical and cognitive characteristics. With
this therapeutic approach where non-invasive neuromodulatory techniques are combined with
CS, the aim is to improve the quality of care for patients with aMCI, considering that
neuromodulation alternatives can delay the process of deterioration in each patient
admitted.
The hypotheses in this study are: 1) The combined application of non-invasive
neuromodulation techniques with cognitive stimulation will significantly improve the
cognitive performance of patients with aMCI, compared to the single application of
non-invasive neuromodulation techniques or cognitive stimulation alone. 2) There will be
differences in the protein expression in the olfactory epithelial neural progenitor cells
of patients with aMCI who are treated with some non-invasive neuromodulation techniques
and those who only receive cognitive stimulation. 3) The soluble factors in the serum of
patients with aMCI before and after treatment will differentially modulate microglia. 4)
There will be differences in brain morphology such as cortical thickness and surface
area, white matter integrity, as well as structural connectivity between different brain
areas before and after treatment with non-invasive stimulation techniques. 5) There will
be differences in the amplitude and latency of the MEP as well as changes in EEG of
patients with aMCI who are treated with one of the non-invasive neuromodulation
techniques and patients who only receive CS.