Matthew J. Betts

In Vivo MRI Mapping of Brain Iron Deposition across the Adult Lifespan

Disruption of iron homeostasis as a consequence of aging is thought to cause iron levels to increase, potentially promoting oxidative cellular damage. Therefore, understanding how this process evolves through the lifespan could offer insights into both the aging process and the development of aging-related neurodegenerative brain diseases. This work aimed to map, in vivo for the first time with an unbiased whole-brain approach, age-related iron changes using quantitative susceptibility mapping (QSM)—a new postprocessed MRI contrast mechanism. To this end, a full QSM standardization routine was devised and a cohort of N = 116 healthy adults (20–79 years of age) was studied. The whole-brain and ROI analyses confirmed that the propensity of brain cells to accumulate excessive iron as a function of aging largely depends on their exact anatomical location. Whereas only patchy signs of iron scavenging were observed in white matter, strong, bilateral, and confluent QSM–age associations were identified in several deep-brain nuclei—chiefly the striatum and midbrain—and across motor, premotor, posterior insular, superior prefrontal, and cerebellar cortices. The validity of QSM as a suitable in vivo imaging technique with which to monitor iron dysregulation in the human brain was demonstrated by confirming age-related increases in several subcortical nuclei that are known to accumulate iron with age. The study indicated that, in addition to these structures, there is a predilection for iron accumulation in the frontal lobes, which when combined with the subcortical findings, suggests that iron accumulation with age predominantly affects brain regions concerned with motor/output functions. SIGNIFICANCE STATEMENT This study used a whole-brain imaging approach known as quantitative susceptibility mapping (QSM) to provide a novel insight into iron accumulation in the brain across the adult lifespan. Validity of the method was demonstrated by showing concordance with ROI analysis and prior knowledge of iron accumulation in subcortical nuclei. We discovered that, beyond these regions, there is extensive involvement of the frontal lobes that has been missed by past ROI analyses. Broadly speaking, therefore, the motor system selectively accumulates iron with age. The results offer insights into the aging process, but also offer a new approach to studying the role of iron dysregulation in the evolution of age-related neurodegenerative diseases.

The whole-brain pattern of magnetic susceptibility perturbations in Parkinson's disease.

Although iron-mediated oxidative stress has been proposed as a potential pathomechanism in Parkinson’s disease, the global distribution of iron accumulation in Parkinson’s disease has not yet been elucidated. This study used a new magnetic resonance imaging contrast, quantitative susceptibility mapping, and state-of-the-art methods to map for the first time the whole-brain landscape of magnetostatic alterations as a surrogate for iron level changes in n = 25 patients with idiopathic Parkinson’s disease versus n = 50 matched controls. In addition to whole-brain analysis, a regional study including sub-segmentation of the substantia nigra into dorsal and ventral regions and qualitative assessment of susceptibility maps in single subjects were also performed. The most remarkable basal ganglia effect was an apparent magnetic susceptibility increase—consistent with iron deposition—in the dorsal substantia nigra, though an effect was also observed in ventral regions. Increased bulk susceptibility, additionally, was detected in rostral pontine areas and in a cortical pattern tightly concordant with known Parkinson’s disease distributions of &agr;-synuclein pathology. In contrast, the normally iron-rich cerebellar dentate nucleus returned a susceptibility reduction suggesting decreased iron content. These results are in agreement with previous post-mortem studies in which iron content was evaluated in specific regions of interest; however, extensive neocortical and cerebellar changes constitute a far more complex pattern of iron dysregulation than was anticipated. Such findings also stand in stark contrast to the lack of statistically significant group change using conventional magnetic resonance imaging methods namely voxel-based morphometry, cortical thickness analysis, subcortical volumetry and tract-based diffusion tensor analysis; confirming the potential of whole-brain quantitative susceptibility mapping as an in vivo biomarker in Parkinson’s disease.

High-resolution characterisation of the aging brain using simultaneous quantitative susceptibility mapping (QSM) and R2* measurements at 7 T

Quantitative susceptibility mapping (QSM) has recently emerged as a novel magnetic resonance imaging (MRI) method to detect non-haem iron deposition, calcifications, demyelination and vascular lesions in the brain. It has been suggested that QSM is more sensitive than the more conventional quantifiable MRI measure, namely the transverse relaxation rate, R2*. Here, we conducted the first high-resolution, whole-brain, simultaneously acquired, comparative study of the two techniques using 7Tesla MRI. We asked which of the two techniques would be more sensitive to explore global differences in tissue composition in elderly adults relative to young subjects. Both QSM and R2* revealed strong age-related differences in subcortical regions, hippocampus and cortical grey matter, particularly in superior frontal regions, motor/premotor cortices, insula and cerebellar regions. Within the basal ganglia system-but also hippocampus and cerebellar dentate nucleus-, QSM was largely in agreement with R2* with the exception of the globus pallidus. QSM, however, provided superior anatomical contrast and revealed age-related differences in the thalamus and in white matter, which were otherwise largely undetected by R2* measurements. In contrast, in occipital cortex, age-related differences were much greater with R2* compared to QSM. The present study, therefore, demonstrated that in vivo QSM using ultra-high field MRI provides a novel means to characterise age-related differences in the human brain, but also combining QSM and R2* using multi-gradient recalled echo imaging can potentially provide a more complete picture of mineralisation, demyelination and/or vascular alterations in aging and disease.

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 Alzheimers disease (AD) and Parkinsons 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.

Locus coeruleus integrity in old age is selectively related to memories linked with salient negative events

Significance Locus coeruleus (LC) integrity in cognitively normal older adults is a potentially important preclinical marker in dementia. Our study establishes a link between variability in LC integrity and cognitive decline related to noradrenergic modulation in old age. We find that in older adults, reduced LC integrity explains lower memory performance. This effect was more pronounced for memory related to negative events, and accompanied by increased pupil diameter size in response to negative events. The study provides a strong motivation for future research investigating the role of LC integrity in healthy, as well as in pathological, aging. The locus coeruleus (LC) is the principal origin of noradrenaline in the brain. LC integrity varies considerably across healthy older individuals, and is suggested to contribute to altered cognitive functions in aging. Here we test this hypothesis using an incidental memory task that is known to be susceptible to noradrenergic modulation. We used MRI neuromelanin (NM) imaging to assess LC structural integrity and pupillometry as a putative index of LC activation in both younger and older adults. We show that older adults with reduced structural LC integrity show poorer subsequent memory. This effect is more pronounced for emotionally negative events, in accord with a greater role for noradrenergic modulation in encoding salient or aversive events. In addition, we found that salient stimuli led to greater pupil diameters, consistent with increased LC activation during the encoding of such events. Our study presents novel evidence that a decrement in noradrenergic modulation impacts on specific components of cognition in healthy older adults. The findings provide a strong motivation for further investigation of the effects of altered LC integrity in pathological aging.

Midbrain fMRI: Applications, Limitations and Challenges

The human midbrain and pons contain nuclei of major neurotransmitter systems that send long-range projections to regulate brain activity in cortical and subcortical structures. Despite being small structures, these nuclei are critically implicated in a very wide range of cognitive and bodily functions, and their dysfunction plays an important role in a number of neurological and neuropsychiatric conditions. Hence, there is a considerable interest to develop functional MRI approaches that allow to image their activity in health and disease.

In vivo visualization of age-related differences in the locus coeruleus

The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, may play an important role in neuropsychiatric disorders including Parkinsons disease and Alzheimers disease. The pattern of age-related change of the LC across the life span is unclear. We obtained normalized, mean LC signal intensity values, that is, contrast ratios (CRs), from magnetization transfer–weighted images to investigate the relationship between LC CR and age in cognitively normal healthy adults (N = 605, age range 18–88 years). Study participants were part of the Cambridge Centre for Ageing and Neuroscience—an open-access, population-based data set. We found a quadratic relationship between LC CR and age, the peak occurring around 60 years, with no differences between males and females. Subregional analyses revealed that age-related decline in LC CR was confined to the rostral portion of the LC. Older adults showed greater variance in overall LC CR than younger adults, and the functional and clinical implications of these observed age-related differences require further investigation. Visualization of the LC in this study may inform how future scanning parameters can be optimized, and provides insight into how LC integrity changes across the life span.

Commentary: Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice

German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany, 2 Institute of Cognitive Neurology and Dementia Research, Otto von Guericke University Magdeburg, Magdeburg, Germany, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States, 4 Institute of Cognitive Neuroscience, University College London, London, United Kingdom, 5 The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom

USING NEUROMELANIN-SENSITIVE MRI TO CHARACTERISE THE STRUCTURAL INTEGRITY OF THE HUMAN LOCUS COERULEUS AT DIFFERENT STAGES OF ALZHEIMER’S DISEASE

P3-395 USING NEUROMELANIN-SENSITIVE MRI TO CHARACTERISE THE STRUCTURAL INTEGRITY OF THE HUMAN LOCUS COERULEUS AT DIFFERENT STAGES OF ALZHEIMER’S DISEASE Matthew J. Betts, Arturo Cardenas-Blanco, Martin Kanowski, Annika Spottke, Stefan J. Teipel, Frank Jessen, Emrah D€uzel, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany; University Hospital of Magdeburg, Otto-von-Guericke-University, Magdeburg, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; University of Bonn, Bonn, Germany; University Medicine Rostock, Rostock, Germany; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany; University Hospital Cologne, Cologne, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn-Cologne, Germany; University College London, London, United Kingdom. Contact e-mail: matthew.betts@dzne.de

MODELING OF HIDDEN CAUSES FOR DYNAMIC CHANGES IN STRUCTURAL INTEGRITY AND COGNITION IN SUBJECTIVE COGNITIVE DECLINE: A DELCODE PROJECT

Alzheimer’s disease) were anesthetized with intraperitoneal (i.p.) injection of propofol (150 mg/kg body weight) in combination with inhalation of 2.5% sevoflurane for 1 or 3 hrs. After awaken from anesthesia, the mice were returned to their home cages. Behavioral tests (Morris water maze, open field test, one-trial novel object recognition test, contextual and cued fear conditioning test, and elevated plus maze) were performed on various dates after anesthesia. Results:We found that anesthesia with propofol and sevoflurane caused significant deficits in spatial learning and memory, as tested using Morris Water maze 2-6 days after anesthesia exposure, in aged (17-18 months old) wild-type (WT) mice and in adult (7-8 months old) 3xTg-AD mice, but not in adult WT mice. Anesthesia resulted in long-term neurobehavioral changes in the fear conditioning task carried out 65 days after exposure to anesthesia in 3xTg-AD mice. Importantly, daily intranasal administration of insulin (1.75 U/mouse/day) for only three days prior to anesthesia completely prevented the anesthesia-induced deficits in spatial learning and memory and the long-term neurobehavioral changes tested 65 days after exposure to anesthesia in 3xTg-AD mice. Conclusions:Our results indicate that aging and Alzheimer-like brain pathology increase the vulnerability to cognitive impairment after anesthesia and that intranasal treatment with insulin can prevent anesthesia-induced cognitive impairment.