ISL1 is necessary for auditory neuron development and contributes toward tonotopic organization.

A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

Corneal nerve and nerve conduction abnormalities in children with type 1 diabetes.

OBJECTIVE: In vivo corneal confocal microscopy (CCM) is a novel, rapid, and non-invasive technique that identifies early small fiber damage and can predict the progression and development of clinical neuropathy in adults with type 1 diabetes. However, its usefulness in children is not well established. This study compared corneal confocal microscopy with neuropathic symptoms, signs, and objective measures of neuropathy for the diagnosis of diabetic neuropathy in children with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 83 children with type 1 diabetes and 83 healthy participants of similar age underwent assessment of neuropathy symptoms, signs, nerve conduction studies, quantitative sensory and autonomic function testing, and in vivo CCM. RESULTS: Only of 3/83 (4%) children with type 1 diabetes had subclinical neuropathy. However, corneal nerve fiber density (p = 0.001), branch density (p = 0.006), fiber length (p = 0.002), tibial motor nerve amplitude and conduction velocity, and sural sensory nerve amplitude and conduction velocity (all p < 0.004) were lower in participants with type 1 diabetes than in the controls. Vibration, cooling, and warm perception thresholds and deep breathing heart rate variability were not found to be different (all p > 0.05) between children with type 1 diabetes and healthy controls. Multivariate regression analysis identified a possible association between body mass index and decreased corneal nerves. CONCLUSIONS: Decreased corneal nerves and abnormal nerve conduction were found in children with type 1 diabetes. CCM may allow rapid objective detection of subclinical diabetic neuropathy in children and adolescents with type 1 diabetes.

Corneal confocal microscopy for identification of diabetic sensorimotor polyneuropathy: a pooled multinational consortium study.

AIMS/HYPOTHESIS: Small cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP. METHODS: Nine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard. RESULTS: Type 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm2 in type 1 diabetes and 12.3 mm/mm2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm2 to rule in DSP and an upper value of 15.3 mm/mm2 to rule out DSP were associated with 88% specificity and 88% sensitivity. CONCLUSIONS/INTERPRETATION: We established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.

Explanations for less small fibre neuropathy in South Asian versus European subjects with type 2 diabetes in the UK.

BACKGROUND: Low foot ulcer risk in South Asian, compared with European, people with type 2 diabetes in the UK has been attributed to their lower levels of neuropathy. We have undertaken a detailed study of corneal nerve morphology and neuropathy risk factors, to establish the basis of preserved small nerve fibre function in South Asians versus Europeans. METHODS: In a cross-sectional, population-based study, age- and sex-matched South Asians (n = 77) and Europeans (n = 78) with type 2 diabetes underwent neuropathy assessment using corneal confocal microscopy, symptoms, signs, quantitative sensory testing, electrophysiology and autonomic function testing. Multivariable linear regression analyses determined factors accounting for ethnic differences in small fibre damage. RESULTS: Corneal nerve fibre length (22.0 ± 7.9 vs. 19.3 ± 6.3 mm/mm2 ; P = 0.037), corneal nerve branch density (geometric mean (range): 60.0 (4.7-246.2) vs. 46.0 (3.1-129.2) no./mm2 ; P = 0.021) and heart rate variability (geometric mean (range): 7.9 (1.4-27.7) vs. 6.5 (1.5-22.0); P = 0.044), were significantly higher in South Asians vs. Europeans. All other neuropathy measures did not differ, except for better sural nerve amplitude in South Asians (geometric mean (range): 10.0 (1.3-43.0) vs. 7.2 (1.0-30.0); P = 0.006). Variables with the greatest impact on attenuating the P value for age- and HbA1C -adjusted ethnic difference in corneal nerve fibre length (P = 0.032) were pack-years smoked (P = 0.13), BMI (P = 0.062) and triglyceride levels (P = 0.062). CONCLUSIONS: South Asians have better preserved small nerve fibre integrity than equivalent Europeans; furthermore, classic, modifiable risk factors for coronary heart disease are the main contributors to these ethnic differences. We suggest that improved autonomic neurogenic control of cutaneous blood flow in Asians may contribute to their protection against foot ulcers.

Small-fibre neuropathy in men with type 1 diabetes and erectile dysfunction: a cross-sectional study.

AIMS/HYPOTHESIS: The aim of this study was to identify the contribution of small- and large-fibre neuropathy to erectile dysfunction in men with type 1 diabetes mellitus. METHODS: A total of 70 participants (29 without and 41 with erectile dysfunction) with type 1 diabetes and 34 age-matched control participants underwent a comprehensive assessment of large- and small-fibre neuropathy. RESULTS: The prevalence of erectile dysfunction in participants with type 1 diabetes was 58.6%. After adjusting for age, participants with type 1 diabetes and erectile dysfunction had a significantly higher score on the Neuropathy Symptom Profile (mean ± SEM 5.3 ± 0.9 vs 1.8 ± 1.2, p = 0.03), a higher vibration perception threshold (18.3 ± 1.9 vs 10.7 ± 2.4 V, p = 0.02), and a lower sural nerve amplitude (5.0 ± 1.1 vs 11.7 ± 1.5 mV, p = 0.002), peroneal nerve amplitude (2.1 ± 0.4 vs 4.7 ± 0.5 mV, p < 0.001) and peroneal nerve conduction velocity (34.8 ± 1.5 vs 41.9 ± 2.0 m/s, p = 0.01) compared with those without erectile dysfunction. There was also evidence of a marked small-fibre neuropathy with an impaired cold threshold (19.7 ± 1.4°C vs 27.3 ± 1.8°C, p = 0.003), warm threshold (42.9 ± 0.8°C vs 39.0 ± 0.9°C, p = 0.005) and heart rate variability (21.5 ± 3.1 vs 30.0 ± 3.7 beats/min, p = 0.001) and reduced intraepidermal nerve fibre density (2.8 ± 0.7 vs 5.9 ± 0.7/mm, p = 0.008), corneal nerve fibre density (12.6 ± 1.5 vs 23.9 ± 2.0/mm2, p < 0.001), corneal nerve branch density (12.7 ± 2.5 vs 31.6 ± 3.3/mm2, p < 0.001) and corneal nerve fibre length (8.3 ± 0.7 vs 14.5 ± 1.0 mm/mm2, p < 0.001) in participants with type 1 diabetes and erectile dysfunction. Erectile dysfunction correlated significantly with measures of both large- and small-fibre neuropathy. CONCLUSIONS/INTERPRETATION: Small-fibre neuropathy is prominent in patients with type 1 diabetes, and is associated with erectile dysfunction and can be objectively quantified using corneal confocal microscopy. This may allow the identification of patients who are less likely to respond to conventional therapies such as phosphodiesterase type 5 inhibitors.

Rare human nerve growth factor-ß mutation reveals relationship between C-afferent density and acute pain evaluation.

The rare nerve growth factor-ß (NGFB) mutation R221W causes a selective loss of thinly myelinated fibers and especially unmyelinated C-fibers. Carriers of this mutation show altered pain sensation. A subset presents with arthropathic symptoms, with the homozygous most severely affected. The aim of the present study was to investigate the relationship between peripheral afferent loss and pain evaluation by performing a quantification of small-fiber density in the cornea of the carriers, relating density to pain evaluation measures. In vivo corneal confocal microscopy (CCM) was used to quantify C-fiber loss in the cornea of 19 R221W mutation carriers (3 homozygous) and 19 age-matched healthy control subjects. Pain evaluation data via the Situational Pain Questionnaire (SPQ) and the severity of neuropathy based on the Neuropathy Disability Score (NDS) were assessed. Homozygotes, heterozygotes, and control groups differed significantly in corneal C-nerve fiber density, with the homozygotes showing a significant afferent reduction. Importantly, peripheral C-fiber loss correlated negatively with pain evaluation, as revealed by SPQ scores. This study is the first to investigate the contribution of small-fiber density to the perceptual evaluation of pain. It demonstrates that the lower the peripheral small-fiber density, the lower the degree of reported pain intensity, indicating a functional relationship between small-fiber density and higher level pain experience.

Corneal confocal microscopy for the diagnosis of diabetic autonomic neuropathy.

BACKGROUND: Diabetic autonomic neuropathy (DAN) results in increased morbidity and mortality. The early diagnosis of DAN can be difficult and is commonly evaluated using cardiac autonomic function tests as a surrogate. However, they are not widely available, have limited sensitivity and specificity, and can be confounded by concomitant cardiovascular disease and medications. METHODS: The diagnostic utility of corneal confocal microscopy for diagnosis of DAN was assessed. Thirty-four diabetic patients without [Composite Autonomic Scoring Scale (CASS)≤2] vs with (CASS>2) DAN and 18 healthy control subjects (HC) underwent detailed assessment of somatic and autonomic neuropathy, Composite Autonomic Symptom Scale (COMPASS), (CASS), and Corneal Confocal Microscopy (CCM). RESULTS: Corneal nerve fiber density, branch density, and length showed a progressive and significant reduction in patients with DAN vs HC and those without DAN. CCM correlated highly significantly with COMPASS and CASS, and corneal nerve fiber parameters demonstrated a high sensitivity and specificity for diagnosis of DAN. CONCLUSIONS: This study demonstrates that corneal nerve damage detected using CCM can be deployed to diagnose subclinical and overt DAN. It therefore represents a rapid, non-invasive, highly sensitive and specific diagnostic test for DAN.

Adenylyl Cyclase in Ocular Health and Disease: A Comprehensive Review.

Adenylyl cyclases (ACs) are a group of enzymes that convert adenosine-5'-triphosphate (ATP) to cyclic adenosine 3',5' monophosphate (cAMP), a vital and ubiquitous signalling molecule in cellular responses to hormones and neurotransmitters. There are nine transmembrane (tmAC) forms, which have been widely studied; however, the tenth, soluble AC (sAC) is less extensively characterised. The eye is one of the most metabolically active sites in the body, where sAC has been found in abundance, making it a target for novel therapeutics and biomarking. In the cornea, AC plays a role in endothelial cell function, which is vital in maintaining stromal dehydration, and therefore, clarity. In the retina, AC has been implicated in axon cell growth and survival. As these cells are irreversibly damaged in glaucoma and injury, this molecule may provide focus for future therapies. Another potential area for glaucoma management is the source of aqueous humour production, the ciliary body, where AC has also been identified. Furthering the understanding of lacrimal gland function is vital in managing dry eye disease, a common and debilitating condition. sAC has been linked to tear production and could serve as a therapeutic target. Overall, ACs are an exciting area of study in ocular health, offering multiple avenues for future medical therapies and diagnostics. This review paper explores the diverse roles of ACs in the eye and their potential as targets for innovative treatments.

The landscape of global research on diabetic neuropathy.

Introduction: Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes, imposing a significant burden on individuals and healthcare systems worldwide. This study presents a comprehensive analysis of the global research landscape in DN, aiming to provide scientists, funders, and decision-makers with valuable insights into the current state of research and future directions. Methods: Through a systematic review of published articles, key trends in DN research, including epidemiology, diagnosis, treatment strategies, and gaps in knowledge, are identified and discussed. Results: The analysis reveals an increasing prevalence of DN alongside the rising incidence of diabetes, emphasizing the urgent need for effective prevention and management strategies. Furthermore, the study highlights the geographical imbalance in research activity, with a majority of studies originating from high-income countries. Discussion: This study underscores the importance of fostering international collaboration to address the global impact of DN. Key challenges and limitations in DN research are also discussed, including the need for standardized diagnostic criteria, reliable biomarkers, and innovative treatment approaches. By addressing these gaps, promoting collaboration, and increasing research funding, we can pave the way for advancements in DN research and ultimately improve the lives of individuals affected by this debilitating condition.

Innovative Macula Capillaries Plexuses Visualization with OCTA B-Scan Graph Representation: Transforming OCTA B-Scan into OCTA Graph Representation.

Purpose: The aim of this study is to transform optical coherence tomography angiography (OCTA) scans into innovative OCTA graphs, serving as novel biomarkers representing the macular vasculature. Patients and Methods: The study included 90 healthy subjects and 39 subjects with various abnormalities (29 with diabetic retinopathy, 5 with age-related macular degeneration, and 5 with choroid neovascularization). OCTA 5µm macular coronal views (MCVs) were generated for each subject, followed by blood vessel segmentation and skeleton processing. Subsequently, the blood vessel density index, blood vessel skeleton index, and blood vessel tortuosity index were computed. The graphs of each metric were plotted against the axial axes of the OCTA B-scan, representing the integrity of vasculature at successive 5µm macular depths. Results: The results revealed two significant findings. First, the B-scans from OCTA can be transformed into OCTA graphs, yielding three specific OCTA graphs in this study. These graphs provide new biomarkers for assessing the integrity of deep vascular complex (DVC) and superficial vascular complex (SVC) within the macula. Second, a statistically significant difference was observed between normal (n=90) and abnormal (n=39) subjects, with a t-test p-value significantly lower than 0.001. The Mann-Whitney u-test also yielded significant difference but only between the 90 normal and 29 DR subjects. Conclusion: The novel OCTA graphs offer a unique representation of the macula's SVC and DVC, suggesting their potential in aiding physicians in the diagnosis of eye health within OCTA clinics. Further research is warranted to finalize the shape of these newly derived OCTA graphs and establish their clinical relevance and utility.

Corneal confocal microscopy detects small-fiber neuropathy in Charcot-Marie-Tooth disease type 1A patients.

INTRODUCTION: Although unmyelinated nerve fibers are affected in Charcot-Marie-Tooth type 1A (CMT1A) disease, they have not been studied in detail due to the invasive nature of the techniques needed to study them. We established alterations in C-fiber bundles of the cornea in patients with CMT1A using non-invasive corneal confocal microscopy (CCM). METHODS: Twelve patients with CMT1A and 12 healthy control subjects underwent assessment of neuropathic symptoms and deficits, electrophysiology, quantitative sensory testing, corneal sensitivity, and corneal confocal microscopy. RESULTS: Corneal sensitivity, corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length, and corneal nerve fiber tortuosity were significantly reduced in CMT1A patients compared with controls. There was a significant correlation between corneal sensation and CCM parameters with the severity of painful neuropathic symptoms, cold and warm thresholds, and median nerve CMAP amplitude. CONCLUSIONS: CCM demonstrates significant damage to C-fiber bundles, which relates to some measures of neuropathy in CMT1A patients.

Sodium Glucose Cotransporter-2 Inhibitor Protects Against Diabetic Neuropathy and Nephropathy in Modestly Controlled Type 2 Diabetes: Follow-Up Study.

Aims: This three-year follow-up study aimed to elucidate whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) have any protection against diabetic neuropathy and nephropathy in patients with type 2 diabetes via reducing variability in glycemia and extraglycemic factors or their averages. Methods: Two type 2 diabetic cohorts of 40 and 73 patients treated with or without SGLT2i along with 60 control subjects were recruited. Two diabetic cohorts matched for HbA1c levels and oral hypoglycemic agents other than SGLT2is underwent glycemic control with or without SGLT2is more than two years. The urinary albumin to creatinine ratio (ACR), estimated glomerular filtration rate (eGFR) every 3 months and neuropathy outcome measures and mean Z-score of 8 neurophysiological tests were determined at the baseline and endpoint. Glycemic variability, evaluated by the coefficient of variation of monthly measured HbA1c levels and casual postprandial plasma glucose (CPPG), and coefficient of variation and average of extraglycemic parameters in diabetic cohorts were determined. Results: The glycemic variability and variability of some extraglycemic factors in SGLT2i cohort were smaller than those in non-SGLT2i cohort. However, only smaller coefficient of variation of HbA1c improved some neuropathy outcome measures, and ameliorated eGFR decline. SGLT2i improved the Z-score of neurophysiological tests. The optimized changes in the blood pressure, HDL-cholesterol and uric acid by SGLT2i led to neurological and renal protection. SGLT2i decreased the prevalence of nephropathy significantly and the prevalence of neuropathy insignificantly. Conclusion: Over 3 years period, SGLT2i significantly improved some neuropathy outcome measures, mean Z-score of 8 neurophysiological tests, and attenuated nephropathy in modestly controlled type 2 diabetes by reducing glycemic variability and mean nonglycemic factors of diabetic microvascular complication.

Neurodegeneration of the cornea and retina in patients with type 1 diabetes without clinical evidence of diabetic retinopathy.

Aim: Diabetic retinopathy (DR) is widely considered the earliest and most common microvascular complication of diabetes. However, recent studies have shown that retinal nerve fiber layer and corneal nerve abnormalities may be present in diabetic patients without retinopathy. This preliminary study aimed to establish if structural and functional changes in the nerve fiber layer of the retina and cornea occur in patients with type 1 diabetes (T1DM) without retinopathy. Methods: Twenty patients with T1DM, without clinical evidence of retinopathy (Age: 47.0 ± 2.5 years; Duration diabetes: 27.0 ± 3 years) and 15 age-matched healthy control subjects underwent detailed medical neurological examinations. Ophthalmic examinations using Spectral Domain Optical coherence tomography (SD-OCT), Standard Automated Perimetry (SAP), Flicker Defined Form High Edge Perimetry (FDF), Corneal Confocal Microscopy (CCM) and Non-contact corneal Aesthesiometry (NCCA) were performed to quantify the structure and function of the nerves in the retina and cornea, respectively. Results: At the structural level, retinal nerve fiber layer thickness (RNFL) was significantly reduced in the superior nasal (p=0.001) and inferior temporal (p=0.004) sectors, in diabetic patients. Retinal ganglion layer function was reduced in the patient group when assessed using Flicker Defined Form Perimetry (FDF), but this was not significant. The function of the cornea assessed by corneal sensitivity, using a non-contact corneal aesthesiometer (NCCA), was significantly reduced (p=0.001). Structural assessment of corneal nerves using corneal confocal microscopy (CCM) showed reduction at corneal nerve fiber density (CNFD) (p=0.01), branch density (CNBD) (p=0.006) and length (CNFL) (p=0.01) in patients with diabetes. Compared to control subjects, the percentage of abnormality in patients with T1DM for RNFL was 32% while the FDF was abnormal in 61% of patients. Corneal abnormality was observed in 47% for NCCA, 28% for CNFD, and 17% for CNFL. There was no correlation between neuronal damage in the retina and cornea. Conclusions: Neuronal abnormalities were observed in both the retina and cornea of diabetic patients without evidence of retinopathy. The prevalence of structural and functional changes was higher in the retina compared to the cornea. This preliminary study suggests that structural neuronal changes may occur in parallel and correlate with functional changes. The assessment of corneal and retinal nerve structure may be clinically useful for detecting and monitoring the earliest stages of diabetic microvascular abnormalities.

Early Deletion of Neurod1 Alters Neuronal Lineage Potential and Diminishes Neurogenesis in the Inner Ear.

Neuronal development in the inner ear is initiated by expression of the proneural basic Helix-Loop-Helix (bHLH) transcription factor Neurogenin1 that specifies neuronal precursors in the otocyst. The initial specification of the neuroblasts within the otic epithelium is followed by the expression of an additional bHLH factor, Neurod1. Although NEUROD1 is essential for inner ear neuronal development, the different aspects of the temporal and spatial requirements of NEUROD1 for the inner ear and, mainly, for auditory neuron development are not fully understood. In this study, using Foxg1Cre for the early elimination of Neurod1 in the mouse otocyst, we showed that Neurod1 deletion results in a massive reduction of differentiating neurons in the otic ganglion at E10.5, and in the diminished vestibular and rudimental spiral ganglia at E13.5. Attenuated neuronal development was associated with reduced and disorganized sensory epithelia, formation of ectopic hair cells, and the shortened cochlea in the inner ear. Central projections of inner ear neurons with conditional Neurod1 deletion are reduced, unsegregated, disorganized, and interconnecting the vestibular and auditory systems. In line with decreased afferent input from auditory neurons, the volume of cochlear nuclei was reduced by 60% in Neurod1 mutant mice. Finally, our data demonstrate that early elimination of Neurod1 affects the neuronal lineage potential and alters the generation of inner ear neurons and cochlear afferents with a profound effect on the first auditory nuclei, the cochlear nuclei.

Implementation of corneal confocal microscopy for screening and early detection of diabetic neuropathy in primary care alongside retinopathy screening: Results from a feasibility study.

Objective: Screening for diabetic peripheral neuropathy (DPN) is essential for early detection and timely intervention. Quantitative assessment of small nerve fiber damage is key to the early diagnosis and assessment of its progression. Corneal confocal microscopy (CCM) is a non-invasive, in-vivo diagnostic technique that provides an accurate surrogate biomarker for small-fiber neuropathy. In this novel study for the first time, we introduced CCM to primary care as a screening tool for DPN alongside retinopathy screening to assess the level of neuropathy in this novel cohort. Research design and methods: 450 consecutive subjects with type 1 or type 2 diabetes attending for annual eye screening in primary care optometry settings underwent assessment with CCM to establish the prevalence of sub-clinical diabetic peripheral neuropathy. Subjects underwent assessment for neurological and ocular symptoms of diabetes and a history of diabetic foot disease, neuropathy and diabetic retinopathy (DR). Results: CCM examination was completed successfully in 427 (94.9%) subjects, 22% of whom had neuropathy according to Diabetic Neuropathy Symptom (DNS) score. The prevalence of sub-clinical neuropathy as defined by abnormal corneal nerve fiber length (CNFL) was 12.9%. In the subjects with a short duration of type 2 diabetes, 9.2% had abnormal CNFL. CCM showed significant abnormalities in corneal nerve parameters in this cohort of subjects with reduction of corneal nerve fiber density (CNFD, p<0.001), CNFL (p<0.001) and corneal nerve branch density (CNBD, p<0.001) compared to healthy subjects. In subjects who had no evidence of DR (67% of all subjects), 12.0% had abnormal CNFL. Conclusions: CCM may be a sensitive biomarker for early detection and screening of DPN in primary care alongside retinopathy screening.

The Impact of Glycemic Control on Retinal Photoreceptor Layers and Retinal Pigment Epithelium in Patients With Type 2 Diabetes Without Diabetic Retinopathy: A Follow-Up Study.

Aims: To establish the sequential changes by glycemic control in the mean thickness, volume and reflectance of the macular photoreceptor layers (MPRLs) and retinal pigment epithelium in patients with type 2 diabetes without diabetic retinopathy. Methods: Thirty-one poorly controlled (HbA1c > 8.0%) patients with type 2 diabetes without diabetic retinopathy undergoing glycemic control and 39 control subjects with normal HbA1c levels (< 5.9%) underwent periodical full medical, neurological and ophthalmological examinations over 2 years. Glycemic variability was evaluated by standard deviation and coefficient of variation of monthly measured HbA1c levels and casual plasma glucose. 3D swept source-optical coherence tomography (OCT) and OCT-Explorer-generated enface thickness, volume and reflectance images for 9 subfields defined by Early Treatment Diabetic Retinopathy Study of 4 MPRLs {outer nuclear layer, ellipsoid zone, photoreceptor outer segment (PROS) and interdigitation zone} and retinal pigment epithelium were acquired every 3 months. Results: Glycemic control sequentially restored the thickness and volume at 6, 4 and 5 subfields of outer nuclear layer, ellipsoid zone and PROS, respectively. The thickness and volume of outer nuclear layer were restored related to the decrease in HbA1c and casual plasma glucose levels, but not related to glycemic variability and neurological tests. The reflectance of MPRLs and retinal pigment epithelium in patients was marginally weaker than controls, and further decreased at 6 or 15 months during glycemic control. The reduction at 6 months coincided with high HbA1c levels. Conclusion: Glycemic control sequentially restored the some MPRL thickness, especially of outer nuclear layer. In contrast, high glucose during glycemic control decreased reflectance and may lead to the development of diabetic retinopathy induced by glycemic control. The repeated OCT examinations can clarify the benefit and hazard of glycemic control to the diabetic retinopathy.

Ophthalmic Biomarkers for Alzheimer's Disease: A Review.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by neuronal loss, extracellular amyloid-ß (Aß) plaques, and intracellular neurofibrillary tau tangles. A diagnosis is currently made from the presenting symptoms, and the only definitive diagnosis can be done post-mortem. Over recent years, significant advances have been made in using ocular biomarkers to diagnose various neurodegenerative diseases, including AD. As the eye is an extension of the central nervous system (CNS), reviewing changes in the eye's biology could lead to developing a series of non-invasive, differential diagnostic tests for AD that could be further applied to other diseases. Significant changes have been identified in the retinal nerve fiber layer (RNFL), cornea, ocular vasculature, and retina. In the present paper, we review current research and assess some ocular biomarkers' accuracy and reliability that could potentially be used for diagnostic purposes. Additionally, we review the various imaging techniques used in the measurement of these biomarkers.

Advances in Screening, Early Diagnosis and Accurate Staging of Diabetic Neuropathy.

The incidence of both type 1 and type 2 diabetes is increasing worldwide. Diabetic peripheral neuropathy (DPN) is among the most distressing and costly of all the chronic complications of diabetes and is a cause of significant disability and poor quality of life. This incurs a significant burden on health care costs and society, especially as these young people enter their peak working and earning capacity at the time when diabetes-related complications most often first occur. DPN is often asymptomatic during the early stages; however, once symptoms and overt deficits have developed, it cannot be reversed. Therefore, early diagnosis and timely intervention are essential to prevent the development and progression of diabetic neuropathy. The diagnosis of DPN, the determination of the global prevalence, and incidence rates of DPN remain challenging. The opinions vary about the effectiveness of the expansion of screenings to enable early diagnosis and treatment initiation before disease onset and progression. Although research has evolved over the years, DPN still represents an enormous burden for clinicians and health systems worldwide due to its difficult diagnosis, high costs related to treatment, and the multidisciplinary approach required for effective management. Therefore, there is an unmet need for reliable surrogate biomarkers to monitor the onset and progression of early neuropathic changes in DPN and facilitate drug discovery. In this review paper, the aim was to assess the currently available tests for DPN's sensitivity and performance.

Small Fibre Neuropathy Is Associated With Impaired Vascular Endothelial Function in Patients With Type 2 Diabetes.

Diabetic polyneuropathy (DPN) and endothelial dysfunction are prevalent complications of diabetes mellitus. Currently, there are two non-invasive markers for endothelial dysfunction: flow-mediated dilation and reactive hyperaemia peripheral arterial tonometry (RH-PAT). However, the relationship between diabetic small fibre neuropathy and macroangiopathy remains obscure thus far. Corneal confocal microscopy (CCM) has emerged as a new diagnostic modality to assess DPN, especially of small fibre. To clarify the relationship between diabetic small fibre neuropathy and vascular dysfunction, we aimed to determine the functions of peripheral nerves and blood vessels through clinical tests such as nerve conduction study, coefficient of variation in the R-R interval, CCM, and RH-PAT in 82 patients with type 2 diabetes. Forty healthy control subjects were also included to study corneal nerve parameters. Correlational and multiple linear regression analyses were performed to determine the associations between neuropathy indices and markers for vascular functions. The results revealed that patients with type 2 diabetes had significantly lower values for most variables of CCM than healthy control subjects. RH-PAT solely remained as an explanatory variable significant in multiple regression analysis for several CCM parameters and vice versa. Other vascular markers had no significant multiple regression with any CCM parameters. In conclusion, endothelial dysfunction as revealed by impaired RH-PAT was significantly associated with CCM parameters in patients with type 2 diabetes. This association may indicate that small fibre neuropathy results from impaired endothelial dysfunction in type 2 diabetes. CCM parameters may be considered surrogate markers of autonomic nerve damage, which is related to diabetic endothelial dysfunction. This study is the first to report the relationship between corneal nerve parameter as small fibre neuropathy in patients with type 2 diabetes and RH-PAT as a marker of endothelial dysfunction.

Early detection of neuropathy in patients with type 2 diabetes with or without microalbuminuria in the absence of peripheral neuropathy and retinopathy.

PURPOSE: Our goal is early detection of neuropathy in patients with type 2 diabetes with or without microalbuminuria in the absence of diabetic retinopathy and peripheral neuropathy by using in vivo corneal confocal microscopy (IVCCM). METHODS: A total of 60 type-2 diabetic patients, assigned to either a diabetes mellitus (DM) with microalbuminuria group (DM/MA+, n=30) or a DM without microalbuminuria group (DM/MA-, n=30), and 30 age-matched control subjects were enrolled in this study. All cases underwent evaluation of blood glucose level, HbA1c, lipid fractions, body mass index (BMI), and corneal sensitivity (CS). Corneal nerve fiber length (NFL), nerve fiber density (NFD), nerve branch density (NBD), and tortuosity coefficient (TC) were quantified by IVCCM. None of the patients had peripheral neuropathy or retinopathy. RESULTS: Compared with the healthy subjects, NFL and NFD were reduced in both diabetic groups (P<0.0001), while NBD was significantly reduced in the DM/MA+ group. Between the diabetic groups, NFL, NFD, and NBD were significantly higher in the DM/MA- group (all P's<0.001). CS was significantly lower in DM/MA+ compared with DM/MA- and controls (both P's<0.0001). NFD and NFL were inversely correlated with age, triglyceride level, and BMI. CONCLUSION: These results indicate that significant damage to small nerves, quantified using IVCCM, can be detected in the absence of retinopathy, peripheral neuropathy or microalbuminuria in type 2 diabetic patients. The severity of corneal nerve involvement may further increase in the presence of nephropathy. This feature may also be valuable for early detection of microvascular complications of DM, allowing for the prevention of progression of life threatening microvascular complications.