Mental health during the COVID-19 pandemic: the importance of social support in midlife women.

OBJECTIVE: This study aimed to examine sex differences in factors associated with mood and anxiety in midlife men and women during the COVID-19 pandemic. METHODS: During a remote visit, 312 adults aged 40-60 years (167 female; 23.6% perimenopausal) from the Human Connectome Project in Aging completed PROMIS measures of depression, anxiety and anger/irritability; perceived stress; and questions about social support, financial stress and menopause stage. Multivariate linear regression models assessed sex differences in mental health and the association of social support, financial stress and menopause stage with mental health. RESULTS: Anxiety was higher in women than in men (b = 2.39, p = 0.02). For women only, decreased social support was associated with increased anxiety (b = -2.26, p = 0.002), anger/irritability (b = -1.89, p = 0.02) and stress (b = -1.67, p = 0.002). For women only, not having close family was associated with increased depressive symptoms (b = -6.60, p = 0.01) and stress (b = -7.03, p < 0.001). For both sexes, having children was associated with lower depressive symptoms (b = -3.08, p = 0.002), anxiety (b = -1.93, p = 0.07), anger/irritability (b = -2.73, p = 0.02) and stress (b = -1.44, p = 0.07). Menopause stage was unrelated to mental health. CONCLUSION: Social support, but not financial stress, influenced mental health during the COVID-19 pandemic at midlife, particularly for women.

Age-related differences in macromolecular resonances observed in ultra-short-TE STEAM MR spectra at 7T.

PURPOSE: To understand how macromolecular content varies in the human brain with age in a large cohort of healthy subjects. METHODS: In-vivo 1H-MR spectra were acquired using ultra-short TE STEAM at 7T in the posterior cingulate cortex. Macromolecular content was studied in 147 datasets from a cohort ranging in age from 19 to 89 y. Three fitting approaches were used to evaluate the macromolecular content: (1) a macromolecular resonances model developed for this study; (2) LCModel-simulated macromolecules; and (3) a combination of measured and LCModel-simulated macromolecules. The effect of age on the macromolecular content was investigated by considering age both as a continuous variable (i.e., linear regressions) and as a categorical variable (i.e., multiple comparisons among sub-groups obtained by stratifying data according to age by decade). RESULTS: While weak age-related effects were observed for macromolecular peaks at ˜0.9 (MM09), ˜1.2 (MM12), and ˜1.4 (MM14) ppm, moderate to strong effects were observed for peaks at ˜1.7 (MM17), and ˜2.0 (MM20) ppm. Significantly higher MM17 and MM20 content started from 30 to 40 y of age, while for MM09, MM12, and MM14, significantly higher content started from 60 to 70 y of age. CONCLUSIONS: Our findings provide insights into age-related differences in macromolecular contents and strengthen the necessity of using age-matched measured macromolecules during quantification.

Map-based B0 shimming for single voxel brain spectroscopy at 7T.

While B0 shimming is an important requirement for in vivo brain spectroscopy, for single voxel spectroscopy (SVS), the role for advanced shim methods has been questioned. Specifically, with the small spatial dimensions of the voxel, the extent to which inhomogeneities higher than second order exist and the ability of higher order shims to correct them is controversial. To assess this, we acquired SVS from two loci of neurophysiological interest, the rostral prefrontal cortex (rPFC; 8 cc) and hippocampus (Hc; 9 cc). The rPFC voxel was placed using SUsceptibility Managed Optimization (SUMO) and an initial B0 map that covers the entire cerebrum to cerebellum. In each location, we compared map-based shimming (Bolero) with projection-based shimming (FAST(EST)MAP). We also compared vendor-provided spherical harmonic first- and second-order shims with additional third- and fourth-order shim hardware. The 7T SVS acquisition used stimulated echo acquisition mode (STEAM) TR/TM/TE of 6 s/20 ms/8 ms, a tissue water acquisition for concentration reference, and LCModel for spectral analysis. In the rPFC (n = 7 subjects), Bolero shimming with first- and second-order shims reduced the residual inhomogeneity σ B 0 from 9.8 ± 4.5 Hz with FAST(EST)MAP to 6.5 ± 2.0 Hz. The addition of third- and fourth-order shims further reduced σ B 0 to 4.0 ± 0.8 Hz. In the Hc (n = 7 subjects), FAST(EST)MAP, Bolero with first- and second-order shims, and Bolero with first- to fourth-order shims achieved σ B 0 values of 8.6 ± 1.9, 5.6 ± 1.0, and 4.6 ± 0.9 Hz, respectively. The spectral linewidth, Δ v σ B 0 , was estimated with a Voigt lineshape using σ B 0 and T2 = 130 ms. Δ v σ B 0 significantly correlated with the Cramer-Rao lower bounds and concentrations of several metabolites, including glutamate and glutamine in the rPFC. In both loci, if the B0 distribution is well described by a Gaussian model, the variance of the metabolite concentrations is reduced, consistent with the LCModel fit based on a unimodal lineshape. Overall, the use of the high order and map-based B0 shim methods improved the accuracy and consistency of spectroscopic data.

Cardiovascular and metabolic health is associated with functional brain connectivity in middle-aged and older adults: Results from the Human Connectome Project-Aging study.

Several cardiovascular and metabolic indicators, such as cholesterol and blood pressure have been associated with altered neural and cognitive health as well as increased risk of dementia and Alzheimer's disease in later life. In this cross-sectional study, we examined how an aggregate index of cardiovascular and metabolic risk factor measures was associated with correlation-based estimates of resting-state functional connectivity (FC) across a broad adult age-span (36-90+ years) from 930 volunteers in the Human Connectome Project Aging (HCP-A). Increased (i.e., worse) aggregate cardiometabolic scores were associated with reduced FC globally, with especially strong effects in insular, medial frontal, medial parietal, and superior temporal regions. Additionally, at the network-level, FC between core brain networks, such as default-mode and cingulo-opercular, as well as dorsal attention networks, showed strong effects of cardiometabolic risk. These findings highlight the lifespan impact of cardiovascular and metabolic health on whole-brain functional integrity and how these conditions may disrupt higher-order network integrity.

Associations between age, sex, APOE genotype, and regional vascular physiology in typically aging adults.

Altered blood flow in the human brain is characteristic of typical aging. However, numerous factors contribute to inter-individual variation in patterns of blood flow throughout the lifespan. To better understand the mechanisms behind such variation, we studied how sex and APOE genotype, a primary genetic risk factor for Alzheimer's disease (AD), influence associations between age and brain perfusion measures. We conducted a cross-sectional study of 562 participants from the Human Connectome Project - Aging (36 to >90 years of age). We found widespread associations between age and vascular parameters, where increasing age was associated with regional decreases in cerebral blood flow (CBF) and increases in arterial transit time (ATT). When grouped by sex and APOE genotype, interactions between group and age demonstrated that females had relatively greater CBF and lower ATT compared to males. Females carrying the APOEε4 allele showed the strongest association between CBF decline and ATT incline with age. This demonstrates that sex and genetic risk for AD modulate age-associated patterns of cerebral perfusion measures.

Default mode network failure and neurodegeneration across aging and amnestic and dysexecutive Alzheimer's disease.

From a complex systems perspective, clinical syndromes emerging from neurodegenerative diseases are thought to result from multiscale interactions between aggregates of misfolded proteins and the disequilibrium of large-scale networks coordinating functional operations underpinning cognitive phenomena. Across all syndromic presentations of Alzheimer's disease, age-related disruption of the default mode network is accelerated by amyloid deposition. Conversely, syndromic variability may reflect selective neurodegeneration of modular networks supporting specific cognitive abilities. In this study, we leveraged the breadth of the Human Connectome Project-Aging cohort of non-demented individuals (N = 724) as a normative cohort to assess the robustness of a biomarker of default mode network dysfunction in Alzheimer's disease, the network failure quotient, across the aging spectrum. We then examined the capacity of the network failure quotient and focal markers of neurodegeneration to discriminate patients with amnestic (N = 8) or dysexecutive (N = 10) Alzheimer's disease from the normative cohort at the patient level, as well as between Alzheimer's disease phenotypes. Importantly, all participants and patients were scanned using the Human Connectome Project-Aging protocol, allowing for the acquisition of high-resolution structural imaging and longer resting-state connectivity acquisition time. Using a regression framework, we found that the network failure quotient related to age, global and focal cortical thickness, hippocampal volume, and cognition in the normative Human Connectome Project-Aging cohort, replicating previous results from the Mayo Clinic Study of Aging that used a different scanning protocol. Then, we used quantile curves and group-wise comparisons to show that the network failure quotient commonly distinguished both dysexecutive and amnestic Alzheimer's disease patients from the normative cohort. In contrast, focal neurodegeneration markers were more phenotype-specific, where the neurodegeneration of parieto-frontal areas associated with dysexecutive Alzheimer's disease, while the neurodegeneration of hippocampal and temporal areas associated with amnestic Alzheimer's disease. Capitalizing on a large normative cohort and optimized imaging acquisition protocols, we highlight a biomarker of default mode network failure reflecting shared system-level pathophysiological mechanisms across aging and dysexecutive and amnestic Alzheimer's disease and biomarkers of focal neurodegeneration reflecting distinct pathognomonic processes across the amnestic and dysexecutive Alzheimer's disease phenotypes. These findings provide evidence that variability in inter-individual cognitive impairment in Alzheimer's disease may relate to both modular network degeneration and default mode network disruption. These results provide important information to advance complex systems approaches to cognitive aging and degeneration, expand the armamentarium of biomarkers available to aid diagnosis, monitor progression and inform clinical trials.

Quantification of GABA concentration measured noninvasively in the human posterior cingulate cortex with 7 T ultra-short-TE MR spectroscopy.

PURPOSE: The increased spectral dispersion achieved at ultra-high field permits quantification of γ-aminobutyric acid (GABA) concentrations at ultra-short-TE without editing. This work investigated the influence of spectral quality and different LCModel fitting approaches on quantification of GABA. Additionally, the sensitivity with which cross-sectional and longitudinal variations in GABA concentrations can be observed was characterized. METHODS: In - vivo spectra were acquired in the posterior cingulate cortex of 10 volunteers at 7 T using a STEAM sequence. Synthetically altered spectra with different levels of GABA signals were used to investigate the reliability of GABA quantification with different LCModel fitting approaches and different realizations of SNR. The synthetically altered spectra were also used to characterize the sensitivity of GABA quantification. RESULTS: The best LCModel fitting approach used stiff spline baseline, no soft constraints, and measured macromolecules in the basis set. With lower SNR, coefficients of variation increased dramatically. Longitudinal and cross-sectional variations in GABA of 10% could be detected with 79 and 48 participants per group, respectively. However, the small cohort may bias the calculation of the coefficients of variation and of the sample size that would be needed to detect variations in GABA. CONCLUSION: Reliable quantification of normal and abnormal GABA concentrations was achieved for high quality 7 T spectra using LCModel fitting.

Influence of fitting approaches in LCModel on MRS quantification focusing on age-specific macromolecules and the spline baseline.

Quantification of neurochemical concentrations from 1 H MR spectra is challenged by incomplete knowledge of contributing signals. Some experimental conditions hinder the acquisition of artifact-free spectra and impede the acquisition of condition-specific macromolecule (MM) spectra. This work studies differences caused by fitting solutions routinely employed to manage resonances from MM and lipids. High quality spectra (free of residual water and lipid artifacts and for which condition-specific MM spectra are available) are used to understand the influences of spline baseline flexibility and noncondition-specific MM on neurochemical quantification. Fitting with moderate spline flexibility or using noncondition-specific MM led to quantification that differed from when an appropriate, fully specified model was used. This occurred for all neurochemicals to an extent that varied in magnitude among and within approaches. The spline baseline was more tortuous when less constrained and when used in combination with noncondition-specific MM. Increasing baseline flexibility did not reproduce concentrations quantified under appropriate conditions when spectra were fitted using a MM spectrum measured from a mismatched cohort. Using the noncondition-specific MM spectrum led to quantification differences that were comparable in size with using a fitting model that had moderate freedom, and these influences were additive. Although goodness of fit was better with greater fitting flexibility, quantification differed from when fitting with a fully specified model that is appropriate for low noise data. Notable GABA and PE concentration differences occurred with lower estimates of measurement error when fitting with greater spline flexibility or noncondition-specific MM. These data support the need for improved metrics of goodness of fit. Attempting to correct for artifacts or absence of a condition-specific MM spectrum via increased spline flexibility and usage of noncondition-specific MM spectra cannot replace artifact-free data quantified with a condition-specific MM spectrum.

Spectral editing in 1 H magnetic resonance spectroscopy: Experts' consensus recommendations.

Spectral editing in in vivo 1 H-MRS provides an effective means to measure low-concentration metabolite signals that cannot be reliably measured by conventional MRS techniques due to signal overlap, for example, γ-aminobutyric acid, glutathione and D-2-hydroxyglutarate. Spectral editing strategies utilize known J-coupling relationships within the metabolite of interest to discriminate their resonances from overlying signals. This consensus recommendation paper provides a brief overview of commonly used homonuclear editing techniques and considerations for data acquisition, processing and quantification. Also, we have listed the experts' recommendations for minimum requirements to achieve adequate spectral editing and reliable quantification. These include selecting the right editing sequence, dealing with frequency drift, handling unwanted coedited resonances, spectral fitting of edited spectra, setting up multicenter clinical trials and recommending sequence parameters to be reported in publications.

MEGA-PRESS of GABA+: Influences of acquisition parameters.

γ-aminobutyric acid (GABA) was the first molecule that was edited with MEGA-PRESS. GABA edited spectroscopy is challenged by limited selectivity of editing pulses. Coediting of resonances from macromolecules (MM) is the greatest single limitation of GABA edited spectroscopy. In this contribution, relative signal contributions from GABA, MM and homocarnosine to the total MEGA-PRESS edited signal at ~3 ppm, i.e., GABA+, are simulated at 3 tesla using several acquisition schemes. The base scheme is modeled after those currently supplied by vendors: it uses typical pulse shapes and lengths, it minimizes the first echo time (TE), and the delay between the editing pulses is kept at TE/2. Edited spectra are simulated for imperfect acquisition parameters such as incorrect frequency, larger chemical shift displacement, incorrect transmit B1 -field calibration for localization and editing pulses, and longer TE. An alternative timing scheme and longer editing pulses are also considered. Additional simulations are performed for symmetric editing around the MM frequency to suppress the MM signal. The relative influences of these acquisition parameters on the constituents of GABA+ are examined from the perspective of modern experimental designs for investigating brain GABA concentration differences in healthy and diseased humans. Other factors that influence signal contributions, such as T1 and T2 relaxation times are also considered.

Terminology and concepts for the characterization of in vivo MR spectroscopy methods and MR spectra: Background and experts' consensus recommendations.

With a 40-year history of use for in vivo studies, the terminology used to describe the methodology and results of magnetic resonance spectroscopy (MRS) has grown substantially and is not consistent in many aspects. Given the platform offered by this special issue on advanced MRS methodology, the authors decided to describe many of the implicated terms, to pinpoint differences in their meanings and to suggest specific uses or definitions. This work covers terms used to describe all aspects of MRS, starting from the description of the MR signal and its theoretical basis to acquisition methods, processing and to quantification procedures, as well as terms involved in describing results, for example, those used with regard to aspects of quality, reproducibility or indications of error. The descriptions of the meanings of such terms emerge from the descriptions of the basic concepts involved in MRS methods and examinations. This paper also includes specific suggestions for future use of terms where multiple conventions have emerged or coexisted in the past.

Distinctive Neurochemistry in Alzheimer's Disease via 7 T In Vivo Magnetic Resonance Spectroscopy.

This study's objective was to increase understanding of biological mechanisms underlying clinical Alzheimer's disease (AD) by noninvasively measuring an expanded neurochemical profile and exploring how well this advanced technology distinguishes AD from cognitively normal controls. We measured concentrations of 14 neurochemicals using ultra-high field (7 T) ultra-short echo time (8 ms) magnetic resonance spectroscopy (MRS) in 16 participants with mild to moderate clinical AD and 33 age- and gender-matched control participants. MRS was localized to the posterior cingulate cortex (PCC), a region known to be impacted by AD, and the occipital cortex (OCC), a control region. Participants with AD were recruited from dementia specialty clinics. Concentration of the antioxidant ascorbate was higher (p < 0.0007) in both brain regions. Concentrations of the glial marker myo-inositol and the choline-containing compounds involved in membrane turnover were higher (p≤0.0004) in PCC of participants with AD. Ascorbate and myo-inositol concentrations were strongly associated, especially in the PCC. Random forests, using the 14 neurochemicals in the two regions, distinguished participants with AD from controls: same-sample sensitivity and specificity were 88% and 97%, respectively, though out-of-sample-values would be lower. Ultra-high field ultra-short echo time MRS identified the co-occurrence of elevated ascorbate and myo-inositol in the PCC as markers that distinguish participants with mild to moderate AD from controls. While elevated myo-inositol may be a surrogate marker of neuroinflammation, the unexpected elevation of the antioxidant ascorbate may reflect infiltration of ascorbate-rich leukocytes.

The Lifespan Human Connectome Project in Aging: An overview.

The original Human Connectome Project yielded a rich data set on structural and functional connectivity in a large sample of healthy young adults using improved methods of data acquisition, analysis, and sharing. More recent efforts are extending this approach to include infants, children, older adults, and brain disorders. This paper introduces and describes the Human Connectome Project in Aging (HCP-A), which is currently recruiting 1200 + healthy adults aged 36 to 100+, with a subset of 600 + participants returning for longitudinal assessment. Four acquisition sites using matched Siemens Prisma 3T MRI scanners with centralized quality control and data analysis are enrolling participants. Data are acquired across multimodal imaging and behavioral domains with a focus on factors known to be altered in advanced aging. MRI acquisitions include structural (whole brain and high resolution hippocampal) plus multiband resting state functional (rfMRI), task fMRI (tfMRI), diffusion MRI (dMRI), and arterial spin labeling (ASL). Behavioral characterization includes cognitive (such as processing speed and episodic memory), psychiatric, metabolic, and socioeconomic measures as well as assessment of systemic health (with a focus on menopause via hormonal assays). This dataset will provide a unique resource for examining how brain organization and connectivity changes across typical aging, and how these differences relate to key characteristics of aging including alterations in hormonal status and declining memory and general cognition. A primary goal of the HCP-A is to make these data freely available to the scientific community, supported by the Connectome Coordination Facility (CCF) platform for data quality assurance, preprocessing and basic analysis, and shared via the NIMH Data Archive (NDA). Here we provide the rationale for our study design and sufficient details of the resource for scientists to plan future analyses of these data. A companion paper describes the related Human Connectome Project in Development (HCP-D, Somerville et al., 2018), and the image acquisition protocol common to both studies (Harms et al., 2018).

Extending the Human Connectome Project across ages: Imaging protocols for the Lifespan Development and Aging projects.

The Human Connectome Projects in Development (HCP-D) and Aging (HCP-A) are two large-scale brain imaging studies that will extend the recently completed HCP Young-Adult (HCP-YA) project to nearly the full lifespan, collecting structural, resting-state fMRI, task-fMRI, diffusion, and perfusion MRI in participants from 5 to 100+ years of age. HCP-D is enrolling 1300+ healthy children, adolescents, and young adults (ages 5-21), and HCP-A is enrolling 1200+ healthy adults (ages 36-100+), with each study collecting longitudinal data in a subset of individuals at particular age ranges. The imaging protocols of the HCP-D and HCP-A studies are very similar, differing primarily in the selection of different task-fMRI paradigms. We strove to harmonize the imaging protocol to the greatest extent feasible with the completed HCP-YA (1200+ participants, aged 22-35), but some imaging-related changes were motivated or necessitated by hardware changes, the need to reduce the total amount of scanning per participant, and/or the additional challenges of working with young and elderly populations. Here, we provide an overview of the common HCP-D/A imaging protocol including data and rationales for protocol decisions and changes relative to HCP-YA. The result will be a large, rich, multi-modal, and freely available set of consistently acquired data for use by the scientific community to investigate and define normative developmental and aging related changes in the healthy human brain.

Altered macromolecular pattern and content in the aging human brain.

The resonances originating from proteins underlie those of metabolites in brain 1 H nuclear magnetic resonance (NMR) spectra. These resonances have different physical properties from those of metabolites, such as shorter T1 and T2 relaxation time constants. The age dependence of the macromolecular pattern and content in the human brain was investigated with a focus on adults over 66 years of age using ultrahigh-field in vivo magnetic resonance spectroscopy. Eighteen young and 23 cognitively normal older adults were studied at 7 T. Metabolite spectra were acquired in the occipital cortex and the posterior cingulate cortex with single-voxel stimulated echo acquisition mode (STEAM) spectroscopy in 14 young and 20 older adults. Macromolecular spectra were acquired in the occipital cortex using an inversion recovery STEAM sequence in four young and three older adults. The macromolecular pattern was apparent over the 0.5-4.5-ppm range in the inversion recovery spectra and the 0.5-2-ppm range in the metabolite spectra. Macromolecular content was quantified from metabolite spectra using LCModel and from inversion recovery spectra using integration. Age-associated differences in the macromolecular pattern were apparent via both types of spectra, with the largest difference observed for the 1.7- and 2-ppm macromolecular resonances. A higher macromolecular content was observed in the older adults for both brain regions. Age-specific macromolecular spectra are needed when comparing metabolite spectra from subjects of differing ages because of age-associated differences in macromolecular pattern. Age-associated pattern and content differences may provide information about the aging process.

Repeated-Dose Oral N-Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress.

Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using 1 H-MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations and the reduced-to-oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration-time profiles were described by a first-order absorption, 1-compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4-HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.

Hypothalamic Glucose Transport in Humans During Experimentally Induced Hypoglycemia-Associated Autonomic Failure.

Context: Upregulated brain glucose transport in response to recurrent hypoglycemia may contribute to the development of hypoglycemia-associated autonomic failure (HAAF) and impaired awareness of hypoglycemia. Whether recurrent hypoglycemia alters glucose transport in the hypothalamus is unknown. Objective: To test the hypothesis that hypothalamic glucose transport will increase in healthy volunteers preconditioned with recurrent hypoglycemia to induce HAAF. Setting: University medical center. Design and Participants: Thirteen healthy subjects underwent paired euglycemic and hypoglycemic preconditioning studies separated by at least 1 month. Following preconditioning, hypothalamic glucose transport was measured by magnetic resonance spectroscopy (MRS) in the afternoon on day 2 of each preconditioning protocol. Outcome Measure: The ratio of maximal transport rate to cerebral metabolic rate of glucose (Tmax/CMRglc), obtained from MRS-measured glucose in the hypothalamus as a function of plasma glucose. Results: HAAF was successfully induced based on lower epinephrine, glucagon, and cortisol during the third vs first hypoglycemic preconditioning clamp (P ≤ 0.01). Hypothalamic glucose transport was not different following recurrent euglycemia vs hypoglycemia (Tmax/CMRglc 1.62 ± 0.09 after euglycemia preconditioning and 1.75 ± 0.14 after hypoglycemia preconditioning; P was not significant). Hypothalamic glucose concentrations measured by MRS were not different following the two preconditioning protocols. Conclusions: Glucose transport kinetics in the hypothalamus of healthy humans with experimentally induced HAAF were not different from those measured without HAAF. Future studies of patients with diabetes and impaired awareness of hypoglycemia will be necessary to determine if the existence of the diabetes state is required for this adaptation to hypoglycemia to occur.

Region-specific aging of the human brain as evidenced by neurochemical profiles measured noninvasively in the posterior cingulate cortex and the occipital lobe using 1H magnetic resonance spectroscopy at 7 T.

The concentrations of fourteen neurochemicals associated with metabolism, neurotransmission, antioxidant capacity, and cellular structure were measured noninvasively from two distinct brain regions using 1H magnetic resonance spectroscopy. Seventeen young adults (age 19-22years) and sixteen cognitively normal older adults (age 70-88years) were scanned. To increase sensitivity and specificity, 1H magnetic resonance spectra were obtained at the ultra-high field of 7T and at ultra-short echo time. The concentrations of neurochemicals were determined using water as an internal reference and accounting for gray matter, white matter, and cerebrospinal fluid content of the volume of interest. In the posterior cingulate cortex (PCC), the concentrations of neurochemicals associated with energy (i.e., creatine plus phosphocreatine), membrane turnover (i.e., choline containing compounds), and gliosis (i.e., myo-inositol) were higher in the older adults while the concentrations of N-acetylaspartylglutamate (NAAG) and phosphorylethanolamine (PE) were lower. In the occipital cortex (OCC), the concentration of N-acetylaspartate (NAA), a marker of neuronal viability, concentrations of the neurotransmitters Glu and NAAG, antioxidant ascorbate (Asc), and PE were lower in the older adults while the concentration of choline containing compounds was higher. Altogether, these findings shed light on how the human brain ages differently depending on region.

Sensitivity and specificity of human brain glutathione concentrations measured using short-TE (1)H MRS at 7 T.

Although the MR editing techniques that have traditionally been used for the measurement of glutathione (GSH) concentrations in vivo address the problem of spectral overlap, they suffer detriments associated with inherently long TEs. The purpose of this study was to characterize the sensitivity and specificity for the quantification of GSH concentrations without editing at short TE. The approach was to measure synthetically generated changes in GSH concentrations from in vivo stimulated echo acquisition mode (STEAM) spectra after in vitro GSH spectra had been added to or subtracted from them. Spectra from five test subjects were synthetically altered to mimic changes in the GSH signal. To account for different background noise between measurements, retest spectra (from the same individuals as used to generate the altered data) and spectra from five other individuals were compared with the synthetically altered spectra to investigate the reliability of the quantification of GSH concentration. Using STEAM spectroscopy at 7 T, GSH concentration differences on the order of 20% were detected between test and retest studies, as well as between differing populations in a small sample (n = 5) with high accuracy (R(2) > 0.99) and certainty (p ≤ 0.01). Both increases and decreases in GSH concentration were reliably quantified with small impact on the quantification of ascorbate and γ-aminobutyric acid. These results show the feasibility of using short-TE (1)H MRS to measure biologically relevant changes and differences in human brain GSH concentration. Although these outcomes are specific to the experimental approach used and the spectral quality achieved, this study serves as a template for the analogous scrutiny of quantification reliability for other compounds, methodologies and spectral qualities.

Test-retest reproducibility of neurochemical profiles with short-echo, single-voxel MR spectroscopy at 3T and 7T.

PURPOSE: To determine the test-retest reproducibility of neurochemical concentrations obtained with a highly optimized, short-echo, single-voxel proton MR spectroscopy (MRS) pulse sequence at 3T and 7T using state-of-the-art hardware. METHODS: A semi-LASER sequence (echo time = 26-28 ms) was used to acquire spectra from the posterior cingulate and cerebellum at 3T and 7T from six healthy volunteers who were scanned four times weekly on both scanners. Spectra were quantified with LCModel. RESULTS: More neurochemicals were quantified with mean Cramér-Rao lower bounds (CRLBs) ≤20% at 7T than at 3T despite comparable frequency-domain signal-to-noise ratio. Whereas CRLBs were lower at 7T (P < 0.05), between-session coefficients of variance (CVs) were comparable at the two fields with 64 transients. Five metabolites were quantified with between-session CVs ≤5% at both fields. Analysis of subspectra showed that a minimum achievable CV was reached with a lower number of transients at 7T for multiple metabolites and that between-session CVs were lower at 7T than at 3T with fewer than 64 transients. CONCLUSION: State-of-the-art MRS methodology allows excellent reproducibility for many metabolites with 5-min data averaging on clinical 3T hardware. Sensitivity and resolution advantages at 7T are important for weakly represented metabolites, short acquisitions, and small volumes of interest. Magn Reson Med 76:1083-1091, 2016. © 2015 Wiley Periodicals, Inc.