Physiological neuronal decline in healthy aging human brain — An in vivo study with MRI and short echo-time whole-brain 1H MR spectroscopic imaging

doi:10.1016/j.neuroimage.2016.05.014

NeuroImage

Volume 137, 15 August 2016, Pages 45-51

https://doi.org/10.1016/j.neuroimage.2016.05.014 Get rights and content

Highlights

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Physiological neuronal decline in aging human brain is presented by reduction of gray matter volume and neuronal density, which is a predominant reason for reduced brain NAA content.
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Aging resulted in altered cell membrane turnover, gliosis, and energy metabolism with microstructural alterations in white matter.
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Aging resulted in altered energy metabolism in cerebellum.

Abstract

Knowledge of physiological aging in healthy human brain is increasingly important for neuroscientific research and clinical diagnosis. To investigate neuronal decline in normal aging brain eighty-one healthy subjects aged between 20 and 70 years were studied with MRI and whole-brain ¹H MR spectroscopic imaging. Concentrations of brain metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), myo-inositol (mI), and glutamine + glutamate (Glx) in ratios to internal water, and the fractional volumes of brain tissue were estimated simultaneously in eight cerebral lobes and in cerebellum. Results demonstrated that an age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Both lobar NAA and the fractional volume of gray matter (FVGM) decreased with age in all cerebral lobes, indicating that the decreased NAA was predominantly associated with decreased gray matter volume and neuronal density or metabolic activity. In cerebral white matter Cho, tCr, and mI increased with age in association with increased fractional volume, showing altered cellular membrane turn-over, energy metabolism, and glial activity in human aging white matter. In cerebellum tCr increased while brain tissue volume decreased with age, showing difference to cerebral aging. The observed age-related metabolic and microstructural variations suggest that physiological neuronal decline in aging human brain is associated with a reduction of gray matter volume and neuronal density, in combination with cellular aging in white matter indicated by microstructural alterations and altered energy metabolism in the cerebellum.

Introduction

Knowledge of physiological aging in healthy human brain is increasingly important for neuroscientific research and clinical diagnosis. As a complex and heterogeneous process, cerebral aging in humans involves a large variety of molecular changes and multiple neuronal networks. Many structural and functional studies have been carried out to investigate how cognitive abilities result from dynamic interactions in large-scale cortical network under the influences of aging or diseases (Lustig et al., 2003, Romero-Garcia et al., 2014). It has been reported that normal aging has indirect effects on cognition that are associated with brain markers such as gray matter (GM) thickness and volume, white matter (WM) hyperintensities, fractional anisotropy, and resting-state functional connectivity, with markers varying across cognitive domains (Hedden et al., 2014). Neurodegenerative disorders are found to be associated with specific patterns of gray matter atrophy within distinct functional connectivity networks, which involve nearly all gray matter (Seeley et al., 2009). Age-related changes of metabolite concentrations could provide information about human brain aging at the molecular level, because the observed brain metabolites of N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), myo-inositol (mI), glutamine (Gln), and glutamate (Glu), are related to neurometabolic activity as well as neuronal integrity (NAA), membrane turnover (Cho), energy metabolism (tCr), gliosis (mI), or neurotransmitter function (Glu) (Barker et al., 2009, Grachev and Apkarian, 2001). Numerous ¹H MR spectroscopy studies on aging brains have been reported; however, due to limitations in the spatial coverage of the acquisition techniques used, most of these studies have been carried out on one or a few small brain regions with varying results (Haga et al., 2009). Only in a retrospective study Maudsley et al. used a whole brain ¹H MR spectroscopic imaging (wbMRSI) acquisition with an intermediate echo time (TE) to study age-related metabolite changes within the whole brain, with the metabolite concentrations being reported in an institutional unit over bilaterally averaged lobar structures (Maudsley et al., 2012). Moreover, few reports have examined associations between age-related changes of metabolite concentrations and brain tissue volume. This report describes a prospective study on healthy subjects that used MRI and a recently established short-TE wbMRSI acquisition (Ding et al., 2015) to estimate age-related changes in metabolite concentrations and in the fractional volume of brain tissue, with the aim of investigating physiological neuronal decline and to obtain reference data for studies of brain disorders.

Section snippets

Subjects

Ninety-six healthy volunteers were recruited from the local population. All subjects had no neurological disorder or other systemic diseases according to a self-report. To exclude potential cognitive or psychiatric impairments each subject received two screening tests prior to the MR examination: 1) The Beck Depression Inventory (BDI-II (Steer et al., 1999); and 2) The DemTect (Kalbe et al., 2004). Subjects with abnormal results of screening tests (n = 3), incomplete MR examinations (n = 3), excess

Results

Example metabolite images of NAA, Cho, tCr, Glx and mI with corresponding T1-weighted images (T1w) at two axial sections around the level of centrum semiovale are shown in Fig. 1, which were obtained from female subjects of 25 (Fig. 1A) and 70 years old (Fig. 1B), note that the signal intensities of NAA maps of the older volunteer are lower and those in Cho, tCr, and mI are slightly higher in comparison to those of the younger volunteer, indicating qualitatively the age-dependencies of the

Discussion

This study has determined age-related lobar and cerebellar concentrations of five metabolites and the corresponding fractional volumes of the brain tissue and CSF in normal aging human brain. The results for regional [NAA], [Cho], [tCr], [Glx], and [mI] distributions are consistent with those reported by studies that used conventional MRS acquisition techniques (Deelchand et al., 2015, Guerrini et al., 2009, Hennig et al., 1992, Jacobs et al., 2001, Pouwels et al., 1999, Pouwels and Frahm, 1998

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White matter and neurochemical mechanisms underlying age-related differences in motor processing speed
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Aging is associated with changes in the central nervous system and leads to reduced life quality. Here, we investigated the age-related differences in the CNS underlying motor performance deficits using magnetic resonance spectroscopy and diffusion MRI. MRS measured N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr) concentrations in the sensorimotor and occipital cortex, whereas dMRI quantified apparent fiber density (FD) in the same voxels to evaluate white matter microstructural organization. We found that aging was associated with increased reaction time and reduced FD and NAA concentration in the sensorimotor voxel. Both FD and NAA mediated the association between age and reaction time. The NAA concentration was found to mediate the association between age and FD in the sensorimotor voxel. We propose that the age-related decrease in NAA concentration may result in reduced axonal fiber density in the sensorimotor cortex which may ultimately account for the response slowness of older participants.
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Citation Excerpt :
In line with previous findings our observations showed lower levels of NAA and higher levels of Cho and mIns in older participants across different brain regions (Cichocka and Bereś, 2018; Cleeland et al., 2019; Marjanska et al., 2017; Sailasuta et al., 2008; Suri et al., 2017; Yang et al., 2014). These neurometabolic differences are thought to reflect age-related neuronal density decrease and demyelination (NAA), increased glial cell activity (mIns), and membrane alterations (Cho), among others (e.g., Chiu et al. 2014, Ding et al. 2016, Eylers et al. 2016, García Santos et al. 2010, Lind et al. 2021, Moffett et al. 2007, Vints et al. 2022, Weerasekera et al. 2020, for a review see Cleeland et al. 2019). In our study, the age-related differences of NAA were more prominent in the bilateral SM1 and OCC cortices.
Aging is associated with alterations in the brain including structural and metabolic changes. Previous research has focused on neurometabolite level differences associated to age in a variety of brain regions, but the relationship among metabolites across the brain has been much less studied. Investigating these relationships can reveal underlying neurometabolic processes, their interdependency, and their progress throughout the lifespan. Using ¹H-MRS, we investigated the relationship among metabolite concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myo-Inositol (mIns) and glutamate-glutamine complex (Glx) in seven voxel locations, i.e., bilateral sensorimotor cortex, bilateral striatum, pre-supplementary motor area, right inferior frontal gyrus and occipital cortex. These measurements were performed on 59 human participants divided in two age groups: young adults (YA: 23.2 ± 4.3; 18–34 years) and older adults (OA: 67.5 ± 3.9; 61–74 years). Our results showed age-related differences in NAA, Cho, and mIns across brain regions, suggesting the presence of neurodegeneration and altered gliosis. Moreover, associative patterns among NAA, Cho and Cr were observed across the selected brain regions, which differed between young and older adults. Whereas most of metabolite concentrations were inhomogeneous across different brain regions, Cho levels were shown to be strongly related across brain regions in both age groups. Finally, we found metabolic associations between homologous brain regions (SM1 and striatum) in the OA group, with NAA showing a significant correlation between bilateral sensorimotor cortices (SM1) and mIns levels being correlated between the bilateral striata. We posit that a network perspective provides important insights regarding the potential interactions among neurochemicals underlying metabolic processes at a local and global level and their relationship with aging.
Replicability of proton MR spectroscopic imaging findings in mild traumatic brain injury: Implications for clinical applications
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Proton magnetic resonance spectroscopy (¹H MRS) offers biomarkers of metabolic damage after mild traumatic brain injury (mTBI), but a lack of replicability studies hampers clinical translation. In a conceptual replication study design, the results reported in four previous publications were used as the hypotheses (H1-H7), specifically: abnormalities in patients are diffuse (H1), confined to white matter (WM) (H2), comprise low N-acetyl-aspartate (NAA) levels and normal choline (Cho), creatine (Cr) and myo-inositol (mI) (H3), and correlate with clinical outcome (H4); additionally, a lack of findings in regional subcortical WM (H5) and deep gray matter (GM) structures (H6), except for higher mI in patients’ putamen (H7).
26 mTBI patients (20 female, age 36.5 ± 12.5 [mean ± standard deviation] years), within two months from injury and 21 age-, sex-, and education-matched healthy controls were scanned at 3 Tesla with 3D echo-planar spectroscopic imaging. To test H1-H3, global analysis using linear regression was used to obtain metabolite levels of GM and WM in each brain lobe. For H4, patients were stratified into non-recovered and recovered subgroups using the Glasgow Outcome Scale Extended. To test H5-H7, regional analysis using spectral averaging estimated metabolite levels in four GM and six WM structures segmented from T1-weighted MRI. The Mann-Whitney U test and weighted least squares analysis of covariance were used to examine mean group differences in metabolite levels between all patients and all controls (H1-H3, H5-H7), and between recovered and non-recovered patients and their respectively matched controls (H4). Replicability was defined as the support or failure to support the null hypotheses in accordance with the content of H1-H7, and was further evaluated using percent differences, coefficients of variation, and effect size (Cohen’s d).
Patients’ occipital lobe WM Cho and Cr levels were 6.0% and 4.6% higher than controls’, respectively (Cho, d = 0.37, p = 0.04; Cr, d = 0.63, p = 0.03). The same findings, i.e., higher patients’ occipital lobe WM Cho and Cr (both p = 0.01), but with larger percent differences (Cho, 8.6%; Cr, 6.3%) and effect sizes (Cho, d = 0.52; Cr, d = 0.88) were found in the comparison of non-recovered patients to their matched controls. For the lobar WM Cho and Cr comparisons without statistical significance (frontal, parietal, temporal), unidirectional effect sizes were observed (Cho, d = 0.07 – 0.37; Cr, d = 0.27 – 0.63). No differences were found in any metabolite in any lobe in the comparison between recovered patients and their matched controls. In the regional analyses, no differences in metabolite levels were found in any GM or WM region, but all WM regions (posterior, frontal, corona radiata, and the genu, body, and splenium of the corpus callosum) exhibited unidirectional effect sizes for Cho and Cr (Cho, d = 0.03 – 0.34; Cr, d = 0.16 – 0.51).
We replicated findings of diffuse WM injury, which correlated with clinical outcome (supporting H1-H2, H4). These findings, however, were among the glial markers Cho and Cr, not the neuronal marker NAA (not supporting H3). No differences were found in regional GM and WM metabolite levels (supporting H5-H6), nor in putaminal mI (not supporting H7). Unidirectional effect sizes of higher patients’ Cho and Cr within all WM analyses suggest widespread injury, and are in line with the conclusion from the previous publications, i.e., that detection of WM injury may be more dependent upon sensitivity of the ¹H MRS technique than on the selection of specific regions. The findings lend further support to the corollary that clinic-ready ¹H MRS biomarkers for mTBI may best be achieved by using high signal-to-noise-ratio single-voxels placed anywhere within WM. The biochemical signature of the injury, however, may differ and therefore absolute levels, rather than ratios may be preferred. Future replication efforts should further test the generalizability of these findings.
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Citation Excerpt :
Decreased levels of tNAA and increased levels of tCho and mIns can underlie important structural and physiological changes in the brain that are related to cognitive aging. These neurometabolic differences are thought to reflect age-related neuronal density decrease and demyelination (tNAA), increased glial cell activity (mIns), and membrane alterations (tCho) (e.g., Ding et al., 2016; Eylers et al., 2016; Lind et al., 2021; Vints et al., 2022; Waragai et al., 2017; for a review see Cleeland et al., 2019). Elevated tCho and mIns in the aging brain appears to be a potential marker of brain inflammation, demyelination, gliosis and cognitive decline (Harris et al., 2014; Langer et al., 2021; Lind et al., 2021; Vints et al., 2022).
Proton magnetic resonance spectroscopy (¹H-MRS) holds promise for revealing and understanding neurodegenerative processes associated with cognitive and functional impairments in aging. In the present study, we examined the neurometabolic correlates of balance performance in 42 cognitively intact older adults (healthy controls - HC) and 26 older individuals that were diagnosed with mild cognitive impairment (MCI). Neurometabolite ratios of total N-acetyl aspartate (tNAA), glutamate-glutamine complex (Glx), total choline (tCho) and myo-inositol (mIns) relative to total creatine (tCr) were assessed using single voxel ¹H-MRS in four different brain regions. Regions of interest were the left hippocampus (HPC), dorsal posterior cingulate cortex (dPCC), left sensorimotor cortex (SM1), and right dorsolateral prefrontal cortex (dlPFC). Center-of-pressure velocity (Vcop) and dual task effect (DTE) were used as measures of balance performance. Results indicated no significant group differences in neurometabolite ratios and balance performance measures. However, our observations revealed that higher tCho/tCr and mIns/tCr in hippocampus and dPCC were generic predictors of worse balance performance, suggesting that neuroinflammatory processes in these regions might be a driving factor for impaired balance performance in aging. Further, we found that higher tNAA/tCr and mIns/tCr and lower Glx/tCr in left SM1 were predictors of better balance performance in MCI but not in HC. The latter observation hints at the possibility that individuals with MCI may upregulate balance control through recruitment of sensorimotor pathways.
Neurometabolic timecourse of healthy aging
2022, NeuroImage
The neurometabolic timecourse of healthy aging is not well-established, in part due to diversity of quantification methodology. In this study, a large structured cross-sectional cohort of male and female subjects throughout adulthood was recruited to investigate neurometabolic changes as a function of age, using consensus-recommended magnetic resonance spectroscopy quantification methods.
102 healthy volunteers, with approximately equal numbers of male and female participants in each decade of age from the 20s, 30s, 40s, 50s, and 60s, were recruited with IRB approval. MR spectroscopic data were acquired on a 3T MRI scanner. Metabolite spectra were acquired using PRESS localization (TE=30 ms; 96 transients) in the centrum semiovale (CSO) and posterior cingulate cortex (PCC). Water-suppressed spectra were modeled using the Osprey algorithm, employing a basis set of 18 simulated metabolite basis functions and a cohort-mean measured macromolecular spectrum. Pearson correlations were conducted to assess relationships between metabolite concentrations and age for each voxel; Spearman correlations were conducted where metabolite distributions were non-normal. Paired t-tests were run to determine whether metabolite concentrations differed between the PCC and CSO. Finally, robust linear regressions were conducted to assess both age and sex as predictors of metabolite concentrations in the PCC and CSO and separately, to assess age, signal-noise ratio, and full width half maximum (FWHM) linewidth as predictors of metabolite concentrations.
Data from four voxels were excluded (2 ethanol; 2 unacceptably large lipid signal). Statistically-significant age*metabolite Pearson correlations were observed for tCho (r(98)=0.33, p<0.001), tCr (r(98)=0.60, p<0.001), and mI (r(98)=0.32, p=0.001) in the CSO and for NAAG (r(98)=0.26, p=0.008), tCho(r(98)=0.33, p<0.001), tCr (r(98)=0.39, p<0.001), and Gln (r(98)=0.21, p=0.034) in the PCC. Spearman correlations for non-normal variables revealed a statistically significant correlation between sI and age in the CSO (r(86)=0.26, p=0.013). No significant correlations were seen between age and tNAA, NAA, Glx, Glu, GSH, PE, Lac, or Asp in either region (all p>0.20). Age associations for tCho, tCr, mI and sI in the CSO and for NAAG, tCho, and tCr in the PCC remained when controlling for sex in robust regressions. CSO NAAG and Asp, as well as PCC tNAA, sI, and Lac were higher in women; PCC Gln was higher in men. When including an age*sex interaction term in robust regression models, a significant age*sex interaction was seen for tCho (F(1,96)=11.53, p=0.001) and GSH (F(1,96)=7.15, p=0.009) in the CSO and tCho (F(1,96)=9.17, p=0.003), tCr (F(1,96)=9.59, p=0.003), mI (F(1,96)=6.48, p=0.012), and Lac (F(1,78)=6.50, p=0.016) in the PCC. In all significant interactions, metabolite levels increased with age in females, but not males. There was a significant positive correlation between linewidth and age. Age relationships with tCho, tCr, and mI in the CSO and tCho, tCr, mI, and sI in the PCC were significant after controlling for linewidth and FWHM in robust regressions.
The primary (correlation) results indicated age relationships for tCho, tCr, mI, and sI in the CSO and for NAAG, tCho, tCr, and Gln in the PCC, while no age correlations were found for tNAA, NAA, Glx, Glu, GSH, PE, Lac, or Asp in either region. Our results provide a normative foundation for future work investigating the neurometabolic time course of healthy aging using MRS.

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^☆: Grant support: This work was partially supported by Deutsche Forschungsgemeinschaft and by NIH grant R01 EB016064 (A.A.M.).

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Physiological neuronal decline in healthy aging human brain — An in vivo study with MRI and short echo-time whole-brain 1H MR spectroscopic imaging☆

Highlights

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Neurobiol. Aging

Life Sci.

Neurobiol. Aging

Magn. Reson. Imaging

NeuroImage

Neurobiol. Aging

Neurobiol. Aging

NeuroImage

Neurochem. Int.

Magn. Reson. Imaging

Neuron

Front. Neuroenerg.

Behav. Res. Ther.

Clinical MR Spectroscopy: Techniques and Applications

Age changes in myelinated nerve fibers of the cingulate bundle and corpus callosum in the rhesus monkey

J. Comp. Neurol.

A proton magnetic resonance spectroscopy study of age-related changes in frontal lobe metabolite concentrations

Cereb. Cortex

Design and construction of a realistic digital brain phantom

IEEE Trans. Med. Imaging

Two-site reproducibility of cerebellar and brainstem neurochemical profiles with short-echo, single-voxel MRS at 3T

Magn. Reson. Med.

Reproducibility and reliability of short-TE whole-brain MR spectroscopic imaging of human brain at 3T

Magn. Reson. Med.

Aging alters regional multichemical profile of the human brain: an in vivo 1H-MRS study of young versus middle-aged subjects

J. Neurochem.

Physiological neuronal decline in healthy aging human brain — An in vivo study with MRI and short echo-time whole-brain ¹H MR spectroscopic imaging☆