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Retina  |   June 2023
The Retinal Nerve Fiber Layer Thickness Is Associated with Systemic Neurodegeneration in Long-Term Type 1 Diabetes
Author Affiliations & Notes
  • Christina Brock
    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
    Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
    Steno Diabetes Center North Denmark, Aalborg, Denmark
  • Anne-Marie Wegeberg
    Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
    Thisted Research Unit, Aalborg University Hospital Thisted, Thisted, Denmark
  • Thomas Arendt Nielsen
    Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
    Department of Ophthalmology, Aalborg University Hospital, Aalborg, Denmark
  • Bassam Karout
    Milltons Consulting Ltd, Cambridge, UK
  • Per M. Hellström
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  • Asbjørn Mohr Drewes
    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
    Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
    Steno Diabetes Center North Denmark, Aalborg, Denmark
  • Henrik Vorum
    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
    Department of Ophthalmology, Aalborg University Hospital, Aalborg, Denmark
  • Correspondence: Henrik Vorum, Department of Ophthalmology, Aalborg University Hospital, Aalborg, Denmark and Department of Clinical Medicine, Aalborg University, Hobrovej 18-22, 9000 Aalborg, Aalborg, Denmark. e-mail: henrik.vorum@rn.dk 
Translational Vision Science & Technology June 2023, Vol.12, 23. doi:https://doi.org/10.1167/tvst.12.6.23
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      Christina Brock, Anne-Marie Wegeberg, Thomas Arendt Nielsen, Bassam Karout, Per M. Hellström, Asbjørn Mohr Drewes, Henrik Vorum; The Retinal Nerve Fiber Layer Thickness Is Associated with Systemic Neurodegeneration in Long-Term Type 1 Diabetes. Trans. Vis. Sci. Tech. 2023;12(6):23. https://doi.org/10.1167/tvst.12.6.23.

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Abstract

Purpose: To determine whether the retinal nerve fiber layer thickness can be used as an indicator for systemic neurodegeneration in diabetes.

Methods: We used existing data from 38 adults with type 1 diabetes and established polyneuropathy. Retinal nerve fiber layer thickness values of four scanned quadrants (superior, inferior, temporal, and nasal) and the central foveal thickness were extracted directly from optical coherence tomography. Nerve conduction velocities were recorded using standardized neurophysiologic testing of the tibial and peroneal motor nerves and the radial and median sensory nerves, 24-hour electrocardiographic recordings were used to retrieve time- and frequency-derived measures of heart rate variability, and a pain catastrophizing scale was used to assess cognitive distortion.

Results: When adjusted for hemoglobin A1c, the regional thickness of the retinal nerve fiber layers was (1) positively associated with peripheral nerve conduction velocities of the sensory and motor nerves (all P < 0.036), (2) negatively associated with time and frequency domains of heart rate variability (all P < 0.033), and (3) negatively associated to catastrophic thinking (all P < 0.038).

Conclusions: Thickness of the retinal nerve fiber layer was a robust indicator for clinically meaningful measures of peripheral and autonomic neuropathy and even for cognitive comorbidity.

Translational Relevance: The findings indicate that the thickness of the retinal nerve fiber layer should be studied in adolescents and people with prediabetes to determine whether it is useful to predict the presence and severity of systemic neurodegeneration.

Introduction
People with diabetes differ strikingly in their susceptibility to microvascular complications, despite similar disease duration and glycemic control. Diabetic neuropathy is the most common and burdensome microvascular complication, leading to systemic neurodegeneration through progressive loss of neuronal structures and function.1,2 The underlying pathophysiology is insufficiently understood but includes compromised blood flow, inflammatory processes, and oxidative stress. Other disease processes, including mitochondrial dysfunction, metabolic syndrome, and dyslipidemia, have also been suggested.35 
Classical signs of diabetic peripheral neuropathy include sensory abnormalities of nerve fibers, evident as pain or dysesthesia, or of the large nerve fibers, causing numbness and loss of protective sensation.68 The clinical suspicions are verified by pinprick testing temperature and vibration thresholds, and the final diagnosis needs abnormal nerve conduction velocities that are unpleasant and time-consuming.6,9 
Neurodegeneration of the autonomic nervous system causes disturbances in the neuro-signaling of the organ–brain nexus, responsible for upholding homeostasis.10,11 Dysautonomia reveals many symptoms (e.g., difficulty in tight glucose control,12 gastroenteropathy,1315 urogenital challenges,16,17 orthostatic hypotension,18 and cardiac arrhythmias, myocardial infarction, and sudden death19,20). The concluding diagnosis needs abnormal cardiovascular autonomic reflex testing6,11 or decreased heart rate variability.6,21 However, both are demanding methods that are not clinically applicable on a larger scale. 
Degenerative processes in the central nervous system are also present but need typically advanced imaging techniques to reveal. However, studies have shown that diabetes leads to altered structure,22,23 function,24 and miscommunication between brain centers.25 In addition, such structural alterations are associated with diabetes-related cognitive decline.26 As such, negative cognitive distortion can be reflected in catastrophic thinking. 
Newer studies consider the optic nerve and the retina as protrusions from the central nervous system. Detailed assessments of the optic nerve, the retinal thickness, and the retinal nerve fiber layer (RNFL) can be obtained by noninvasive, cheap, and easily operated optical coherence tomography (OCT) scans.27 The thickness of the RNFL has been suggested as a prognostic marker in systemic neuroinflammatory and neurodegenerative diseases28 (e.g., Parkinson disease,29 amyotrophic lateral sclerosis, multiple sclerosis,30 and Alzheimer disease28,31). Furthermore, in diabetes, the thickness of the RNFL is diminished in children and adolescents before the development of retinopathy32 and in adults without retinopathy.33 Finally, a large meta-analysis showed that the thickness of the RNFL was decreased in people with diabetes and diabetic polyneuropathy in comparison to those without polyneuropathy,34 making the measure a potential prognostic indicator. 
We hypothesize that the thickness of the RNFL reflects systemic neurodegeneration and thus is associated with measures of peripheral neuropathy, autonomic dysfunction, and negative cognitive distortion. Consequently, our study aimed to investigate associations between the thickness of the RNFL and (1) sensory and motor nerve conduction velocities, (2) measures of heart rate variability, and (3) level of catastrophic thinking. 
Methods
Cohort
To test whether the RNFL thickness was associated with systemic neurodegeneration, we used existing data (EUDRA CT: 2013-004375-12, Ethics Ref: N-20130077)35 on 38 adults with type 1 diabetes and confirmed distal symmetric polyneuropathy based on Toronto criteria6 who had a complete OCT scan. Inclusion criteria were stable antidiabetic treatment for at least 3 months before enrollment, age 18 to 65 years, and body mass index >22 kg/m2. Exclusion criteria were type 2 diabetes, glycosylated hemoglobin (HbA1c) level <7% (48 mmol/mol), decreased kidney function estimated glomerular filtration rate <60 mL/min/1.37m2, neurologic disorders other than distal symmetrical polyneuropathy, psychiatric disease, and treatment for other endocrine disorders. All patients had blood drawn for routinely analyzed biochemistry, including hemoglobin A1c. 
Measures of Retinal Nerve Fiber Layer Thickness
Papillary and macular OCT scans were performed through the dilated pupil using the Topcon 3D OCT-2000 (Topcon Corporation, Tokyo, Japan). The scan consisted of 1024 A-scans on a 3.4-mm diameter circle, fixed at the center of the optic disk or fovea, and compensated for eye movements by superimposing an image over the optic disk and foveal area. Peripapillary retinal nerve fiber layer thickness values of the four scanned quadrants (superior, inferior, temporal, and nasal) and the minimum central foveal thickness were extracted directly from the OCT software. All scans were collected under standardized mesopic lighting conditions. 
Measures of Peripheral Nerve Conduction Velocity
Nerve conduction velocities were evaluated using standardized neurophysiologic testing according to the American Association of Electrodiagnostic Medicine36 on the peroneal and tibial motor nerves and the radial and median sensory nerves. 
Measures of Cardiovascular Autonomic Function
Twenty‐four‐hour electrocardiographic recordings were undertaken (Lifecard CF; Del Mar Reynolds, Spacelabs Healthcare, Snoqualmie, WA, USA) according to internationally recommended standards37 and used to assess heart rate variability (HRV) (Impresario Software version 3; Spacelabs Healthcare). The following time domain HRV indices were obtained: standard deviation of the averages of N–N intervals in all 5‐minute segments of a 24‐hour recording, reflecting autonomic imbalance, and the mean root square of the difference of successive normal R–R intervals reflecting parasympathetic tone (RMSSD).38 In addition, fast Fourier transformation provided frequency domain HRV indices: very low frequency, low frequency, and high frequency. All HRV indices were adjusted for baseline heart rate. Blood pressure was measured noninvasively in a sitting and supine position (Omron M4, Hoofddorp, Netherlands). 
Measures of Catastrophic Thinking
We used the patient-reported pain catastrophizing scale to assess a patient's propensity to catastrophic thinking.36,37 It contains 13 questions revealing a summed score and three domains: rumination, magnification, and helplessness. The pain catastrophizing scale has successfully been used in healthy individuals without pain39 and in patients with acute and chronic pain.4043 In diabetes, it has been shown that catastrophic thinking is an independent contributor to greater depression and anxiety.44,45 Finally, magnetic resonance imaging brain scans suggest that pain catastrophizing, in healthy individuals and pain patients, is associated with more significant activity in brain regions broadly implicated in emotional and cognitive processes.46 
Statistics
Data are presented as mean ± standard deviation, median (25–75th percentiles), or number (%), dependent on data type and distribution. Linear regression analyses were performed with nerve fiber layer thickness as the dependent variable and measures of neuropathies as independent variables and adjusted for hemoglobin A1c, age, and gender. The significance level was set at P < 0.05. All statistical analyses were performed in Stata (version 17; StataCorp, College Station, TX, USA). 
Results
The baseline characteristics of the cohort are presented in Table 1
Table 1.
 
Baseline Characteristics
Table 1.
 
Baseline Characteristics
Thickness of the RNFL and Nerve Conduction Velocities
We show a positive association between the thinning of the RNFL and diminished nerve conduction velocities. For example, the crude regression analysis showed that the superior RNFL thickness decreases by 12 µm. However, to avoid the influence of the glycosylated hemoglobin level, age and gender results are adjusted for these (see Table 2). A thinning in the nasal and inferior quadrants was associated with a decrease in nerve conduction velocity of the radial sensory nerve: more specifically, a thinning in the superior quadrant was associated with a decreased nerve conduction velocity of the radial and median sensory nerves. 
Table 2.
 
Regression Analysis Between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Value of Central Fovea and Nerve Conduction Velocities of Sensory and Motor Nerves From the Upper and Lower Extremities
Table 2.
 
Regression Analysis Between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Value of Central Fovea and Nerve Conduction Velocities of Sensory and Motor Nerves From the Upper and Lower Extremities
A thinning in the inferior quadrant was further associated with a decrease in nerve conduction velocity of the tibial motor nerves. A thinning in the temporal quadrant was associated with a decrease in the nerve conduction velocity of the peroneal motor nerves. In contrast, a thickening in the temporal quadrant was associated with decreased tibial nerve conduction velocity. Finally, a thinning of the minimum retinal thickness in the central fovea area was associated with decreased nerve conduction velocity of the peroneal motor nerve. Specific P values adjusted for hemoglobin A1c, age, and gender can be found in Table 2
Thickness of the RNFL and HRV
We show a negative association between the RNFL thickness of the temporal quadrant or the thickness of the retina in the central fovea and HRV time and frequency domains. For example, a crude regression shows that when RMSSD decreases by 10, the temporal RNFL thickness increases by 5 µm. However, to avoid the influence of glycemia, age, and gender, the results are adjusted for these (see Table 3). Data show that the thickening of the RNFL and the retina itself is associated with diminished HRV independent of glycosylated hemoglobin, age, and gender. More specifically, a thickening of the temporal quadrant was associated with decreased RMSSD and very low-frequency content. A thickening of the retina in the central fovea was associated with very low-frequency content. 
Table 3.
 
Regression Analysis Between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Value of the Central Fovea and HRV Time and Frequency Domains
Table 3.
 
Regression Analysis Between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Value of the Central Fovea and HRV Time and Frequency Domains
Thickness of the RNFL and the Level of Catastrophic Thinking
We show a negative association between the thickness of the RNFL and the degree of catastrophic thinking assessed with scales of rumination, magnification, helplessness, and a combined score. For example, a crude regression analysis shows that when the pain catastrophizing scale decreases by 10 points, nasal RNFL thickness increases by 10 µm. We show consistently that thickening of the RNFL in the nasal quadrant was associated with level of catastrophic thinking independent of the level of glycosylated hemoglobin, age, and gender (see Table 4). For example, the crude regression analysis shows that when the pain catastrophizing scale decreases by 10 points, nasal RNFL thickness increases by 10 µm. However, to adjust for the glycosylated hemoglobin level, age and gender results have been adjusted for these (see Table 4). 
Table 4.
 
Regression Analysis between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Measure of the Central Fovea and the Subjective Pain Catastrophizing Scale
Table 4.
 
Regression Analysis between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Measure of the Central Fovea and the Subjective Pain Catastrophizing Scale
Discussion
The regional thickness of the RNFL in people with diabetes was lower in the superior and inferior quadrants and thicker in the nasal and temporal quadrants compared to the existing literature in healthy controls.47 Furthermore, we showed that retinal nerve fiber thickness was (1) positively associated with peripheral nerve conduction velocity of the sensory and motor nerves, indicating that thinning of the RNFL is more pronounced in people with diminished conduction velocities; (2) negatively associated with RMSSD and LF content, indicative of thickening of the RNFL is more pronounced in people with parasympathetic withdrawal and sympathetic dominance; and (3) negatively associated with catastrophic thinking in all three domains of rumination, magnification, and helplessness, as well as the total pain catastrophizing scale (PCS) score, indicating strong temporal stability and validity. In conclusion, the RNFL thickness is associated with measures of systemic neurodegeneration in this cohort with long-term type 1 diabetes. 
Associations between the Thickness of the RNFL and Peripheral Polyneuropathy
Ambiguous results have been reported regarding the association between the thickness of the RNFL and the severity of diabetic peripheral neuropathy. We showed an association between conduction velocities of peripheral axons and RNFL thickness. The findings are supported by a recent meta-analysis from Liu et al.,34 who collected data from 1229 people with diabetes and 573 people with diabetes and diabetic polyneuropathy. They concluded that RNFL thickness was significantly decreased in the inferior and superior quadrants in those with diabetic polyneuropathy in comparison to those without polyneuropathy.34 Although we found similar results for the inferior and superior quadrants, our current data also showed a thickening in the temporal quadrant. A similar negative association between the thickening of the RNFL in the temporal quadrant and conduction velocities was also found by Zafar et al.,48 indicating that the nerve degeneration in this specific area is characterized by swollen cells, possibly due to clinical or subclinical macular edema, neuroinflammation, or apoptosis. Taken together, our preliminary cross-sectional data support the notion that the retinal nerve fiber layer may have future potential to indicate the severity of diabetic polyneuropathy in motor and sensory nerves of the upper and lower extremities. 
Associations Between the Thickness of the RNFL and Dysautonomia
Changes in the thickness of distinct retinal layers precede the classical neovascularization indicative of diabetic retinopathy. Choi et al.49 took this concept further by studying the association between retinal thickness and cardiovascular complications in type 2 diabetes. The authors showed that thinning of the retinal ganglion cell layer and the inner plexiform layer was associated with the severity of cardiovascular autonomic neuropathy, particularly when categorizing cardiovascular autonomic neuropathy into early and established stages. Our study did not measure the ganglion cell layer thickness. However, we did find negative associations between the thickening of the RNFL in the temporal quadrant and reduced measures of HRV. The HRV measures are diminished in the case of dysautonomia characterized by sympathetic dominance and parasympathetic withdrawal, and temporal thickening may represent swelling, edema, and apoptosis as part of neurodegenerative processes. 
Associations Between the Thickness of the RNFL and Catastrophic Thinking
Catastrophizing, which has been described as a “cognitive distortion” that may contribute to the development of symptoms of depression and catastrophic thinking, has been defined by Sullivan et al.50 as “a negative mental set brought to bear” (e.g., during actual or anticipated pain experience). The scale has also been used successfully in healthy individuals without pain, underpinning its multidimensional utility.39 We used catastrophic thinking as a proxy for a negative cognitive set, reflecting the central nervous system’s structural and functional neurodegenerative alterations. In this cohort with long-term type 1 diabetes, we showed associations between the thinning of the RNFL and the degree of subjective catastrophic thinking. Our analysis is the first of its kind, but the results seem robust since all three domains and the scale’s total score were represented. They may reflect the daily challenges of managing long-term diabetes. 
Influence of Hyperglycemia, Age, and Gender and Thickness of the RNFL
Glycemic control is known to be associated with neural function. Recently, Zafar et al.48 showed that, per unit increase in percent HbA1c from 7076 participants with diabetes, the RNFL thickness in the inferior quadrant correspondingly decreased. Furthermore, subclinical thickening of the retina is positively associated with HbA1c levels,51 indicating retinal edema/neurodegeneration in response to hyperglycemia. Thus, to minimize the confounding effect of hyperglycemia, we adjusted for HbA1c in our models. 
Furthermore, since RNFL occurs with increasing age,52,53 independent of the presense of diabetes, with significant differences in retinal thickness between men and women,52,54 we have adjusted for age and gender in our model. 
Strengths and Limitations
To our knowledge, this is the first time that the thickness of the RNFL has been investigated with peripheral, autonomic, and cognitive measures of systemic neurodegeneration. However, our preliminary analyses are based on cross-sectional secondary data from a relatively small (n = 38) cohort with long-term type 1 diabetes and established polyneuropathy. Thus, the external generalizability is poor, and it would have strengthened the study to include a cohort with diabetes but without neuropathy and hence should be interpreted with caution. Consequently, use of the thickness of the RNFL as an indicator for progressive neurodegeneration needs to be challenged in cohorts with short-term type 1 and type 2 diabetes and even in individuals with prediabetes. Finally, due to the study's cross-sectional nature, the results do not allow any speculations on causality, so prospective longitudinal studies are needed. 
Conclusion
The thickness of the RNFL in our study has proven to be a robust marker for clinically meaningful measures of peripheral and autonomic neuropathy and even for cognitive distortion. We suggest that the thickness of the RNFL should be studied in adolescents and people with prediabetes to determine whether it is useful to predict the onset, presence, and severity of systemic neurodegeneration in diabetes. If successful, this could contribute to our knowledge of the pathogenesis of diabetic neuropathy and possibly identify individuals at heightened risk for developing these complications. Ultimately, it would be a powerful tool to predict prognostic outcomes and tailor individual management in diabetes. 
Acknowledgments
Disclosure: C. Brock, None; A.-M. Wegeberg, None; T.A. Nielsen, None; B. Karout, None; P.M. Hellström, None; A.M. Drewes, None; H. Vorum, None 
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Table 1.
 
Baseline Characteristics
Table 1.
 
Baseline Characteristics
Table 2.
 
Regression Analysis Between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Value of Central Fovea and Nerve Conduction Velocities of Sensory and Motor Nerves From the Upper and Lower Extremities
Table 2.
 
Regression Analysis Between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Value of Central Fovea and Nerve Conduction Velocities of Sensory and Motor Nerves From the Upper and Lower Extremities
Table 3.
 
Regression Analysis Between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Value of the Central Fovea and HRV Time and Frequency Domains
Table 3.
 
Regression Analysis Between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Value of the Central Fovea and HRV Time and Frequency Domains
Table 4.
 
Regression Analysis between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Measure of the Central Fovea and the Subjective Pain Catastrophizing Scale
Table 4.
 
Regression Analysis between the RNFL Thickness of the Superior, Nasal, Inferior, and Temporal Quadrants and the Minimum Measure of the Central Fovea and the Subjective Pain Catastrophizing Scale
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