Volumetric Analysis of Prodromal DLB and AD

Accurate differentiation of prodromal dementia with Lewy bodies (MCI-LB) from
mild cognitive impairment due to Alzheimer’s disease (MCI-AD) remains a challenge
in clinical neurodegeneration. Although cerebrospinal fluid (CSF) biomarkers
enable in vivo detection of α-Synucline and amyloid/tau pathology, it remains unclear
whether these molecular processes produce distinct patterns of brain atrophy
during the prodromal stage. This thesis investigated whether LB and AD pathologies
are associated with structural MRI signatures and trajectories of neurodegeneration.
Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
The first study used a 2×2 factorial design based on CSF α-Synuclein seed amplification
assay (SAA) and CSF Aβ42 together with the p-tau181/Aβ42 ratio
to determine the effects of LB and AD pathology on cortical thickness and subcortical
volumes. The second study reconstructed defined MCI-LB and MCI-AD
cohorts within ADNI to evaluate the translational relevance of pathology-driven
structural findings. The third study applied longitudinal MRI processing and linear
mixed–effects modelling to characterise brain atrophy, cognitive decline, and
brain–behaviour relationships.
AD pathology was associated with widespread medial temporal and temporoparietal
atrophy, whereas LB pathology showed hippocampal preservation and predominantly
subcortical involvement, indicating partially distinct anatomical signatures.
Mixed pathology produced additive rather than synergistic effects. In defined cohorts,
structural differences between MCI-LB and MCI-AD were less pronounced,
highlighting discordance between clinical phenotype and molecular pathology. Longitudinal
analyses demonstrated accelerated medial temporal atrophy and memory
decline in MCI-AD, while MCI-LB exhibited slower hippocampal degeneration with
greater executive and visuospatial impairment. Rates of regional brain atrophy were
associated with domain-specific cognitive decline.
Collectively, these findings demonstrate that AD and LB pathologies produce partially
dissociable structural and longitudinal neurodegenerative patterns during the
prodromal stage. They further show that volumetric MRI reflects biological pathology
more closely than clinical phenotype, supporting biomarker–informed diagnosis
and pathology–specific stratification in early neurodegenerative disease.