INVESTIGATE THE ROLE OF GLOBAL BRAIN ACTIVITY IN NEURODEGENERATION AND AGING
Restricted (Penn State Only)
- Author:
- Han, Feng
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 24, 2022
- Committee Members:
- Xiao Liu, Chair & Dissertation Advisor
Nanyin Zhang, Major Field Member
Michele Diaz, Major Field Member
Daniel Hayes, Program Head/Chair
Xuemei Huang, Outside Unit & Field Member
Xiang Zhang, Outside Field Member - Keywords:
- Resting-state functional magnetic resonance imaging
global brain activity
global signal
glymphatic system
amyloid-β
cross-hierarchy difference
Alzheimer's disease
cerebrospinal fluid
Parkinson’s disease
healthy aging
the coupling between the global brain and the cerebrospinal fluid fMRI signals - Abstract:
- Resting-state functional magnetic resonance imaging (rsfMRI) has been widely used to probe brain activity and neurological dysfunction. The majority of clinical rsfMRI studies to date were focused on the abnormal activation and connectivity at specific brain regions, but the overall rsfMRI signals from the global brain activity (global rsfMRI signal) were largely overlooked. Although global rsfMRI signal has been linked to a variety of noise or nuisance components and often removed from fMRI signals, it recently has been found to reflect a characteristic brain-wide activity related to neuronal spiking activity, physiological modulation, and arousal fluctuation. In addition, a newly discovered “glymphatic system” plays an important role in clearing protein wastes, e.g., toxic species of amyloid-β (Aβ), α-synuclein, or tau, from the brain during the processes of neurodegeneration and normal aging, and may be related to sleep-dependent global brain activity. Interestingly, the global brain signal presents predominantly at lower-order primary sensory cortices, including the visual, somatosensory, and auditory regions, compared with the higher-order association cortices, including the precuneus, posterior cingulate, and orbitofrontal cortices. It shows a consistent spatial pattern of cross-hierarchy difference with the accumulation of Aβ at the earliest preclinical Alzheimer's disease (AD) stage and thus may imply their close link. It is important to investigate the role of global brain activity in glymphatic clearance and the pathology/mechanism of neurodegenerative diseases and aging. In this dissertation, we first examined the role of global brain activity in the clearance of AD-related brain waste by quantifying the glymphatic function with a recently derived sleep-dependent metric, the coupling between the global brain and the cerebrospinal fluid (CSF) fMRI signals. By analyzing multimodal data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) project, we found that the coupling metric is closely associated with AD-related pathology, including various risk factors for AD, the cortical Aβ level, and 2-year cognitive decline. Then, we showed the glymphatic function reflected by the coupling metric was significantly associated with cognitive decline in Parkinson’s disease (PD) patients, as well as age in a large cohort of old healthy subjects, particularly after 50 years old. The declining trajectory of the coupling between the global brain and CSF fMRI signals with aging in males was different from that in the females whose coupling strength appeared to decrease more abruptly after around 50s. Next, our further inspection of the coupling between the regional brain and CSF fMRI signals in the early-stage AD subjects suggested that weaker local glymphatic function and the withdrawal of the global brain activity in the default mode network (DMN) may explain the preferential Aβ accumulation there at the earliest preclinical AD, in contrast with the slower accumulation rate at the lower-order sensory-motor regions. We also found such a feature of the cross-hierarchy contrast between higher-order DMN and lower-order sensory-motor in the cortical thickness and functional connectivity strength changes could be linked to the positive-negative trait of human behavior/demographics in healthy young adults. Overall, this dissertation work inspected the effect of global brain activity on neurodegeneration and aging via the close link between glymphatic clearance and the coupled global brain and CSF fMRI signals. It provides novel insights into the interpretation of the driving force of glymphatic function and emphasizes the role of global brain activity and the cross-hierarchy contrast in neuroimaging studies.