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Background: First-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer's disease (AD). Here, we investigate "estimated years to onset of dementia" (EYO) as a surrogate marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers., Methods: 89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). MPRAGE, ASL and DWI data were processed using Freesurfer, FSL-BASIL and DTI-TK. White matter lesion maps were segmented from FLAIR scans. The SPM Sandwich Estimator Toolbox was used to test for the main effects of EYO and interactions between EYO, Time, and APOE-ε4+. Threshold free cluster enhancement and family wise error rate correction (TFCE FWER ) was performed on voxelwise statistical maps., Results: There were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum (TFCE FWER p < 0.05). The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample., Conclusions: Amongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with incipient brain abnormalities, characterised by white matter disruptions and perfusion abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. Further clinical follow-up of our longitudinal sample would provide critical validation of these findings., (Copyright © 2021. Published by Elsevier Inc.)

Early and profound pathological changes are evident in the locus coeruleus (LC) in dementia and Parkinson's disease, with effects on arousal, attention, cognitive and motor control. The LC can be identified in vivo using non-invasive magnetic resonance imaging techniques which have potential as biomarkers for detecting and monitoring disease progression. Technical limitations of existing imaging protocols have impaired the sensitivity to regional contrast variance or the spatial variability on the rostrocaudal extent of the LC, with spatial mapping consistent with post mortem findings. The current study employs a sensitive magnetisation transfer sequence using ultrahigh field 7T MRI to investigate the LC structure in vivo at high-resolution (0.4 × 0.4 × 0.5 mm). Magnetisation transfer images from 53 healthy older volunteers (52 - 84 years) clearly revealed the spatial features of the LC and were used to create a probabilistic LC atlas for older adults. This atlas may be especially relevant for studying disorders associated with older age. To use the atlas does not require use of the same MT sequence of 7T MRI, provided good co-registration and normalisation is achieved. Consistent rostrocaudal gradients of slice-wise volume, contrast and variance along the LC were observed, mirroring distinctive ex vivo spatial distributions of LC cells in its subregions. The contrast-to-noise ratios were calculated for the peak voxels, and for the averaged signals within the atlas, to accommodate the volumetric differences in estimated contrast. The probabilistic atlas is freely available, and the MRI dataset will be made available for non-commercial research, for replication or to facilitate accurate LC localisation and unbiased contrast extraction in future studies., (Copyright © 2020. Published by Elsevier Inc.)

The impact of in-scanner head movement on functional magnetic resonance imaging (fMRI) signals has long been established as undesirable. These effects have been traditionally corrected by methods such as linear regression of head movement parameters. However, a number of recent independent studies have demonstrated that these techniques are insufficient to remove motion confounds, and that even small movements can spuriously bias estimates of functional connectivity. Here we propose a new data-driven, spatially-adaptive, wavelet-based method for identifying, modeling, and removing non-stationary events in fMRI time series, caused by head movement, without the need for data scrubbing. This method involves the addition of just one extra step, the Wavelet Despike, in standard pre-processing pipelines. With this method, we demonstrate robust removal of a range of different motion artifacts and motion-related biases including distance-dependent connectivity artifacts, at a group and single-subject level, using a range of previously published and new diagnostic measures. The Wavelet Despike is able to accommodate the substantial spatial and temporal heterogeneity of motion artifacts and can consequently remove a range of high and low frequency artifacts from fMRI time series, that may be linearly or non-linearly related to physical movements. Our methods are demonstrated by the analysis of three cohorts of resting-state fMRI data, including two high-motion datasets: a previously published dataset on children (N=22) and a new dataset on adults with stimulant drug dependence (N=40). We conclude that there is a real risk of motion-related bias in connectivity analysis of fMRI data, but that this risk is generally manageable, by effective time series denoising strategies designed to attenuate synchronized signal transients induced by abrupt head movements. The Wavelet Despiking software described in this article is freely available for download at www.brainwavelet.org., (Copyright © 2014. Published by Elsevier Inc.)

No study so far has attempted to map the 3D topography of brain hypoxia in the individual rat in vivo following middle cerebral artery occlusion (MCAo). In a previous microPET study, we reported that (18)F-fluoromisonidazole ((18)F-MISO) trapping in the brain after MCAo was specific for the hypoxic viable tissue. Here, we used (18)F-MISO microPET to map the 3D topography of brain hypoxia in the acute stage of permanent distal MCAo in individual spontaneously hypertensive rats. Normal rats were also studied. (18)F-MISO was intravenously injected approximately 1 h after clip placement and PET data were acquired for 2 hours. Animals were sacrificed and the brains harvested 48 h later for infarct mapping using standard histopathology. As expected, continuous (18)F-MISO trapping was found over the affected relative to unaffected and control MCA cortex. Using single-subject voxel-based statistical mapping, tracer accumulation 90-120 min after injection was consistently significantly higher in the anterior MCA cortex (proximal relative to clip site) and gradually decreased towards posterior areas, a pattern consistent with the classic penumbra concept. The data also suggested that (i) a portion of the significant (18)F-MISO trapping area may sit outside the contours of the final infarct despite the permanent MCAo, suggesting that (18)F-MISO may be a marker not only of severe (penumbral) but also of milder (oligemic) hypoxia, and (ii) small portions of the final infarct may not exhibit early tracer trapping, suggesting that by the time the tracer was administered this tissue had already progressed to irreversible damage. This study shows the feasibility of single-subject mapping of brain hypoxia following MCAo in the rat, which has potential applications in pathophysiological investigations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Not only finger tapping speed, but also tapping regularity can be impaired after stroke, contributing to reduced dexterity. The neural substrates of impaired tapping regularity after stroke are unknown. Previous work suggests damage to the dorsal premotor cortex (PMd) and prefrontal cortex (PFCx) affects externally-cued hand movement. We tested the hypothesis that these two areas are involved in impaired post-stroke tapping regularity. In 19 right-handed patients (15 men/4 women; age 45-80 years; purely subcortical in 16) partially to fully recovered from hemiparetic stroke, tri-axial accelerometric quantitative assessment of tapping regularity and BOLD fMRI were obtained during fixed-rate auditory-cued index-thumb tapping, in a single session 10-230 days after stroke. A strong random-effect correlation between tapping regularity index and fMRI signal was found in contralesional PMd such that the worse the regularity the stronger the activation. A significant correlation in the opposite direction was also present within contralesional PFCx. Both correlations were maintained if maximal index tapping speed, degree of paresis and time since stroke were added as potential confounds. Thus, the contralesional PMd and PFCx appear to be involved in the impaired ability of stroke patients to fingertap in pace with external cues. The findings for PMd are consistent with repetitive TMS investigations in stroke suggesting a role for this area in affected-hand movement timing. The inverse relationship with tapping regularity observed for the PFCx and the PMd suggests these two anatomically-connected areas negatively co-operate. These findings have implications for understanding the disruption and reorganization of the motor systems after stroke., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)