Frontotemporal dementia - symptoms and brain pathology

Frontotemporal dementia (FTD) is the clinical term for a heterogeneous group of dementia disorders with symptoms emerging
from frontotemporal lobar degeneration (FTLD). FTD encompasses the behavioural variant (bvFTD) and the progressive
aphasias: progressive non-fluent aphasia (PNFA) and semantic dementia (SD). Neuropathological classification is based on
protein pathology with three major subgroups: Tau, TDP-43 and FUS. Early clinical diagnosis is challenging and prediction of
neuropathological subtype is often not possible.
The objective was to identify clinical markers (biomarkers or specific symptoms), of possible diagnostic value. In paper I
potential cerebrospinal fluid biomarkers were examined. Increased neurofilament light protein (NFL) was seen in FTD
compared to Alzheimer’s disease and healthy controls, particularly in the clinical subtype SD and in tau-negative cases. In
paper II clinical and neuropathological characteristics in a large bvFTD family with a newly identified mutation (C9ORF72
expansion) were analysed. Despite age variations at onset and duration, symptomatology was strikingly homogenous.
Unexpectedly, psychotic symptoms and extensive somatic complaints, not included in current FTD criteria, were common.
These symptoms were further analysed in an extended neuropathologically verified cohort (paper III, IV) and both symptom
categories were found in about 1/3 of all cases. There was no clear correlation with protein pathology. Psychotic symptoms
correlated strongly with right-predominant brain pathology. Clinical misdiagnosis, often psychiatric, was especially common
among young patients and in those with psychotic symptoms. Our findings highlight the clinical importance of recognizing
symptoms not included in current criteria to achieve a better understanding of these phenomena and to improve diagnostics.