Examining iron-related off-target binding effects of 18F-AV1451 PET in the cortex of Aß+ individuals.

The presence of neurofibrillary tangles containing hyper-phosphorylated tau is a characteristic of Alzheimer's disease (AD) pathology. The positron emission tomography (PET) radioligand sensitive to tau neurofibrillary tangles (18F-AV1451) also binds with iron. This off-target binding effect may be enhanced in older adults on the AD spectrum, particularly those with amyloid-positive biomarkers. Here, we examined group differences in 18F-AV1451 PET after controlling for iron-sensitive measures from magnetic resonance imaging (MRI) and its relationships to tissue microstructure and cognition in 40 amyloid beta positive (Aß+) individuals, 20 amyloid beta negative (Aß-) with MCI and 31 Aß- control participants. After controlling for iron, increased 18F-AV1451 PET uptake was found in the temporal lobe and hippocampus of Aß+ participants compared to Aß- MCI and control participants. Within the Aß+ group, significant correlations were seen between 18F-AV1451 PET uptake and tissue microstructure and these correlations remained significant after controlling for iron. These findings indicate that off-target binding of iron to the 18F-AV1451 ligand may not affect its sensitivity to Aß status or cognition in early-stage AD.

Transition and reversal: long-term experience of the MACE procedure in children.

PURPOSE: Analysis of outcomes and follow-up of children who underwent the Malone antegrade continence enema (MACE) procedure in a UK tertiary paediatric surgery unit. METHODS: Children who underwent a MACE procedure from 1998 to 2020 were identified. Demographic and clinical data were obtained from contemporaneous records. Outcomes were categorised as full (success), partial or failure. RESULTS: Ninety-five children were identified for inclusion (chronic idiopathic constipation (CIC, 59), anorectal malformations (ARM, 23) and Hirschsprung's disease (HD, 13)). Mean age at surgery was 9.4 years (3-19 years) and mean follow-up time was 6 years (0.3-16.8 years). Outcomes were successful in 69% of CIC patients, 78% in ARM and 69% in HD. Twenty (21%) underwent MACE reversal after developing independent continence, with a significant difference between groups (CIC 19%, ARM 9%, HD 54%, p = 0.0047). 50% of patients > 16 years old were transitioned to adult services. CONCLUSION: We report a success rate of 72% for MACE procedures in our unit, with a significant difference in reversal rate between diagnostic groups. Long term, a fifth of patients no longer required their MACE. When these patients reach adolescence, those who require ongoing support outside of the paediatric surgery setting should be safely transitioned to adult services.

Reproducible detection of nigral iron deposition in 2 Parkinson's disease cohorts.

BACKGROUND: Previous studies investigating nigral iron accumulation used T2 or T2 *-weighted contrasts to define the regions of interest (ROIs) in the substantia nigra with mixed results. Because these contrasts are not sensitive to neuromelanin, ROIs may have inadvertently missed the SNpc. An approach sensitive to neuromelanin should yield consistent results. We examine iron deposition in ROIs derived from neuromelanin-sensitive and T2 *-weighted contrasts, respectively. METHODS: T1 -weighted and multiecho gradient echo imaging data were obtained in 2 cohorts. Multiecho gradient echo imaging data were analyzed using neuromelanin-sensitive SNpc ROIs as well as T2 *-weighted SNr ROIs. RESULTS: When compared with controls, significantly larger R2 * values were seen in the SNpc of PD patients in both cohorts. Mean R2 * values in the SNr of PD patients showed no consistency, with 1 cohort showing a small, statistically significant increase, whereas the other cohort exhibited no statistical difference. CONCLUSION: Mean R2 * in the SNpc defined by neuromelanin-sensitive MRI is significantly increased in PD. © 2018 International Parkinson and Movement Disorder Society.

Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging.

With available MRI techniques, primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents without Gd(3+) toxicity. We have developed a protein contrast agent (ProCA32) that exhibits high stability for Gd(3+) and a 10(11)-fold greater selectivity for Gd(3+) over Zn(2+) compared with existing contrast agents. ProCA32, modified from parvalbumin, possesses high relaxivities (r1/r2: 66.8 mmol(-1)⋅s(-1)/89.2 mmol(-1)⋅s(-1) per particle). Using T1- and T2-weighted, as well as T2/T1 ratio imaging, we have achieved, for the first time (to our knowledge), robust MRI detection of early liver metastases as small as ∼0.24 mm in diameter, much smaller than the current detection limit of 10-20 mm. Furthermore, ProCA32 exhibits appropriate in vivo preference for liver sinusoidal spaces and pharmacokinetics for high-quality imaging. ProCA32 will be invaluable for noninvasive early detection of primary and metastatic liver cancers as well as for monitoring treatment and guiding therapeutic interventions, including drug delivery.

In vivo detection of lateral-ventral tier nigral degeneration in Parkinson's disease.

The objective of this study was to measure neuromelanin-sensitive MRI contrast changes in the lateral-ventral tier of substantia nigra pars compacta in Parkinson's disease (PD). Histopathological studies of PD have demonstrated both massive loss of melanized dopamine neurons and iron accumulation in the substantia nigra pars compacta. Neurodegeneration is most profound in the lateral-ventral tier of this structure. We have previously shown in both healthy controls and individuals with PD that neuromelanin-sensitive MRI and iron-sensitive MRI contrast regions in substantia nigra overlap. This overlap region is located in the lateral-ventral tier. Exploiting this area of contrast overlap for region of interest selection, we developed a semi-automated image processing approach to characterize the lateral-ventral tier in MRI data. Here we apply this approach to measure magnetization transfer contrast, which corresponds to local neuromelanin density, in both the lateral-ventral tier and the entire pars compacta in 22 PD patients and 19 controls. Significant contrast reductions were seen in PD in both the entire pars compacta (P = 0.009) and in its lateral-ventral tier (P = 0.0002); in PD contrast was significantly lower in the lateral-ventral tier than in the entire pars compacta (P = 0.0008). These findings are the first in vivo evidence of the selective vulnerability of this nigral subregion in PD, and this approach may be developed for high impact biomarker applications. Hum Brain Mapp 38:2627-2634, 2017. © 2017 Wiley Periodicals, Inc.

Dentate nucleus iron deposition is a potential biomarker for tremor-dominant Parkinson's disease.

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with variable clinicopathologic phenotypes and underlying neuropathologic mechanisms. Each clinical phenotype has a unique set of motor symptoms. Tremor is the most frequent initial motor symptom of PD and is the most difficult symptom to treat. The dentate nucleus (DN) is a deep iron-rich nucleus in the cerebellum and may be involved in PD tremor. In this study, we test the hypothesis that DN iron may be elevated in tremor-dominant PD patients using quantitative susceptibility mapping. Forty-three patients with PD [19 tremor dominant (TD)/24 akinetic rigidity (AR) dominant] and 48 healthy gender- and age-matched controls were recruited. Multi-echo gradient echo data were collected for each subject on a 3.0-T MR system. Inter-group susceptibility differences in the bilateral DN were investigated and correlations of clinical features with susceptibility were also examined. In contrast with the AR-dominant group, the TD group was found to have increased susceptibility in the bilateral DN when compared with healthy controls. In addition, susceptibility was positively correlated with tremor score in drug-naive PD patients. These findings indicate that iron load within the DN may make an important contribution to motor phenotypes in PD. Moreover, our results suggest that TD and AR-dominant phenotypes of PD can be differentiated on the basis of the susceptibility of the DN, at least at the group level. Copyright © 2016 John Wiley & Sons, Ltd.

Parkinson's disease-related increase of T2*-weighted hypointensity in substantia nigra pars compacta.

BACKGROUND: In PD, at the time of diagnosis, approximately 50% of melanized dopaminergic neurons in SNpc have died, yet ongoing neuronal death and neuromelanin release with associated neuroinflammation and microglial activation continue, as does local iron accumulation. Previous studies investigating nigral iron accumulation used T2 / T2*-weighted contrasts to define the regions of interest in the SN. Given that T2 / T2*-weighted contrasts lack sensitivity to neuromelanin and thereby SNpc, neuromelanin-sensitive MRI provides better delineation of SNpc and allows the examination of increased iron deposition in SNpc more specifically and accurately. OBJECTIVES: To examine regions of the SNpc, defined by neuromelanin-sensitive MRI, exhibiting iron deposition in PD. METHODS: T1 -weighted and susceptibility weighted imaging data were obtained in a cohort of 82 subjects (54 controls and 28 PD patients). The PD patients were clinically diagnosed with an average UPDRS-III score of 37.9 ± 12.5 in the off medication state. Susceptibility weighted imaging data were analyzed using SNpc regions of interest defined by neuromelanin-sensitive MRI. RESULTS: Compared to control subjects, significantly more hypointense signal was observed in the SNpc defined by neuromelanin-sensitive MRI in the PD patients. In the PD group, the lateral ventral region of SNpc exhibited the greatest increase of hypointensity. This increase in the lateral ventral region of SNpc robustly differentiated PD patients from controls. CONCLUSION: T2*-weighted hypointense signal in the SNpc defined by neuromelanin-sensitive MRI is significantly increased in PD. It is most likely a measure sensitive to PD-related iron deposition and may serve as a robust biomarker of PD. © 2016 International Parkinson and Movement Disorder Society.

Improved Neuroimaging Atlas of the Dentate Nucleus.

The dentate nucleus (DN) of the cerebellum is the major output nucleus of the cerebellum and is rich in iron. Quantitative susceptibility mapping (QSM) provides better iron-sensitive MRI contrast to delineate the boundary of the DN than either T2-weighted images or susceptibility-weighted images. Prior DN atlases used T2-weighted or susceptibility-weighted images to create DN atlases. Here, we employ QSM images to develop an improved dentate nucleus atlas for use in imaging studies. The DN was segmented in QSM images from 38 healthy volunteers. The resulting DN masks were transformed to a common space and averaged to generate the DN atlas. The center of mass of the left and right sides of the QSM-based DN atlas in the Montreal Neurological Institute space was -13.8, -55.8, and -36.4 mm, and 13.8, -55.7, and -36.4 mm, respectively. The maximal probability and mean probability of the DN atlas with the individually segmented DNs in this cohort were 100 and 39.3%, respectively, in contrast to the maximum probability of approximately 75% and the mean probability of 23.4 to 33.7% with earlier DN atlases. Using QSM, which provides superior iron-sensitive MRI contrast for delineating iron-rich structures, an improved atlas for the dentate nucleus has been generated. The atlas can be applied to investigate the role of the DN in both normal cortico-cerebellar physiology and the variety of disease states in which it is implicated.

Reproducibility of locus coeruleus and substantia nigra imaging with neuromelanin sensitive MRI.

OBJECTIVES: The purpose of this study was to assess the reproducibility of substantia nigra pars compacta (SNpc) and locus coeruleus (LC) delineation and measurement with neuromelanin-sensitive MRI. MATERIALS AND METHODS: Eleven subjects underwent two neuromelanin-sensitive MRI scans. SNpc and LC volumes were extracted for each scan. Reproducibility of volume and magnetization transfer contrast measurements in SNpc and LC was assessed using intraclass correlation coefficients (ICC) and dice similarity coefficients (DSC). RESULTS: SNpc and LC volume measurements showed excellent reproducibility (SNpc-ICC: 0.94, p < 0.001; LC-ICC: 0.96, p < 0.001). SNpc and LC were accurately delineated between scans (SNpc-DSC: 0.80 ± 0.03; LC-DSC: 0.63 ± 0.07). CONCLUSION: Neuromelanin-sensitive MRI can consistently delineate SNpc and LC.

Test Re-Test Reliability of Four Versions of the 3-Cone Test in Non-Athletic Men.

Until recently, measurement and evaluation in sport science, especially agility testing, has not always included key elements of proper test construction. Often tests are published without reporting reliability and validity analysis for a specific population. The purpose of the present study was to examine the test re-test reliability of four versions of the 3-Cone Test (3CT), and provide guidance on proper test construction for testing agility in athletic populations. Forty male students enrolled in classes in the Department of Physical Education at a mid-Atlantic university participated. On each of test day participants performed 10 trials. In random order, they performed three trials to the right (3CTR, standard test), three to the left (3CTL), and two modified trials (3CTAR and 3CTAL), which included a reactive component in which a visual cue was given to indicate direction. Intra-class correlation coefficients (ICC) indicated a moderate to high reliability for the four tests, 3CTR 0.79 (0.64-0.88, 95%CI), 3CTL 0.73 (0.55-0.85), 3CTAR 0.85(0.74-0.92), and 3CTAL 0.79 (0.64-0.88). Small standard error of the measurement (SEM) was found; range 0.09 to 0.10. Pearson correlations between tests were high (0.82-0.92) on day one as well as day two (0.72-0.85). These results indicate each version of the 3-Cone Test is reliable; however, further tests are needed with specific athletic populations. Only the 3CTAR and 3CTAL are tests of agility due to the inclusion of a reactive component. Future studies examining agility testing and training should incorporate technological elements, including automated timing systems and motion capture analysis. Such instrumentation will allow for optimal design of tests that simulate sport-specific game conditions.

Diffusion tensor imaging of the substantia nigra in Parkinson's disease revisited.

OBJECTIVE: To analyze diffusion tensor imaging (DTI) data in the substantia nigra (SN) using a more consistent region of interest (ROI) defined by neuromelanin-sensitive MRI in order to assess Parkinson's disease (PD) related changes in diffusion characteristics in the SN. METHODS: T1 -weighted and DTI data were obtained in a cohort of 37 subjects (17 control subjects and 20 subjects with PD). The subjects in the PD group were clinically diagnosed PD patients with an average Unified Parkinsonian Disease Rating Scale (UPDRS)-III score of 23.2 ± 9.3. DTI data were analyzed using SN ROIs defined by neuromelanin-sensitive MRI and, for comparison, with ROIs defined on T2 -weighted images (b = 0 images). RESULTS: Compared with control subjects, significantly lower fractional anisotropy was observed in PD in the neuromelanin SN ROI but not in the ROI derived from the T2 -weighted image. This decrease was largest in the rostral and lateral portions of the neuromelanin volume, which were found to have more hypointensity in the T2 -weighted image and, presumably, higher iron content in the PD group. In addition, a larger decrease in fractional anisotropy was seen in the SN region of interest on the side contralateral to the side exhibiting more severe symptoms. These results indicate that the use of neuromelanin sensitive MRI to define the ROI in the SN for analyzing DTI data leads to more significant results, enhancing the robustness of DTI study and DTI based biomarkers of PD. Hum Brain Mapp 37:2547-2556, 2016. © 2016 Wiley Periodicals, Inc.

Dynamic thalamus parcellation from resting-state fMRI data.

The thalamus is a relay center between various subcortical brain areas and the cerebral cortex with delineation of its constituent nuclei being of particular interest in many applications. While previous studies have demonstrated efficacy of connectivity-based thalamus segmentation, they used approaches that do not consider the dynamic nature of thalamo-cortical interactions. In this study, we explicitly exploited the dynamic variation of thalamo-cortical connections to identify different states of functional connectivity and performed state-specific thalamus parcellation. With normalized spectral clustering successively applied in temporal and spatial domains, nine thalamo-cortical connectivity states were identified and the dynamic thalamus parcellation revealed finer thalamic structures with improved atlas correspondence. The present results extend our understanding of thalamo-cortical connectivity and provide a more comprehensive view of the thalamo-cortical interaction.

A multicontrast approach for comprehensive imaging of substantia nigra.

We characterize the contrast behavior of substantia nigra (SN) in both magnetization transfer (MT) imaging, which is believed to be sensitive to neuromelanin (NM), and susceptibility weighted imaging (SWI). Images were acquired with a MT prepared dual echo gradient echo sequence. The first echo was taken as the MT contrast image and the second was used to generate the SWI image. SN volumes were segmented from these two types of images using a thresholding method. The spatial and signal characteristics of the extracted SWI and MT volumes were compared. Both images showed the presence of SN but the volumes of the SN identified in the two are spatially incongruent. The MT volume was more caudal than the SWI volume and with only a 12% overlap between the two volumes. Considering the SN volumes in each hemisphere separately, the average distances between the centers of mass of the volumes from the two types images are 5.1±1.1mm and 4.1±1.2mm, respectively. The frequency offsets (homodyne filtered phase/echo time) for the volumes derived from MT (NM) images and SWI images are 0.09±0.32radians/s and -1.12±0.57radians/s (p<0.0001), respectively. The MT contrasts for the two volumes are 0.16±0.02 and 0.10±0.03 (p<0.001), respectively. Our results indicate that the two contrasts are sensitive to different portions of the SN, with MT seeing the more caudal portion of the SN than SWI, likely due to variations of NM and iron content in the SN. Despite the small overlap, these regions are complementary. Our results provide a new understanding of the contrast behavior of the SN in the two imaging approaches commonly used to image it and indicate that using both may yield a more comprehensive visualization of the SN.

Locus coeruleus contrast and diffusivity metrics differentially relate to age and memory performance.

Neurocognitive aging researchers are increasingly focused on the locus coeruleus, a neuromodulatory brainstem structure that degrades with age. With this rapid growth, the field will benefit from consensus regarding which magnetic resonance imaging (MRI) metrics of locus coeruleus structure are most sensitive to age and cognition. To address this need, the current study acquired magnetization transfer- and diffusion-weighted MRI images in younger and older adults who also completed a free recall memory task. Results revealed significantly larger differences between younger and older adults for maximum than average magnetization transfer-weighted contrast (MTC), axial than mean or radial single-tensor diffusivity (DTI), and free than restricted multi-compartment diffusion (NODDI) metrics in the locus coeruleus; with maximum MTC being the best predictor of age group. Age effects for all imaging modalities interacted with sex, with larger age group differences in males than females for MTC and NODDI metrics. Age group differences also varied across locus coeruleus subdivision for DTI and NODDI metrics, and across locus coeruleus hemispheres for MTC. Within older adults, however, there were no significant effects of age on MTC or DTI metrics, only an interaction between age and sex for free diffusion. Finally, independent of age and sex, higher restricted diffusion in the locus coeruleus was significantly related to better (lower) recall variability, but not mean recall. Whereas MTC has been widely used in the literature, our comparison between the average and maximum MTC metrics, inclusion of DTI and NODDI metrics, and breakdowns by locus coeruleus subdivision and hemisphere make important and novel contributions to our understanding of the aging of locus coeruleus structure.

Nigral volume loss in prodromal, early, and moderate Parkinson's disease.

The loss of melanized neurons in the substantia nigra pars compacta (SNc) is a hallmark pathology in Parkinson's disease (PD). Melanized neurons in SNc can be visualized in vivo using magnetization transfer (MT) effects. Nigral volume was extracted in data acquired with a MT-prepared gradient echo sequence in 33 controls, 83 non-manifest carriers (42 LRRK2 and 41 GBA nonmanifest carriers), 65 prodromal hyposmic participants, 105 de novo PD patients and 26 48-month PD patients from the Parkinson's Progressive Markers Initiative. No difference in nigral volume was seen between controls and LRRK2 and GBA non-manifest carriers (F=0.076; P=0.927). A significant main effect in group was observed between controls, prodromal hyposmic participants, and overt PD patients (F=5.192; P=0.002). Longer disease duration significantly correlated with lower nigral volume (r=-0.252; P=0.010). This study shows that nigral depigmentation can be robustly detected in prodromal hyposmic participants and overt PD patients.

A Novel Hidden Markov Approach to Studying Dynamic Functional Connectivity States in Human Neuroimaging.

Introduction: Hidden Markov models (HMMs) are a popular choice to extract and examine recurring patterns of activity or functional connectivity in neuroimaging data, both in terms of spatial patterns and their temporal progression. Although many diverse HMMs have been applied to neuroimaging data, most have defined states based on activity levels (intensity-based [IB] states) rather than patterns of functional connectivity between brain areas (connectivity-based states), which is problematic if we want to understand connectivity dynamics: IB states are unlikely to provide comprehensive information about dynamic connectivity patterns. Methods: We addressed this problem by introducing a new HMM that defines states based on full functional connectivity (FFC) profiles among brain regions. We empirically explored the behavior of this new model in comparison to existing approaches based on IB or summed functional connectivity states using the Human Connectome Project unrelated 100 functional magnetic resonance imaging "resting-state" dataset. Results: Our FFC model discovered connectivity states with more distinguishable (i.e., unique and separable from each other) patterns than previous approaches, and recovered simulated connectivity-based states more faithfully than the other models tested. Discussion: Thus, if our goal is to extract and interpret connectivity states in neuroimaging data, our new model outperforms previous methods, which miss crucial information about the evolution of functional connectivity in the brain. Impact statement Hidden Markov models (HMMs) can be used to investigate brain states noninvasively. Previous models "recover" connectivity from intensity-based hidden states, or from connectivity "summed" across nodes. In this study, we introduce a novel connectivity-based HMM and show how it can reveal true connectivity hidden states under minimal assumptions.

In vivo detection of substantia nigra and locus coeruleus volume loss in Parkinson's disease using neuromelanin-sensitive MRI: Replication in two cohorts.

Patients with Parkinson's disease undergo a loss of melanized neurons in substantia nigra pars compacta and locus coeruleus. Very few studies have assessed substantia nigra pars compacta and locus coeruleus pathology in Parkinson's disease simultaneously with magnetic resonance imaging (MRI). Neuromelanin-sensitive MRI measures of substantia nigra pars compacta and locus coeruleus volume based on explicit magnetization transfer contrast have been shown to have high scan-rescan reproducibility in controls, but no study has replicated detection of Parkinson's disease-associated volume loss in substantia nigra pars compacta and locus coeruleus in multiple cohorts with the same methodology. Two separate cohorts of Parkinson's disease patients and controls were recruited from the Emory Movement Disorders Clinic and scanned on two different MRI scanners. In cohort 1, imaging data from 19 controls and 22 Parkinson's disease patients were acquired with a Siemens Trio 3 Tesla scanner using a 2D gradient echo sequence with magnetization transfer preparation pulse. Cohort 2 consisted of 33 controls and 39 Parkinson's disease patients who were scanned on a Siemens Prisma 3 Tesla scanner with a similar imaging protocol. Locus coeruleus and substantia nigra pars compacta volumes were segmented in both cohorts. Substantia nigra pars compacta volume (Cohort 1: p = 0.0148; Cohort 2: p = 0.0011) and locus coeruleus volume (Cohort 1: p = 0.0412; Cohort 2: p = 0.0056) were significantly reduced in the Parkinson's disease group as compared to controls in both cohorts. This imaging approach robustly detects Parkinson's disease effects on these structures, indicating that it is a promising marker for neurodegenerative neuromelanin loss.

Neuromelanin-sensitive MRI correlates of cognitive and motor function in Parkinson's disease with freezing of gait.

Substantia nigra pars compacta (SNc) and locus coeruleus (LC) are neuromelanin-rich nuclei implicated in diverse cognitive and motor processes in normal brain function and disease. However, their roles in aging and neurodegenerative disease mechanisms have remained unclear due to a lack of tools to study them in vivo. Preclinical and post-mortem human investigations indicate that the relationship between tissue neuromelanin content and neurodegeneration is complex. Neuromelanin exhibits both neuroprotective and cytotoxic characteristics, and tissue neuromelanin content varies across the lifespan, exhibiting an inverted U-shaped relationship with age. Neuromelanin-sensitive MRI (NM-MRI) is an emerging modality that allows measurement of neuromelanin-associated contrast in SNc and LC in humans. NM-MRI robustly detects disease effects in these structures in neurodegenerative and psychiatric conditions, including Parkinson's disease (PD). Previous NM-MRI studies of PD have largely focused on detecting disease group effects, but few studies have reported NM-MRI correlations with phenotype. Because neuromelanin dynamics are complex, we hypothesize that they are best interpreted in the context of both disease stage and aging, with neuromelanin loss correlating with symptoms most clearly in advanced stages where neuromelanin loss and neurodegeneration are coupled. We tested this hypothesis using NM-MRI to measure SNc and LC volumes in healthy older adult control individuals and in PD patients with and without freezing of gait (FOG), a severe and disabling PD symptom. We assessed for group differences and correlations between NM-MRI measures and aging, cognition and motor deficits. SNc volume was significantly decreased in PD with FOG compared to controls. SNc volume correlated significantly with motor symptoms and cognitive measures in PD with FOG, but not in PD without FOG. SNc volume correlated significantly with aging in PD. When PD patients were stratified by disease duration, SNc volume correlated with aging, cognition, and motor deficits only in PD with disease duration >5 years. We conclude that in severe or advanced PD, identified by either FOG or disease duration >5 years, the observed correlations between SNc volume and aging, cognition, and motor function may reflect the coupling of neuromelanin loss with neurodegeneration and the associated emergence of a linear relationship between NM-MRI measures and phenotype.

Locus coeruleus integrity predicts ease of attaining and maintaining neural states of high attentiveness.

The locus coeruleus (LC), a small subcortical structure in the brainstem, is the brain's principal source of norepinephrine. It plays a primary role in regulating stress, the sleep-wake cycle, and attention, and its degradation is associated with aging and neurodegenerative diseases associated with cognitive deficits (e.g., Parkinson's, Alzheimer's). Yet precisely how norepinephrine drives brain networks to support healthy cognitive function remains poorly understood - partly because LC's small size makes it difficult to study noninvasively in humans. Here, we characterized LC's influence on brain dynamics using a hidden Markov model fitted to functional neuroimaging data from healthy young adults across four attention-related brain networks and LC. We modulated LC activity using a behavioral paradigm and measured individual differences in LC magnetization transfer contrast. The model revealed five hidden states, including a stable state dominated by salience-network activity that occurred when subjects actively engaged with the task. LC magnetization transfer contrast correlated with this state's stability across experimental manipulations and with subjects' propensity to enter into and remain in this state. These results provide new insight into LC's role in driving spatiotemporal neural patterns associated with attention, and demonstrate that variation in LC integrity can explain individual differences in these patterns even in healthy young adults.

Neuromelanin-sensitive MRI correlates of cognitive and motor function in Parkinson's disease with freezing of gait.

Substantia nigra pars compacta (SNc) and locus coeruleus (LC) are neuromelanin-rich nuclei implicated in diverse cognitive and motor processes in normal brain function and disease. However, their roles in aging and neurodegenerative disease mechanisms have remained unclear due to a lack of tools to study them in vivo. Preclinical and post-mortem human investigations indicate that the relationship between tissue neuromelanin content and neurodegeneration is complex. Neuromelanin exhibits both neuroprotective and cytotoxic characteristics, and tissue neuromelanin content varies across the lifespan, exhibiting an inverted U-shaped relationship with age. Neuromelanin-sensitive MRI (NM-MRI) is an emerging modality that allows measurement of neuromelanin-associated contrast in SNc and LC in humans. NM-MRI robustly detects disease effects in these structures in neurodegenerative conditions, including Parkinson's disease (PD). Previous NM-MRI studies of PD have largely focused on detecting disease group effects, but few studies have reported NM-MRI correlations with phenotype. Because neuromelanin dynamics are complex, we hypothesize that they are best interpreted in the context of both disease stage and aging, with neuromelanin loss correlating with symptoms most clearly in advanced stages where neuromelanin loss and neurodegeneration are coupled. We tested this hypothesis using NM-MRI to measure SNc and LC volumes in healthy older adult control individuals and in PD patients with and without freezing of gait (FOG), a severe and disabling PD symptom. We assessed for group differences and correlations between NM-MRI measures and aging, cognition and motor deficits. SNc volume was significantly decreased in PD with FOG compared to controls. SNc volume correlated significantly with motor symptoms and cognitive measures in PD with FOG, but not in PD without FOG. SNc volume correlated significantly with aging in PD. When PD patients were stratified by disease duration, SNc volume correlated with aging, cognition, and motor deficits only in PD with disease duration >5 years. We conclude that in severe or advanced PD, identified by either FOG or disease duration >5 years, the observed correlations between SNc volume and aging, cognition, and motor function may reflect the coupling of neuromelanin loss with neurodegeneration and the associated emergence of a linear relationship between NM-MRI measures and phenotype.