Abstract
This study assessed how BDNF (brain-derived neurotrophic factor) and other genes involved in its signaling influence brain structure and clinical functioning in pre-diagnosis Huntington’s disease (HD). Parallel independent component analysis (pICA), a multivariate method for identifying correlated patterns in multimodal datasets, was applied to gray matter concentration (GMC) and genomic data from a sizeable PREDICT-HD prodromal cohort (N = 715). pICA identified a genetic component highlighting NTRK2, which encodes BDNF’s TrkB receptor, that correlated with a GMC component including supplementary motor, precentral/premotor cortex, and other frontal areas (p < 0.001); this association appeared to be driven by participants with high or low levels of the genetic profile. The frontal GMC profile correlated with cognitive and motor variables (Trail Making Test A (p = 0.03); Stroop Color (p = 0.017); Stroop Interference (p = 0.04); Symbol Digit Modalities Test (p = 0.031); Total Motor Score (p = 0.01)). A top-weighted NTRK2 variant (rs2277193) was protectively associated with Trail Making Test B (p = 0.007); greater minor allele numbers were linked to a better performance. These results support the idea of a protective role of NTRK2 in prodromal HD, particularly in individuals with certain genotypes, and suggest that this gene may influence the preservation of frontal gray matter that is important for clinical functioning.
Highlights
In this PREDICT-Huntington’s disease (HD) prodromal cohort, high or low levels of an single nucleotide polymorphisms (SNPs) profile with substantial contributions from NTRK2 were associated with a gray matter concentration (GMC) profile representing the supplementary and primary motor cortex, as well as other frontal regions
The SNP component was not significantly associated with clinical functioning, but one of its top NTRK2 SNPs had a protective association with performance on TMTB, a measure of task switching and visual attention, indicating some influence on cognition
Correlations between the SNP component and clinical/GMC variables were mainly due to top contributing SNPs, rather than being an aggregate effect of the entire SNP component
Summary
HD, along with Alzheimer’s disease (AD) and Parkinson’s disease (PD), is a proteinopathy distinguished by regionally-selective neuronal death and protein misfolding that manifests as expanded huntingtin in HD, Lewy bodies in PD, and β-amyloid plaques in AD [2]. Across these conditions limited treatment options and no known cures are available. Their shared features have sparked speculation about common underlying mechanisms, and the delayed-onset of these disorders raises the appealing possibility of developing treatments that postpone onset indefinitely, effectively eradicating the disease. Motor impairments associated with HD, such as dystonia and chorea, often lead to diagnosis because their disruptiveness prompts affected individuals to seek medical attention
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