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Introduction
Considerable debate exists regarding neurodegeneration, an umbrella term that incorporates a wide range of neurological disorders with heterogeneous clinical and pathological expressions affecting distinct subsets of neurons in specific functional anatomic systems showing a relentless progression. 1 Traditionally, the study of neurodegenerative disorders has relied on a conventional clinicopathological approach, defining a particular clinical diagnoses (such as Alzheimer's disease), and attempting to match this to a pattern of pathology in the brain. However, it is increasingly recognised that there is considerable clinical and pathological overlap across neurodegenerative disorders ( figure 1 ). Patients with frontotemporal dementia (FTD) may present with amyotrophic lateral sclerosis (ALS) and vice versa; 2 patients with parkinisonian plus syndromes (including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) phenotypes) may present with initial cognitive changes, 3 while patients with FTD may develop prominent extrapyramidal symptoms resembling parkinsonian plus syndromes. 4 Pathologically, there appears to be limited correlation linking specific syndromes such that both tau and Tar-DNA binding protein (TDP)-43 pathology can result in behavioural variant FTD (bvFTD), 2 while corticobasal syndrome (CBS) may be associated with both CBD and Alzheimer's disease pathology. 5 As such, current clinicopathological approaches fail to recognise the heterogeneity of these conditions.
An alternative approach to the classification of neurodegenerative disorders invokes neural networks, defined as a series of interconnected neural nodes that determine physiological function. 6 7 These networks occur at microscopic (neurons and synapses), macroscopic or structural (anatomical regions and fibres), and functional (physiological connections) levels. 6 There is a wealth of literature describing specific networks based on functional and structural imaging modalities. 8 More recently, the concept of pathological networks based on pathogenic proteins, known as 'molecular nexopathies', 6 has been developed. It has been suggested that the susceptibility and phenotype will vary contingent on the involvement of specific neural networks. 7 In this Review the overlap between neurological conditions in terms of clinical phenotype (behaviour, cognitive, primary motor, extrapyramidal, and metabolic) rather than syndromic diagnoses will be discussed, and the evidence suggesting widespread network involvement in neurodegeneration will be critically appraised. Network involvement in neurodegenerative language disorders will not be discussed, but extensive reviews are available. 9 Evidence for network dysfunction at a genetic and pathological level, and how neurodegeneration may spread...