High and low levels of an NTRK2-driven genetic profile affect motor- and cognition-associated frontal gray matter in prodromal Huntington’s disease

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.This project was supported by 1U01NS082074 (V.C. and J.T., co-principal investigators) from the National Institutes of Health, National Institute of Neurological Disorders and Stroke. The PREDICT-HD study was supported by NIH/NINDS grant 5R01NS040068 awarded to J.P.; CHDI Foundation, Inc., A3917 and 6266 awarded to J.P.; Cognitive and Functional Brain Changes in Preclinical Huntington’s Disease (HD) 5R01NS054893 awarded to J.P.; 4D Shape Analysis for Modeling Spatiotemporal Change Trajectories in Huntington’s 1U01NS082086; Functional Connectivity in Premanifest Huntington’s Disease 1U01NS082083; and Basal Ganglia Shape Analysis and Circuitry in Huntington’s Disease 1U01NS082085 awarded to Christopher A. Ross

Neuroimaging Findings in Mild Cognitive Impairment

The clinical construct of mild cognitive impairment (MCI) identifies a syndrome of cognitive deficit which is not significant enough to interfere with daily activities, whose fate is unpredictable without establishing the underlying cause. Thus, MCI, though being the natural \u201creservoir\u201d of subsequent dementing neurodegenerative diseases, can be provoked by a variety of psychiatric and systemic diseases as well as by drugs, alcohol, and substance abuse. In this context, morphological and, especially, functional neuroimaging by means of multitracer SPECT and PET are useful tools to provide clue information on the underlying pathological process. Both MRI and SPECT/PET have been included as indicative or supportive biomarkers in the diagnostic criteria of a variety of neurodegenerative conditions, already at the MCI stage, ranging from Alzheimer\u2019s disease to dementia with Lewy bodies and to frontotemporal dementia. New developments include MRI high-field equipment and functional techniques, fluorinated PET radiopharmaceuticals for protein Tau detection, and receptor studies. In the advanced memory clinics, appropriate use of neuroimaging is nowadays paramount for the correct diagnosis of cognitive disorders