Diabetic Polyneuropathy Is Associated With Pathomorphological Changes in Human Dorsal Root Ganglia: A Study Using 3T MR Neurography

Abstract

Diabetic neuropathy (DPN) is one of the most severe and yet most poorly understood complications of diabetes mellitus. In vivo imaging of dorsal root ganglia (DRG), a key structure for the understanding of DPN, has been restricted to animal studies. These have shown a correlation of decreased DRG volume with neuropathic symptom severity. Our objective was to investigate correlations of DRG morphology and signal characteristics at 3 Tesla (3T) magnetic resonance neurography (MRN) with clinical and serological data in diabetic patients with and without DPN. In this cross-sectional study, participants underwent 3T MRN of both L5 DRG using an isotropic 3D T2-weighted, fat-suppressed sequence with subsequent segmentation of DRG volume and analysis of normalized signal properties. Overall, 55 diabetes patients (66 ± 9 years; 32 men; 30 with DPN) took part in this study. DRG volume was smaller in patients with severe DPN when compared to patients with mild or moderate DPN (134.7 ± 21.86 vs 170.1 ± 49.22; p = 0.040). In DPN patients, DRG volume was negatively correlated with the neuropathy disability score (r = −0.43; 95%CI = −0.66 to −0.14; p = 0.02), a measure of neuropathy severity. DRG volume showed negative correlations with triglycerides (r = −0.40; 95%CI = −0.57 to −0.19; p = 0.006), and LDL cholesterol (r = −0.33; 95%CI = −0.51 to −0.11; p = 0.04). There was a strong positive correlation of normalized MR signal intensity (SI) with the neuropathy symptom score in the subgroup of patients with painful DPN (r = 0.80; 95%CI = 0.46 to 0.93; p = 0.005). DRG SI was positively correlated with HbA1c levels (r = 0.30; 95%CI = 0.09 to 0.50; p = 0.03) and the triglyceride/HDL ratio (r = 0.40; 95%CI = 0.19 to 0.57; p = 0.007). In this first in vivo study, we found DRG morphological degeneration and signal increase in correlation with neuropathy severity. This elucidates the potential importance of MR-based DRG assessments in studying structural and functional changes in DPN.

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ORIGINAL RESEARCH
published: 25 September 2020
doi: 10.3389/fnins.2020.570744
Edited by:
Nico Sollmann,
University Hospital rechts der Isar,
Technical University of Munich,
Germany
Reviewed by:
Dimitrios C. Karampinos,
Technical University of Munich,
Germany
Theodoros Soldatos,
Iasis Diagnostic Center, Greece
Houchun H. Hu,
Hyperfine Research, Inc., United
States
*Correspondence:
Felix T. Kurz
felix.kurz@med.uni-heidelberg.de
Specialty section:
This article was submitted to
Brain Imaging Methods,
a section of the journal
Frontiers in Neuroscience
Received: 08 June 2020
Accepted: 24 August 2020
Published: 25 September 2020
Citation:
Jende JME, Kender Z, Rother C,
Alvarez-Ramos L, Groener JB,
Pham M, Morgenstern J,
Oikonomou D, Hahn A, Juerchott A,
Kollmer J, Heiland S, Kopf S,
Nawroth PP, Bendszus M and Kurz FT
(2020) Diabetic Polyneuropathy Is
Associated With Pathomorphological
Changes in Human Dorsal Root
Ganglia: A Study Using 3T MR
Neurography.
Front. Neurosci. 14:570744.
doi: 10.3389/fnins.2020.570744
Diabetic Polyneuropathy Is
Associated With Pathomorphological
Changes in Human Dorsal Root
Ganglia: A Study Using 3T MR
Neurography
Johann M. E. Jende1, Zoltan Kender2, Christian Rother1, Lucia Alvarez-Ramos2,
Jan B. Groener2,3,4 , Mirko Pham1,5, Jakob Morgenstern2, Dimitrios Oikonomou2,
Artur Hahn1, Alexander Juerchott1, Jennifer Kollmer1, Sabine Heiland1,6 , Stefan Kopf2,3,
Peter P. Nawroth2,3,7, Martin Bendszus1and Felix T. Kurz1*
1Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany, 2Department of Endocrinology,
Diabetology and Clinical Chemistry (Internal Medicine 1), Heidelberg University Hospital, Heidelberg, Germany, 3German
Center of Diabetes Research, München-Neuherberg, Germany, 4Medicover Neuroendokrinologie, Munich, Germany,
5Department of Neuroradiology, Würzburg University Hospital, Würzburg, Germany, 6Division of Experimental Radiology,
Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany, 7Joint Institute for Diabetes
and Cancer at Helmholtz-Zentrum Munich and Heidelberg University, Heidelberg, Germany
Diabetic neuropathy (DPN) is one of the most severe and yet most poorly understood
complications of diabetes mellitus. In vivo imaging of dorsal root ganglia (DRG), a
key structure for the understanding of DPN, has been restricted to animal studies.
These have shown a correlation of decreased DRG volume with neuropathic symptom
severity. Our objective was to investigate correlations of DRG morphology and signal
characteristics at 3 Tesla (3T) magnetic resonance neurography (MRN) with clinical
and serological data in diabetic patients with and without DPN. In this cross-sectional
study, participants underwent 3T MRN of both L5 DRG using an isotropic 3D T2-
weighted, fat-suppressed sequence with subsequent segmentation of DRG volume and
analysis of normalized signal properties. Overall, 55 diabetes patients (66 ±9 years; 32
men; 30 with DPN) took part in this study. DRG volume was smaller in patients with
severe DPN when compared to patients with mild or moderate DPN (134.7 ±21.86
vs 170.1 ±49.22; p= 0.040). In DPN patients, DRG volume was negatively correlated
with the neuropathy disability score (r=−0.43; 95%CI = −0.66 to −0.14; p= 0.02),
a measure of neuropathy severity. DRG volume showed negative correlations with
triglycerides (r=−0.40; 95%CI = −0.57 to −0.19; p= 0.006), and LDL cholesterol
(r=−0.33; 95%CI = −0.51 to −0.11; p= 0.04). There was a strong positive correlation
of normalized MR signal intensity (SI) with the neuropathy symptom score in the
subgroup of patients with painful DPN (r= 0.80; 95%CI = 0.46 to 0.93; p= 0.005).
DRG SI was positively correlated with HbA1c levels (r= 0.30; 95%CI = 0.09 to 0.50;
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Jende et al. DRG Pathomorphological Changes in DPN
p= 0.03) and the triglyceride/HDL ratio (r= 0.40; 95%CI = 0.19 to 0.57; p= 0.007). In
this first in vivo study, we found DRG morphological degeneration and signal increase
in correlation with neuropathy severity. This elucidates the potential importance of
MR-based DRG assessments in studying structural and functional changes in DPN.
Keywords: diabetic polyneuropathy, dorsal root ganglion, magnetic resonance neurography, neuropathic pain,
peripheral nervous system
INTRODUCTION
Distal symmetric diabetic polyneuropathy (DPN) is one of the
most frequent and most severe complications of diabetes mellitus
(Papanas and Ziegler, 2015;Nawroth et al., 2017). Although
several cellular mechanisms and clinical risk factors associated
with DPN have been described, the underlying pathophysiology
remains poorly understood (Feldman et al., 2017). One of the
major challenges for the investigation of structural changes in the
central and the peripheral nervous system in human DPN is that
tissue biopsies are mostly restricted to distal nerves like the sural
nerve or intradermal nerve fibers (Mohseni et al., 2017). Studies
that combine histological analyses of proximal structures like the
sciatic nerve or dorsal root ganglia with serological parameters
or behavioral traits therefore remain restricted to animal models
(Novak et al., 2015).
High resolution magnetic resonance neurography (MRN)
at 3 Tesla (3T), however, is a non-invasive technique that
allows the detection and quantification of structural nerve
lesions in patients at a fascicular level (Jende et al., 2018b,
2019a;Kurz et al., 2018). Recent MRN studies have found
that nerve damage in DPN predominates at a proximal level,
that proximal nerve lesions are reliably correlated with clinical
parameters and serological risk factors, and that structural
remodeling of sciatic nerve fascicles differs between painful
and painless DPN (Pham et al., 2011;Jende et al., 2018a,
2019a;Groener et al., 2019). The finding of a proximal
predominance of nerve lesions in DPN raises the question
whether dorsal root ganglia also show structural alterations in
DPN (Kobayashi and Zochodne, 2018).
Previous histological studies on the dorsal root ganglion
(DRG) of deceased diabetes patients have found morphological
changes like thickening of the perineural cell basement
membrane, indicating that structural changes in DPN are not
restricted to the distal peripheral nerves but also affect the DRG
(Johnson, 1983). In addition, it is known from animal studies in
streptozotocin (STZ) induced DPN that several metabolic and
immunologic processes in the DRG are of importance in painful
DPN and that a decrease in DRG volume is associated with
the severity of neuropathic symptoms (Sidenius and Jakobsen,
1980;Warzok et al., 1987;Novak et al., 2015;Sango et al., 2017;
Kobayashi and Zochodne, 2018). The aim of this study was to
investigate correlations between DRG size and normalized signal
Abbreviations: DPN, diabetic polyneuropathy; DRG, dorsal root ganglion; HDL,
high-density lipoprotein; LDL, low-density lipoprotein; MRI, magnetic resonance
imaging; MRN, magnetic resonance neurography; NDS, neuropathy disability
score; NSS, neuropathy symptom score; SI, normalized signal intensity; T, Tesla.
intensity (SI) in 3T MRN with clinical and serological data in
diabetes patients with and without DPN.
MATERIALS AND METHODS
Study Participants
This study was approved by the local ethics committee (HEIST-
DiC, local ethics number S-383/2016, clinicaltrials.gov identifier
NCT03022721). Participants with either type 1 diabetes or type
2 diabetes took part in this prospective, cross-sectional study
between September 2016 and June 2018. 120 diabetes patients
were approached, of whom 65 were excluded. The process of
patient selection is illustrated in Figure 1. Study participants
were recruited from the Outpatient Clinic of Internal Medicine
of our hospital. Participation in the study was voluntary and
all participants gave written informed consent. Overall exclusion
criteria were age <18, pregnancy, any contraindications for MRI,
any history of lumbar surgery or disc protrusion, any other
risk factors for polyneuropathy such as alcoholism, malignant or
infectious diseases, hypovitaminosis, monoclonal gammopathy,
any previous or ongoing exposure to neurotoxic agents, any
chronic neurological diseases such as Parkinson’s disease, restless
legs syndrome, or multiple sclerosis.
Clinical Examination
A detailed medical history was documented and an assessment
of neuropathic symptoms was performed in every participant
using the neuropathy disability score (NDS) and the neuropathy
symptom score (NSS) (Young et al., 1993). In accordance with
the guidelines issued by the German Society for Diabetology, the
presence of DPN was determined by a score of ≥4 in NDS or NSS.
Polyneuropathy was defined as mild to moderate with an NSS <7
or an NDS ≤8 and as severe with an NSS ≥7 and an NDS >8. If
a discrepancy between NDS and NSS was found, the higher score
was chosen (Haslbeck et al., 2004).
Sensory symptoms were derived from the NSS questionnaire.
While there are many numerical scales to score pain in DPN,
(Shillo et al., 2019) we chose a binary definition for painful
and painless DPN depending on whether participants with DPN
either experienced painful symptoms for more than 3 months,
or not. Painful symptoms were burning, lancinating, or any
other painful sensations that could not be explained by other
causes than DPN. If participants presented with a combination
of painful and painless symptoms (e.g., burning and numbness),
DPN was defined as painful.
Blood was drawn in fasting state and proceeded immediately
under standardized conditions in the Central Laboratory of
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FIGURE 1 | Process of patient recruitment and data acquisition.
our university hospital. The estimated glomerular filtration rate
was calculated with the chronic kidney disease epidemiology
collaboration formula (Levey et al., 2009).
MR Neurography Protocol
All participants underwent high-resolution MR neurography
of the lumbosacral plexus in a 3T MRI scanner (TIM TRIO,
SIEMENS, Erlangen, Germany). The following coils were used:
a 32-channel spine coil (Spine 32 3T TIM Coil, SIEMENS
Healthineers, Erlangen, Germany) and a 18-channel flex coil
(Body 18 3T TIM Coil SIEMENS Healthineers, Erlangen,
Germany). MR images were then acquired using a T2−weighted
(T2w), three−dimensional inversion recovery sequence with
sampling perfection with application−optimized contrasts using
different flip angle evolution with the following parameters: field
of view = 305 mm ×305 mm, voxel size = 0.95 mm ×0.95 mm
×0.95 mm, variable flip angle variation with (pseudo) steady-
state flip angle = 120◦, receiver bandwidth = 504 Hz/pixel,
repetition time = 3000 ms, echo time = 202 ms, inversion
time = 210 ms, echo train length = 209, echo spacing = 14.35 ms,
number of signal averages = 2; no parallel imaging, matrix
size = 320 ×320 ×104, native acquisition plane: coronal,
and acquisition time 8:32 min. Since several studies on DPN in
animal models have investigated the L5 DRG and since previous
studies on DRG imaging in humans have come to show that
L5 DRG are the largest of the lumbar DRG, the sequence was
centered to the intervertebral space of L5/S1 (Wattig et al., 1987;
Silverstein et al., 2015).
Image Post-processing
With 55 participants examined and 104 slices per participant,
a total number of 5720 images were acquired. All images were
pseudonymized. Images were analyzed in a semi-automatic
approach using ImageJ (Rha et al., 2015) and custom-written
code in Matlab v7.14.0.0739 (R2012a, Mathworks, Natwick,
United States). Anatomical segmentation of both left and right
L5 dorsal root ganglion was performed manually for each
participant on coronal reformatted images angulated to the
intervertebral space between L5 and S1. All images that contained
L5 DRG were used for segmentation for each participant.
Segmentation was performed manually by two radiologists (JJ
and FK) with 5 and 7 years of experience in neuroradiology,
respectively, blinded to all clinical data. This produced stacks
of binarized images with values 1 for voxels that contained
DRG and values 0 for voxels that did not. We used coronal
reformats for segmentation since DRG resemble ellipsoids whose
main axes form a smaller angle with the normal vector on
axial planes than with the normal vector on coronal planes,
see e.g., (Hasegawa et al., 1996) that found an angulation of
approximately 28 degrees versus the normal vector on axial
planes for L5 DRG. DRG voxels at the periphery of each DRG
cross-section on every considered plane only contain a part of
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the respective DRG, thus producing a segmentation error that
is proportional to the DRG circumference divided by the DRG
area, and which is smaller for segmentation on coronal versus
axial reformats due to the typical angulation of L5 DRG and
the increased eccentricity of the ellipse-like cross-sections on
coronal reformats. The resulting binarized image stacks of L5
DRG were analyzed in Matlab to obtain total DRG volume as the
sum of all voxel volumes of both ganglia, respectively. DRG signal
intensity values were first standardized to a distribution of signal
intensity values of a representative artifact-free adjacent muscle
tissue VOI with no discernible crossing vessels by subtracting
each DRG signal intensity value with the mean value of the
muscle VOI signal intensity distribution and dividing the result
with the standard deviation of the muscle VOI signal intensity
distribution. The resulting standardized signal intensity values
were then normalized by dividing each value with the maximum
of the standardized DRG signal intensity values among all
participants to obtain units between 0 and 1. An illustration
of DRG segmentation and three-dimensional reconstruction of
nerve lesions is given in Figure 2.
Statistical Analysis
Statistical data analysis was performed with GraphPad Prism 6.
All data were tested for Gaussian normal distribution using
the D’Agostino-Pearson omnibus normality test. If a Gaussian
normal distribution was given, t-tests were used for comparisons
of two groups. If data were not Gaussian distributed, the
Mann-Whitney rank sum test was used for comparisons of two
groups. Non-parametric Spearman correlation was applied for
correlation analysis. All correlations were controlled for age as a
potential confounder using partial correlation analysis adjusted
for age. For all tests, the level of significance was defined at
p<0.05. All results are presented as mean values ±standard
deviation (SD). The inter-rater agreement in DRG volume
segmentation was determined with the intra-class correlation
coefficient (ICC) with the specific model ICC (A,1; McGraw
and Wong, 1996). ICC scores below 0.4 are considered as poor
agreement, 0.4–0.6 as reasonable agreement, 0.6–0.7 as good
agreement, and 0.7–1 as excellent agreement (Bartko, 1991).
RESULTS
Demographic and Clinical Data
Overall, 55 participants (mean age 66 ±9 years, 32 men)
with either DPN (n= 30) or no DPN (n= 25) took part
in this study. Six patients were active smokers, whereas 49
patients did not smoke. Of the 30 DPN patients, 19 had mild
to moderate symptoms, whereas 11 suffered from severe DPN.
Over all participants, NSS and NDS scores were both positively
correlated with age (r= 0.31; 95%CI = 0.04 to 0.54; p= 0.02
and r= 0.31; 95%CI = 0.04 to 0.54; p= 0.02, respectively). All
subsequent correlation analyses were therefore controlled for age
as a potential confounder. Of all acquired serological parameters,
triglycerides and the triglyceride/HDL index were the only
parameters associated with the NDS (r= 0.45; 95%CI = 0.25 to
0.62; p= 0.001 and r= 0.44, 95%CI = 0.24 to 0.61; p= 0.003,
respectively) and the NSS (r= 0.30; 95%CI = 0.08 to 0.49; p= 0.04
and r= 0.34; 95%CI = 0.12 to 0.52; p= 0.03). Triglycerides
were higher in DPN patients compared to patients without DPN
(236.5 mg/dl ±248 vs 114.4 mg/dl ±62.8; p= 0.02), whereas
the triglycerides/HDL ratio was not (4.95 ±5.60 vs 2.41 ±2.16;
p= 0.27). An overview of clinical, demographic and serological
data of study participants is given in Table 1.
MRN Imaging Data
L5 DRG Volume
The ICC for DRG volume segmentation was determined as 0.88.
DRG volume was negatively associated with NDS (r=−0.43;
FIGURE 2 | Human dorsal root ganglia (DRG) segmentation. (A) Left and right L5 dorsal root ganglion on a T2–weighted, three–dimensional inversion recovery
sequence with sampling perfection with application–optimized contrasts using different flip angle evolution. (B) Stacks of binarized masks of the left and right L5
dorsal root ganglion. (C) Three-dimensional reconstruction of DRG volume.
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TABLE 1 | Demographic, MRN, and serologic data in patients with and without diabetic neuropathy.
Parameter DPN (n= 30) No DPN (n= 25) P-Value
Women 9 14 n.a.
Men 21 11 n.a.
Type 1 diabetes 8 11 n.a.
Type 2 diabetes 22 14 n.a.
Mean Age (years) 68.38 ±7.53 (n= 31) 59.24 ±10.08 (n= 24) 0.02M
Disease duration (years) 24.38 ±13.56 (n= 31) 26.75 ±13.98 (n= 24) 0.53T
Body mass index (kg/m2) 28.59 ±4.81 (n= 31) 28.09 ±4.66 (n= 24) 0.70T
DRG volume (mm3) 158.3 ±44.99 150.2 ±35.56 0.47M
DRG normalized signal intensity 0.524 ±0.066 0.519 ±0.114 0.55M
HbA1c (mmol/mol) (%) 59 ±15 59 ±10 0.54M
7.55 ±1.38 (n= 31) 7.58 ±0.98 (n= 24)
Creatinine (mg/dl) 0.93 ±0.24 (n= 31) 0.89 ±0.36 (n= 23) 0.26T
Glomerular filtration rate (ml/min) 80.69 ±21.65 (n= 29) 80 ±23.88 (n= 24) 0.91T
Total cholesterol (mg/dl) 177.60 ±42.62 (n= 29) 176.8 ±32.86 (n= 22) 0.94T
LDL cholesterol (mg/dl) 89.51 ±27.73 (n= 28) 96.14 ±30.75 (n= 21) 0.46T
HDL cholesterol (mg/dl) 54.65 ±20.82 (n= 27) 57.71 ±16.55 (n= 23) 0.59T
Triglycerides (mg/dl) 236.50 ±248.00 (n= 27) 114.4 ±62.80; (n= 22) 0.02M
Triglycerides/HDL ratio 4.95 ±5.60 2.41 ±2.16 0.27M
All values are shown as mean ±standard deviation. M= p-value obtained from a Mann-Whitney test. T= p-value obtained from T-test. n.a., not applicable; HbA1c,
glycated hemoglobin; LDL, low density lipoprotein; HDL, high density lipoprotein.
95%CI = −0.66 to −0.14; p= 0.02, Figures 3A–C) in patients with
DPN, but not in patients without DPN (r= 0.17; 95%CI = −0.26
to 0.54; p= 0.43). No correlation was found between DRG volume
and the NSS score. In patients without DPN, the only correlation
found was between DRG volume and triglycerides (r=−0.49;
95%CI = −0.76 to −0.08; p= 0.020). No further correlations were
found in this group. Although no difference was found between
DRG volume in patients with and without DPN (158.3 ±44.99
vs 150.2 ±35.56; p= 0.47), DRG volume was smaller in patients
with severe DPN when compared to mild or moderate DPN
(134.7 mm3±21.86 vs 170.1 mm3±49.22; p= 0.04). Patients
who were smoking showed smaller DRG volumes than non-
smokers (114.0mm3±14.36 vs 158.7 mm3±40.41; p= 0.02).
There was no difference in DRG size between painful and painless
DPN (149.5 ±30.02 vs 156.1 ±43.54; p= 0.80). Over all
participants, L5 DRG volume showed negative correlations with
triglycerides (r=−0.40; 95%CI = −0.57 to −0.19; p= 0.006), and
LDL cholesterol (r=−0.33; 95%CI = −0.51 to −0.11; p= 0.04).
No such correlation was found for disease duration (r=−0.12;
95%CI = −0.34 to 0.10; p= 0.38), body mass index (r= 0.05;
95%CI = −0.17 to 0.27; p= 0.72), or HbA1c levels (r=−0.17;
95%CI = −0.38 to 0. 06; p= 0.23).
L5 DRG T2-Weighted Normalized Signal Intensity
There was a strong positive correlation of the SI with NSS
(r= 0.80; 95%CI = 0.46 to 0.93; p= 0.005, Figures 3D–F)
and a moderate correlation between SI and NDS (r= 0.66;
95%CI = 0.21 to 0.88; p= 0.04) in patients with painful DPN.
No such correlations were found in patients with non-painful
DPN (r=−0.11; 95%CI = −0.49 to 0.28; p= 0.65) or no DPN
(r=−0.14; 95%CI = −0.52 to 0.29; p= 0.50). Over all participants,
L5 DRG T2w SI was positively correlated with HbA1c levels
(r= 0.30; 95%CI = 0.09 to 0.50; p= 0.03), triglycerides (r= 0.37;
95%CI = 0.16 to 0.55; p= 0.01), and the triglycerides/HDL
ratio (r= 0.40; 95%CI = 0.19 to 0.57; p= 0.007). A negative
correlation was found between SI and serum HDL (r=−0.35;
95%CI = −0.53 to −0.35; p= 0.02). No significant correlations
were found between disease duration (r=−0.08; 95%CI = −0.30
to 0.15; p= 0.58), or body mass index (r= 0.23; 95%CI = −0.01 to
0.44; p= 0.10). No significant difference was found for SI between
patients with and without DPN (0.52 ±0.07 vs 0.52 ±0.11;
p= 0.55), between DPN patients with mild or moderate DPN
and severe DPN (0.52 ±0.06 vs 0.53 ±0.08; p= 0.85), or
between patients with painful and painless DPN (0.52 ±0.10 vs
0.52 ±0.05; p= 0.77). An overview of all correlations of DRG
imaging parameters with demographic, clinical and serological
data is given in in Tables 1–3.
DISCUSSION
To our knowledge, this MRN pilot study on the L5 DRG in
DPN is the first to objectify in vivo signs of DRG morphological
degeneration in DPN and to investigate whether MR signal
alterations of the DRG are correlated with the severity of painful
symptoms in DPN. We found that DRG volume was significantly
smaller in patients with severe DPN when compared to patients
with mild or moderate DPN and, accordingly, that there is a
moderate negative correlation between DRG volume and NDS
in DPN. We further found a strong positive correlation between
DRG SI and NSS in painful DPN. In the context of previous
histological studies on DRG in rodent models of DPN, our
results indicate that a progression in functional loss in both
sensory and motor qualities codified by higher NDS scores is
associated with DRG atrophy (Kobayashi and Zochodne, 2018).
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FIGURE 3 | L5 dorsal root ganglion (DRG) volume and normalized signal intensity (SI) versus neuropathy disability score (NDS) and neuropathy symptom score
(NSS). (A) Correlation of NDS and L5 DRG volume in patients with diabetic polyneuropathy [DPN; (r= –0.43; 95%CI = –0.66 to –0.14; p= 0.02)]. (B) DRG volumetry
of a patient with a total L5 DRG volume of 277 mm3.(C) DRG volumetry of a patient with a total L5 DRG volume of 94 mm3.(D) Correlation of L5 DRG SI and NSS
in painful DPN (r= 0.80; 95%CI = 0.46 to 0.93; p= 0.005). (E) L5 DRG SI in a patient with severe painful DPN (SI = 0.61 ±0.094). (F) L5 DRG SI in a patient with
mild painful DPN (SI = 0.45 ±0.054).
TABLE 2 | Correlation of dorsal root ganglia volume and normalized signal intensity with clinical parameters.
L5 dorsal root ganglia volume L5 dorsal root ganglia normalized
in mm3(n= 55) signal intensity (n= 55)
r95%CI p R 95%CI p
L5 dorsal root ganglia volume (mm3) n.a. n.a. n.a. 0.12 −0.16 to 0.38 0.39
L5 dorsal root ganglia normalized signal intensity 0.12 −0.16 to 0.38 0.39 n.a. n.a. n.a.
NDS (n= 55) <0.01 −0.22 to 0.22 0.99 0.13 −0.10 to 0.34 0.36
NDS DPN (n= 30) −0.43 −0.66 to −0.14 0.02 0.03 −0.28 to 0.34 0.88
NSS (n= 55) 0.02 −0.20 to 0.25 0.87 0.10 −0.12 to 0.32 0.46
NSS DPN (n= 30) −0.06 −0.37 to 0.25 0.74 0.22 −0.10 to 0.49 0.28
NSS painful DPN (n= 11) 0.33 −0.24 to 0.72 0.36 0.80 0.46 to 0.93 0.005
NSS painless DPN (n= 19) −0.11 −0.49 to 0.28 0.65 −0.09 −0.47 to 0.30 0.71
NDS painful DPN (n= 11) −0.05 −0.56 to 0.49 0.90 0.66 0.21 to 0.88 0.04
NDS painless DPN (n= 19) −0.41 −0.69 to −0.01 0.11 −0.11 −0.49 to 0.28 0.64
All correlation coefficients are calculated as Spearman coefficients, corrected for age. 95%CI = 95% confidence interval; n.a. = not applicable. NSS = neuropathy symptom
score; NDS = neuropathy disability score.
The structural equivalent for the DRG normalized signal intensity
that increases with symptom severity in painful DPN remains
to be determined.
The fact that no correlation was found between DRG volume
and SI among study participants indicates that changes in DRG
SI are not necessarily accompanied by changes in DRG volume
and vice versa. This suggests that both parameters are needed to
adequately describe DRG changes in T2D DPN with respect to
DRG function and clinical DPN severity, thus being two potential
indicators for DPN progression.
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TABLE 3 | Correlation of dorsal root ganglia volume and normalized signal intensity with demographic and serologic data.
L5 dorsal root ganglia volume L5 dorsal root ganglia normalized
in mm3(n= 55) signal intensity (n= 55)
r95%CI p R 95%CI p
BMI (kg/m2;n= 55) 0.05 −0.17 to 0.27 0.72 0.23 0.01 to 0.44 0.10
Disease duration (years; n= 55) −0.12 −0.34 to 0.10 0.38 −0.08 −0.30 to 0.15 0.58
Creatinine (mg/dl; n= 54) 0.06 −0.16 to 0.28 0.66 0.21 −0.01 to 0.42 0.14
Glomerular filtration rate (ml/min; n= 53) 0.13 −0.09 to 0.35 0.35 −0.05 −0.27 to 0.18 0.73
Total serum cholesterol (mg/dl; n= 51) −0.25 −0.45 to −0.03 0.08 0.03 −0.19 to 0.25 0.83
LDL (mg/dl; n= 49) −0.33 −0.51 to −0.11 0.04 0.02 −0.20 to 0.25 0.89
HDL (mg/dl; n= 50) 0.04 −0.19 to 0.26 0.81 −0.35 −0.53 to -0.35 0.02
Triglycerides (mg/dl; n= 49) −0.40 −0.57 to −0.19 0.006 0.37 0.16 to 0.55 0.01
Triglycerides/HDL ratio −0.26 −0.46 to −0.04 0.08 0.40 0.19 to 0.57 0.007
HbA1c (mmol/mol; n= 55) −0.17 −0.38 to 0.06 0.23 0.30 0.09 to 0.50 0.03
All correlation coefficients are calculated as Spearman coefficients, corrected for age. 95%CI = 95% confidence interval; n.a. = not applicable. BMI = body mass index;
LDL = low density lipoprotein; HDL = high density lipoprotein; HbA1c = glycated hemoglobin.
With regard to serologic parameters, in our cohort,
triglycerides were higher in DPN patients when compared
to non-DPN patients and showed moderate positive correlations
with both NDS scores and DRG SI, while there was a moderate
negative correlation with DRG volume. The latter finding may
indicate that higher levels of triglycerides are associated with
DRG atrophy represented by DRG volume reduction. As the
DRG consists of an inner layer comprised of nerve fibers and
an outer layer containing the cell bodies of pseudo-unipolar
sensory neurons and an adjacent capillary network, it remains to
be determined whether a reduction in DRG size in severe DPN
is the consequence of damage to one of the two layers or both
layers (Sasaki et al., 1997). Since DRG volume was smaller in
smokers when compared to non-smokers, and since it is known
that smoking causes microvascular damage, it seems likely that
damage to the DRG microcirculation is a contributing factor to
DRG atrophy in DPN (Tesfaye et al., 2005;Clair et al., 2015).
This hypothesis is further supported by the finding of a positive
correlation between L5 DRG SI and triglycerides/HDL ratio,
since an increase in the latter has been reported to be associated
with microvascular pathology (Ain et al., 2019). The correlation
of serum triglycerides with both clinical symptom severity and
reduced DRG volume is in line with data from clinical studies
that have found elevated triglycerides to be a risk factor for
nerve damage and increased severity of neuropathic symptoms
in DPN. (Tesfaye et al., 2005;Jaiswal et al., 2017). The finding,
that both triglycerides and HbA1c levels are associated with
an increase in DRG SI, further is in line with findings from a
previous MRN study on sciatic nerve lesions in DPN that found
T2w-hyperintense nerve lesions to be associated with elevated
triglycerides and HbA1c levels (Jende et al., 2019a).
The negative correlation of the DRG volume with triglycerides
and the negative correlation of DRG SI with HDL levels are
further in line with results from previous MRN studies on
the impact of cholesterol levels on sciatic nerve damage in
DPN (Andersen et al., 2018;Jende et al., 2019b). The negative
correlation between LDL cholesterol and DRG volume, however,
contradicts the previous finding that lower LDL cholesterol is
associated with sciatic nerve damage in DPN (Jende et al., 2019b).
One possible explanation for this discrepancy might be that
LDL is required to supply cholesterol to Schwann cells and
neurite tips for remyelination after damage to peripheral nerves
in DPN, while DRG neurons do not require an equal amount of
cholesterol but, instead, as a well vascularized structure, are prone
to damage caused by microangiopathy, for which elevated LDL
is a risk factor (de Chaves et al., 1997;Vance et al., 2000;Saher
et al., 2011;Toth et al., 2012). This assumption, however, remains
hypothetical and needs to be investigated by larger longitudinal
studies. With regard to the correlation of serum triglycerides
with DPN severity and both DRG volume and SI one may argue
that triglycerides are elevated in patients with reduced renal
function or renal failure and that, accordingly, the correlations
found could just be epiphenomena of a reduced renal function in
our cohort (Zhang et al., 2019). One has to consider, however,
that there was no correlation between GFR or creatinine and
triglycerides in our cohort. Still, our data do not allow proving a
causal relationship between triglycerides and DRG volume or SI.
Our study is limited by the fact that no electrophysiological
recordings were performed on the participants in order to further
elucidate the impact of the DRG volume and SI on peripheral
nerve function. It is unlikely, however, that changes to an
anatomical structure located so far proximally will contribute
to detectable and directly attributable changes to peripheral
nerves especially at early stages of the disease. Furthermore,
nerve conduction studies are limited in localizing disturbances
of conduction or sensory action potentials with high spatial
accuracy so that point localization to the DRG structure itself
remains problematic. Another limitation is that the acquired T2w
signal intensity is a non-quantitative parameter that is prone to
various potential confounders that can differ between different
MRI scanners. One must consider, however, that all images
used in this study were acquired at the same scanner and that
DRG signal intensity was normalized to adjacent muscle tissue,
which should make the results reproducible. In future studies,
quantitative T2 imaging of DRG and the assessment of other
quantitative MRN imaging parameters such as proton density
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Jende et al. DRG Pathomorphological Changes in DPN
and fractional anisotropy, that have been shown to be accurate
markers of structural peripheral nerve integrity for different
neuropathies, should be investigated (Godel et al., 2016;Kollmer
et al., 2018;Jende et al., 2019b, 2020;Sollmann et al., 2019;
Sato et al., 2020).
The aim of this pilot study was to investigate whether there was
a correlation between DRG volume and normalized MR signal
intensity of a typical plexus MR sequence, DPN severity and
serological risk factors for DPN. We therefore chose the validated
scores of NSS and NDS for the assessment of DPN severity.
Although all of the risk factors correlated with DRG volume or SI
have been shown to be risk factors for the development of DPN
in longitudinal clinical studies, (Jaiswal et al., 2017;Andersen
et al., 2018) our study does not allow for definite conclusions
on a causal relation between serological risk factors and DRG
parameters, due to its cross-sectional nature. It should also be
considered that the primary aim of this study was to elucidate the
use and feasibility of DRG imaging in DPN with regards to DPN
severity and serological parameters.
In summary, this study is the first study to image and quantify
the DRG in patients with DPN and the first in vivo DRG imaging
study that found correlations with both clinical parameters of
DPN severity and serological data. The study’s findings suggest
that DRG volume reduction in DPN is associated with higher
levels of triglycerides and that DRG SI, which is associated with
symptom severity in painful DPN, is increased by hyperglycemia,
and a higher triglyceride/HDL ratio. These results parallel those
from peripheral nerve imaging in DPN. Further longitudinal
studies are required to investigate the impact of DRG volume and
SI on the course of neuropathic symptoms in DPN and to further
elucidate the underlying pathophysiological processes.
DATA AVAILABILITY STATEMENT
The data supporting the conclusions of this article will be made
available upon reasonable request by any qualified researcher.
ETHICS STATEMENT
The studies involving human participants were reviewed and
approved by Heidelberg University Hospital Ethics Committee.
The patients/participants provided their written informed
consent to participate in this study.
AUTHOR CONTRIBUTIONS
JJ, MP, MB, SH, PN, and FK designed and coordinated the study.
JJ, DO, JG, JK, AJ, and FK contributed to the organization of
the participants. JJ, CR, MP, AJ, and FK collected the MR data.
AH and FK developed image analysis tools. ZK, LA-R, JG, DO,
and SK collected clinical, serological and electrophysiological the
data. JJ and FK analyzed the data and wrote the manuscript with
input from all co-authors. All authors contributed to the article
and approved the submitted version.
FUNDING
MB received grants from the Dietmar Hopp foundation, the
European Union and the German Research Council (DFG, SFB
1118, and 1158). The German research council (DFG, SFB
1158) provided financial support for personnel expenditure, MR
imaging costs and costs for the technical equipment required for
electrophysiological and serological analysis. The DFG had no
influence on the study design, collection and analysis of data or
on the writing of the article. FK was supported by the German
Research Foundation (KU 3555/1-1) and the Hoffmann-Klose
foundation of Heidelberg University Hospital. JJ was supported
by the International Foundation for Research in Paraplegia
which provided financial support for the development of image
analysis tools.
ACKNOWLEDGMENTS
We thank Mrs. Johanna Kreck (Department of Neuroradiology,
Heidelberg University Hospital) for her ongoing support and
excellent technical performance of all MRN examinations. This
study was supported by the German Research Council (SFB 1158
and 1118) and by the International Foundation for Research in
Paraplegia (IRP).
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Conflict of Interest: MB received grants and personal fees from Codman, Guerbet,
Bayer, and Novartis, personal fees from Roche, Teva, Springer, Boehringer, and
grants from Siemens. JG was employed by company Medicover GmbH.
The remaining authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential
conflict of interest.
Copyright © 2020 Jende, Kender, Rother, Alvarez-Ramos, Groener, Pham,
Morgenstern, Oikonomou, Hahn, Juerchott, Kollmer, Heiland, Kopf, Nawroth,
Bendszus and Kurz. This is an open-access article distributed under the terms
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