Diagnostic Marker Development
Currently there are no diagnostic biomarkers for detecting Parkinson's disease with adequate sensitivity and specificity in the earliest stages of the disease. By the time patients are symptomatic, between 30% and 60% of dopaminergic neurons are lost and the opportunity to effectively protect these neurons has passed. I'm interested in concurrently imaging iron and neuromelanin content in the substantia nigra and analyzing the effects of Parkinson's disease on the substantia nigra. Insight into the relationship between iron content and loss of neuromelanin containing neurons might lead to a new biomarker for early diagnosis of Parkinson's disease.
He, N., Langley, J., Chen, S., Huang, P., Ling, H., Zhang, Y., Yan., F., and Hu, X. Increased iron-deposition in lateral-ventral substantia nigra pars compacta: A promising neuroimaging marker for Parkinson's disease. NeuroImage: Clinical, 28:102391, 2020.
Hwang, K., Langley, J., Tripathi, R., Hu, X., and Huddleston, D., Reproducible in vivo detection of locus coeruleus pathology in Parkinson’s disease
T1 and T2 relaxation rates for substantia nigra and locus coeruleus are similar to those of surrounding tissue. This similarity makes it difficult to delineate these structures from surrounding tissue. Incidental or explicit magnetization transfer effects can be used to generate contrast in these structures. As currently implemented, this sequence suffers from long acquisition times and only allows for partial coverage of the brain. These limitations hinder application of the neuromelanin-sensitive sequence in clinical settings. I'm interested in reducing acquisition time for the neuromelanin sequence.
Imaging Iron in the Brain
Elevated brain iron is seen in many diseases including Parkinson's disease and Alzheimer's disease. This increase can be used as a diagnostic marker for these diseases as seen here. However, it can also occlude changes in other MRI contrasts, such as diffusion tensor imaging (see below), or other imaging modalities. For example, the PET ligand used to image tau deposition (AV-1451) binds to iron in addition to tau. This off target binding confounds interpretation of cross-sectional or longitudinal changes in 18F-AV1451 images as the changes could be due to iron or tau. I use quantitative susceptibility mapping (QSM) or mapping the transverse relaxation rate to quantify iron. These iron values are then used as a diagnostic imaging marker or are used to remove off-target binding effects in 18F-AV1451.
Langley, J., Huddleston, D., Bennett, I., and Hu, X. Accounting for iron-related off-target binding effects of 18F-AV1451 PET in the evaluation of cognition and microstructure in APOE-ε4+ MCI.
Langley, J.*, He, N.*, Huddleston, D., Ling, H., Yan, F., Factor, S., and Hu, X. Reproducible detection of nigral iron deposition in two Parkinson’s disease cohorts. Movement Disorders, 34(3):416-420, 2019
The Effect of Iron of Diffusivity
Imaging studies using diffusion tensor imaging to derive nigral imaging markers of Parkinson’s disease have reported mostly inconsistent results.I showed that selection of nigral regions of interest are partly due to the aforementioned inconsistency but other factors, such as iron, may play a role in this inconsistency. In particular, magnetic field inhomogeneities from iron deposition couple with diffusion gradients and negatively bias diffusivity and positively bias fractional anisotropy in older healthy adults. Thus, iron deposition will occlude any microstructural changes occurring from a loss of melanized neurons in substantia nigra since the iron-related reduction in diffusivity may offset any increases in diffusivity occurring from Parkinson’s-related neuronal loss. These competing effects may partially explain the inconsistency of earlier studies examining microstructural changes in substantia nigra.
Langley, J., Hussain, S., Flores, J., Bennett, I., and Hu, X. Characterization of age-related microstructural changes in locus coeruleus and substantia nigra pars compacta. Neurobiology of Aging, 87(1):89-97, 2020
Langley, J., Huddleston, D., and Hu, X. Nigral diffusivity, but not free water, correlates with iron content in Parkinson’s disease. Brain Communications, 3(4):fcab251, 2021