Early screening of Alzheimer’s disease through the measurement of the hemodynamic responses in the prefrontal lobe by using functional near-infrared spectroscopy

Abstract

In this study, we employed functional near-infrared spectroscopy (fNIRS) to investigate differences in prefrontal hemodynamics across various stages of Alzheimer's disease (AD) during cognitive tasks assessing attention, working memory, and language functions. fNIRS is a non-invasive optical imaging technique that uses diffuse light to measure brain function without penetrating the skull or brain tissue. By converting optical density measurements to hemoglobin concentration changes using the modified Beer-Lambert law, fNIRS quantifies brain activity under cognitive workloads. We hypothesized that functional connectivity in the frontal lobe begins to change during the asymptomatic phase, before the onset of clinical symptoms.

Chapter 1 highlights the urgency of early detection, as AD accounts for 70 \% of dementia cases worldwide. It progresses through three stages: asymptomatic, prodromal, and dementia. The asymptomatic phase can last 10–15 years before noticeable cognitive decline begins, making early diagnosis crucial for improving outcomes. Current methods like positron emission tomography (PET) imaging and cerebrospinal fluid sampling are invasive, underscoring the need for a non-invasive and accessible screening tool.

Chapter 2 introduces the basics of continuous-wave fNIRS and its applications. A portable fNIRS system was developed using light-emitting diodes and photodiodes and validated through experiments. The system measures hemoglobin concentration in the brain with four channels targeting the prefrontal region. Two additional channels were used to filter out noise. The chapter concludes with a summary of clinical studies using fNIRS.

Chapter 3 presents a preliminary comparison between cognitively healthy older adults and individuals with prodromal AD. Using a four-channel fNIRS system, we observed greater amplitude changes in oxyhemoglobin and deoxyhemoglobin, as well as a significantly higher maximum slope of oxyhemoglobin change, in subjects with mild cognitive impairment during a verbal fluency task. Additionally, prefrontal functional connectivity was assessed across multiple cognitive tasks, including resting-state, oddball, 1-back, and verbal fluency tasks.

Chapter 4 focuses on pathological changes across AD-related groups, including asymptomatic, prodromal, and dementia stages. Significant group differences were observed during oddball and 1-back tasks, particularly in deoxyhemoglobin changes, with the highest levels in the asymptomatic group. Resting-state analysis revealed suppressed interhemispheric functional connectivity in asymptomatic and prodromal groups, while the oddball task showed enhanced right prefrontal connectivity. During the verbal fluency task, the prodromal group exhibited increased interhemispheric and left prefrontal connectivity in oxyhemoglobin and right prefrontal connectivity in deoxyhemoglobin. The asymptomatic group showed higher left prefrontal connectivity in deoxyhemoglobin. These findings suggest early neural alterations in the asymptomatic phase, with increased right prefrontal connectivity indicating potential compensatory changes in language-related processing.

In Chapter 5, cognitively healthy controls were divided into amyloid-negative (healthy control) and amyloid-positive (asymptomatic AD) groups to identify potential early screening indicators. Elevated functional connectivity was observed in the asymptomatic AD group, and fNIRS features correlated with amyloid PET standardized uptake value ratio. Combining functional connectivity features with clinical data from neuropsychological test results enhanced the distinction between healthy controls and the asymptomatic AD group. These findings suggest that altered functional connectivity during the asymptomatic phase could be a supportive tool for early screening of AD.

Chapter 6 concludes the dissertation with a summary of studies, limitations, further direction, and perspective.