New Approaches for the Treatment of Early Stages of Cognitive Impairment in Neurodegenerative Diseases

Non-pharmacological intervention may represent adjunctive therapy to medications in order to delay the onset of the cognitive deficits or dementia. Moreover, increasing evidence suggests that environmental and lifestyle factors (education, cognitive engagement, experience..) impact on cognitive functions and brain plasticity during the lifetime and also during aging. These modifiable factors moderate differences in cognitive aging and are protective for the development of dementia.

Among non-pharmacological approaches, previous studies observed a positive effect of Cognitive Training (CT) both in healthy elderly people and patients in the early stage of neurodegenerative diseases. Moreover, the advances in the development of Information & Communication Technologies has prompted the possibility to develop computer-based solution for the training of cognitive functions, being able to overcome traditional-training advantages. However, some issue remain unresolved and larger randomized controlled trials are necessary to examine long-term CT effects, due to the lack of longitudinal studies. Our previous data demonstrated that CT program with Computerized cognitive training (CoRe) software is safe and effective on cognition in patient with Parkinson Disease-Mild Cognitive Impairment, in the attempt of briefly stabilizing cognitive decline, delaying the downward trajectory.

Recently, different forms of non-invasive brain stimulation techniques have been applied to healthy older adults and patients with Alzheimer Disease (AD) in order to improve physiological and pathological aging-related cognitive impairments. Two main forms of non-invasive brain stimulation techniques are repetitive Transcranial Magnetic Stimulation (rTMS) and Transcranial Direct Current Stimulation (tDCS). rTMS is a painless, non-invasive method that modulates cortical activities by delivering strong magnetic pulses to the cortex through the scalp. Depending on stimulation parameters (e.g., duration, stimulus intensity, frequency), rTMS can enhance or suppress cortical excitability in targeted cortical regions. In general, high frequency rTMS facilitates cortical excitability whereas low frequency rTMS suppresses cortical excitability. tDCS delivers weak electrical currents to the scalp to modulate neuronal transmembrane potential towards hyperpolarization or depolarization, thereby altering plasticity in the stimulated brain regions. Depending on whether anodal or cathodal stimulation is applied, tDCS increases or decreases cortical excitability, respectively.These non-invasive brain stimulation techniques can be used alone or in combination with cognitive intervention programs. Some studies suggested that these non-invasive neurostimulation are able to enhance the effect of CT; however other studies yielded conflicting results, likely due to differences in stimulation parameters, experimental design and outcome measures. Thus, the overall efficacy of non-invasive neural stimulation as a therapeutic is still under debate.

In this frame, the primary goal of this double-blind randomized controlled trial is to assess whether the application of non-invasive brain stimulation techniques (tDCS or TMS) during the course of a computerized CT (on-line neurostimulation) enhances the effect on CT. Moreover, the follow-up visits allow to detect if the improvement are maintained over time and if this combined intervention affect the evolution of cognitive decline.

The treatment protocol consists of 12 sessions (4 session/week, 45 minutes/day) of CT with CoRe software (training memory and logical-executive functions) combined with on-line tDCS (anodic tDCS, 2mA for 20 minutes, versus sham tDCS applied to the cortical prefrontal cortex - DLPFC ) or rTMS (rTMS 20 Hz for 20 minutes versus sham TMS applied to DLPFC).