Diagnostic Brain Imaging And Blood Biomarkers For Early Frontotemporal Lobar Degeneration Antti Cajanus by Antti Cajanus 9789526136493, 9526136497 instant download after payment.

Doctoral Dissertation
Frontotemporal lobar degeneration (FTLD) is the second most common early-onset neurodegenerative disorder after Alzheimer’s disease (AD). It is characterised by a change in a patient’s behavior and personality or with problems with speech and language. The neuropathology underlying FTLD is diverse, and the exact mechanisms of pathogenesis remain unknown. Several genetic etiologies have been recognized to cause a predisposition towards
developing FTLD, of which the hexanucleide repeat expansion in the chromosome 9 open reading frame 72 gene (C9orf72) is the most common.
The diagnosis of FTLD is based on clinical phenotype, brain imaging, and detection of pathogenic mutation or brain biopsy. The heterogeneity of the clinical phenotype hinders the diagnostic process. Furthermore, current clinical work is lacking sensitive and specific biomarkers, other than the known genetic mutations for detecting the disease. However, the majority of FTLD cases are sporadic, without any family history, and therefore, as a consequence, delays in the diagnosis, and misdiagnosis often occurs, leading to ineffective and potentially harmful treatments, increased healthcare costs, and patient and caregiver distress.
To date, there is no curative nor disease-modifying treatment for slowing its progression. Given that specific underlying pathologies require specific pharmaceutical treatments, it is essential to distinguish the pathology in vivo for an adequate selection of study subjects. Furthermore, future clinical trials aimed at treatment need biomarkers for assessing disease severity, prognosis, and positive therapeutic effects.
This thesis aimed to evaluate novel biomarkers for detecting early phase FTLD. The aim was to replicate actual differential diagnostic problems in outpatient clinics and to develop tools for disease monitoring. The biomarkers
included structural magnetic resonance imaging (MRI) metrics obtained using automated registration and quantification methods as well as neurofilament light chain (NfL), a protein, which has previously been found to correlate with neuronal damage.
Results showed that the automated structural MRI quantification methods were able to distinguish behavioral variant frontotemporal dementia (bvFTD), a subtype of FTLD, from other neurodegenerative diseases with sensitivity of 60%. The sensitivity reached 70% in a subset of C9orf72 gene hexanucleotide repeat expansion (hereafter called C9-RE) carriers (study I). In addition, the neuroanatomical correlates for behavioral symptoms were assessed in a cohort of bvFTD, AD and mild cognitive impairment (MCI) patients. This suggested that the orbitofrontal cortex and the subcallosal area were a robust anatomical substrate for those symptoms (study II). In the third study (III), NfL was found to be an excellent tool for differentiating between FTLD and primary psychiatric
disorders (PPD). The analysis revealed that this metric had 80% sensitivity and 85% specificity, which is the highest discrimination power reported so far for this disease. In the final study of this thesis (IV), the association between serum NfL levels, disease prognosis and brain atrophy was assessed. Patients with higher serum NfL levels had significantly shorter survival times and faster rates of brain atrophy, indicative of a strong correlation with the disease severity. The work presented in this study has contributed to the field of recognizing early FTLD. The results give new insights into potential biomarkers, which may be exploited in further studies aimed at identifing optimal biomarkers or, preferably, a combination of biomarkers.
Keywords: Frontotemporal lobar degeneration; Frontotemporal dementia; Magnetic resonance imaging; Genes; Biomarkers