Amyotrophic lateral sclerosis and the frontotemporal dementias: using neuroimaging to quantitate disease progression

Abstract

After decades of clinical trials, there remains a lack of effective disease-modifying therapies for amyotrophic lateral sclerosis (ALS). In addition to the complex pathogenic mechanisms that are not fully understood, other important factors contributing to this deficiency include the lack of a sensitive and objective biomarker and the biological heterogeneity of ALS.Diagnosis is dependent on physical signs emanating from the cardinal feature of ALS: combined upper motor neurone (UMN) and lower motor neurone (LMN) degeneration. However, these signs are crude and insensitive. Additionally, UMN signs may be lacking or attenuate over time as LMN degeneration progresses. Thus, typical outcome measures in clinical trials have been composite measures of strength (e.g. manual muscle testing, maximum voluntary isometric contraction) or disability (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)), respiratory function (forced vital capacity), and survival. Drug trials based on such endpoints require hundreds of patients per study arm and are lengthy and expensive. This is a major impediment to early drug development programmes, as achieving such numbers in a timely fashion is difficult given the low prevalence of ALS. Furthermore, disability scales and survival in particular are only indirectly related to the true biological lesion (motor neurone dysfunction/death) and do not discriminate between UMN and LMN function.The heterogeneity of ALS is evident in the simple clinical observations of varied age of onset, site of symptoms onset, progression rate, and survival. This is compounded by the variable presence of frontotemporal lobar degeneration (FTLD), necessitating the designation of ALS as a spectrum rather than a single disease entity. Cognitive impairment secondary to FTLD is highly prevalent and detectable by focused neuropsychometric testing in upwards of 50% of patients. Thus, variability in the clinical phenotype of ALS extends beyond that resulting from motor neurone degeneration (UMN versus LMN predominant versus mixed UMN and LMN, limb versus bulbar onset, slow versus rapid progression) to include a spectrum of cognitive and behavioural dysfunction.There have been important recent developments in elucidating the overlap of FTLD with ALS from a pathological and molecular perspective, as delineated elsewhere in this text. The clinical syndrome is better understood with consensus-based criteria now published to guide clinical evaluation. However, varying prevalence rates, conflicting reports regarding its natural history and an unclear relationship between FTLD and motor neurone degeneration make clinical measures of cognitive impairment unsuitable for monitoring disease progression. A biomarker is required to address these issues of biological and clinical heterogeneity and lack of optimal outcome measures (Table 15.1).Serum, cerebrospinal fluid, and neuroimaging biomarkers have been investigated in ALS, and are areas of intense research. Brain imaging is an obvious candidate as a biomarker of disease because: (a) it is objective; (b) it provides in vivo data; (c) it allows assessment repeatedly during the course of the disease; and (d) it allows assessment of specific regions of the brain, which is vital in understanding the impact of degeneration on behaviour. Magnetic resonance imaging techniques, in particular, are advantageous because, unlike positron emission tomography and single-photon emission tomography, they are non-invasive and do not require exposure to ionizing radiation.This chapter will review the potential role, experience, limitations, and future directions of neuroimaging in monitoring disease progression in ALS and ALS/FTLD. Discussion will be largely limited to magnetic resonance (MR) technology as longitudinal studies with other imaging modalities are scarce, most recent developments are in advanced MR methods, and MR imaging (MRI) installations are becoming ubiquitous.