Does variation in neurodegenerative disease susceptibility and phenotype reflect cerebral differences at the network level?

Abstract

Alzheimer's disease (AD) is 10-fold more frequent than Parkinson's disease (PD), which in turn is 10-fold more frequent than amyotrophic lateral sclerosis (ALS). The differences between these neurodegenerative diseases have been ascribed to a selective vulnerability of specific neuronal sub-types that then determine each disorder. However, there are non-neuronal cells that are ubiquitously and possibly primarily involved in all of them, and they share regulatory mechanisms through similar interneurons and, typically inhibitory, neurotransmitters. There is recognized clinical and neuropathological overlap between AD, PD and ALS, the best example being Guamanian Lytico-Bodig, but increasingly recognized in larger populations, e.g. carriers of C9orf72 hexanucleotide expansions. From early embryogenesis to adulthood, genetic and experience-dependent functional neural networks develop primarily in relation to the neocortex. From an evolutionary standpoint, cognition, memory, executive function, linguistics and fine motor function are most prominent in humans. It is concluded that neural networks, rather than specific neuronal sub-types defined regionally or by individual transmitters, underlie the marked differences between neurodegenerative disorders in terms of susceptibility and clinical features. This requires the continued development of strategies to study brain function in health and disease as the 'system', greater than the sum of its parts.

Cortical synaptic and dendritic spine abnormalities in a presymptomatic TDP-43 model of amyotrophic lateral sclerosis

“…Although our classification system is limited compared to more recent molecular (notably ctip2 expression ref. 64) and functional approaches, (see refs 35, 36, 37 for reviews), our observations of increased spine density in TDP-43 Q331K LVPNs compared to WT, when accounting for neuronal type (tufted and slender) ties into a broadening of ALS clinical features to include callosal and further cerebral involvement656667 and is in line with widespread (regional and layer) cortical changes in rodent models2150.…”

Amyotrophic lateral sclerosis: a long preclinical period?

“…Neural network development begins at conception, and continues into adolescence and young adulthood 46. However, it is the prenatal and perinatal periods that are associated with the greatest metabolic activity.…”

Neuronal network disintegration: common pathways linking neurodegenerative diseases

“…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.…”