In vivo imaging of the nucleus of the solitary tract with Magnetization Transfer at 7 Tesla

The nucleus of the solitary tract (NTS) is a nuclei complex with, among others, a high concentration of noradrenergic neurons (including the noradrenergic subnuclei named A1 and A2) in the medulla. The NTS regulates several cognitive, neuroendocrine and autonomic functions. No method currently exists to anatomically visualize the NTS in vivo. Several noradrenergic and dopaminergic nuclei have been successfully imaged using Magnetization Transfer (MT) contrast manipulation. We therefore hypothesized that an efficient, high-resolution MT-weighted sequence at 7 T might successfully image the NTS. In this study, we found a hyperintensity, similar to hyperintensities found in other noradrenergic and dopaminergic nuclei, consistent with the expected NTS location, and specific to the MT-weighted images. The localization of the hyperintensity was found to be consistent between individuals and slices and in good correspondence to a histological atlas and a meta-analytic map of fMRI-based NTS activation. We conclude that the method may, for the first time, achieve NTS imaging in vivo and within a clinically-feasible acquisition time. To facilitate NTS research at lower field strengths, an NTS template was created and made publicly available

Covid-19 may have a detrimental impact on sensorimotor function

Background: The long-term impact of COVID-19 on global health is still unknown. Sensorimotor biomarkers may be promising indicators of lasting effects of COVID-19. Although normal aging may cause changes in sensorimotor function, more severe changes may indicate the subsequent impacts of COVID-19 on brain health. The objective of this study was to investigate the association between COVID-19 and sensorimotor markers (grip strength, gait, and smell) in the 7T neuroCOVID consortium, which is comprised of 5 sites: The University of Texas Health Science Center at San Antonio, Houston Methodist Research Institute, The University of Pittsburgh, Massachusetts General Hospital, and Nottingham University (UK). Methods: We studied 101 adult participants (mean age 60.9 ± 8.5 years, range 45-80 years, 51% women) without prior cognitive impairment or cerebrovascular disease from the 7T consortium across 3 US and 1 UK sites. The sample included 77 COVID-19 survivors and 24 healthy controls. Sensorimotor markers were measured for olfaction (n=59; 12-item Brief Smell Identification Test (B-SIT)), grip strength (n=97; measured using a hand dynamometer), and Gait (n=101; 4-meter normal walk time and n=99; 4-meter fast-paced walk time). To assess the association between COVID-19 and sensorimotor outcomes, we performed a series of linear regression models adjusting for age, sex, site, and handedness (grip strength only). Statistical significance was set at a 5% level. Results: As compared to healthy controls, COVID-19 survivors, on average had a significantly reduced hand grip in the right hand (β ± standard error: -0.18 ± 0.07, p=0.006). We also observed associations with reduced gait speed. COVID-19 survivors, on average, had a slower walk time in both normal (0.17 ± 0.06, p=0.004) and fast-paced (0.04 ± 0.02, p=0.022) as compared to healthy controls. We did not observe any statistical associations between COVID-19 survivors and left-hand grip strength or B-SIT. Conclusions: These results highlight that Covid-19 infection may have a detrimental impact on sensorimotor function. Additional analysis with a larger sample size are ongoing, which will allow us to further assess the effect of infection severity. Future studies will look to evaluate the association between sensorimotor markers, cognition, and ultra-high field 7T MRI-based imaging markers

Impact of repeated short light exposures on sustained pupil responses in an fMRI environment

Light triggers numerous non-image forming (NIF), or non-visual, biological effects. The brain correlates of these NIF effects have been investigated, notably using Magnetic Resonance Imaging (MRI) and short light exposures varying in irradiance and spectral quality. However, it is not clear whether having light in subsequent blocks may induce carry over effects of one light block onto the next, thus biasing the study. We reasoned that pupil light reflex (PLR) was an easy readout of one of the NIF effects of light that could be used to address this issue. We characterized the sustained PLR in 13 to 16 healthy young individuals under short light exposures during three distinct cognitive processes (executive, emotional and attentional). Light conditions pseudo-randomly alternated between monochromatic orange light [0.16 melanopic Equivalent Daylight Illuminance (mel EDI) lux] and polychromatic blue-enriched white light of three different levels [37, 92, 190 mel EDI lux]. As expected, higher melanopic irradiance was associated with larger sustained PLR in each cognitive domain. This result was stable over the light block sequence under higher melanopic irradiance levels as compared to lower ones. Exploratory frequency-domain analyses further revealed that PLR was more variable within a light block under lower melanopic irradiance levels. Importantly, PLR varied across tasks independently of the light condition pointing to a potential impact of the light history and/or cognitive context on PLR. Together, our results emphasize that the distinct contribution and adaptation of the different retinal photoreceptors influence the NIF effects of light and therefore potentially their brain correlates

Practice makes perfect: High performance gains in older adults engaged in selective attention within and across sensory modalities

Selective attention has been found to decline with aging, possibly depending on the sensory modality through which targets and distractors are presented. We investigated the capacity of older adults to improve performance on visual and auditory selective attention tasks. 31 younger (mean age = 22.8 years, SD = 2.1) and 29 older participants (mean age = 69.5 years, SD = 5.8) performed visual and auditory tasks with and without unimodal and cross-modal distraction across five practice sessions. Reaction time decreased with practice in both age groups. Strikingly, this performance improvement was similar across the age groups. Moreover, distractor modality did not affect performance gains in either age group. Older adults were disproportionally affected by cross-modal visual distraction, however, corroborating previous studies. This age-related effect was mitigated during the practice sessions. Finally, there was no transfer of practice to neuropsychological test performance. These results suggest a high capacity of older individuals to improve selective attention functions within and across sensory modalities

High-resolution in vivo imaging of human locus coeruleus by Magnetization Transfer MRI at 3T and 7T

Locus Coeruleus (LC) is a neuromelanin-rich brainstem structure that is the source of noradrenaline in the cortex and is thought to modulate attention and memory. LC imaging in vivo is commonly performed with a 2D T 1-weighted Turbo Spin Echo (TSE) MRI sequence, an approach that suffers from several drawbacks at 3T, including long acquisition times and highly anisotropic spatial resolution. In this study, we developed a high-resolution Magnetization Transfer (MT) sequence for LC imaging at both 7T and 3T and compared its performance to a TSE sequence. Results indicate that LC imaging can be achieved with an MT sequence at both 7 and 3T at higher spatial resolution than the 3T TSE. Furthermore, we investigated whether the currently disputed source of contrast in the LC region with a TSE sequence relates to MT effects or shortened T 1 and T 2* due to increased iron concentration. Our results suggest that the contrast in the LC area relates to MT effects. To conclude, in this study we managed to image the LC, for the first time, at 7T and at an increased resolution compared to the current state-of-the-art. Imaging the LC is highly relevant for clinical diagnostics as structural tissue properties of the LC may hold promise as a biomarker in neurodegenerative diseases

Associations of 24-Hour Rest-Activity Rhythm Fragmentation, Cognitive Decline, and Postmortem Locus Coeruleus Hypopigmentation in Alzheimer's Disease

Objective: While studies suggested that locus coeruleus (LC) neurodegeneration contributes to sleep–wake dysregulation in Alzheimer's disease (AD), the association between LC integrity and circadian rest-activity patterns remains unknown. Here, we investigated the relationships between 24-hour rest-activity rhythms, cognitive trajectories, and autopsy-derived LC integrity in older adults with and without cortical AD neuropathology. Methods: This retrospective study leveraged multi-modal data from participants of the longitudinal clinical-pathological Rush Memory and Aging Project. Indices of 24-hour rest-activity rhythm fragmentation (intradaily variability) and stability (interdaily stability) were extracted from annual actigraphic recordings, and cognitive trajectories were computed from annual cognitive evaluations. At autopsy, LC neurodegeneration was determined by the presence of hypopigmentation, and cortical AD neuropathology was assessed. Contributions of comorbid pathologies (Lewy bodies, cerebrovascular pathology) were evaluated. Results: Among the 388 cases included in the study sample (age at death = 92.1 ± 5.9 years; 273 women), 98 (25.3%) displayed LC hypopigmentation, and 251 (64.7%) exhibited cortical AD neuropathology. Logistic regression models showed that higher rest-activity rhythm fragmentation, measured up to ~7.1 years before death, was associated with increased risk to display LC neurodegeneration at autopsy (odds ratio [OR] = 1.46, 95% confidence interval [CI95%]: 1.16–1.84, pBONF = 0.004), particularly in individuals with cortical AD neuropathology (OR = 1.56, CI95%: 1.15–2.15, pBONF = 0.03) and independently of comorbid pathologies. In addition, longitudinal increases in rest-activity rhythm fragmentation partially mediated the association between LC neurodegeneration and cognitive decline (estimate = -0.011, CI95%: -0.023–-0.002, pBONF = 0.03). Interpretation: These findings highlight the LC as a neurobiological correlate of sleep–wake dysregulation in AD, and further underscore the clinical relevance of monitoring rest-activity patterns for improved detection of at-risk individuals. ANN NEUROL 2024;95:653–664.</p

Longitudinal predictive modeling of tau progression along the structural connectome

Tau neurofibrillary tangles, a pathophysiological hallmark of Alzheimer’s disease (AD), exhibit a stereotypical spatiotemporal trajectory that is strongly correlated with disease progression and cognitive decline. Personalized prediction of tau progression is, therefore, vital for the early diagnosis and prognosis of AD. Evidence from both animal and human studies is suggestive of tau transmission along the brains preexisting neural connectivity conduits. We present here an analytic graph diffusion framework for individualized predictive modeling of tau progression along the structural connectome. To account for physiological processes that lead to active generation and clearance of tau alongside passive diffusion, our model uses an inhomogenous graph diffusion equation with a source term and provides closed-form solutions to this equation for linear and exponential source functionals. Longitudinal imaging data from two cohorts, the Harvard Aging Brain Study (HABS) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), were used to validate the model. The clinical data used for developing and validating the model include regional tau measures extracted from longitudinal positron emission tomography (PET) scans based on the 18F-Flortaucipir radiotracer and individual structural connectivity maps computed from diffusion tensor imaging (DTI) by means of tractography and streamline counting. Two-timepoint tau PET scans were used to assess the goodness of model fit. Three-timepoint tau PET scans were used to assess predictive accuracy via comparison of predicted and observed tau measures at the third timepoint. Our results show high consistency between predicted and observed tau and differential tau from region-based analysis. While the prognostic value of this approach needs to be validated in a larger cohort, our preliminary results suggest that our longitudinal predictive model, which offers an in vivo macroscopic perspective on tau progression in the brain, is potentially promising as a personalizable predictive framework for AD

Unraveling the contributions to the neuromelanin-MRI contrast

© 2020, The Author(s). The Locus Coeruleus (LC) and the Substantia Nigra (SN) are small brainstem nuclei that change with aging and may be involved in the development of various neurodegenerative and psychiatric diseases. Magnetization Transfer (MT) MRI has been shown to facilitate LC and the SN visualization, and the observed contrast is assumed to be related to neuromelanin accumulation. Imaging these nuclei may have predictive value for the progression of various diseases, but interpretation of previous studies is hindered by the fact that the precise biological source of the contrast remains unclear, though several hypotheses have been put forward. To inform clinical studies on the possible biological interpretation of the LC- and SN contrast, we examined an agar-based phantom containing samples of natural Sepia melanin and synthetic Cys-Dopa-Melanin and compared this to the in vivo human LC and SN. T1 and T2* maps, MT spectra and relaxation times of the phantom, the LC and the SN were measured, and a two-pool MT model was fitted. Additionally, Bloch simulations and a transient MT experiment were conducted to confirm the findings. Overall, our results indicate that Neuromelanin-MRI contrast in the LC likely results from a lower macromolecular fraction, thus facilitating interpretation of results in clinical populations. We further demonstrate that in older individuals T1 lengthening occurs in the LC11sci

Neuromelanin related ultra-high field signal intensity of the locus coeruleus differs between Parkinson’s disease and controls

Introduction: Neuromelanin related signal changes in catecholaminergic nuclei are considered as a promising MRI biomarker in Parkinson’s disease (PD). Until now, most studies have investigated the substantia nigra (SN), while signal changes might be more prominent in the locus coeruleus (LC). Ultra-high field MRI improves the visualisation of these small brainstem regions and might support the development of imaging biomarkers in PD. Objectives: To compare signal intensity of the SN and LC on Magnetization Transfer MRI between PD patients and healthy controls (HC) and to explore its association with cognitive performance in PD. Methods: This study was conducted using data from the TRACK-PD study, a longitudinal 7T MRI study. A total of 78 early-stage PD patients and 36 HC were included. A mask for the SN and LC was automatically segmented and manually corrected. Neuromelanin related signal intensity of the SN and LC was compared between PD and HC. Results: PD participants showed a lower contrast-to-noise ratio (CNR) in the right SN (p = 0.029) and left LC (p = 0.027). After adding age as a confounder, the CNR of the right SN did not significantly differ anymore between PD and HC (p = 0.055). Additionally, a significant positive correlation was found between the SN CNR and memory function. Discussion: This study confirms that neuromelanin related signal intensity of the LC differs between early-stage PD patients and HC. No significant difference was found in the SN. This supports the theory of bottom-up disease progression in PD. Furthermore, loss of SN integrity might influence working memory or learning capabilities in PD patients