In vivo MRI assessment of the human locus coeruleus along its rostrocaudal extent in young and older adults

&NA; The locus coeruleus (LC), a major origin of noradrenergic projections in the central nervous system (CNS), may serve a critical role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). As such, there is considerable interest to develop magnetic resonance imaging (MRI) techniques to assess the integrity of the LC in vivo. The high neuromelanin content of the LC serves as an endogenous contrast for MRI but existing protocols suffer from low spatial resolution along the rostrocaudal axis of the LC rendering it difficult to differentiate its integrity in caudal and rostral portions. This study presents a novel approach to investigate the human LC in vivo using T1‐weighted Fast Low Angle Shot (FLASH) MRI at 3 T (T). Using high‐resolution isotropic imaging to minimise the effect of low spatial resolution in the slice direction, this study aimed to characterise the rostrocaudal distribution of LC signal intensity attributed to neuromelanin from 25 young (22–30) and 57 older (61–80) adults. We found a significant age‐related increase in maximum but not median signal intensity, indicating age‐related differences were not homogenous. Instead, they were confined to the rostral third of the LC with relative sparing of the caudal portion. The findings presented demonstrate in vivo T1‐weighted FLASH imaging may be used to characterise signal intensity changes across the entire rostrocaudal length of the LC (a corresponding standardised LC map is available for download), which may help to identify how the human LC is differentially affected in aging and neurodegenerative disease. HighlightsT1‐weighted FLASH imaging proposed to effectively identify the human LC in vivo.LC signal intensity determined across entire rostrocaudal axis.Signal intensity from 82 adults used to generate standardised map of the human LC in vivo.Age‐related differences in signal intensity confined to the rostral third of the LC.T1‐weighted FLASH imaging may identify how LC is affected in neurodegenerative disease.

[1]  Eduardo E. Benarroch,et al.  Locus coeruleus , 2017, Cell and Tissue Research.

[2]  R. Ponnusamy,et al.  Noradrenergic System in Down Syndrome and Alzheimer's Disease A Target for Therapy. , 2015, Current Alzheimer research.

[3]  Hidekazu Tomimoto,et al.  Neuromelanin Magnetic Resonance Imaging in Parkinson's Disease and Multiple System Atrophy , 2013, European Neurology.

[4]  Eduardo E. Benarroch,et al.  The locus ceruleus norepinephrine system , 2009, Neurology.

[5]  R. Pamphlett Uptake of environmental toxicants by the locus ceruleus: a potential trigger for neurodegenerative, demyelinating and psychiatric disorders. , 2014, Medical hypotheses.

[6]  Eri Shibata,et al.  Age-related changes in locus ceruleus on neuromelanin magnetic resonance imaging at 3 Tesla. , 2006, Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine.

[7]  A. Espay,et al.  Norepinephrine deficiency in Parkinson's disease: The case for noradrenergic enhancement , 2014, Movement disorders : official journal of the Movement Disorder Society.

[8]  S. Sara The locus coeruleus and noradrenergic modulation of cognition , 2009, Nature Reviews Neuroscience.

[9]  J. Bohl,et al.  Unbiased Estimation of Neuronal Numbers in the Human Nucleus Coeruleus during Aging , 1997, Neurobiology of Aging.

[10]  Hans Jørgen G. Gundersen,et al.  Absolute number and size of pigmented locus coeruleus neurons in young and aged individuals , 1994, Journal of Chemical Neuroanatomy.

[11]  J. D. Coulter,et al.  Descending projections of the locus coeruleus and subcoeruleus/medial parabrachial nuclei in monkey: Axonal transport studies and dopamine-β-hydroxylase immunocytochemistry , 1980, Brain Research Reviews.

[12]  Julio Acosta-Cabronero,et al.  High-resolution characterization of the aging brain using simultaneous quantitative susceptibility mapping ( QSM ) and R 2 * measurements at 7 Tesla , 2016 .

[13]  Matthew J. Betts,et al.  The whole-brain pattern of magnetic susceptibility perturbations in Parkinson’s disease , 2017, Brain : a journal of neurology.

[14]  H. Braak,et al.  Staging of brain pathology related to sporadic Parkinson’s disease , 2003, Neurobiology of Aging.

[15]  E. Szabadi,et al.  Functional Neuroanatomy of the Noradrenergic Locus Coeruleus: Its Roles in the Regulation of Arousal and Autonomic Function Part I: Principles of Functional Organisation , 2008, Current neuropharmacology.

[16]  Jonathan D. Cohen,et al.  An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. , 2005, Annual review of neuroscience.

[17]  Sergio Cerutti,et al.  Contrast mechanisms associated with neuromelanin‐MRI , 2017, Magnetic resonance in medicine.

[18]  F. Bloom,et al.  Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle , 1981, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[19]  Paul S. Morgan,et al.  In vivo mapping of the human locus coeruleus , 2009, NeuroImage.

[20]  Dorothee P Auer,et al.  T1‐Weighted MRI shows stage‐dependent substantia nigra signal loss in Parkinson's disease , 2011, Movement disorders : official journal of the Movement Disorder Society.

[21]  Y. Agid,et al.  Preservation of midbrain catecholaminergic neurons in very old human subjects. , 2000, Brain : a journal of neurology.

[22]  M. Mather,et al.  Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging , 2016, Neurobiology of Aging.

[23]  R Weissleder,et al.  Paramagnetic metal scavenging by melanin: MR imaging. , 1997, Radiology.

[24]  J. Neuhaus,et al.  Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery , 2017, Alzheimer's & Dementia.

[25]  J. Schneider,et al.  Neural reserve, neuronal density in the locus ceruleus, and cognitive decline , 2013, Neurology.

[26]  Yasuo Terayama,et al.  Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson's disease using neuromelanin-sensitive MR imaging , 2013, Neuroscience Letters.

[27]  K. G. Baker,et al.  The human locus coeruleus complex: an immunohistochemical and three dimensional reconstruction study , 2004, Experimental Brain Research.

[28]  B. Libet,et al.  The human locus coeruleus and anxiogenesis , 1994, Brain Research.

[29]  E. Szabadi,et al.  Functional Neuroanatomy of the Noradrenergic Locus Coeruleus: Its Roles in the Regulation of Arousal and Autonomic Function Part II: Physiological and Pharmacological Manipulations and Pathological Alterations of Locus Coeruleus Activity in Humans , 2008, Current neuropharmacology.

[30]  Tadeusz Sarna,et al.  Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease , 2017, Progress in Neurobiology.

[31]  Wade K. Smith,et al.  Disease‐specific patterns of locus coeruleus cell loss , 1992, Annals of neurology.

[32]  Wade K. Smith,et al.  The human locus coeruleus: computer reconstruction of cellular distribution , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[33]  Guido Gerig,et al.  User-guided 3D active contour segmentation of anatomical structures: Significantly improved efficiency and reliability , 2006, NeuroImage.

[34]  H. Braak,et al.  Where, when, and in what form does sporadic Alzheimer's disease begin? , 2012, Current opinion in neurology.

[35]  P. Deyn,et al.  Targeting the norepinephrinergic system in Parkinson's disease and related disorders: The locus coeruleus story , 2017, Neurochemistry International.

[36]  Dietmar R. Thal,et al.  Stages of the Pathologic Process in Alzheimer Disease: Age Categories From 1 to 100 Years , 2011, Journal of neuropathology and experimental neurology.

[37]  Habib Benali,et al.  The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease , 2013, Brain : a journal of neurology.

[38]  D. German,et al.  Locus coeruleus cell loss in the aging human brain: A non‐random process , 1995, The Journal of comparative neurology.

[39]  Brian B. Avants,et al.  Symmetric diffeomorphic image registration with cross-correlation: Evaluating automated labeling of elderly and neurodegenerative brain , 2008, Medical Image Anal..

[40]  Julio Acosta-Cabronero,et al.  In Vivo MRI Mapping of Brain Iron Deposition across the Adult Lifespan , 2016, The Journal of Neuroscience.

[41]  V. Chan‐Palay,et al.  Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression , 1989, The Journal of comparative neurology.

[42]  R. Pamphlett,et al.  Different Populations of Human Locus Ceruleus Neurons Contain Heavy Metals or Hyperphosphorylated Tau: Implications for Amyloid-β and Tau Pathology in Alzheimer's Disease. , 2015, Journal of Alzheimer's disease : JAD.

[43]  Yasuo Terayama,et al.  Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson's disease , 2006, Neuroreport.

[44]  K. Double,et al.  The comparative biology of neuromelanin and lipofuscin in the human brain , 2008, Cellular and Molecular Life Sciences.

[45]  S. Kalinin,et al.  The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer's disease , 2012, Neurobiology of Aging.

[46]  Oliver Speck,et al.  Midbrain fMRI: Applications, Limitations and Challenges , 2015 .

[47]  H Brody,et al.  A QUANTITATIVE STUDY OF THE PIGMENTED NEURONS IN THE NUCLEI LOCUS COERULEUS AND SUBCOERULEUS IN MAN AS RELATED TO AGING , 1979, Journal of neuropathology and experimental neurology.

[48]  Shosuke Ito,et al.  Norepinephrine and its metabolites are involved in the synthesis of neuromelanin derived from the locus coeruleus , 2015, Journal of neurochemistry.

[49]  Yasuo Terayama,et al.  Detection of changes in the locus coeruleus in patients with mild cognitive impairment and Alzheimer's disease: High-resolution fast spin-echo T1-weighted imaging , 2014, Geriatrics & gerontology international.

[50]  Thomas H. B. FitzGerald,et al.  Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging , 2014, Neurobiology of Aging.

[51]  T. Robbins,et al.  Cortical noradrenaline, attention and arousal , 1984, Psychological Medicine.

[52]  G. Blessed,et al.  Cell loss in the locus coeruleus in senile dementia of Alzheimer type , 1981, Journal of the Neurological Sciences.

[53]  F. Bloom,et al.  Efferent projections of nucleus locus coeruleus: Topographic organization of cells of origin demonstrated by three-dimensional reconstruction , 1986, Neuroscience.

[54]  M. Sasaki,et al.  Visual discrimination among patients with depression and schizophrenia and healthy individuals using semiquantitative color-coded fast spin-echo T1-weighted magnetic resonance imaging , 2010, Neuroradiology.

[55]  L. Zecca,et al.  Neuromelanin and iron in human locus coeruleus and substantia nigra during aging: consequences for neuronal vulnerability , 2006, Journal of Neural Transmission.

[56]  D. Jeste,et al.  Locus ceruleus morphometry in aging and schizophrenia , 1988, Acta psychiatrica Scandinavica.

[57]  E. Hirsch,et al.  Neuronal vulnerability in Parkinson's disease. , 1997, Journal of neural transmission. Supplementum.

[58]  H. Braak,et al.  The preclinical phase of the pathological process underlying sporadic Alzheimer's disease. , 2015, Brain : a journal of neurology.

[59]  Mark A. Eckert,et al.  Histologic validation of locus coeruleus MRI contrast in post-mortem tissue , 2015, NeuroImage.

[60]  Xiaoping Hu,et al.  Reproducibility of locus coeruleus and substantia nigra imaging with neuromelanin sensitive MRI , 2017, Magnetic Resonance Materials in Physics, Biology and Medicine.

[61]  S. H. Koenig,et al.  Sources of the increased longitudinal relaxation rates observed in melanotic melanoma. An in vitro study of synthetic melanins. , 1989, Investigative radiology.

[62]  M. Mather,et al.  The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain , 2016, Trends in Cognitive Sciences.

[63]  Evelyne Balteau,et al.  The Locus Ceruleus Is Involved in the Successful Retrieval of Emotional Memories in Humans , 2006, The Journal of Neuroscience.

[64]  Sander Nieuwenhuis,et al.  In vivo visualization of the locus coeruleus in humans: quantifying the test–retest reliability , 2017, Brain Structure and Function.

[65]  D. Dickson,et al.  Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease , 2008, Acta Neuropathologica.

[66]  P. Yates,et al.  Loss of nerve cells from locus coeruleus in Alzheimer's disease is topographically arranged , 1986, Neuroscience Letters.