Jack, Clifford R

Altered cortical thickness has been observed in aging and various neurodegenerative disorders. Furthermore, reduced hippocampal volume has been reported in late-life depression. Even mild depressive symptoms are common in the elderly. However, little is known about the structural MRI measures of depressive symptoms in normal cognitive aging. Thus we sought to examine the association between depressive symptoms with cortical thickness and hippocampal volume as measured by brain MRI among community-dwelling participants. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging, involving cognitively normal participants ( N = 1,507) aged≥70 years. We observed that depressive symptoms were associated with lower global cortical thickness and lower thickness in specific prefrontal and temporal cortical regions, labeled by FreeSurfer software, version 5.3. As expected, the strength of correlation was very small, given that participants were community-dwelling with only mild depressive symptoms. We did not observe associations between hippocampal volume and depressive symptoms. These findings may provide insight into the structural correlates of mild depressive symptoms in elderly participants.

Objective There is a need for inexpensive noninvasive tests to identify older healthy persons at risk for Alzheimer disease (AD) for enrollment in AD prevention trials. Our objective was to examine whether abnormalities in neuroimaging measures of amyloid and neurodegeneration are correlated with odor identification (OI) in the population‐based Mayo Clinic Study of Aging. Methods Cognitively normal (CN) participants had olfactory function assessed using the Brief Smell Identification Test (B‐SIT), underwent magnetic resonance imaging (n = 829) to assess a composite AD signature cortical thickness and hippocampal volume (HVa), and underwent 11 C‐Pittsburgh compound B (n = 306) and 18 fluorodeoxyglucose (n = 305) positron emission tomography scanning to assess amyloid accumulation and brain hypometabolism, respectively. The association of neuroimaging biomarkers with OI was examined using multinomial logistic regression and simple linear regression models adjusted for potential confounders. Results Among 829 CN participants (mean age = 79.2 years; 51.5% men), 248 (29.9%) were normosmic and 78 (9.4%) had anosmia (B‐SIT score < 6). Abnormal AD signature cortical thickness and reduced HVa were associated with decreased OI as a continuous measure (slope = −0.43, 95% confidence interval [CI] = −0.76 to −0.09, p = 0.01 and slope = −0.72, 95% CI = −1.15 to −0.28, p < 0.01, respectively). Reduced HVa, decreased AD signature cortical thickness, and increased amyloid accumulation were significantly associated with increased odds of anosmia. Interpretation Our findings suggest that OI may be a noninvasive, inexpensive marker for risk stratification, for identifying participants at the preclinical stage of AD who may be at risk for cognitive impairment and eligible for inclusion in AD prevention clinical trials. These cross‐sectional findings remain to be validated prospectively. Ann Neurol 2017;81:871–882

Background Diffusion tensor imaging measures of white matter ( WM ) microstructural integrity appear to provide earlier indication of WM injury than WM hyperintensities; however, risk factors for poor WM microstructural integrity have not been established. Our study quantifies the association between vascular risk factors in midlife and late life with measures of late‐life WM microstructural integrity. Methods and Results We used data from 1851 participants in ARIC (Atherosclerosis Risk in Communities Study) who completed 3‐T magnetic resonance imaging, including diffusion tensor imaging, as part of the ARIC Neurocognitive Study (ARIC‐NCS). We quantified the association among lipids, glucose, and blood pressure from the baseline ARIC visit (1987–1989, ages 44–65, midlife) and visit 5 of ARIC (2011–2013, ages 67–90, late life, concurrent with ARIC‐NCS) with regional and overall WM mean diffusivity and fractional anisotropy obtained at ARIC visit 5 for ARIC participants. We also considered whether these associations were independent of or modified by WM hyperintensity volumes. We found that elevated blood pressure in midlife and late life and elevated glucose in midlife, but not late life, were associated with worse late‐life WM microstructural integrity. These associations were independent of the degree of WM hyperintensity, and the association between glucose and WM microstructural integrity appeared stronger for those with the least WM hyperintensity. There was little support for an adverse association between lipids and WM microstructural integrity. Conclusions Hypertension in both midlife and late life and elevated glucose in midlife are related to worse WM microstructural integrity in late life.

PurposeThe homeostasis of intracranial pressure (ICP) is of paramount importance for maintaining normal brain function. A noninvasive technique capable of making direct measurements of ICP currently does not exist. MR elastography (MRE) is capable of noninvasively measuring brain tissue stiffness in vivo, and may act as a surrogate to measure ICP. The objective of this study was to investigate the impact of changing ICP on brain stiffness using MRE in a swine model.MethodsBaseline MRE measurements were obtained, and then catheters were surgically placed into the left and right lateral ventricles of three animals. ICP was systematically increased over the range of 0 to 55 millimeters mercury (mmHg), and stiffness measurements were made using brain MRE at vibration frequencies of 60 hertz (Hz), 90 Hz, 120 Hz, and 150 Hz.ResultsA significant linear correlation between stiffness and ICP in the cross‐subject comparison was observed for all tested vibrational frequencies (P ≤ 0.01). The 120 Hz (0.030 ± 0.004 kilopascal (kPa)/mmHg, P < 0.0001) and 150 Hz (0.031 ± 0.008 kPa/mmHg, P = 0.01) vibrational frequencies had nearly identical slopes, which were approximately two‐ to three‐fold higher than the 90 Hz (0.017 ± 0.002 kPa/mmHg, P < 0.0001) and 60 Hz (0.009 ± 0.002 kPa/mmHg, P = 0.001) slopes, respectively.ConclusionIn this study, MRE demonstrated the potential for noninvasive measurement of changes in ICP. Magn Reson Med 79:1043–1051, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Background: There is growing interest in white matter (WM) imaging with positron emission tomography (PET). Objectives: We studied the association of cognitive function in late multiple sclerosis (MS) with cortical and WM Pittsburgh compound-B PET (PiB-PET) binding. Methods: In the population-based Mayo Clinic Study of Aging, 24 of 4869 participants had MS (12 underwent PiB-PET). Controls were age and sex matched (5:1). We used automated or semi-automated processing for quantitative image analyses and conditional logistic regression for group differences. Results: MS patients had lower memory ( p = 0.03) and language ( p = 0.02) performance; smaller thalamic volumes ( p = 0.003); and thinner temporal ( p = 0.001) and frontal ( p = 0.045) cortices on magnetic resonance imaging (MRI) than controls. There was no difference in global cortical PiB standardized uptake value ratios between MS and controls ( p = 0.35). PiB uptake was lower in areas of WM hyperintensities compared to normal-appearing white matter (NAWM) in MS ( p = 0.0002). Reduced PiB uptake in both the areas of WM hyperintensities ( r = 0.65; p = 0.02) and NAWM ( r = 0.69; p = 0.01) was associated with decreased visuospatial performance in MS. Conclusion: PiB uptake in the cortex in late MS is not different from normal age-matched controls. PiB uptake in the WM in late MS may be a marker of the large network structures’ integrity such as those involved in visuospatial performance.

AbstractQuantitative measurement of β‐amyloid from amyloid PET scans typically relies on localizing target and reference regions by image registration to MRI. In this work, we present a series of simulations where 50 small random perturbations of starting location and orientation were applied to each subject's PET scan, and rigid registration usingspm_coregwas performed between each perturbed PET scan and its corresponding MRI. We then measured variation in the output PET‐MRI registrations and how this variation affected the resulting SUVR measurements. We performed these experiments using scans of 1196 participants, half using 18F florbetapir and half using 11C PiB. From these experiments, we measured the magnitude of the imprecision in the rigid registration steps used to localize measurement regions, and how this contributes to the overall imprecision in SUVR measurements. Unexpectedly, we found for both tracers that the imprecision in these measurements depends on the degree of amyloid tracer uptake, and thus also indirectly on Alzheimer's disease clinical status. We then examined common choices of reference regions, and we show that SUVR measurements using supratentorial white matter references are relatively resistant to this source of error. We also show that the use of partial volume correction further magnifies the effects of registration imprecision on SUVR measurements. Together, these results suggest that this rigid registration step is an attractive target for future work in improving measurement techniques.Hum Brain Mapp 38:3323–3336, 2017. ©2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Introduction The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. Methods We used standard searches to find publications using ADNI data. Results (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β‐amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white‐matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion‐like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by “classic” AD pathology but also by normal biomarkers, accelerated decline, and suspected non‐Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and surrogate outcome measures using longitudinal structural magnetic resonance imaging may further reduce clinical trial cost and duration; (11) Advances in machine learning techniques such as neural networks have improved diagnostic and prognostic accuracy especially in challenges involving MCI subjects; and (12) Network connectivity measures and genetic variants show promise in multimodal classification and some classifiers using single modalities are rivaling multimodal classifiers. Discussion Taken together, these studies fundamentally deepen our understanding of AD progression and its underlying genetic basis, which in turn informs and improves clinical trial design.