Connecting the dots in neuromodulatory systems: Pathological sensitivity of diffusion MRI in Alzheimer's and Parkinson's disease

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most prevalent neurodegenerative disorders, each with distinct clinical and pathological features. AD typically presents with memory loss and behavioral deficits but can manifest as atypical subtypes, involving visuospatial, language, or behavioral impairments while sparing memory initially. Pathologically, AD is characterized by tau neurofibrillary tangles (NFTs) and amyloid-β (Aβ) plaques. PD, on the other hand, is defined by bradykinesia, resting tremors, or rigidity, accompanied by cognitive impairments, depression, and anxiety, which may occur before or after motor symptoms. PD progresses to mild cognitive impairment (PD-MCI) or dementia (PDD), with approximately 80% of patients developing PDD within ten years. If dementia appears within a year of motor symptoms, it is classified as dementia with Lewy bodies (DLB). Pathological hallmarks of PD(D) and DLB include α-synuclein aggregates forming Lewy bodies and dopaminergic neuronal loss in the substantia nigra (SN). Neuromodulatory systems, such as the noradrenergic, dopaminergic, and cholinergic systems, play critical roles in the progression of both AD and PD. The locus coeruleus (LC) synthesizes noradrenaline, modulating cognition, sleep, and wakefulness; the substantia nigra pars compacta (SNpc) produces dopamine for motor coordination; and the nucleus basalis of Meynert (NbM) generates acetylcholine, essential for cognitive functions. Pathological changes in these systems disrupt neurotransmitter transmission, contributing to the cognitive and neurological symptoms in AD and PD. Structural MRI, including diffusion MRI, offers a promising non-invasive tool for characterizing microstructural brain changes and monitoring disease progression. Metrics such as fractional anisotropy (FA) and mean diffusivity (MD) reflect brain integrity and are increasingly investigated for their potential as biomarkers. However, MRI findings have not been validated against human histopathological data. This thesis leverages in situ post-mortem diffusion MRI combined with histopathology to explore the microstructural changes in neuromodulatory nuclei and their pathways, aiming to bridge the gap between neuropathology and MRI measures. Chapter II highlights microstructural alterations in the LC and its tracts in AD and PD. AD patients showed degeneration in the LC-dorsolateral prefrontal cortex (DLPFC) tract, while PD patients exhibited damage in the LC-motor cortex (M1) tract. These changes were driven by noradrenergic neuronal loss in the LC rather than cortical pathology. These findings emphasize the need for LC-sensitive imaging techniques combined with diffusion MRI to develop early-stage biomarkers for neurodegenerative diseases. Chapter III demonstrates the ability of diffusion MRI to capture SN microstructural alterations and its projections to the caudate nucleus and DLPFC in PD and PDD/DLB. PDD/DLB patients showed severe tract damage, linked to dopaminergic degeneration and Lewy neurites. Notably, the caudate nucleus, not the putamen, was implicated in PDD, suggesting its potential role in cognitive decline. These findings highlight diffusion MRI’s capacity to develop reliable markers for diagnosing and monitoring PD progression. Chapters IV-I and IV-II reveal diffusion MRI’s ability to detect NbM and tract degeneration in AD and PD. In AD, NbM-temporal lobe tract damage varied between subtypes and correlated with dementia severity. In PD-MCI, the NbM-insula tract was damaged, associated with cognitive impairments across domains. These findings suggest that cholinergic neuronal loss in the NbM underlies MRI-measured alterations, underscoring its value in monitoring cognitive decline and dementia onset in both diseases. This thesis establishes a novel framework for integrating in situ post-mortem diffusion MRI and histopathology to refine the biological interpretation of MRI biomarkers in neuromodulatory systems. By clarifying the neuronal and pathological underpinnings of these imaging markers, this work provides critical insights into AD and PD progression. Future research should adopt holistic, interdisciplinary approaches to unravel the complexity of neuromodulatory dysfunction across disease stages, leveraging large, longitudinal cohort studies for early diagnosis, prognosis, and therapeutic interventions.