Using Light Therapy for Mild Cognitive Impairment

Amyloid Pathology, Mild Cognitive Impairment (MCI)

Cognition, Neurovascular Coupling Mechanism and Cognitive Function, Neurovascular Control, Brain Aging, Brain Activity, Mild Congitive Impairment (MCI), Amyloid, Transcranial photobiomodulation, Near-infrared spectroscopy, Cerebral hemodynamics, Near-infrared light therapy, NIH Toolbox Cognition Battery, Electroencephalography, Amyloid-positive mild cognitive impairment, Amyloid-negative mild cognitive impairment, Extracellular vesicles, Neuroinflammation, Proinflammatory cytokines, Home-based neuromodulation, Non-invasive brain stimulation, Sham-controlled clinical trial, Randomized clinical trial, photobiomodulation therapy

The goal of this clinical trial is to test whether transcranial photobiomodulation (tPBM), a non-invasive brain stimulation technique using near-infrared light, can improve brain blood flow regulation (neurovascular coupling) and cognitive function in people with mild cognitive impairment (MCI). The main questions it aims to answer are: * Does tPBM enhance cognitive function and cerebral hemodynamic responses during memory and finger tapping tasks? * Does tPBM reduce oxidative stress, inflammation, and mitigate brain cell damage? * Is cognitive improvement linked to amyloid status, greater cerebral hemodynamic response, and lower levels of brain inflammation and oxidative stress? Researchers will compare an active tPBM treatment arm to a sham treatment arm to see if tPBM leads to measurable improvements in brain activity and cognitive function compared to no active stimulation. Participants will: * Receive a 20-minute-long active tPBM or sham stimulation session once per day, 6 times per week, for 12 weeks. * Complete questionnaires and an iPad-based cognitive testing protocol. * Complete memory and motor tasks while their brain activity is measured using non-invasive techniques: simultaneous functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG). Dynamic analysis of the vessels in the eye will also be performed based on eligibility. Transcranial Doppler (TCD) flowmetry is optionally performed. * Provide blood samples to test for biomarkers of inflammation, oxidative stress, and brain cell damage.

Cognitive impairment represents a major source of disability, with vascular pathologies playing a critical role in the development and progression of cognitive dysfunction. In particular, vascular cognitive impairment (VCI) is a common and clinically relevant contributor to cognitive decline in individuals with MCI. Despite substantial advances in understanding the underlying mechanisms of VCI, effective therapeutic interventions remain limited. Neurons require continuous energy supply, which is provided by the physiological process, called Neurovascular coupling (NVC), a dynamical redistribution of local cerebral blood flow to meet neuronal activity. NVC is essential to maintain optimal brain function. Evidence from our preclinical and clinical work, in line with findings from other research groups, increasingly implicates NVC dysregulation as a key mechanism underlying cognitive deficits in MCI, underscoring the need for targeted interventions aimed at restoring neurovascular function. Transcranial photobiomodulation has emerged as a promising, non-invasive approach with the potential to support both neuronal and vascular health. By delivering near-infrared light to cortical tissue, tPBM has the potential to enhance mitochondrial activity, reduce oxidative stress, and improve cerebral hemodynamics. A growing body of literature demonstrates the beneficial effects of red and near-infrared light across a range of neurological, cardiovascular, and cerebrovascular conditions. However, the neurophysiological mechanisms underlying these effects remain insufficiently characterized in humans, and the therapeutic potential of tPBM has yet to be fully explored in clinical populations such as individuals with MCI. Optical imaging modalities, including near-infrared spectroscopy (NIRS), provide an opportunity to assess tPBM-induced changes in cerebral oxygenation and hemodynamics in real-world settings, thereby improving the feasibility and translational relevance of studies investigating cerebrovascular mechanisms in MCI. Further practical advantages of tPBM lie in its documented safe application, affordability, and simplicity of use; these factors support the utilization of tPBM in potential home-based interventions. Recent studies have demonstrated a close association between cognitive performance and NVC responses both in healthy individuals and in patients with MCI. Neuronal activity-induced vasodilation is largely mediated by nitric oxide, whose bioavailability is enhanced by tPBM through its dissociation from cytochrome c oxidase. In addition, tPBM has been shown to exert anti-inflammatory effects within the brain, a mechanism that is particularly relevant given evidence of elevated neuroinflammatory processes in MCI. Despite these promising findings, clinical evidence directly examining the effects of tPBM on NVC remains limited. Existing studies have primarily focused on cognitive outcomes, with relatively little emphasis on underlying neurophysiological or hemodynamic changes and minimal integration of these measures. Addressing this gap, the present study aims to employ advanced multimodal neuroimaging techniques to investigate tPBM-induced modulation of NVC in individuals with MCI and to examine its relationship with cognitive performance. Preclinical and early clinical studies indicate that tPBM enhances microvascular perfusion and tissue oxygenation while concurrently reducing neuroinflammation and oxidative stress. These complementary effects highlight tPBM as a multifaceted intervention capable of targeting both neural and vascular dysfunction. To date, tPBM has demonstrated a favorable safety profile across diverse populations, with transient and mild headache being the most commonly reported adverse effect. Its non-pharmacological nature and compatibility with existing therapeutic strategies further support its potential role in cognitive rehabilitation. The significance of this project lies in its potential to advance a novel, non-invasive intervention for cognitive impairment in patients with MCI, as well as in its capacity to elucidate the neurovascular mechanisms through which tPBM exerts its effects. By clarifying how tPBM modulates NVC and related cognitive outcomes, this research will provide a foundation for future mechanism-driven and combination therapeutic approaches aimed at mitigating cognitive decline associated with MCI.

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