# Selective cellular and regional vulnerability in frontotemporal lobar degeneration: a scoping review

## TL;DR

This review explores which brain cells and regions are most affected in frontotemporal lobar degeneration, focusing on protein accumulation and cell vulnerability.

## Contribution

The paper systematically compiles histological evidence on cell-specific vulnerability in FTLD subtypes, highlighting gaps in non-inclusion-related changes.

## Key findings

- Current knowledge is limited on specific cell subtypes affected by FTLD protein inclusions.
- Non-cell autonomous mechanisms may influence disease progression differently across FTLD subtypes.
- Changes in cell types without pathological inclusions remain largely unexplored.

## Abstract

The three main types of frontotemporal lobar degeneration (FTLD) are
characterized by the accumulation of abnormal proteins, namely tau, TDP-43 and
FUS. The distribution of these proteins within different human brain regions is
well known, as is the range of morphological variability of the cellular
inclusions they form. Compared to the extensive knowledge that exists about
distinct protein aggregates in FTLD, surprisingly little is known about the
specific cell (sub)types that these inclusions affect. Even less is known about
disease-specific abnormalities other than protein inclusions in affected and
unaffected areas. These are non-trivial knowledge gaps. First, knowing which
cell subtypes are vulnerable or resilient to the development of pathological
protein inclusions is crucial to understand the cellular disease mechanisms.
Second, mounting evidence suggests that non-cell autonomous mechanisms may play
important roles in neurodegenerative conditions. For example, astrocytic tau
pathology is associated with synaptic loss in corticobasal degeneration but not
in progressive supranuclear palsy. Furthermore, changes that are more difficult
and time-consuming to quantify, for example loss of a specific neuronal subtype
that does not develop pathological inclusions, remain virtually unexplored and
their relevance for disease progression are unknown. This scoping review is an
attempt to collate all histological evidence from human studies that address the
question of cell-specific vulnerability in the most common FTLD subtypes. By
taking a systematic approach including various brain cell types such as neurons
and their subtypes as well as astrocytes, microglia and oligodendrocytes and the
entire central nervous system with its affected and unaffected regions, this
review summarizes the current status in the field and highlights important
knowledge gaps.