Central and peripheral neurodegeneration in diabetes and dementia

Background: Diabetic peripheral neuropathy (DPN) affects ~50% of people with diabetes and leads to painful DPN (pDPN), diabetic foot ulceration (DFU) and amputation imposing a significant health and economic burden. Given that there are currently no European Medicines Agency (EMA) and FDA approved therapies for DPN it is important to establish the current prevalence and modifiable risk factors for DPN and assess the benefit of treatments utilizing corneal confocal microscopy (CCM), a sensitive technique to quantify early nerve regeneration in DPN. Furthermore, CCM has shown corneal nerve loss in central neurodegenerative disorders such as Parkinson’s disease and multiple sclerosis, therefore the diagnostic utility of this technique was assessed in subjects with mild cognitive impairment (MCI) and dementia. Aims: This work established the prevalence and risk factors of DPN and those at high risk of DFU in Chapter 3; the prevalence and risk factors of pDPN in Chapter 4 and the prevalence of DPN and pDPN in both primary (PHC) and secondary health care (PHC) in type 2 diabetes (T2D) in Qatar in Chapter 5. It investigated the effect of hypertension on neuropathic symptoms and deficits in type 1 diabetes (T1D) in Chapter 6, the association between metformin induced B12 deficiency and DPN in Chapter 7, and the effect of exenatide and pioglitazone or basal-bolus insulin on DPN in patients with poorly controlled T2D as an exploratory sub-study of the Qatar study, an open-label, randomized controlled trial (clinicaltrials.gov identifier NCT02887625) in Chapter 8. It assessed the association of corneal nerve morphology with cognitive impairment in MCI and dementia in Chapter 9 and compared the diagnostic ability of CCM to visual rating of medial temporal lobe atrophy (MTA) on brain MRI to distinguish subjects with MCI or dementia from subjects with no cognitive impairment (NCI) in Chapter 10. Methods: All the research work was conducted in Qatar apart from Chapter 6 which was performed in Manchester, UK. The study design, inclusion and exclusion criteria, diagnosis and assessments for each study are described in detail in the methods section in each chapter. Subjects were randomly enrolled and screened for eligibility on the day they attended the clinic. Demographic, clinical and metabolic characteristics and list of medications were recorded

Corneal nerve fractal dimension: a novel corneal nerve metric for the diagnosis of diabetic sensorimotor polyneuropathy

Objective: Corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, is a noninvasive and objective imaging biomarker for identifying small nerve fiber damage. We have evaluated the diagnostic performance of previously established CCM parameters to a novel automated measure of corneal nerve complexity called the corneal nerve fiber fractal dimension (ACNFrD).Methods: A total of 176 subjects (84 controls and 92 patients with type 1 diabetes) with and without diabetic sensorimotor polyneuropathy (DSPN) underwent CCM. Fractal dimension analysis was performed on CCM images using purpose-built corneal nerve analysis software, and compared with previously established manual and automated corneal nerve fiber measurements.Results: Manual and automated subbasal corneal nerve fiber density (CNFD) (P < 0.0001), length (CNFL) (P < 0.0001), branch density (CNBD) (P < 0.05), and ACNFrD (P < 0.0001) were significantly reduced in patients with DSPN compared to patients without DSPN. The areas under the receiver operating characteristic curves for identifying DSPN were comparable: 0.77 for automated CNFD, 0.74 for automated CNFL, 0.69 for automated CNBD, and 0.74 for automated ACNFrD.Conclusions: ACNFrD shows comparable diagnostic efficiency to identify diabetic patients with and without DSPN

Corneal nerve fractal dimension: a novel corneal nerve metric for the diagnosis of diabetic sensorimotor polyneuropathy

Objective: Corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, is a noninvasive and objective imaging biomarker for identifying small nerve fiber damage. We have evaluated the diagnostic performance of previously established CCM parameters to a novel automated measure of corneal nerve complexity called the corneal nerve fiber fractal dimension (ACNFrD). Methods: A total of 176 subjects (84 controls and 92 patients with type 1 diabetes) with and without diabetic sensorimotor polyneuropathy (DSPN) underwent CCM. Fractal dimension analysis was performed on CCM images using purpose-built corneal nerve analysis software, and compared with previously established manual and automated corneal nerve fiber measurements. Results: Manual and automated subbasal corneal nerve fiber density (CNFD) (P < 0.0001), length (CNFL) (P < 0.0001), branch density (CNBD) (P < 0.05), and ACNFrD (P < 0.0001) were significantly reduced in patients with DSPN compared to patients without DSPN. The areas under the receiver operating characteristic curves for identifying DSPN were comparable: 0.77 for automated CNFD, 0.74 for automated CNFL, 0.69 for automated CNBD, and 0.74 for automated ACNFrD. Conclusions: ACNFrD shows comparable diagnostic efficiency to identify diabetic patients with and without DSPN

Corneal nerve loss detected with corneal confocal microscopy is symmetrical and related to the severity of diabetic polyneuropathy

OBJECTIVE: To establish if corneal nerve loss, detected using in vivo corneal confocal microscopy (IVCCM), is symmetrical between right and left eyes and relates to the severity of diabetic neuropathy. RESEARCH DESIGN AND METHODS: Patients (n = 111) with type 1 and type 2 diabetes and 47 age-matched healthy control subjects underwent detailed assessment and stratification into no (n = 50), mild (n = 26), moderate (n = 17), and severe (n = 18) neuropathy. IVCCM was performed in both eyes and corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) and the tortuosity coefficient were quantified. RESULTS: All corneal nerve parameters differed significantly between diabetic patients and control subjects and progressively worsened with increasing severity of neuropathy. The reduction in CNFD, CNBD, and CNFL was symmetrical in all groups except in patients with severe neuropathy. CONCLUSIONS: IVCCM noninvasively detects corneal nerve loss, which relates to the severity of neuropathy, and is symmetrical, except in those with severe diabetic neuropathy

Diagnosing and managing diabetic somatic and autonomic neuropathy

The diagnosis and management of diabetic neuropathy can be a major challenge. Late diagnosis contributes to significant morbidity in the form of painful diabetic neuropathy, foot ulceration, amputation, and increased mortality. Both hyperglycaemia and cardiovascular risk factors are implicated in the development of somatic and autonomic neuropathy and an improvement in these risk factors can reduce their rate of development and progression. There are currently no US Food and Drug Administration (FDA)-approved disease-modifying treatments for either somatic or autonomic neuropathy, as a consequence of multiple failed phase III clinical trials. While this may be partly attributed to premature translation, there are major shortcomings in trial design and outcome measures. There are a limited number of partially effective FDA-approved treatments for the symptomatic relief of painful diabetic neuropathy and autonomic neuropathy

Small Nerve Fiber Damage and Langerhans Cells in Type 1 and Type 2 Diabetes and LADA Measured by Corneal Confocal Microscopy.

PurposeIncreased corneal and epidermal Langerhans cells (LCs) have been reported in patients with diabetic neuropathy. The aim of this study was to quantify the density of LCs in relation to corneal nerve morphology and the presence of diabetic neuropathy and to determine if this differed in patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and latent autoimmune diabetes of adults (LADA).MethodsPatients with T1DM (n = 25), T2DM (n = 36), or LADA (n = 23) and control subjects (n = 23) underwent detailed assessment of peripheral neuropathy and corneal confocal microscopy. Corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and total, immature and mature LC densities were quantified.ResultsLower CNFD (P ConclusionsThis study shows significant corneal nerve loss and an increase in LC density in patients with T1DM, T2DM, and LADA. Furthermore, increased LC density correlated with corneal nerve loss in patients with T1DM

Prevalence and risk factors for painful diabetic neuropathy in secondary health care in Qatar.

AIMS/INTRODUCTION:Painful diabetic peripheral neuropathy (PDPN) has a significant impact on the patient's quality of life. The prevalence of PDPN in the Middle East and North Africa (MENA) region has been reported to be almost double that of populations in the UK. We sought to determine the prevalence of PDPN and its associated factors in T2DM patients attending secondary care in Qatar. MATERIALS AND METHODS:This is a cross-sectional study of 1095 participants with T2DM attending Qatar's two national diabetes centers. PDPN and impaired vibration perception on the pulp of the large toes were assessed using the DN4 questionnaire with a cut-off ≥4 and the Neurothesiometer with a cut-off ≥15V, respectively. RESULTS:The prevalence of PDPN was 34.5% (95% CI: 31.7%-37.3%), but 80% of these patients had not previously been diagnosed or treated for this condition. Arabs had a higher prevalence of PDPN compared to South Asians (P<0.05). PDPN was associated with impaired vibration perception AOR=4.42 (95%CI: 2.92-6.70), smoking AOR=2.43 (95%CI: 1.43-4.15), obesity AOR=1.74 (95%CI: 1.13-2.66), being female AOR=1.65 (95%CI: 1.03-2.64) and duration of diabetes AOR=1.08 (95%CI: 1.05-1.11). Age, poor glycemic control, hypertension, physical activity and proteinuria showed no association with PDPN. CONCLUSIONS:PDPN occurs in 1/3 of T2DM patients attending secondary care in Qatar, but the majority have not been diagnosed. Arabs are at higher risk for PDPN. Impaired vibration perception, obesity and smoking are associated with PDPN in Qatar. This article is protected by copyright. All rights reserved

Prevalence and management of diabetic neuropathy in secondary care in Qatar

Aims Diabetic neuropathy (DN) is a “Cinderella” complication, particularly in the Middle East. A high prevalence of undiagnosed DN and those at risk of diabetic foot ulceration (DFU) is a major concern. We have determined the prevalence of DN and its risk factors, DFU and those at risk of (DFU) in patients with T2DM in secondary care in Qatar. Materials and methods Adults with T2DM were randomly selected from the two National Diabetes Centers in Qatar. DN was defined by the presence of neuropathic symptoms and a vibration perception threshold (VPT) ≥ 15 V. Participants with a VPT≥25 V were categorized as high risk for DFU. Painful DN was defined by a DN4 score ≥ 4. Logistic regression analysis was used to identify predictors of DN. Results In 1082 adults with T2DM (age 54 ± 11 years, duration of diabetes 10.0 ± 7.7 years, 60.6% males) the prevalence of DN was 23.0% (95% CI: 20.5%‐25.5%), of whom 33.7% (95% CI: 27.9%‐39.6%) were at high risk of DFU and 6.3% had DFU. 82.0% of the patients with DN were previously undiagnosed. The prevalence of DN increased with age and duration of diabetes and was associated with poor glycemic control (HbA1c ≥ 9%) AOR = 2.1 (95%CI: 1.3‐3.2), hyperlipidemia AOR = 2.7 (95%CI: 1.5‐5.0) and hypertension AOR = 2.0 (95%CI: 1.2‐3.4). Conclusions Despite, DN affecting 23% of adults with T2DM, 82% had not been previously diagnosed with 1/3 at high risk for DFU. This argues for annual screening and identification of patients with DN. Furthermore, we identify hyperglycemia, hyperlipidemia and hypertension as predictors of DN

Association of Cerebral Ischemia With Corneal Nerve Loss and Brain Atrophy in MCI and Dementia

IntroductionThis study assessed the association of cerebral ischemia with neurodegeneration in mild cognitive impairment (MCI) and dementia.MethodsSubjects with MCI, dementia and controls underwent assessment of cognitive function, severity of brain ischemia, MRI brain volumetry and corneal confocal microscopy.ResultsOf 63 subjects with MCI (n = 44) and dementia (n = 19), 11 had no ischemia, 32 had subcortical ischemia and 20 had both subcortical and cortical ischemia. Brain volume and corneal nerve measures were comparable between subjects with subcortical ischemia and no ischemia. However, subjects with subcortical and cortical ischemia had a lower hippocampal volume (P &lt; 0.01), corneal nerve fiber length (P &lt; 0.05) and larger ventricular volume (P &lt; 0.05) compared to those with subcortical ischemia and lower corneal nerve fiber density (P &lt; 0.05) compared to those without ischemia.DiscussionCerebral ischemia was associated with cognitive impairment, brain atrophy and corneal nerve loss in MCI and dementia