- Email: [email protected]
Role of T1 mapping to evaluate brain aging in a healthy population
Journal Pre-proof Role of T1 mapping to evaluate brain aging in a healthy population
Ali Kupeli, Mehmet Kocak, Mehmet Goktepeli, Erdal Karavas, Gurkan Danisan PII:
S0899-7071(19)30179-2
DOI:
https://doi.org/10.1016/j.clinimag.2019.09.005
Reference:
JCT 8741
To appear in:
Clinical Imaging
Received date:
15 April 2019
Revised date:
24 July 2019
Accepted date:
23 September 2019
Please cite this article as: A. Kupeli, M. Kocak, M. Goktepeli, et al., Role of T1 mapping to evaluate brain aging in a healthy population, Clinical Imaging(2019), https://doi.org/ 10.1016/j.clinimag.2019.09.005
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof
Role of T1 mapping to evaluate brain aging in a healthy population Ali Kupelia, Mehmet Kocaka, Mehmet Goktepelia, Erdal Karavasa, Gurkan Danisanb, a
Department of Radiology, Faculty of Medicine, Erzincan Binali Yıldırım University,
24000/Erzincan, Turkey Mus State Hospital, Department of Radiology, 49000 / Mus, Turkey
-p
ro
of
b
re
Corresponding author:
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Ali Kupeli, M.D.
24000/Erzincan, Turkey Tel: +90 4362120670
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Department of Radiology, Faculty of Medicine, Erzincan Binali Yıldırım University,
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Email: [email protected]
Journal Pre-proof Role of T1 mapping to evaluate brain aging in a healthy population
ABSTRACT Purpose: To investigate the relationship between healthy brain aging and T1 relaxation time obtained by T1 mapping. Materials and methods: A total of 211 (102 males, 109 females; age range: 20–89 years; mean age: 54 years) healthy volunteers underwent T1 mapping between July 2018 and January 2019. Regions of interest (ROIs) were placed on T1 maps in different anatomical regions, including the thalamus, putamen, globus pallidus, head of the caudate nucleus,
of
nucleus accumbens, genu of the corpus callosum, and frontal lobe white matter (WM). Additionally, linear and quadratic regression analyses of ROIs were performed.
ro
Results: There were significant quadratic and negative linear correlations between T1
-p
relaxation times in the thalamus, putamen, and age (p<0.001). Although the nucleus accumbens did not show a significant relationship between T1 relaxation times and age by
re
linear regression (p=0.624), a statistically significant relationship was obtained by quadratic regression (p<0.001). For the globus pallidus, head of the caudate nucleus, genu of the corpus
than the linear correlation analysis.
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callosum and frontal lobe WM the quadratic regression analysis showed a better relationship
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Conclusion: Age-related changes in T1 relaxation time vary by location in GM and WM.
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Keywords: Aging, Mapping, MRI
Journal Pre-proof 1. Introduction With aging, there are several changes in anatomical structures in the brain that can be noninvasively evaluated by magnetic resonance imaging (MRI). The major age-related findings are ventricular enlargement, gray matter (GM) volume reductions, white matter (WM) microstructure alterations and iron deposition [1-3]. Throughout life, brain GM and WM undergo important biophysical changes, so knowing normal brain aging may contribute to understanding and preventing neurodegenerative disease [4]. MRI has played a critical role in understanding and evaluating the healthy aging process [5]. With conventional MRI methods, cortical thinning, regional atrophy and brain
of
surface morphology can be assessed during aging [6-8]. However, conventional MRI has a limited potential to clarify the underlying microstructural tissue processes [9]. On the other
ro
hand, quantitative MRI (qMRI) provides the calculation of the T1, T2 and T2* relaxation
-p
times, and qMRI is particularly sensitive to the biophysiological processes of aging in GM and WM [10,11].
re
The T1 relaxation time is affected by the microstructural properties of the tissue, including cell density, water content, myelin and iron content [12,13]. Aging causes axonal
lP
demyelination, iron deposition, water content reduction and synaptic degeneration; thus, T1 relaxation time can be used to analyze brain aging processes [14,15]. T1-weighted images are
na
routinely used for evaluating anatomical details; however, quantitative measurements of T1 recovery time cannot be accurately obtained with conventional MRI methods. T1 mapping
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provides a quantitative analysis of MR images with measurements of iron overload, contrast agent uptake, and blood perfusion and volume [16]. After calculating the T1 value of each voxel, color maps that provide better visual distinctions are obtained. The measurements of T1 relaxation time in the older healthy population may help to distinguish normal brain aging from pathological brain aging.
In this study, we aimed to determine the relationship between healthy brain aging and T1 relaxation time obtained by T1 mapping. 2. Materials and methods 2.1. Study population Between July 2018 and January 2019, 217 volunteers were recruited to our study. Patients with neurological or psychiatric disease, multiple sclerosis, alcohol or substance abuse, hypertension, diabetes mellitus, benign or malignant brain tumor, traumatic brain injury, previous brain surgery and contraindications to MRI were not included in the study. Total six patients were excluded from the study due to extensive WM hyperintensities (n=2),
Journal Pre-proof motion artifact (n=2), newly diagnosed multiple sclerosis (n=1), and newly diagnosed brain tumor (n=1). Therefore, 211 healthy volunteers (mean age, 54; age range, 20–89 years) were included in the study. The T1 mapping images were reevaluated by two radiologists (A.K. 8 years neuroradiology experience and M.K. 7 years neuroradiology experience) with joint consensus. The study was approved by the Institutional Ethics Committee, and written informed consent was obtained from all subjects before MRI examination. 2.2. T1 mapping protocol All MRI examinations were performed using a Siemens 1.5T scanner (MAGNETOM Aera, Siemens Healthcare, Erlangen, Germany). After obtaining routine brain MRI sequences,
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including T1- and T2-weighted images and FLAİR sequence, T1 mapping was obtained with a dual flip-angle 3D gradient-echo sequence with volumetric interpolated breath-hold
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examination (VIBE). The T1 mapping protocol was as follows: TR = 5.36 ms; TE = 1.95 ms;
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flip angle, 2° and 12°; FOV, 224 × 216 mm; matrix, 216 × 288; slice thickness, 5 mm. Generalized auto calibrating partially parallel acquisition (GAPPA) was performed as a
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parallel imaging technique (R = 2). Then, the T1 map images were obtained automatically on a voxel-by-voxel basis. If intravenous contrast agent use was required, T1 mapping was
2.3. Analysis of images
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performed before the contrast agent administration.
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The MR images were reevaluated by two radiologists to reach a consensus. The images were transferred to the Syngo workstation (Siemens Medical Solutions) for the
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measurement of T1 relaxation times. First, T1- and T2-weighted images and FLAİR sequences were evaluated. Then, regions of interest (ROIs) were placed on the T1 maps in seven different anatomical regions, including the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM. After detailed anatomic evaluation of these anatomical structures on T1 weighted images, the ROIs were carefully and manually traced on map images by radiologists (Fig. 1). 2.4. Statistical analysis All of the data were analyzed using the Statistical Package for the Social Sciences (SPSS 13.0 Statistical Software, SPSS Inc., Chicago, IL, USA) and the MedCalc package MedCalc Statistical Software version 16.8 (MedCalc Software bvba, Ostend, Belgium). The means and ranges of age and T1 relaxation times in the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM. The Kolmogorov–Smirnov test was used to show deviations from the normal distribution. Additionally, the parametric Student's t-test was used to compare the T1
Journal Pre-proof relaxation times in the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM between males and females. Correlations between age and T1 relaxation times in the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM were analyzed using Pearson’s correlation analysis. A p value of less than 0.05 was considered to indicate a significant difference. 3. Results In the present study, 211 healthy participants (102 males, 109 females; age range: 20–
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89 years; mean age: 54 years) were evaluated. The T1 relaxation times in the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus
ro
callosum, and frontal lobe WM are presented in Table 1. There was no sex effect on the T1
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relaxation time in any ROI (p>0.389). The results of linear and quadratic regression analyses performed between age and T1 relaxation times in the thalamus, putamen, globus pallidus,
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head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM are shown in Table 2 and Fig. 2.
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There were significant moderate negative linear correlation in putamen (r=-0.32), weak negative linear correlation in thalamus and head of the caudate nucleus (r=-0.25 and r=-
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0.15), weak positive linear correlation in frontal lobe WM, globus pallidus and genu of the corpus callosum (r=0.22, r=0.20 and r=0.23) between T1 relaxation times and age. Also, there
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were significant quadratic correlation in all these anatomical structures between T1 relaxation times and age (p<0.001). Although the nucleus accumbens did not show a significant relationship between T1 relaxation times and age in the linear regression (p=0.624), a statistically significant relationship was observed in the quadratic regression (p<0.001). For the globus pallidus, head of the caudate nucleus, and frontal lobe WM, the quadratic regression analysis showed a better relationship than linear correlation analysis.
4. Discussion In the present prospective study, we found that T1 relaxation times in the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM are associated with aging. Among these regions, the T1 relaxation times of the thalamus had the greatest correlation with age, with r2 value of 0.28 in the quadratic regressions.
Journal Pre-proof The use of quantitative imaging such as T1 mapping in MRI could provide considerable understanding of changing normal and pathologic conditions. MRI has been used to evaluate the development of the human brain, and myelination plays a key role in brain maturation with microarchitectural changes [17]. The T1 relaxation time is affected by myelin, water and iron concentrations in brain tissue, so demyelination increases the T1 value and increased iron accumulation shortens the T1 value [18,19]. The brain largely consists of myelin composed of different proteins and lipids. Because myelin alters T1 relaxation, T1 relaxation can be thought to be a biomarker of brain maturation. Stueber et al. showed that T1 relaxation times were correlated with myelin concentrations in postmortem human brain
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tissue [20]. A positive linear relationship exists between T1 relaxation time and water content [21,22]. Neeb et al. revealed that the water content of GM showed a continued reduction
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during physiological aging [14]. A decrease in water content after adjusting for
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macromolecules is another factor that decreases T1 relaxation times with aging. Additionally, increased iron deposition is negatively correlated with T1 values.
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In our study, we found a weak, significant positive correlation between T1 relaxation times in the frontal lobe WM and corpus callosum and age. WM demyelination and axonal
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loss related to aging can be assessed by increased T1 time, and indistinct intensity alterations in WM on T2-weighted images can be detected with T1 relaxation time. The mean T1
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relaxation time of the WM and corpus callosum was reported to be approximately 760 ms 850 ms and 725 ms - 840 ms, respectively [23-26]. In accordance with these values, the mean
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T1 relaxation time in the WM and corpus callosum were 786 ms and 737 ms in our study. The quadratic regression analysis revealed better r2 values than the linear correlation analysis in evaluating frontal lobe WM.
The deep GM structure, such as globus pallidus, thalamus and putamen, has higher iron concentrations than the WM [15]. However, the T1 relaxation times in these structures did not show significant decreases in our study. Additionally, Okubo et al. demonstrated that WM did not have higher T1 relaxation times than deep GM assessed by T1 mapping [29]. Aquino et al. reported that iron accumulation increased in putamen, globus pallidus, caudate nucleus during life and may vary in each structure [3]. However, Steen et al. demonstrated that T1 increased with age in the putamen and thalamus [27]. Also, Jara et al. showed a a positive linear correlation between age and T1 value in the globus pallidus [28]. This discordance may be related with heterogeneity in the ages and number of subjects in the studies. Additionally, Okubo et al. revealed a similar relationship between age and T1 relaxation times in these structures [23].
Journal Pre-proof Perivascular spaces are pial-lined, fluid-filled areas enclosing perforating vessels, and they are mostly located in the basal ganglia [29]. Small perivascular spaces can be detected in all age groups, and they become more frequent and larger with aging [29]. Furthermore, the dilatation of perivascular spaces can cause an increase in T1 relaxation times, particularly in the basal ganglia. This study has a number of limitations. First, we did not evaluate the inter- or intraobserver variability in the study. The second limitation was that there were not enough patients to investigate the T1 relaxation times for all decades. The third limitation was that participants younger than 20 years old were not included in our study. Fourth, there were no
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long-term follow-up results of T1 relaxation times.
In conclusion, the T1 relaxation times obtained by T1 mapping had a significant
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correlation with GM and WM affected by aging. In the present study, decreases in T1
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relaxation times were observed in GM structures except for plobus pallidus and increases were observed in WM structures. Additionally, the quadratic regression analysis revealed
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better r2 values than the linear correlation analysis. However, extensive studies with larger
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healthy brain aging.
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populations are needed to clearly confirm the effectiveness of T1 mapping to understand
References
Journal Pre-proof [1] Greenberg DL, Messer DF, Payne ME, Macfall JR, Provenzale JM, Steffens DC, et al. Aging, gender, and the elderly adult brain: an examination of analytical strategies. Neurobiol Aging 2008;29:290-302. [2] Lemaitre H, Goldman AL, Sambataro F, Verchinski BA, Meyer-Lindenberg A, et al. Normal age-related brain morphometric changes: nonuniformity across cortical thickness, surface area and gray matter volume? Neurobiol Aging 2012;33:617.e1-9. [3] Aquino D, Bizzi A, Grisoli M, Garavaglia B, Bruzzone MG, Nardocci N, et al. Agerelated iron deposition in the basal ganglia: quantitative analysis in healthy subjects. Radiology 2009;252:165-72.
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[4] Pannese E. Morphological changes in nerve cells during normal aging. Brain Struct Funct 2011;216:85-9.
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[5] Fjell AM, Westlye LT, Amlien I, Espeseth T, Reinvang I, Raz N, et al. High consistency
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of global and regional morphological alterations of human brain. Acad Radiol 2012;19:785– 93.
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[8] Walhovd KB, Fjell AM, Reinvang I, Lundervold A, Dale AM, Eilertsen DE, et al. Effects of age on volumes of cortex, white matter and subcortical structures. Neurobiol Aging
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2005;26:1261-70.
[9] Sengupta S, Fritz FJ, Harms RL, Hildebrand S, Tse DHY, Poser BA, et al. High resolution anatomical and quantitative MRI of the entire human occipital lobe exvivo at 9.4T. Neuroimage 2018;168:162-71.
[10] Deoni SC. Quantitative relaxometry of the brain. Top Magn Reson Imaging 2010;21:101-13. [11] Callaghan MF, Freund P, Draganski B, Anderson E, Cappelletti M, Chowdhury R, et al. Wide spread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging. Neurobiol Aging 2014;35:1862-72. [12] Lutti A, Dick F, Sereno MI, Weiskopf N. Using high resolution quantitative mapping of R1 as an index of cortical myelination. Neuroimage 2014;93:176–88. [13] Fatouros PP, Marmarou A, Kraft KA, Inao S, Schwarz FP. Invivo brain water determination by T1 measurements: effect of total water content, hydration fraction, and field strength. Magn Reson Med 1991;17:402–13.
Journal Pre-proof [14] Neeb H, Zilles K, Shah NJ. Fully-automated detection of cerebral water content changes: study of age- and gender-related H2O patterns with quantitative MRI. Neuroimage 2006;29:910–22. [15] Lim IA, Faria AV, Li X, Hsu JT, Airan RD, Mori S, et al. Human brain atlas for automated region of interest selection in quantitative susceptibility mapping: application to determine iron content in deep gray matter structures. Neuroimage 2013;82:449–69. [16] Stikov N, Boudreau M, Levesque IR, Tardif CL, Barral JK, Pike GB. On the accuracy of T1 mapping: searching for common ground. Magn Reson Med 2015;73:514-22. [17] Eminian S, Hajdu SD, Meuli RA, Maeder P, Hagmann P. Rapid high resolution T1
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mapping as a marker of brain development: Normative ranges in key regions of interest. PloS One 2018;13:e0198250.
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concentration. Magn Reson Med 1998;40:749–53.
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[18] Ogg RJ, Steen RG. Age-related changes in brain T1 are correlated with iron
[19] Stüber C, Morawski M, Schäfer A, Labadie C, Wähnert M, Leuze C, et al. Myelin and
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iron concentration in the human brain: a quantitative study of MRI contrast. Neuroimage 2014;93:95-106.
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[20] Hametner S, Endmayr V, Deistung A, Palmrich P, Prihoda M, Haimburger E, et al. The influence of brain iron and myelin on magnetic susceptibility and effective transverse
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relaxation - A biochemical and histological validation study. Neuroimage 2018;179:117-33. [21] Fatouros PP, Marmarou A, Kraft KA, Inao S, Schwarz FP. Invivo brain water
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determination by T1 measurements: effect of total water content, hydration fraction, and field strength. Magn Reson Med 1991;17:402–13. [22] Gelman N, Ewing JR, Gorell JM, Spickler EM, Solomon EG. Interregional variation of longitudinal relaxation rates in human brain at 3.0 T: relation to estimated iron and water contents. Magn Reson Med 2001;45:71–9. [23] Okubo G, Okada T, Yamamoto A, Fushimi Y, Okada T, Murata K, et al. Relationship between aging and T(1) relaxation time in deep graymatter: A voxel-based analysis. J Magn Reson Imaging 2017;46:724-31. [24] Wright PJ, Mougin OE, Totman JJ, Peters AM, Brookes MJ, Coxon R, et al. Water proton T1 measurements in brain tissue at 7, 3, and 1.5 T using IR-EPI, IR-TSE, and MPRAGE: results and optimization. MAGMA 2008;21:121-30. [25] Lu H, Nagae-Poetscher LM, Golay X, Lin D, Pomper M, vanZijl PC. Routine clinical brain MRI sequences for use at 3.0 Tesla. J Magn Reson Imaging 2005;22:13–22.
Journal Pre-proof [26] Gelman N, Ewing JR, Gorell JM, Spickler EM, Solomon EG. Inter regional variation of longitudinal relaxation rates in human brain at 3.0 T: relation to estimated iron and water contents. Magn Reson Med 2001;45:71–9. [27] Steen RG, Gronemeyer SA, Taylor JS. Age-related changes in proton T1 values of normal human brain. J Magn Reson Imaging 1995;5:43–48. [28] Jara H, Sakai O, Mankal P, Irving RP, Norbash AM. Multispectral quantitative magnetic resonance imaging of brain iron stores: a theoretical perspective. Top Magn Reson Imaging 2006;17:19-30. [29] Kwee RM, Kwee TC. Virchow-Robins paces at MR imaging. Radiographics 2007;27:
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1071-86.
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Figure Legends; Fig. 1. T1 relaxation times of the thalamus, putamen, globus pallidus, head of the caudate nucleus, genu of the corpus callosum (a), and frontal lobe WM (b) are obtained by placing ROIs with T1 mapping. Fig. 2. Scatter plots represent the relation ship between T1 relaxation time of frontal lobe WM (a), thalamus (b), head of the caudate nucleus (c), putamen (d), globus pallidus (e), genu of the corpus callosum (f), nucleus accumbens (g) and age with for the linear (redline) and
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quadratic (blueline) regression analyses.
Journal Pre-proof Table1 Mean T1 relaxation times of different anatomical regions Total (n=211)
Male (n=102)
Famale (n=109)
P value
Thalamus (ms)
1101.9 ± 62.3 (976-1284)
1103,9 ± 67.6 (986-1284)
1100.4 ± 58.2 (976-1235)
0.684
Putamen (ms)
1155.6 ± 63.8 (1010-1307)
1157.2 ±65.7 (1010-1307)
1154,6 ±62.6 (1033-1291)
0.789
Globus pallidus (ms)
940.4 ± 56.8 (784-1119)
939.4 ± 62.2 (784-1119)
941.3 ± 52.6 (830-1069)
0.812
Head of caudate nucleus (ms)
1169.1 ± 63.5 (908-1342)
1172.3 ± 58.4 (1038-1342)
1166.6 ± 67.2 (908-1324)
0.516
Nucleus accumbens (ms)
1170.2 ± 71.7 (897-1302)
1171.2 ± 70.2 (897-1302)
1169.0 ± 67.2 (950-1289)
0.389
732.5 ± 42.5 (639-818)
741.7 ± 58.2 (626-875)
0.426
786.4 ± 53.7 (709-952)
786.9 ± 40.3 (687-898)
0.951
rn
Genu of the corpus callosum (ms)
737.7 ± 53.3 (626-879)
Frontal lobe WM (ms)
786.7 ± 46.4 (687-952)
WM: white matter
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e
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f o
Journal Pre-proof
Table 2 Results of regression analyses R2 (linear)
P value (linear)
R2 (Quadratic)
P value (Quadratic)
Thalamus
-0.25
0.06
<0.001
0.28
<0.001
Putamen
-0.32
0.10
<0.001
0.20
<0.001
Globus pallidus
0.20
0.03
0.004
0.11
<0.001
Head of caudate nucleus Nucleus accumbens
-0.15
0.02
0.027
0.03
0.01
Genu of the corpus callosum Frontal lobe WM
0.23
0.05
<0.001
0.624
0.15
<0.001
<0.001
0.09
<0.001
0.002
0.19
<0.001
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0.09
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WM: white matter
0.04
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0.22
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R (linear)
Journal Pre-proof Highlights The T1 relaxation times obtained by T1 mapping had a significant correlation with GM and WM affected by aging. The quadratic regression analysis revealed better r2 values than the linear correlation analysis.
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na
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re
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The thalamus had higher r2 values in the correlation analysis.
Figure 1
Figure 2
Ali Kupeli, Mehmet Kocak, Mehmet Goktepeli, Erdal Karavas, Gurkan Danisan PII:
S0899-7071(19)30179-2
DOI:
https://doi.org/10.1016/j.clinimag.2019.09.005
Reference:
JCT 8741
To appear in:
Clinical Imaging
Received date:
15 April 2019
Revised date:
24 July 2019
Accepted date:
23 September 2019
Please cite this article as: A. Kupeli, M. Kocak, M. Goktepeli, et al., Role of T1 mapping to evaluate brain aging in a healthy population, Clinical Imaging(2019), https://doi.org/ 10.1016/j.clinimag.2019.09.005
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof
Role of T1 mapping to evaluate brain aging in a healthy population Ali Kupelia, Mehmet Kocaka, Mehmet Goktepelia, Erdal Karavasa, Gurkan Danisanb, a
Department of Radiology, Faculty of Medicine, Erzincan Binali Yıldırım University,
24000/Erzincan, Turkey Mus State Hospital, Department of Radiology, 49000 / Mus, Turkey
-p
ro
of
b
re
Corresponding author:
lP
Ali Kupeli, M.D.
24000/Erzincan, Turkey Tel: +90 4362120670
na
Department of Radiology, Faculty of Medicine, Erzincan Binali Yıldırım University,
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Email: [email protected]
Journal Pre-proof Role of T1 mapping to evaluate brain aging in a healthy population
ABSTRACT Purpose: To investigate the relationship between healthy brain aging and T1 relaxation time obtained by T1 mapping. Materials and methods: A total of 211 (102 males, 109 females; age range: 20–89 years; mean age: 54 years) healthy volunteers underwent T1 mapping between July 2018 and January 2019. Regions of interest (ROIs) were placed on T1 maps in different anatomical regions, including the thalamus, putamen, globus pallidus, head of the caudate nucleus,
of
nucleus accumbens, genu of the corpus callosum, and frontal lobe white matter (WM). Additionally, linear and quadratic regression analyses of ROIs were performed.
ro
Results: There were significant quadratic and negative linear correlations between T1
-p
relaxation times in the thalamus, putamen, and age (p<0.001). Although the nucleus accumbens did not show a significant relationship between T1 relaxation times and age by
re
linear regression (p=0.624), a statistically significant relationship was obtained by quadratic regression (p<0.001). For the globus pallidus, head of the caudate nucleus, genu of the corpus
than the linear correlation analysis.
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callosum and frontal lobe WM the quadratic regression analysis showed a better relationship
na
Conclusion: Age-related changes in T1 relaxation time vary by location in GM and WM.
Jo ur
Keywords: Aging, Mapping, MRI
Journal Pre-proof 1. Introduction With aging, there are several changes in anatomical structures in the brain that can be noninvasively evaluated by magnetic resonance imaging (MRI). The major age-related findings are ventricular enlargement, gray matter (GM) volume reductions, white matter (WM) microstructure alterations and iron deposition [1-3]. Throughout life, brain GM and WM undergo important biophysical changes, so knowing normal brain aging may contribute to understanding and preventing neurodegenerative disease [4]. MRI has played a critical role in understanding and evaluating the healthy aging process [5]. With conventional MRI methods, cortical thinning, regional atrophy and brain
of
surface morphology can be assessed during aging [6-8]. However, conventional MRI has a limited potential to clarify the underlying microstructural tissue processes [9]. On the other
ro
hand, quantitative MRI (qMRI) provides the calculation of the T1, T2 and T2* relaxation
-p
times, and qMRI is particularly sensitive to the biophysiological processes of aging in GM and WM [10,11].
re
The T1 relaxation time is affected by the microstructural properties of the tissue, including cell density, water content, myelin and iron content [12,13]. Aging causes axonal
lP
demyelination, iron deposition, water content reduction and synaptic degeneration; thus, T1 relaxation time can be used to analyze brain aging processes [14,15]. T1-weighted images are
na
routinely used for evaluating anatomical details; however, quantitative measurements of T1 recovery time cannot be accurately obtained with conventional MRI methods. T1 mapping
Jo ur
provides a quantitative analysis of MR images with measurements of iron overload, contrast agent uptake, and blood perfusion and volume [16]. After calculating the T1 value of each voxel, color maps that provide better visual distinctions are obtained. The measurements of T1 relaxation time in the older healthy population may help to distinguish normal brain aging from pathological brain aging.
In this study, we aimed to determine the relationship between healthy brain aging and T1 relaxation time obtained by T1 mapping. 2. Materials and methods 2.1. Study population Between July 2018 and January 2019, 217 volunteers were recruited to our study. Patients with neurological or psychiatric disease, multiple sclerosis, alcohol or substance abuse, hypertension, diabetes mellitus, benign or malignant brain tumor, traumatic brain injury, previous brain surgery and contraindications to MRI were not included in the study. Total six patients were excluded from the study due to extensive WM hyperintensities (n=2),
Journal Pre-proof motion artifact (n=2), newly diagnosed multiple sclerosis (n=1), and newly diagnosed brain tumor (n=1). Therefore, 211 healthy volunteers (mean age, 54; age range, 20–89 years) were included in the study. The T1 mapping images were reevaluated by two radiologists (A.K. 8 years neuroradiology experience and M.K. 7 years neuroradiology experience) with joint consensus. The study was approved by the Institutional Ethics Committee, and written informed consent was obtained from all subjects before MRI examination. 2.2. T1 mapping protocol All MRI examinations were performed using a Siemens 1.5T scanner (MAGNETOM Aera, Siemens Healthcare, Erlangen, Germany). After obtaining routine brain MRI sequences,
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including T1- and T2-weighted images and FLAİR sequence, T1 mapping was obtained with a dual flip-angle 3D gradient-echo sequence with volumetric interpolated breath-hold
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examination (VIBE). The T1 mapping protocol was as follows: TR = 5.36 ms; TE = 1.95 ms;
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flip angle, 2° and 12°; FOV, 224 × 216 mm; matrix, 216 × 288; slice thickness, 5 mm. Generalized auto calibrating partially parallel acquisition (GAPPA) was performed as a
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parallel imaging technique (R = 2). Then, the T1 map images were obtained automatically on a voxel-by-voxel basis. If intravenous contrast agent use was required, T1 mapping was
2.3. Analysis of images
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performed before the contrast agent administration.
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The MR images were reevaluated by two radiologists to reach a consensus. The images were transferred to the Syngo workstation (Siemens Medical Solutions) for the
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measurement of T1 relaxation times. First, T1- and T2-weighted images and FLAİR sequences were evaluated. Then, regions of interest (ROIs) were placed on the T1 maps in seven different anatomical regions, including the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM. After detailed anatomic evaluation of these anatomical structures on T1 weighted images, the ROIs were carefully and manually traced on map images by radiologists (Fig. 1). 2.4. Statistical analysis All of the data were analyzed using the Statistical Package for the Social Sciences (SPSS 13.0 Statistical Software, SPSS Inc., Chicago, IL, USA) and the MedCalc package MedCalc Statistical Software version 16.8 (MedCalc Software bvba, Ostend, Belgium). The means and ranges of age and T1 relaxation times in the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM. The Kolmogorov–Smirnov test was used to show deviations from the normal distribution. Additionally, the parametric Student's t-test was used to compare the T1
Journal Pre-proof relaxation times in the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM between males and females. Correlations between age and T1 relaxation times in the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM were analyzed using Pearson’s correlation analysis. A p value of less than 0.05 was considered to indicate a significant difference. 3. Results In the present study, 211 healthy participants (102 males, 109 females; age range: 20–
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89 years; mean age: 54 years) were evaluated. The T1 relaxation times in the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus
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callosum, and frontal lobe WM are presented in Table 1. There was no sex effect on the T1
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relaxation time in any ROI (p>0.389). The results of linear and quadratic regression analyses performed between age and T1 relaxation times in the thalamus, putamen, globus pallidus,
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head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM are shown in Table 2 and Fig. 2.
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There were significant moderate negative linear correlation in putamen (r=-0.32), weak negative linear correlation in thalamus and head of the caudate nucleus (r=-0.25 and r=-
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0.15), weak positive linear correlation in frontal lobe WM, globus pallidus and genu of the corpus callosum (r=0.22, r=0.20 and r=0.23) between T1 relaxation times and age. Also, there
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were significant quadratic correlation in all these anatomical structures between T1 relaxation times and age (p<0.001). Although the nucleus accumbens did not show a significant relationship between T1 relaxation times and age in the linear regression (p=0.624), a statistically significant relationship was observed in the quadratic regression (p<0.001). For the globus pallidus, head of the caudate nucleus, and frontal lobe WM, the quadratic regression analysis showed a better relationship than linear correlation analysis.
4. Discussion In the present prospective study, we found that T1 relaxation times in the thalamus, putamen, globus pallidus, head of the caudate nucleus, nucleus accumbens, genu of the corpus callosum, and frontal lobe WM are associated with aging. Among these regions, the T1 relaxation times of the thalamus had the greatest correlation with age, with r2 value of 0.28 in the quadratic regressions.
Journal Pre-proof The use of quantitative imaging such as T1 mapping in MRI could provide considerable understanding of changing normal and pathologic conditions. MRI has been used to evaluate the development of the human brain, and myelination plays a key role in brain maturation with microarchitectural changes [17]. The T1 relaxation time is affected by myelin, water and iron concentrations in brain tissue, so demyelination increases the T1 value and increased iron accumulation shortens the T1 value [18,19]. The brain largely consists of myelin composed of different proteins and lipids. Because myelin alters T1 relaxation, T1 relaxation can be thought to be a biomarker of brain maturation. Stueber et al. showed that T1 relaxation times were correlated with myelin concentrations in postmortem human brain
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tissue [20]. A positive linear relationship exists between T1 relaxation time and water content [21,22]. Neeb et al. revealed that the water content of GM showed a continued reduction
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during physiological aging [14]. A decrease in water content after adjusting for
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macromolecules is another factor that decreases T1 relaxation times with aging. Additionally, increased iron deposition is negatively correlated with T1 values.
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In our study, we found a weak, significant positive correlation between T1 relaxation times in the frontal lobe WM and corpus callosum and age. WM demyelination and axonal
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loss related to aging can be assessed by increased T1 time, and indistinct intensity alterations in WM on T2-weighted images can be detected with T1 relaxation time. The mean T1
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relaxation time of the WM and corpus callosum was reported to be approximately 760 ms 850 ms and 725 ms - 840 ms, respectively [23-26]. In accordance with these values, the mean
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T1 relaxation time in the WM and corpus callosum were 786 ms and 737 ms in our study. The quadratic regression analysis revealed better r2 values than the linear correlation analysis in evaluating frontal lobe WM.
The deep GM structure, such as globus pallidus, thalamus and putamen, has higher iron concentrations than the WM [15]. However, the T1 relaxation times in these structures did not show significant decreases in our study. Additionally, Okubo et al. demonstrated that WM did not have higher T1 relaxation times than deep GM assessed by T1 mapping [29]. Aquino et al. reported that iron accumulation increased in putamen, globus pallidus, caudate nucleus during life and may vary in each structure [3]. However, Steen et al. demonstrated that T1 increased with age in the putamen and thalamus [27]. Also, Jara et al. showed a a positive linear correlation between age and T1 value in the globus pallidus [28]. This discordance may be related with heterogeneity in the ages and number of subjects in the studies. Additionally, Okubo et al. revealed a similar relationship between age and T1 relaxation times in these structures [23].
Journal Pre-proof Perivascular spaces are pial-lined, fluid-filled areas enclosing perforating vessels, and they are mostly located in the basal ganglia [29]. Small perivascular spaces can be detected in all age groups, and they become more frequent and larger with aging [29]. Furthermore, the dilatation of perivascular spaces can cause an increase in T1 relaxation times, particularly in the basal ganglia. This study has a number of limitations. First, we did not evaluate the inter- or intraobserver variability in the study. The second limitation was that there were not enough patients to investigate the T1 relaxation times for all decades. The third limitation was that participants younger than 20 years old were not included in our study. Fourth, there were no
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long-term follow-up results of T1 relaxation times.
In conclusion, the T1 relaxation times obtained by T1 mapping had a significant
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correlation with GM and WM affected by aging. In the present study, decreases in T1
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relaxation times were observed in GM structures except for plobus pallidus and increases were observed in WM structures. Additionally, the quadratic regression analysis revealed
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better r2 values than the linear correlation analysis. However, extensive studies with larger
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healthy brain aging.
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populations are needed to clearly confirm the effectiveness of T1 mapping to understand
References
Journal Pre-proof [1] Greenberg DL, Messer DF, Payne ME, Macfall JR, Provenzale JM, Steffens DC, et al. Aging, gender, and the elderly adult brain: an examination of analytical strategies. Neurobiol Aging 2008;29:290-302. [2] Lemaitre H, Goldman AL, Sambataro F, Verchinski BA, Meyer-Lindenberg A, et al. Normal age-related brain morphometric changes: nonuniformity across cortical thickness, surface area and gray matter volume? Neurobiol Aging 2012;33:617.e1-9. [3] Aquino D, Bizzi A, Grisoli M, Garavaglia B, Bruzzone MG, Nardocci N, et al. Agerelated iron deposition in the basal ganglia: quantitative analysis in healthy subjects. Radiology 2009;252:165-72.
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Journal Pre-proof [26] Gelman N, Ewing JR, Gorell JM, Spickler EM, Solomon EG. Inter regional variation of longitudinal relaxation rates in human brain at 3.0 T: relation to estimated iron and water contents. Magn Reson Med 2001;45:71–9. [27] Steen RG, Gronemeyer SA, Taylor JS. Age-related changes in proton T1 values of normal human brain. J Magn Reson Imaging 1995;5:43–48. [28] Jara H, Sakai O, Mankal P, Irving RP, Norbash AM. Multispectral quantitative magnetic resonance imaging of brain iron stores: a theoretical perspective. Top Magn Reson Imaging 2006;17:19-30. [29] Kwee RM, Kwee TC. Virchow-Robins paces at MR imaging. Radiographics 2007;27:
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Figure Legends; Fig. 1. T1 relaxation times of the thalamus, putamen, globus pallidus, head of the caudate nucleus, genu of the corpus callosum (a), and frontal lobe WM (b) are obtained by placing ROIs with T1 mapping. Fig. 2. Scatter plots represent the relation ship between T1 relaxation time of frontal lobe WM (a), thalamus (b), head of the caudate nucleus (c), putamen (d), globus pallidus (e), genu of the corpus callosum (f), nucleus accumbens (g) and age with for the linear (redline) and
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quadratic (blueline) regression analyses.
Journal Pre-proof Table1 Mean T1 relaxation times of different anatomical regions Total (n=211)
Male (n=102)
Famale (n=109)
P value
Thalamus (ms)
1101.9 ± 62.3 (976-1284)
1103,9 ± 67.6 (986-1284)
1100.4 ± 58.2 (976-1235)
0.684
Putamen (ms)
1155.6 ± 63.8 (1010-1307)
1157.2 ±65.7 (1010-1307)
1154,6 ±62.6 (1033-1291)
0.789
Globus pallidus (ms)
940.4 ± 56.8 (784-1119)
939.4 ± 62.2 (784-1119)
941.3 ± 52.6 (830-1069)
0.812
Head of caudate nucleus (ms)
1169.1 ± 63.5 (908-1342)
1172.3 ± 58.4 (1038-1342)
1166.6 ± 67.2 (908-1324)
0.516
Nucleus accumbens (ms)
1170.2 ± 71.7 (897-1302)
1171.2 ± 70.2 (897-1302)
1169.0 ± 67.2 (950-1289)
0.389
732.5 ± 42.5 (639-818)
741.7 ± 58.2 (626-875)
0.426
786.4 ± 53.7 (709-952)
786.9 ± 40.3 (687-898)
0.951
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Genu of the corpus callosum (ms)
737.7 ± 53.3 (626-879)
Frontal lobe WM (ms)
786.7 ± 46.4 (687-952)
WM: white matter
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Table 2 Results of regression analyses R2 (linear)
P value (linear)
R2 (Quadratic)
P value (Quadratic)
Thalamus
-0.25
0.06
<0.001
0.28
<0.001
Putamen
-0.32
0.10
<0.001
0.20
<0.001
Globus pallidus
0.20
0.03
0.004
0.11
<0.001
Head of caudate nucleus Nucleus accumbens
-0.15
0.02
0.027
0.03
0.01
Genu of the corpus callosum Frontal lobe WM
0.23
0.05
<0.001
0.624
0.15
<0.001
<0.001
0.09
<0.001
0.002
0.19
<0.001
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0.09
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WM: white matter
0.04
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0.22
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R (linear)
Journal Pre-proof Highlights The T1 relaxation times obtained by T1 mapping had a significant correlation with GM and WM affected by aging. The quadratic regression analysis revealed better r2 values than the linear correlation analysis.
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The thalamus had higher r2 values in the correlation analysis.
Figure 1
Figure 2