The Vulnerable Island
Authors:   , Fathy Yasmine Yousri 
Published: September 2023

This “Vulnerable Island” thesis combines post-mortem human brain studies and
in-vivo MRI to investigate the role of the insular cortex in neurodegenerative diseases,
particularly PD and DLB. The first part of the thesis, in chapter III and IV, highlights the
various neuropathological features, including the presence of neurofibrillary tangles
(p-Tau), β-amyloid plaques, and α-synuclein pathology, and their distribution pattern
within the insular sub-regions. This is followed by a close-up investigation of the specific
cellular phenotypes affected, axonal degeneration, and myelin irregularities associated
with the presence of these neuropathological aggregates. After careful observation of
the distribution of pathology in the insula and its role in various neurodegenerative
diseases, a clear pattern could be observed: the insular cortex along with its partner,
the cingulate cortex, is one of the first cortical regions displaying neuropathological
aggregates. Chapter II particularly emphasizes the striking microscopic, anatomical,
neuropathological, and functional similarities between the insular and cingulate cortices
and discusses the clinical deficits subsequent to their joint degeneration.
The second part of the thesis focuses on the connectivity and network changes of the
insular cortex. Using Diffusion tensor imaging and functional MRI modalities, this part
of the thesis explores the structural and functional connections of each insular sub-
region significantly disrupted by degeneration in PD. In chapters VI and VII, we show
that connections between the insular and cingulate cortices are significantly disrupted
in PD leading to cognitive deficits and disrupted activity within other major brain
network associated with control of cognition. Chapter V sheds light on the behavioral,
cognitive, affective, and psychiatric deficits associated with distinct insular sub-regional
atrophy in common neurodegenerative disease such as Frontotemporal dementia,
Alzheimer’s disease, PD, and DLB.
Overall, the research presented in this thesis discussed significant points about the
insular cortex and its crucial role in neurodegeneration:
1. The insular cortex consists of distinct sub-regions each with a unique set of cellular,
structural, and functional characteristics influencing disease development
2. Variations within insular sub-regions, such as von Economo neuron vulnerability,
axonal and myelin abnormalities, astroglial pathology and the combination of
multiple pathological aggregates are key defining features
3. The insula is vital for complex intellectual functions, as a brain hub through its inter-
actions with various other brain regions, integration of information, and potentially
serving as a hub for pathological aggregates
4. Insular degeneration and atrophy impact specialized functions through disruption of
its integrative abilities and other large-scale networks involved in control of cognition
5. The anterior insula and cingulate cortices share unique cellular features, circuitries,
networks, and disease-specific patterns

In light of these findings, the “Vulnerable Island” delves into the intricate insular charac-
teristics underlying the complex nature of degeneration in PD and DLB, shedding light
on the role of specific neuron types, axonal changes, astroglial involvement, and insular
connectivity changes and their clinical impact in disease. It further questions whether
disease management strategies should target essential brain hubs such as the insula
and cingulate cortices given their position in brain networks, their co-activation, their
unique similarities, and shared stages of proteinopathy. Although the thesis focuses on
PD and DLB, the implications of insular damage are extended to other neurodegenera-
tive diseases to provide further evidence on the potential role of the insula as a gateway
to cortical degeneration due to its early vulnerability and pivotal role in brain networks.