Estudio de la conectividad estructural y genética del cerebro humano

El cerebro humano, pese a su homogénea apariencia externa, presenta un intrincado patrón de conexiones internas que interconectan las diferentes regiones cerebrales. Estas conexiones, conocidas como tractos neuronales, están formadas por miles de neuronas agrupadas de forma ordenada y son la base de la correcta intercomunicación en un cerebro sano. Los recientes avances en técnicas de neuroimagen y análisis genético han dado pie a diversos estudios que apuntan a que la genética podría jugar un rol fundamental en la construcción y correcto funcionamiento de los tractos neuronales. El presente Trabajo Fin de Máster busca avanzar en la comprensión sobre cómo la expresión genética determina o condiciona la interconexión entre las distintas regiones cerebrales. Para ello, se ha llevado a cabo en primer lugar un preprocesado de datos de expresión genética que han permitido su adecuación a los análisis planteados en éste y futuros trabajos. Los análisis realizados parten de un enfoque basado en la ciencia de redes donde el cerebro es modelado como una red o grafo que es posteriormente analizado desde múltiples vertientes. En un primer análisis estadístico se ha estudiado si regiones genéticamente similares tienen mayor probabilidad de estar conectadas. Posteriormente, se ha observado en qué medida criterios basados en genética o conectividad agrupan las regiones cerebrales de forma distinta. Finalmente, se ha planteado el uso de técnicas de procesado de señal sobre grafos como una nueva herramienta de análisis. Este enfoque permite obtener una representación frecuencial de los patrones de expresión genética, y ha sido introducido para mejorar la comprensión de dichos patrones.The human brain, despite its external homogeneous appearance, hides a complex intern pattern of connections that interconnect the different brain regions. Underneath the brain surface, thousands of neurons group together in an organized way to form the so-called neural tracts. These connections are the basis of a correct intercommunication in a healthy brain. Recent progress in both neuroimaging and genetic analysis techniques has given rise to several studies that, all together, point to a fundamental role of genomics in the development and correct functioning of neural tracts. The aim of this Master’s Thesis is to improve the understanding of how genetic expression actually determines the interconnection between brain regions. In this sense, several steps of preprocessing were carried out to adapt genetic expression data for further analysis performed in this and future projects. Following a network science approach, the brain was modelled as a network or graph that was later studied using different analysis types. In a first statistical analysis, it was tested whether genetically similar regions are more likely to be connected or not. Later, the way brain regions group together based on different genetic and connectivity criteria was observed. Finally, a novel approach based on graph signal processing techniques was proposed. More specifically, a spectral representation of genetic data was used to better understand gene expression patterns along the brain.Giza garunak, nahiz eta kanpotik itxura homogeneoa eduki, garun eskualde ezberdinak konektatzen dituen konexio patroi korapilatsua aurkezten du barrutik. Traktu neuronalak deritzen konexio hauek era antolatuan elkartutako milaka neuronaz osatuta daude, eta garun osasuntsu batetan barne komunikazioaren oinarria dira. Neuroirudi eta analisi genetikoen arloetako azken aurrerapenak ikerketa lan ugari sustatu dituzte. Dirudienez, lortutako emaitzak traktu neuronalen garapen eta funtzionamendu egokietan genetikak garrantzi handia daukala antzematen dute. Master Amaierako Lan honen helburu nagusia adierazpen genetiko eta garun eskualdeen interkomunikazioaren arteko erlazioaren ulermenean aurrera egitea da. Horretarako, lehenik eta behin, adierazpen genetikoko datu-baseen tratamendu eta egokitzapen prozesu bat jarraitu da. Prozesu honen emaitzak lan honetan egindako analisiak eta baita etorkizuneko beste lan batzuetan egin daitezkeenak posible egin ditu. Egindako analisi guztiak sare-zientzian oinarritutako ikuspegitik garatu dira. Honen arabera, giza garuna sare edo grafo bat balitz bezala modelatu eta ikertu egin da. Lehen urrats batean, analisi estatistikoa erabili da genetikoki antzekoak diren garun eskualdeak konektatuta egoteko probabilitate handiagoa ote duten aztertzeko. Ondoren, garun eskualdeak genetika edo konektibitatea banaka kontuan hartuta nola elkartzen diren aztertu da. Azkenik, grafoen domeinurako egokitutako seinale tratamendu teknikak erabiliz, gene adierazpen balioen maiztasun irudikapenak kalkulatu dira. Balio hauek aztertuz, adierazpen patroiak hobeto ulertzea izan da helburua

Foveal Pit Morphology Characterization: A Quantitative Analysis of the Key Methodological Steps

Disentangling the cellular anatomy that gives rise to human visual perception is one of the main challenges of ophthalmology. Of particular interest is the foveal pit, a concave depression located at the center of the retina that captures light from the gaze center. In recent years, there has been a growing interest in studying the morphology of the foveal pit by extracting geometrical features from optical coherence tomography (OCT) images. Despite this, research has devoted little attention to comparing existing approaches for two key methodological steps: the location of the foveal center and the mathematical modelling of the foveal pit. Building upon a dataset of 185 healthy subjects imaged twice, in the present paper the image alignment accuracy of four different foveal center location methods is studied in the first place. Secondly, state-of-the-art foveal pit mathematical models are compared in terms of fitting error, repeatability, and bias. The results indicate the importance of using a robust foveal center location method to align images. Moreover, we show that foveal pit models can improve the agreement between different acquisition protocols. Nevertheless, they can also introduce important biases in the parameter estimates that should be considered

Spatial characterization of the effect of age and sex on macular layer thicknesses and foveal pit morphology

Characterizing the effect of age and sex on macular retinal layer thicknesses and foveal pit morphology is crucial to differentiating between natural and disease-related changes. We applied advanced image analysis techniques to optical coherence tomography (OCT) to: 1) enhance the spatial description of age and sex effects, and 2) create a detailed open database of normative retinal layer thickness maps and foveal pit shapes. The maculae of 444 healthy subjects (age range 21–88) were imaged with OCT. Using computational spatial data analysis, thickness maps were obtained for retinal layers and averaged into 400 (20 x 20) sectors. Additionally, the geometry of the foveal pit was radially analyzed by computing the central foveal thickness, rim height, rim radius, and mean slope. The effect of age and sex on these parameters was analyzed with multiple regression mixed-effects models. We observed that the overall age-related decrease of the total retinal thickness (TRT) (-1.1% per 10 years) was mainly driven by the ganglion cell-inner plexiform layer (GCIPL) (-2.4% per 10 years). Both TRT and GCIPL thinning patterns were homogeneous across the macula when using percentual measurements. Although the male retina was 4.1 μm thicker on average, the greatest differences were mainly present for the inner retinal layers in the inner macular ring (up to 4% higher TRT than in the central macula). There was an age-related decrease in the rim height (1.0% per 10 years) and males had a higher rim height, shorter rim radius, and steeper mean slope. Importantly, the radial analysis revealed that these changes are present and relatively uniform across angular directions. These findings demonstrate the capacity of advanced analysis of OCT images to enhance the description of the macula. This, together with the created dataset, could aid the development of more accurate diagnosis models for macular pathologies

Caracterización de la morfología foveal: parametrización, diferencias de sexo y efectos de la edad

Frente a los análisis convencionales de grosores de la retina, el análisis morfológico de la fóvea presenta una metodología alternativa de gran potencial pero poco explorada. En este estudio se implementa un pipeline completo de análisis morfológico basado en imágenes OCT (Optical Coherence Tomography), comparando los modelos matemáticos existentes para estudiar la fóvea y demostrando su capacidad de ajuste y mejora de la fiabilidad test-retest. Asimismo, se analiza la influencia de la edad y el sexo en parámetros morfológicos como la altura, anchura, pendiente o área de la fóvea en una cohorte de 272 sujetos sanos. Los resultados muestran un claro dimorfismo sexual en la fóvea junto con relevantes cambios experimentados durante el envejecimiento

Foveal Pit Morphology Characterization: A Quantitative Analysis of the Key Methodological Steps

Disentangling the cellular anatomy that gives rise to human visual perception is one of the main challenges of ophthalmology. Of particular interest is the foveal pit, a concave depression located at the center of the retina that captures light from the gaze center. In recent years, there has been a growing interest in studying the morphology of the foveal pit by extracting geometrical features from optical coherence tomography (OCT) images. Despite this, research has devoted little attention to comparing existing approaches for two key methodological steps: the location of the foveal center and the mathematical modelling of the foveal pit. Building upon a dataset of 185 healthy subjects imaged twice, in the present paper the image alignment accuracy of four different foveal center location methods is studied in the first place. Secondly, state-of-the-art foveal pit mathematical models are compared in terms of fitting error, repeatability, and bias. The results indicate the importance of using a robust foveal center location method to align images. Moreover, we show that foveal pit models can improve the agreement between different acquisition protocols. Nevertheless, they can also introduce important biases in the parameter estimates that should be considered.This research was funded by the Department of Health of the Basque Government through the projects 2019111100 and 2020333033, Instituto de Salud Carlos III through the project PI16/00005 (Co-funded by European Regional Development Fund/European Social Fund “A way to make Europe”/”Investing in your future”) and the Basque Foundation for Health Innovation and Research (BIOEF) through the 2017 EITB Telemaratoia call (BIO17/ND/010)

Spatial characterization of the effect of age and sex on macular layer thicknesses and foveal pit morphology

Characterizing the effect of age and sex on macular retinal layer thicknesses and foveal pit morphology is crucial to differentiating between natural and disease-related changes. We applied advanced image analysis techniques to optical coherence tomography (OCT) to: 1) enhance the spatial description of age and sex effects, and 2) create a detailed open database of normative retinal layer thickness maps and foveal pit shapes. The maculae of 444 healthy subjects (age range 21–88) were imaged with OCT. Using computational spatial data analysis, thickness maps were obtained for retinal layers and averaged into 400 (20 x 20) sectors. Additionally, the geometry of the foveal pit was radially analyzed by computing the central foveal thickness, rim height, rim radius, and mean slope. The effect of age and sex on these parameters was analyzed with multiple regression mixed-effects models. We observed that the overall age-related decrease of the total retinal thickness (TRT) (-1.1% per 10 years) was mainly driven by the ganglion cell-inner plexiform layer (GCIPL) (-2.4% per 10 years). Both TRT and GCIPL thinning patterns were homogeneous across the macula when using percentual measurements. Although the male retina was 4.1 μm thicker on average, the greatest differences were mainly present for the inner retinal layers in the inner macular ring (up to 4% higher TRT than in the central macula). There was an age-related decrease in the rim height (1.0% per 10 years) and males had a higher rim height, shorter rim radius, and steeper mean slope. Importantly, the radial analysis revealed that these changes are present and relatively uniform across angular directions. These findings demonstrate the capacity of advanced analysis of OCT images to enhance the description of the macula. This, together with the created dataset, could aid the development of more accurate diagnosis models for macular pathologies.This study was partially co-funded by the Instituto de Salud Carlos III (https://www.isciii.es) through the projects PI14/00679 (IG) and PI16/00005 (IG), by the Basque Foundation for Health Innovation and Research (https://www.bioef.org) through the project BIO17/ND/010 (IG), and by the Department of Health of the Basque Government (https://www.euskadi.eus/gobierno-vasco/departamento-salud) through the projects 2019111100 (IG), 2020333033(IG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Foveal remodeling of retinal microvasculature in Parkinson’s disease

[EN] Background: Retinal microvascular alterations have been previously described in Parkinson’s disease (PD) patients using optical coherence tomography angiography (OCT-A). However, an extensive description of retinal vascular morphological features, their association with PD-related clinical variables and their potential use as diagnostic biomarkers has not been explored. Methods: We performed a cross-sectional study including 49 PD patients (87 eyes) and 40 controls (73 eyes). Retinal microvasculature was evaluated with Spectralis OCT-A and cognitive status with Montreal Cognitive Assessment. Unified PD Rating Scale and disease duration were recorded in patients. We extracted microvascular parameters from superficial and deep vascular plexuses of the macula, including the area and circularity of foveal avascular zone (FAZ), skeleton density, perfusion density, vessel perimeter index, vessel mean diameter, fractal dimension (FD) and lacunarity using Python and MATLAB. We compared the microvascular parameters between groups and explored their association with thickness of macular layers and clinical outcomes. Data were analyzed with General Estimating Equations (GEE) and adjusted for age, sex, and hypertension. Logistic regression GEE models were fitted to predict diagnosis of PD versus controls from microvascular, demographic, and clinical data. The discrimination ability of models was tested with receiver operating characteristic curves. Results: FAZ area was significantly smaller in patients compared to controls in superficial and deep plexuses, whereas perfusion density, skeleton density, FD and lacunarity of capillaries were increased in the foveal zone of PD. In the parafovea, microvascular parameters of superficial plexus were associated with ganglion cellinner plexiform layer thickness, but this was mainly driven by PD with mild cognitive impairment. No such associations were observed in controls. FAZ area was negatively associated with cognition in PD (non-adjusted models). Foveal lacunarity, combined with demographic and clinical confounding factors, yielded an outstanding diagnostic accuracy for discriminating PD patients from controls. Conclusion: Parkinson’s disease patients displayed foveal microvascular alterations causing an enlargement of the vascular bed surrounding FAZ. Parafoveal microvascular alterations were less pronounced but were related to inner retinal layer thinning. Retinal microvascular abnormalities helped discriminating PD from controls. All this supports OCT-A as a potential non-invasive biomarker to reveal vascular pathophysiology and improve diagnostic accuracy in PD.This study was partially co-funded by the Instituto de Salud Carlos III through the projects PI14/00679 and PI16/00005 (co-funded by European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future”), and by the Department of Health of the Basque Government through the projects “2019111100” and “2020333033”

Periodontitis and outer retinal thickness:A cross-sectional analysis of the UK Biobank cohort

PurposePeriodontitis, a ubiquitous severe gum disease affecting the teeth and surrounding alveolar bone can heighten systemic inflammation. We investigated the association between very severe periodontitis and early biomarkers of age-related macular degeneration, in individuals with no eye disease.DesignCross-sectional analysis of the prospective community-based cohort United Kingdom (UK) Biobank.ParticipantsSixty-seven thousand three hundred eleven UK residents aged 40-70 years recruited between 2006-2010 underwent retinal imaging.MethodsMacular-centered optical coherence tomography images acquired at the baseline visit were segmented for retinal sublayer thicknesses. Very severe periodontitis was ascertained through a touchscreen questionnaire. Linear mixed effects regression modeled the association between very severe periodontitis and retinal sublayer thicknesses adjusting for age, sex, ethnicity, socioeconomic status, alcohol consumption, smoking status, diabetes mellitus, hypertension, refractive error, and previous cataract surgery.Main Outcome MeasuresPhotoreceptor layer (PRL) and retinal pigment epithelium-Bruch’s membrane (RPE-BM) thicknesses.ResultsAmong 36,897 participants included in the analysis, 1,571 (4.3%) reported very severe periodontitis. Affected individuals were older, lived in areas of greater socioeconomic deprivation and were more likely to be hypertensive, diabetic and current smokers (all p<0.001). On average, those with very severe periodontitis were myopic (-0.29 ± 2.40 diopters) while those unaffected were hyperopic (0.05 ± 2.27 diopters, p<0.001). Following adjusted analysis, very severe periodontitis was associated with thinner PRL (-0.55 μm, 95% CI: -0.97, -0.12, p=0.022) but there was no difference in RPE-BM thickness (0.00 μm, 95% CI: -0.12, 0.13, p=0.97). The association between PRL thickness and very severe periodontitis was modified by age (p<0.001). Stratifying individuals by age, thinner PRL was seen among those aged 60-69 years with disease (-1.19 μm, 95% CI: -1.85, -0.53, p<0.001) but not among those under 60 years.ConclusionsAmong those with no known eye disease, very severe periodontitis is statistically associated with a thinner PRL, consistent with incipient age-related macular degeneration. Optimizing oral hygiene may hold additional relevance for people at risk of degenerative retinal disease

Association Between Retinal Features From Multimodal Imaging and Schizophrenia

Importance: The potential association of schizophrenia with distinct retinal changes is of clinical interest but has been challenging to investigate because of a lack of sufficiently large and detailed cohorts./ Objective: To investigate the association between retinal biomarkers from multimodal imaging (oculomics) and schizophrenia in a large real-world population./ Design, Setting, and Participants: This cross-sectional analysis used data from a retrospective cohort of 154 830 patients 40 years and older from the AlzEye study, which linked ophthalmic data with hospital admission data across England. Patients attended Moorfields Eye Hospital, a secondary care ophthalmic hospital with a principal central site, 4 district hubs, and 5 satellite clinics in and around London, United Kingdom, and had retinal imaging during the study period (January 2008 and April 2018). Data were analyzed from January 2022 to July 2022./ Main Outcomes and Measures: Retinovascular and optic nerve indices were computed from color fundus photography. Macular retinal nerve fiber layer (RNFL) and ganglion cell–inner plexiform layer (mGC-IPL) thicknesses were extracted from optical coherence tomography. Linear mixed-effects models were used to examine the association between schizophrenia and retinal biomarkers./ Results: A total of 485 individuals (747 eyes) with schizophrenia (mean [SD] age, 64.9 years [12.2]; 258 [53.2%] female) and 100 931 individuals (165 400 eyes) without schizophrenia (mean age, 65.9 years [13.7]; 53 253 [52.8%] female) were included after images underwent quality control and potentially confounding conditions were excluded. Individuals with schizophrenia were more likely to have hypertension (407 [83.9%] vs 49 971 [48.0%]) and diabetes (364 [75.1%] vs 28 762 [27.6%]). The schizophrenia group had thinner mGC-IPL (−4.05 μm, 95% CI, −5.40 to −2.69; P = 5.4 × 10−9), which persisted when investigating only patients without diabetes (−3.99 μm; 95% CI, −6.67 to −1.30; P = .004) or just those 55 years and younger (−2.90 μm; 95% CI, −5.55 to −0.24; P = .03). On adjusted analysis, retinal fractal dimension among vascular variables was reduced in individuals with schizophrenia (−0.14 units; 95% CI, −0.22 to −0.05; P = .001), although this was not present when excluding patients with diabetes./ Conclusions and Relevance: In this study, patients with schizophrenia had measurable differences in neural and vascular integrity of the retina. Differences in retinal vasculature were mostly secondary to the higher prevalence of diabetes and hypertension in patients with schizophrenia. The role of retinal features as adjunct outcomes in patients with schizophrenia warrants further investigation.

Retinal Optical Coherence Tomography Features Associated With Incident and Prevalent Parkinson Disease

Background and objectives: Cadaveric studies have shown disease-related neurodegeneration and other morphological abnormalities in the retina of individuals with Parkinson disease (PD), however it remains unclear whether this can be reliably detected with in vivo imaging. We investigated inner retinal anatomy, measured using optical coherence tomography (OCT), in prevalent PD and subsequently assessed the association of these markers with the development of PD using a prospective research cohort.// Methods: This cross-sectional analysis used data from two studies. For the detection of retinal markers in prevalent PD, we used data from AlzEye, a retrospective cohort of 154,830 patients aged 40 years and over attending secondary care ophthalmic hospitals in London, UK between 2008 and 2018. For the evaluation of retinal markers in incident PD, we used data from UK Biobank, a prospective population-based cohort where 67,311 volunteers aged 40-69 years were recruited between 2006 and 2010 and underwent retinal imaging. Macular retinal nerve fibre layer (mRNFL), ganglion cell-inner plexiform layer (GCIPL), and inner nuclear layer (INL) thicknesses were extracted from fovea--centred OCT. Linear mixed effects models were fitted to examine the association between prevalent PD and retinal thicknesses. Hazard ratios for the association between time to PD diagnosis and retinal thicknesses were estimated using frailty models.// Results: Within the AlzEye cohort, there were 700 individuals with prevalent PD and 105,770 controls (mean age 65.5 ± 13.5 years, 51.7% female). Individuals with prevalent PD had thinner GCIPL (-2.12 μm, 95% confidence interval: -3.17, -1.07, p = 8.2 × 10⁻⁵) and INL (-0.99 μm, 95% confidence interval: -1.52, -0.47, p = 2.1 × 10⁻⁴). The UK Biobank included 50,405 participants (mean age 56.1 ± 8.2 years, 54.7% female), of whom 53 developed PD at a mean of 2653 ± 851 days. Thinner GCIPL (hazard ratio: 0.62 per standard deviation increase, 95% confidence interval: 0.46, 0.84, p=0.002) and thinner INL (hazard ratio: 0.70, 95% confidence interval: 0.51, 0.96, p=0.026) were also associated with incident PD.// Discussion: Individuals with PD have reduced thickness of the INL and GCIPL of the retina. Involvement of these layers several years before clinical presentation highlight a potential role for retinal imaging for at-risk stratification of PD