Eur Spine J DOI 10.1007/s00586-014-3285-z

ORIGINAL ARTICLE

Assessment of apparent diffusion coefficient in lumbar intervertebral disc degeneration Wei Zhang • Xiaohui Ma • Yan Wang Jian Zhao • Xujing Zhang • Yu Gao • Shiling Li

•

Received: 7 May 2013 / Revised: 6 January 2014 / Accepted: 25 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Objective The aim of this study was to determine the relationship between the apparent diffusion coefficient (ADC) and lumbar intervertebral disc degeneration using diffusion-weighted magnetic resonance imaging (DWI). Materials and methods Using a 3 T magnetic resonance scanner, DWI of the lumbar spine was assessed in 109 patients, with a total of 545 lumbar discs analyzed. Apparent diffusion coefficient values were recorded for each disc, and all discs were visually graded by two independent observers using Pfirrmann’s grading system. Apparent diffusion coefficient values of disc were tested by correlation with qualitative clinical grading of degeneration severity, patient age, and sex. Correlations were investigated using Pearson’s and Spearman’s rank correlation analysis, and multiple regression analysis. W. Zhang (&)
X. Ma
J. Zhao
X. Zhang
Y. Gao
S. Li Department of Radiology, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China e-mail: [email protected]

Results Intervertebral disc degeneration was negatively correlated with ADC values of all levels (Spearman’s correlation coefficient ranged from -0.381 to -0.604, p \ 0.001). There was a significant negative association between age and ADC values at all spinal levels (Pearson’s correlation coefficient ranged from -0.353 to -0.650, p \ 0.001). When stepwise regression models were analyzed, both disc degeneration and age remained negatively associated with ADC values at each lumbar level (standardized coefficients ranged from -0.231 to -0.505, p \ 0.01 and standardized coefficients ranged from -0.179 to -0.523, p \ 0.05 respectively). Conclusion Apparent diffusion coefficient values obtained using DWI can assess lumbar intervertebral disc degeneration, and the ADC values were negatively correlated with the degree of disc degeneration. Keywords Lumbar disc degeneration
Diffusionweighted imaging
Apparent diffusion coefficient

X. Ma e-mail: [email protected]

Introduction

J. Zhao e-mail: [email protected]

Disc degeneration has been attributed to the biochemical and structural alterations of the disc under physiological and pathological conditions. Degeneration of the disc changes the stress patterns in the vertebral endplate and annulus, leading to narrowing of the intervertebral space and irritation or compression of the adjacent tissue, which causes various signs and symptoms. Disc degeneration is a complex process involving both decomposition of collagen and proteoglycan, as well as water loss. Magnetic resonance imaging (MRI), with its high sensitivity to tissue water content, has become a simple and accurate tool for assessing intervertebral disc degeneration

X. Zhang e-mail: [email protected] Y. Gao e-mail: [email protected] S. Li e-mail: [email protected] Y. Wang Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China e-mail: [email protected]

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[1, 2]. MRI is based on the conventional T2-weighted (T2WI) sequence with fat suppression in the diagnosis of disc degeneration. However, there are some limitations for finding changes in the nucleus pulposus (NP) during early intervertebral disc degeneration; moreover, this evaluation is susceptible to inter- and intra-observer variabilities [3]. Quantitative assessment has significantly improved the diagnosis of intervertebral disc degeneration. Diffusionweighted imaging (DWI) based on MRI can provide valuable information regarding the microstructure of tissues by monitoring the random movement of water molecules. The diffusion data can be used to determine quantitative diffusion values, such as the apparent diffusion coefficient (ADC). The ADC map reflects these changes and potentially serves as a radiological biomarker of tissue response. Changes on the DWI are also seen before they are seen on T1- or T2-weighted images [4]. It has been reported that DWI is useful for evaluating and diagnosing lesions [5, 6]. Modifications of the NP matrix content, specifically of water and glycosaminoglycan content with age and disc degeneration, correlated with changes in the ADCs [7]. Apparent diffusion coefficient values can be used as a quantitative tool to estimate degenerative changes. The ADC of the nuclear region of the lumbar intervertebral discs (IVDs) can be reliably measured from diffusion-weighted images. However, the challenging nature of diffusion imaging of the spine and limited numbers of subjects in earlier studies has resulted in contradictory findings. Evidence suggests that mean ADC values in degenerated discs were lower than those obtained from normal discs [8, 9], while Niinima¨ki et al. [10] concluded that ADC is somewhat dependent on disc degeneration, but cannot be used clinically. In the present paper, we explore the novel application of using DWI with ADC values for the detection of intervertebral disc degeneration. The aim of our study was to investigate the suitability of DWI sequence for the quantification of intervertebral disc degeneration and to determine if a relationship exists between disc ADC and MR findings of disc degeneration.

Materials and methods Study subjects Apparent diffusion coefficient values were obtained for 545 lumbar intervertebral discs obtained from diffusionweighted imaging of the lumbar spine in 109 patients (mean age 41, SD 12 years), including 60 women and 49 men. Participants were recruited from the Third Hospital of Hebei Medical University. All participants gave written informed consent. The study protocol and procedures were

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approved by the ethics committee of the hospital, and the procedures followed were in accordance with the Helsinki Declaration [11]. All patients had no history of chronic back pain or back surgery. MR imaging Data were acquired using a 3.0 T MRI scanner (Verio; Siemens, Erlangen, Germany), T1WI, T2WI fat-suppressed sequence, and DWI were routinely acquired in one imaging plane. T1WI sequence was carried out using the following parameters: repetition time (TR), 650 ms; echo time (TE), 9.6 ms; number of averages (NEX), 1; slice thickness, 4 mm; slice gap, 0.4 mm; matrix, 384 9 307; field of view (FOV), 30 cm 9 30 cm. T2-weighted sequence was carried out using the following parameters: TR, 4000 ms; TE, 43 ms; NEX, 1; slice thickness, 4.0 mm; slice gap, 0.4 mm; matrix, 384 9 288; FOV, 30 cm 9 30 cm. Diffusion-weighted magnetic resonance imaging were obtained with spin-echo echo planar imaging (SE-EPI) sequence using b-values (‘‘b’’ represents diffusion sensitivity coefficient in the MRI set-up) of 800 s/mm2. Parameters were as follows: TR, 7500 ms; TE, 83 ms; NEX, 6; matrix, 160 9 128; slice thickness, 4.0 mm; slice gap, 0.4 mm; FOV, 30 cm 9 30 cm. Disc degeneration was graded on routine T2WI MRI using the Pfirrmann’s grading system in all patients [12]. Two experienced radiologists independently reviewed the images and classified each one of the 545 discs into one of five classes of degeneration severity. Disagreement between the two readers were resolved through discussion. A single operator placed small, round regions of interest (ROIs) (90–110 mm2) within the central portion of each of the five lumbar discs (L1/2 to L5/S1) and within the central portion of the water tube on the ADC map. The ADC values within these ROIs were then recorded (Fig. 1). Statistical methods Apparent diffusion coefficient values of all five discs were analyzed using ANOVA randomized block design and the Student–Newman–Keuls (SNK) test. Pearson’s correlation coefficient was used for measuring the association between age and ADC values, while Spearman’s rank correlation coefficient was used to measure the association between the qualitative clinical grading of disc degeneration according to Pfirrmann’s scale and ADC values. A two independent samples t test was used to examine significant differences in ADC values between genders. Multiple linear regression analysis was used to investigate the relative influences of gender, age, and class of degeneration upon the ADC values. Statistical analysis was carried out using the SPSS 13.0 statistical software program, and p values less than 0.05 were considered statistically significant.

Eur Spine J

Fig. 1 MR images of lumbar spine in 38-year-old man. a Sagittal T1weighted MR image on participant’s back. b Sagittal T2-weighted MR image. Intervertebral disc at L4/5 was designated as showing reduction in T2 signal intensity. ROI has been placed centrally on

intervertebral disc at L4/5. c Corresponding diffusion-weighted image (b value, 800 s/mm2; TR, 7500 ms; TE, 83 ms; NEX, 6; section thickness, 4 mm; section gap, 0.4 mm) and d ADC map derived from c, with ROI placed over L4-5 intervertebral disc

Results

Table 1 Number of intervertebral discs in various age groups of men and women according to Pfirrmann’s grading system

Age and sex distribution

Gender

Subjects were grouped according to age as follows: 30 (27.5 %) in the 20–29-year age group; 24 (22 %) in the 30–39-year age group; 23 (21 %) in the 40–49-year age group; and 32 (29.5 %) in the 50–59-year age group. Among the individuals 49 (45 %) were males and 60 (55 %) were females. Prevalence of disc degeneration A total of 545 intervertebral discs were studied in the 109 participants. According to Pfirrmann’s grading system, grade 1–5 disc degeneration was seen in all age groups. Table 1 shows the number of intervertebral discs obtained and their Pfirrmann grade. In both sexes, most intervertebral discs were graded 1–4. A few grade 5 discs were found in all age groups except in females aged 40–49 years and in males aged 20–29 and 50–59 years. Grade 1 to grade 4 discs were found in all age groups; grade 1 and 2 discs decreased with age, while grade 3 and 4 discs increased with age. In males, the highest percentage of grade 2 discs (44 %) was observed in the 20–29 years age group, whereas the highest percentage of grade 4 discs (48 %) was observed in those aged 50–59 years. Similarly, in females,

Male

Female

Age groups

Number of intervertebral discs Grade 1

Grade 2 Grade 3

Grade 4

Grade 5

20–29

19

31

15

5

30–39

4

18

14

13

0 1

40–49

11

14

17

17

1

50–59

2

8

24

31

0

20–29 30–39

14 17

29 17

23 19

12 15

2 1

40–49

7

10

16

23

0

50–59

0

9

28

54

4

the highest percentage of grade 2 discs (36 %) was observed in those aged 20–29 years while the highest percentage of grade 4 discs (57 %) was observed in those between 50 and 59 years. Comparison of disc ADC values at different spinal levels The mean ADC value for each of the five intervertebral disc levels are shown in Table 2. There was a statistically significant difference in mean ADC values for the five intervertebral disc levels using ANOVA randomized block

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Eur Spine J Table 2 Mean ADC values in discs according to spinal level (means ± standard deviations)

Table 3 Spearman correlation of ADC value with degeneration and Pearson correlation of ADC value with age

Intervertebral disc level

Mean ADC values (910-3 mm2/s)

Intervertebral disc level

Degeneration

Age

L1/2 (ADC1)

1.63 ± 0.22

L1/2 (ADC1)

-0.381a

-0.417a

L2/3 (ADC2)

a

-0.561a

a

-0.650a

a

-0.606a

a

-0.353a

L2/3 (ADC2)

1.58 ± 0.38

L3/4 (ADC3)

1.55 ± 0.37

L4/5 (ADC4)

L3/4 (ADC3)

1.44 ± 0.45

L5/S1 (ADC5)

L4/5 (ADC4)

1.39 ± 0.42

L5/S1 (ADC5) a

2500

Mean ADC

-0.537 -0.576 -0.604

p \ 0.001

association between age and ADC values of all levels (Pearson’s correlation coefficient = - 0.417, -0.561, -0.650, -0.606, and -0.353 for L1/2, L2/3, L3/4, L4/5, and L5/S1, respectively; all p \ 0.001). A two independent samples t test results demonstrated no significant relationship between men and women (all p [ 0.05).

2000 1500 1000 500

Effects of disc degeneration, age and gender on ADC values

0

L1/2

L2/3

L3/4

L4/5

L5/S1

Fig. 2 Graph of mean ADC values in lumbar intervertebral discs. Apparent diffusion coefficient values of discs decrease as one proceeds in caudal direction. There was a statistically significant difference in ADC values between each of the three upper lumbar discs and each of the two lower lumbar discs. The error bars represent standard deviation

design (F = 8.071, p \ 0.001). Apparent diffusion coefficient values reduced with decreasing spinal level, with lower ADC values seen in more caudal lumbar discs compared with more cephalad lumbar discs. A further comparison was carried out using the SNK test. No significant differences were found between ADC1 and ADC2 or ADC3 values. Similarly, there were no significant differences between ADC4 and ADC5 values. Nevertheless, statistically significant differences were found in mean ADC values between the upper lumbar discs (L1/2, L2/3, and L3/4) and the lower discs (L4/5 and L5/S1), with lower lumbar levels having lower ADC values (see Fig. 2). Comparison between ADC values and intervertebral disc degeneration, age, and gender Table 3 shows the outcomes of the correlation tests. According to rank correlation analysis, intervertebral disc degeneration negatively correlated with ADC values of all levels (Spearman’s correlation coefficient = - 0.381, -0.518, -0.537, -0.576, and -0.604 for L1/2, L2/3, L3/4, L4/5, and L5/S1, respectively; all p \ 0.001). Pearson’s correlation analysis results showed a strong negative

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-0.518

Table 4 shows the outcomes of multiple regression analysis. Multivariate analysis was carried out, with degeneration, age, and gender as independent variables and ADC values as the dependent variable. The results indicated that both degeneration and age were significant factors. Intervertebral disc classification was negatively associated with ADC values at every level of intervertebral discs (all p \ 0.05). Similarly, there was a negative correlation between age and ADC values at every level of intervertebral disc (all p \ 0.05); however, except for L3/4 disc, gender did not affect ADC values at other levels of intervertebral discs (all p [ 0.05).

Discussion We observed 545 intervertebral discs from 109 participants of different gender and age. ADC values by DWI and clinical grading of each IVD were acquired by MRI, and correlation analysis was completed between classification of discs and ADC values. Our results showed that disc degeneration was negatively correlated with ADC values at all spinal levels, ADC values in degenerating discs may vary according to the severity of degeneration, and disc degeneration had the strongest effect on ADC values at the L5/S1 level. Apparent diffusion coefficient values directly reflect the microenvironment of the diffusing water molecules, the main factors affecting the ADC value is tissue perfusion and extracellular water molecular motion [13]. There was decreased extracellular polysaccharide and

Eur Spine J Table 4 The output from multiple linear regression analysis

Predictor variables

Regression coefficients

Standardized regression coefficients

t value

p value

-72.368

-0.314

-3.243

0.002

-4.667

-0.266

-2.745

0.007

-36.606

-0.084

-0.999

0.320

L1/2 (ADC1) Disc degeneration Age Gender L2/3 (ADC2) -130.308

-0.357

-4.075

0.000

Age

Disc degeneration

-11.702

-0.378

-4.310

0.000

Gender

-14.844

-0.019

-0.257

0.797

-102.483

-0.231

-2.715

0.008

-15.578

-0.523

-6.132

0.000

-141.190

-0.192

-2.763

0.007

-160.436

-0.284

-3.146

0.002

-16.177 3.787

-0.445 0.004

-4.938 0.056

0.000 0.955

L3/4 (ADC3) Disc degeneration Age Gender L4/5 (ADC4) Disc degeneration Age Gender L5/S1 (ADC5) Disc degeneration

-234.729

-0.505

-6.154

0.000

Age

-6.091

-0.179

-2.192

0.031

Gender

106.075

0.126

1.630

0.106

water content in the early course of disc degeneration, the loss of water in the NP caused decreased ADC values [14]. Research suggests that decreased ADC values reflect the lost integrity of the intervertebral disc [15]. Apparent diffusion coefficient measurements at MR may provide a sensitive indicator of early degenerative changes in intervertebral discs. Moreover, our findings demonstrate that more cephalic discs (L1/2, L2/3, and L3/4) had higher ADC values than more caudal (L4/5 and L5/S1) discs. Kealey et al. [9] showed that the rate of IVD degeneration is highest at the L5/S1 motion segment, one of the reasons is secondary to the high magnitude of compressive forces seen at the lumbosacral junction [16]. Furthermore, anterior shear forces at the L5/S1 motion segment increase proportionally with increasing sacral angle [17]. Anterior and posterior disc postural loads, which are balanced at T8/T9, show the greatest difference at L5/S1 [17]. Therefore increased biomechanical stress on lower lumbar discs causes a greater loss of water from the disc and may reduce ADC values in lower discs. In addition, under higher pressure, IVD cells in the lower lumbar region regulate metabolism in various ways, resulting in increased production of proinflammatory cytokines such as interleukin-1 (IL-1) and secretion of matrix metalloproteinases (MMPs) and aggrecanases [18]. These enzymatically degrade the matrix, destroy hydrophilic glycosaminoglycans within the NP

(particularly aggrecan), and lead to the accumulation of cleaved matrix fragments such as fibronectin [19], which bind to cell surface receptors and further stimulate catabolic responses [20]. These biochemical changes result in decreased osmotic pressure and loss of water from the disc [21]. The increased compressive loads seen at L5/S1 may trigger a more robust increase in MMPs leading to an increased rate of IVD degradation. A gross anatomic and MRI study of IVD degeneration in fresh cadaveric lumbar spines showed the relatively early degeneration at L5/S1 in all races [16]. In addition, the associations between age and ADC values were also seen in the present study. Age is negatively associated with ADC value, and this relationship was observed at every spinal level. Interestingly, age has the greater influence at L3/4 and L4/5 levels. Human intervertebral discs undergo multifactorial biochemical and morphologic degenerative changes during the process of aging. Evidence has shown that the intervertebral disc is an avascular tissue element occupied by inadequately characterized cells in an extensive extracellular matrix. While the annulus fibrosus is predominantly collagenous, the matrix of the central NP is rich in proteoglycans. With aging, the substance of proteoglycans significantly decreases, which is believed to be a critical factor in intervertebral disc degeneration [22].

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There are many reports which correlate age with disc degeneration [23, 24]. Intervertebral disc degeneration is believed to begin as early as the second decade of life, and is seen by most as an inevitable consequence of aging [16]. Diminished blood supply to the intervertebral disc in the first half of the second decade appears to initiate tissue breakdown [23]. At present, the relationship between aging and degenerative processes of discs is unclear. Previous findings suggest that human NP cells are involved in repairing and replacing the diminishing extracellular matrix during age-related degeneration [25, 26]. An in vivo study showed that senescent NP chondrocytes increase or accumulate in the NP with increasing age and advancing disc degeneration [27]. Recent work has shown that porosity and permeability of the endplates increase with age and disc degeneration, which suggests that factors other than nutrition are probably more important [28, 29]. It is still uncertain whether gender is an independent risk factor for intervertebral disc degeneration. There is general agreement that young men are more susceptible to disc degeneration than young women, most likely due to increased mechanical stress and physical injury. Using data from 16 published reports, the authors correlated macroscopic disc degeneration grades with gender in 600 lumbar intervertebral discs from 273 cadavers. Male discs were more degenerated than female discs at most ages; significantly so in the second, fifth, sixth, and seventh decades of life [30]. However, this trend is reversed in elderly subjects, with women tending to have more severe lumbar disc degeneration than men. Estrogen deficiency likely contributes to the accelerated disc degeneration seen in postmenopausal women, through either a direct stimulating effect on disc cells or indirectly through an effect on vertebral marrow perfusion [26]. Nevertheless, in the present study, there was no significant difference in lumbar disc degeneration between male and female subjects, aged between 20 and 59 years, except at the L3/4 level. The reasons for this might to be due to fewer samples and a relatively high proportion of female subjects. The present study has some limitations. First, it is not population based. Second, it is limited to evaluating DWI by MRI; neither biochemical nor histologic assessment of IVDs was carried out. Finally, our study does not account for other possible determinants of disc degeneration, including physical loading specific to occupation and sport, body mass index, and so on.

Conclusion Our data suggest that both disc degeneration and age can influence ADC values. Apparent diffusion coefficient values were negatively correlated with the degrees of disc

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degeneration at all spinal levels; and ADC values of disc decreased with aging. In conclusion, this study shows that DWI may be an useful method for assessing changes in lumbar disc degeneration. Acknowledgments We thank Ph.D PengXue for analysis and interpretation of data (Department of Endocrinology, the Third Hospital of Hebei medical University, Shijiazhuang, Hebei 050051, China). Conflict of interest None of the authors has any conflicts of interest to declare.

References 1. An HS, Anderson PA, Haughton VM, Iatridis JC, Kang JD, Lotz JC et al (2004) Introduction: disc degeneration: summary. Spine (Phila Pa 1976) 29(23):2677–2678 2. Smith LJ, Kurmis AP, Slavotinek JP, Fazzalari NL (2011) In vitro evaluation of a manganese chloride phantom-based MRI technique for quantitative determination of lumbar intervertebral disc composition and condition. Eur Spine J 20(3):434–439 3. Kettler A, Wilke H (2006) Review of existing grading systems for cervical or lumbar disc and facet joint degeneration. Eur Spine J 15(6):705–718 4. Theilmann RJ, Borders R, Trouard TP, Xia G, Outwater E, Ranger-Moore J et al (2004) Changes in water mobility measured by diffusion MRI predict response of metastatic breast cancer to chemotherapy. Neoplasia 6(6):831–837 5. Ohgiya Y, Oka M, Hiwatashi A, Liu X, Kakimoto N, Westesson PA et al (2007) Diffusion tensor MR imaging of the cervical spinal cord in patients with multiple sclerosis. Eur Radiol 17(10):2499–2504 6. Khalil C, Hancart C, Le Thuc V, Chantelot C, Chechin D, Cotton A (2008) Diffusion tensor imaging and tractography of the median nerve in carpal tunnel syndrome: preliminary results. Eur Radiol 18(10):2283–2291 7. Antoniou J, Demers CN, Beaudoin G, Goswami T, Mwale F, Aebi M et al (2004) Apparent diffusion coefficient of intervertebral discs related to matrix composition and integrity. Magn Reson Imaging 22(7):963–972 8. Beattie PF, Morgan PS, Peters D (2008) Diffusion-weighted magnetic resonance imaging of normal and degenerative lumbar intervertebral discs: a new method to potentially quantify the physiologic effect of physical therapy intervention. J Orthop Sports Phys Ther 38(2):42–49 9. Kealey SM, Aho T, Delong D, Barboriak DP, Provenzale JM, Eastwood JD (2005) Assessment of apparent diffusion coefficient in normal and degenerated intervertebral lumbar disks: initial experience. Radiology 235(2):569–574 10. Niinima¨ki J, Korkiakoski A, Ojala O, Karppinen J, Ruohonen J, Haapea M et al (2009) Association between visual degeneration of intervertebral discs and the apparent diffusion coefficient. Magn Reson Imaging 27(5):641–647 11. Williams JR (2008) The Declaration of Helsinki and public health. Bull World Health Organ 86(8):650–652 12. Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N (2001) Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976) 26(17):1873–1878 13. Ichikawa T, Haradome H, Hachiya J, Nitatori T, Araki T (1999) Diffusion-weighted MR imaging with single-shot echo-planar imaging in the upper abdomen: preliminary clinical experience in 61 patients. Abdom Imaging 24(5):456–461

Eur Spine J 14. Urban JP, Winlove CP (2007) Pathophysiology of the intervertebral disc and the challenges for MRI. J Magn Reson Imaging 25(2):419–432 15. Kerttula L, Kurunlahti M, Jauhiainen J, Koivula A, Oikarinen J, Tervonen O (2001) Apparent diffusion coefficients and T2 relaxation time measurements to evaluate disc degeneration: a quantitative MR study of young patients with previous vertebral fracture. Acta Radiol 42(6):585–591 16. Siemionow K, An H, Masuda K, Andersson G, Cs-Szabo G (2011) The Effects of age, gender, ethnicity, and spinal level on the rate of intervertebral disc degeneration. A review of 1712 intervertebral discs. Spine (Phila Pa 1976) 36(17):1333–1339 17. Keller TS, Colloca CJ, Harrison DE, Harrison DD, Janik TJ (2005) Influence of spine morphology on intervertebral disc loads and stresses in asymptomatic adults: implications for the ideal spine. Spine J 5(3):297–309 18. Anderson DG, Tannoury C (2005) Molecular pathogenic factors in symptomatic disc degeneration. Spine J 5(6 Suppl):260S–266S 19. Roughley PJ (2004) Biology of intervertebral disc aging and degeneration: involvement of the extracellular matrix. Spine (Phila Pa 1976) 29(23):2691–2699 20. Feng H, Danfelter M, Stro¨mqvist B, Heinega˚rd D (2006) Extracellular matrix in disc degeneration. J Bone Joint Surg Am 88(Suppl 2):25–29 21. Roberts S, Evans H, Trivedi J, Menage J (2006) Histology and pathology of the human intervertebral disc. J Bone Joint Surg Am 88(Suppl 2):10–14 22. Podichetty VK (2007) The aging spine: the role of inflammatory mediators in intervertebral disc degeneration. Cell Mol Biol (Noisy-le-grand) 53(5):4–18

23. Boos N, Weissbach S, Rohrbach H, Weiler C, Spratt KF, Nerlich AG (2002) Classification of age-related changes in lumbar intervertebral discs: 2002 volvo award in basic science. Spine (Phila Pa 1976) 27(23):2631–2644 24. Antoniou J, Steffen T, Nelson F, Winterbottom N, Hollander AP, Poole RA et al (1996) The human lumbar intervertebral disc. Evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin Invest 98(4):996–1003 25. Takatalo J, Karppinen J, Niinima¨ki J, Taimela S, Mutanen P, Sequeiros RB et al (2012) Association of modic changes, Schmorl’s nodes, spondylolytic defects, high-intensity zone lesions, disc herniations, and radial tears with low back symptom severity among young Finnish adults. Spine 37(14):1231–1239 26. Wang YX, Griffith JF (2010) Effect of menopause on lumbar disc degeneration: potential etiology. Radiology 257(2):318–320 27. Kim KW, Chung HN, Ha KY, Lee JS, Kim YY (2009) Senescence mechanisms of nucleus pulposus chondrocytes in human intervertebral discs. Spine J 9(8):658–666 28. Rodriguez AG, Slichter CK, Acosta FL, Rodriguez-Soto AE, Burghardt AJ, Majumdar S et al (2011) Human disc nucleus properties and vertebral endplate permeability. Spine (Phila Pa 1976) 36(7):512–520 29. Rodriguez AG, Rodriguez-Soto AE, Burghardt AJ, Berven S, Majumdar S, Lotz JC (2012) Morphology of the human vertebral endplate. J Orthop Res 30(2):280–287 30. Miller JA, Schmatz C, Schultz AB (1988) Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens. Spine (Phila Pa 1976) 13(2):173–178

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