Epigenetic clock explains white matter hyperintensity burden irrespective of chronological age

In this manuscript we studied the relationship between WMH and biological age (B-age) in patients with acute stroke. We included in this study 247 patients with acute stroke recruited at Hospital del Mar having both epigenetic (DNA methylation) and magnetic resonance imaging data. WMH were measured using a semi-automated method. B-age was calculated using two widely used methods: the Hannum and Horvath formulas. We used multiple linear regression models to interrogate the role of B-age on WMH volume after adjusting for chronological age (C-age) and other covariables. Average C-age of the sample was 68.4 (±11.8) and we observed a relatively high median WMH volume (median = 8.8 c

New candidate blood biomarkers potentially associated with white matter hyperintensities progression

We aimed to discover blood biomarkers associated with longitudinal changes in white matter hyperintensities (WMH). This study was divided into a discovery phase and a replication phase. Subjects in both studies were patients with hypertension, aged 50-70, who underwent two magnetic resonance imaging (MRI) sessions and blood extractions over a 4-year follow-up period. In the discovery phase, we screened 1305 proteins in 12 subjects with WMH progression and in 12 matched control subjects. We found that 41 proteins were differentially expressed: 13 were upregulated and 28 were downregulated. We subsequently selected three biomarkers for replication in baseline and follow-up samples in 80 subjects with WMH progression and in 80 control subjects. The selected protein candidates for the replication were MMP9 (matrix metalloproteinase-9), which was higher in cases, MET (hepatocyte growth factor receptor) and ASAH2 (neutral ceramidase), which were both lower in cases of WMH progression. Baseline biomarker concentrations did not predict WMH progression. In contrast, patients with WMH progression presented a steeper decline in MET over time. Furthermore, cases showed higher MMP9 and lower ASAH2 levels than controls at the follow-up. These results indicate that MMP9, MET, and ASAH2 are potentially associated with the progression of WMH, and could therefore be interesting candidates to validate in future studie

New candidate blood biomarkers potentially associated with white matter hyperintensities progression

We aimed to discover blood biomarkers associated with longitudinal changes in white matter hyperintensities (WMH). This study was divided into a discovery phase and a replication phase. Subjects in both studies were patients with hypertension, aged 50-70, who underwent two magnetic resonance imaging (MRI) sessions and blood extractions over a 4-year follow-up period. In the discovery phase, we screened 1305 proteins in 12 subjects with WMH progression and in 12 matched control subjects. We found that 41 proteins were differentially expressed: 13 were upregulated and 28 were downregulated. We subsequently selected three biomarkers for replication in baseline and follow-up samples in 80 subjects with WMH progression and in 80 control subjects. The selected protein candidates for the replication were MMP9 (matrix metalloproteinase-9), which was higher in cases, MET (hepatocyte growth factor receptor) and ASAH2 (neutral ceramidase), which were both lower in cases of WMH progression. Baseline biomarker concentrations did not predict WMH progression. In contrast, patients with WMH progression presented a steeper decline in MET over time. Furthermore, cases showed higher MMP9 and lower ASAH2 levels than controls at the follow-up. These results indicate that MMP9, MET, and ASAH2 are potentially associated with the progression of WMH, and could therefore be interesting candidates to validate in future studie

Machine learning approximations to predict epigenetic age acceleration in stroke patients

Age acceleration (Age-A) is a useful tool that is able to predict a broad range of health outcomes. It is necessary to determine DNA methylation levels to estimate it, and it is known that Age-A is influenced by environmental, lifestyle, and vascular risk factors (VRF). The aim of this study is to estimate the contribution of these easily measurable factors to Age-A in patients with cerebrovascular disease (CVD), using different machine learning (ML) approximations, and try to find a more accessible model able to predict Age-A. We studied a CVD cohort of 952 patients with information about VRF, lifestyle habits, and target organ damage. We estimated Age-A using Hannum\u27s epigenetic clock, and trained six different models to predict Age-A: a conventional linear regression model, four ML models (elastic net regression (EN), K-Nearest neighbors, random forest, and support vector machine models), and one deep learning approximation (multilayer perceptron (MLP) model). The best-performing models were EN and MLP; although, the predictive capability was modest (

Epigenetic Clock Explains White Matter Hyperintensity Burden Irrespective of Chronological Age

In this manuscript we studied the relationship between WMH and biological age (B-age) in patients with acute stroke. We included in this study 247 patients with acute stroke recruited at Hospital del Mar having both epigenetic (DNA methylation) and magnetic resonance imaging data. WMH were measured using a semi-automated method. B-age was calculated using two widely used methods: the Hannum and Horvath formulas. We used multiple linear regression models to interrogate the role of B-age on WMH volume after adjusting for chronological age (C-age) and other covariables. Average C-age of the sample was 68.4 (±11.8) and we observed a relatively high median WMH volume (median = 8.8 cm3, Q1–Q3 = 4.05–18.8). After adjusting for potential confounders, we observed a significant effect of B-ageHannum on WMH volume (βHannum = 0.023, p-value = 0.029) independently of C-age, which remained significant (βC-age = 0.021, p-value = 0.036). Finally, we performed a mediation analysis, which allowed us to discover that 42.7% of the effect of C-age on WMH is mediated by B-ageHannum. On the other hand, B-ageHoarvath showed no significant associations with WMH after being adjusted for C-age. In conclusion, we show for the first time that biological age, measured through DNA methylation, contributes substantially to explain WMH volumetric burden irrespective of chronological age

Progresión de la enfermedad de pequeño vaso cerebral: factores de riesgo, mecanismos implicados y consecuencias clínicas

Es calcula que la malaltia de petit vas cerebral (MPVC) és la causant del 20-25% dels ictus isquèmics i de fins al 45% de les demències. El seu estudi es realitza principalment avaluant les seves conseqüències en ressonància magnètica cerebral (RMC)—les lesions de la substància blanca (LSB), els microsangrats cerebrals, els infarts llacunars i els espais perivasculars dilatats—. La MPVC es caracteritza per un llarg període encobert en que aquests marcadors radiològics s’acumulen en el parènquima cerebral. Tot i que es coneix la presentació d’aquesta malaltia, els factors de risc i mecanismes implicats en la seva evolució no són ben coneguts. Tampoc es sap si ritmes de progressió més marcats es relacionen amb pitjors evolucions clíniques. Aquesta tesis s’ha realitzat en la cohort de l’estudi ISSYS (Investigating Silent Strokes in hYpertensives, a magnetic resonance imaging Study). Aquesta cohort està formada per 976 subjectes hipertensos de 50-70 anys, sense ictus ni demència prèvies. Entre 2010-2012 se’ls va realitzar una visita clínica, una RMC, una exploració cognitiva, la monitorització ambulatòria de la pressió arterial (MAPA) i es van recollir mostres de sang i orina. Entre 2014-2016 es va tornar a visitar a 356 pacients en una visita amb les mateixes característiques de la visita basal, el que ens va permetre avaluar la progressió de la MPVC, així com el canvi de la resta de variables. D’aquesta manera, hem vist que la progressió de la MPVC és altament prevalent en població hipertensa, observant que el 26.2% i el 9.9% dels subjectes presentaven una progressió significativa en 1 i ≥2 marcadors radiològic, respectivament. Aquesta progressió hem trobat que correlaciona amb el declivi de les funcions cognitives i amb l’aparició del diagnòstic de deteriorament cognitiu lleu —observat en el 9.1% de la mostra—. No obstant, això dependrà del grau, tipus i localització de les lesions, sent la progressió de les LSB periventriculars el marcador més associat amb l’empitjorament cognitiu. Anàlogament, mitjançant estudis de supervivència en tota la cohort (n=976), hem constatat que els pacients amb infarts cerebrals silents tenen un risc triplicat de patir un event de tipus cardiovascular. Altrament, la MAPA pot ajudar a predir l’aparició de les lesions, si bé els seus valors haurien de ser combinats amb altres fonts de informació, com els biomarcadors. D’aquesta manera hem vist que els marcadors de funció renal mostren un declivi paral·lel a la progressió de la MPVC i al deteriorament cognitiu. Per mitjà d’estudis proteòmics, hem proposat diverses molècules (MET, MMP9 i ASAH-2) que correlacionen amb l’evolució de les LSB i que serà interessant seguir estudiant el seu possible ús clínic i rol en la fisiopatologia de les LSB. Finalment, hem avaluat els espais perivasculars dilatats del hipocamp, i trobat que es relacionen amb altres lesions de la MPVC i la cognició. Això podria indicar que formen part del conjunt de canvis de la MPVC i que l’avaluació de la seva progressió podria ser un interessant objectiu futur.Se calcula que la enfermedad de pequeño vaso cerebral (EPVC) es la causante del 20-25% de los ictus isquémicos y de hasta el 45% de las demencias. Su estudio se realiza principalmente evaluando en resonancia magnética cerebral (RMC) sus consecuencias—las lesiones de la sustancia blanca (LSB), los microsangrados cerebrales, los infartos lacunares y los espacios perviasculares dilatados. La EPVC se caracteriza por un largo periodo encubierto en que estos marcadores radiológicos se acumulan en el parénquima cerebral. A pesar de que se conoce la presentación de esta enfermedad, los factores de riesgo y mecanismos implicados en su evolución no son bien conocidos. Tampoco se sabe si ritmos de progresión más marcados se relacionan con peores evoluciones clínicas. Esta tesis se ha realizado en la cohorte del estudio ISSYS (Investigating Silent Strokes in hYpertensives, a magnetic resonance imaging Study). Esta cohorte está formada por 976 sujetos hipertensos de 50-70 años, sin ictus o demencia previos. En 2010-2012 se les realizó una visita clínica, una RMC, una exploración cognitiva, la monitorización ambulatoria de la presión arterial (MAPA) y se tomaron muestras de sangre y orina. En 2014-2016 se volvió a visitar a 356 pacientes en una visita con las mismas características que la visita basal, lo que nos permitió evaluar la progresión de la EPVC, así como el cambio del resto de variables. De este modo, hemos visto que la progresión de la EPVC es altamente prevalente en población hipertensa, observando que el 26.2% y el 9.9% de los sujetos presentaron una progresión significativa en 1 y ≥2 marcadores radiológicos, respectivamente. Esta progresión hemos encontrado que correlaciona con el declive de las funciones cognitivas y con la aparición del diagnóstico de deterioro cognitivo leve —observado en el 9.1% de la muestra—. No obstante, esto dependerá del grado, tipo y localización de las lesiones, siendo la progresión de las LSB periventriculares el marcador más asociado con el empeoramiento cognitivo. Análogamente, mediante estudios de supervivencia en toda la cohorte (n=976) hemos constatado que los pacientes con infartos cerebrales silentes tienen un riesgo triplicado de padecer un evento de tipo cardiovascular. Por otro lado, la MAPA puede ayudar a predecir la aparición de las lesiones, si bien sus valores deberían ser combinados con otras fuentes de información, como los biomarcadores. Así que hemos visto que los marcadores de función renal muestran un declive paralelo a la progresión de la EPVC y al deterioro cognitivo. Por medio de estudios proteómicos hemos propuesto diversas moléculas (MET, MMP9, ASAH-2) que correlacionan con la evolución de las LSB y será interesante seguir estudiando su posible uso clínico y rol en la fisiopatología de las LSB. Finalmente, hemos evaluado los espacios perivasculares dilatados del hipocampo, y encontrado que se relacionan con otras lesiones de la EPVC y con la cognición. Esto podría indicar que forman parte del conjunto de cambios de la EPVC y que la evaluación de su progresión podría ser un interesante objetivo futuro.Cerebral small vessel disease may be the cause of up to 20-25% of ischemic strokes and 45% of dementia cases. CSVD is principally studied by assessing its consequences via magnetic resonance imaging (MRI) —white matter hyperintensities (WMH), cerebral microbleeds, lacunar infarcts and enlarged perivascular spaces—. CSVD presents a long subclinical course in which these markers may accumulate on brain parenchyma. Although we know the radiological markers of cSVD, nowadays the vascular risk factors and implicated mechanisms in their progression are not well understood. Furthermore, it is unknown whether to present a marked progression of cSVD is associated with a worse clinical evolution. This thesis has been conducted in the ISSYS study (Investigating Silent Strokes in hYpertensives, a magnetic resonance imaging Study). This cohort is composed of 976 patients with hypertension aged 50-70, and dementia and stroke-free. Between 2010 and 2012 they underwent a clinical visit, a MRI, a cognitive evaluation, the ambulatory blood pressure monitoring (ABPM), and a urine and blood sampling collection. Between 2014 and 2016 a sample consisting of 356 subjects underwent a second visit with the same characteristics as at the baseline. In this sample we could evaluate the progression of cSVD, as well as the change in the rest of variables. Thereby, we observed that the progression of cSVD is a prevalent phenomenon in patients with hypertension. Concretely, 26.2% and 9.9% of subjects showed 1 and ≥ 2 incident cSVD lesions over the follow-up, respectively. This progression was correlated with the decline in cognition and incident mild cognitive impairment diagnosis —9.1% of the sample—. However, this relationship depends on the severity of these changes, and the type and localization of the lesion/s. Periventricular WMH was the marker of cSVD which was more significantly associated with cognitive decline. Similarly, by means of a survival analysis conducted in the complete cohort (n=976) we found that patients with silent brain infarcts were at three-fold increased risk of suffer an incident cardiovascular event within 5 years. On the other hand, ABPM may help to predict the progression of cSVD, although its information should be combined with other variables (e.g., clinical information, blood biomarkers) in order to achieve a clinically significant predictive model. Markers of kidney function (microalbuminuria and estimated glomerular filtration rate) presented a parallel decline with the progression of cSVD and cognitive impairment. Hence, these markers may help to identify patients at risk of progression of cSVD. Moreover, by means of a proteomic study, we proposed several proteins which were correlated with the progression of WMH (MET, MMP9, ASAH-2). Therefore, to study the clinical usefulness of these molecules in future studies, as well as their role in the pathophysiology of WMH, may be of greater interest. Finally, we assessed the burden of hippocampal enlarged perivascular spaces in the sample. We found that these radiological markers were related to other cSVD lesions and to cognitive performance. These results may indicate that hippocampal enlarged perivascular spaces are part of cSVD manifestations. Hence, further research should determine their progression in additional longitudinal studies

Progresión de la enfermedad de pequeño vaso cerebral: factores de riesgo, mecanismos implicados y consecuencias clínicas /

Departament responsable de la tesi: Departament de Bioquímica i Biologia Molecular.Es calcula que la malaltia de petit vas cerebral (MPVC) és la causant del 20-25% dels ictus isquèmics i de fins al 45% de les demències. El seu estudi es realitza principalment avaluant les seves conseqüències en ressonància magnètica cerebral (RMC)-les lesions de la substància blanca (LSB), els microsangrats cerebrals, els infarts llacunars i els espais perivasculars dilatats-. La MPVC es caracteritza per un llarg període encobert en que aquests marcadors radiològics s'acumulen en el parènquima cerebral. Tot i que es coneix la presentació d'aquesta malaltia, els factors de risc i mecanismes implicats en la seva evolució no són ben coneguts. Tampoc es sap si ritmes de progressió més marcats es relacionen amb pitjors evolucions clíniques. Aquesta tesis s'ha realitzat en la cohort de l'estudi ISSYS (Investigating Silent Strokes in hYpertensives, a magnetic resonance imaging Study). Aquesta cohort està formada per 976 subjectes hipertensos de 50-70 anys, sense ictus ni demència prèvies. Entre 2010-2012 se'ls va realitzar una visita clínica, una RMC, una exploració cognitiva, la monitorització ambulatòria de la pressió arterial (MAPA) i es van recollir mostres de sang i orina. Entre 2014-2016 es va tornar a visitar a 356 pacients en una visita amb les mateixes característiques de la visita basal, el que ens va permetre avaluar la progressió de la MPVC, així com el canvi de la resta de variables. D'aquesta manera, hem vist que la progressió de la MPVC és altament prevalent en població hipertensa, observant que el 26.2% i el 9.9% dels subjectes presentaven una progressió significativa en 1 i ≥2 marcadors radiològic, respectivament. Aquesta progressió hem trobat que correlaciona amb el declivi de les funcions cognitives i amb l'aparició del diagnòstic de deteriorament cognitiu lleu -observat en el 9.1% de la mostra-. No obstant, això dependrà del grau, tipus i localització de les lesions, sent la progressió de les LSB periventriculars el marcador més associat amb l'empitjorament cognitiu. Anàlogament, mitjançant estudis de supervivència en tota la cohort (n=976), hem constatat que els pacients amb infarts cerebrals silents tenen un risc triplicat de patir un event de tipus cardiovascular. Altrament, la MAPA pot ajudar a predir l'aparició de les lesions, si bé els seus valors haurien de ser combinats amb altres fonts de informació, com els biomarcadors. D'aquesta manera hem vist que els marcadors de funció renal mostren un declivi paral·lel a la progressió de la MPVC i al deteriorament cognitiu. Per mitjà d'estudis proteòmics, hem proposat diverses molècules (MET, MMP9 i ASAH-2) que correlacionen amb l'evolució de les LSB i que serà interessant seguir estudiant el seu possible ús clínic i rol en la fisiopatologia de les LSB. Finalment, hem avaluat els espais perivasculars dilatats del hipocamp, i trobat que es relacionen amb altres lesions de la MPVC i la cognició. Això podria indicar que formen part del conjunt de canvis de la MPVC i que l'avaluació de la seva progressió podria ser un interessant objectiu futur.Se calcula que la enfermedad de pequeño vaso cerebral (EPVC) es la causante del 20-25% de los ictus isquémicos y de hasta el 45% de las demencias. Su estudio se realiza principalmente evaluando en resonancia magnética cerebral (RMC) sus consecuencias-las lesiones de la sustancia blanca (LSB), los microsangrados cerebrales, los infartos lacunares y los espacios perviasculares dilatados. La EPVC se caracteriza por un largo periodo encubierto en que estos marcadores radiológicos se acumulan en el parénquima cerebral. A pesar de que se conoce la presentación de esta enfermedad, los factores de riesgo y mecanismos implicados en su evolución no son bien conocidos. Tampoco se sabe si ritmos de progresión más marcados se relacionan con peores evoluciones clínicas. Esta tesis se ha realizado en la cohorte del estudio ISSYS (Investigating Silent Strokes in hYpertensives, a magnetic resonance imaging Study). Esta cohorte está formada por 976 sujetos hipertensos de 50-70 años, sin ictus o demencia previos. En 2010-2012 se les realizó una visita clínica, una RMC, una exploración cognitiva, la monitorización ambulatoria de la presión arterial (MAPA) y se tomaron muestras de sangre y orina. En 2014-2016 se volvió a visitar a 356 pacientes en una visita con las mismas características que la visita basal, lo que nos permitió evaluar la progresión de la EPVC, así como el cambio del resto de variables. De este modo, hemos visto que la progresión de la EPVC es altamente prevalente en población hipertensa, observando que el 26.2% y el 9.9% de los sujetos presentaron una progresión significativa en 1 y ≥2 marcadores radiológicos, respectivamente. Esta progresión hemos encontrado que correlaciona con el declive de las funciones cognitivas y con la aparición del diagnóstico de deterioro cognitivo leve -observado en el 9.1% de la muestra-. No obstante, esto dependerá del grado, tipo y localización de las lesiones, siendo la progresión de las LSB periventriculares el marcador más asociado con el empeoramiento cognitivo. Análogamente, mediante estudios de supervivencia en toda la cohorte (n=976) hemos constatado que los pacientes con infartos cerebrales silentes tienen un riesgo triplicado de padecer un evento de tipo cardiovascular. Por otro lado, la MAPA puede ayudar a predecir la aparición de las lesiones, si bien sus valores deberían ser combinados con otras fuentes de información, como los biomarcadores. Así que hemos visto que los marcadores de función renal muestran un declive paralelo a la progresión de la EPVC y al deterioro cognitivo. Por medio de estudios proteómicos hemos propuesto diversas moléculas (MET, MMP9, ASAH-2) que correlacionan con la evolución de las LSB y será interesante seguir estudiando su posible uso clínico y rol en la fisiopatología de las LSB. Finalmente, hemos evaluado los espacios perivasculares dilatados del hipocampo, y encontrado que se relacionan con otras lesiones de la EPVC y con la cognición. Esto podría indicar que forman parte del conjunto de cambios de la EPVC y que la evaluación de su progresión podría ser un interesante objetivo futuro.Cerebral small vessel disease may be the cause of up to 20-25% of ischemic strokes and 45% of dementia cases. CSVD is principally studied by assessing its consequences via magnetic resonance imaging (MRI) -white matter hyperintensities (WMH), cerebral microbleeds, lacunar infarcts and enlarged perivascular spaces-. CSVD presents a long subclinical course in which these markers may accumulate on brain parenchyma. Although we know the radiological markers of cSVD, nowadays the vascular risk factors and implicated mechanisms in their progression are not well understood. Furthermore, it is unknown whether to present a marked progression of cSVD is associated with a worse clinical evolution. This thesis has been conducted in the ISSYS study (Investigating Silent Strokes in hYpertensives, a magnetic resonance imaging Study). This cohort is composed of 976 patients with hypertension aged 50-70, and dementia and stroke-free. Between 2010 and 2012 they underwent a clinical visit, a MRI, a cognitive evaluation, the ambulatory blood pressure monitoring (ABPM), and a urine and blood sampling collection. Between 2014 and 2016 a sample consisting of 356 subjects underwent a second visit with the same characteristics as at the baseline. In this sample we could evaluate the progression of cSVD, as well as the change in the rest of variables. Thereby, we observed that the progression of cSVD is a prevalent phenomenon in patients with hypertension. Concretely, 26.2% and 9.9% of subjects showed 1 and ≥ 2 incident cSVD lesions over the follow-up, respectively. This progression was correlated with the decline in cognition and incident mild cognitive impairment diagnosis -9.1% of the sample-. However, this relationship depends on the severity of these changes, and the type and localization of the lesion/s. Periventricular WMH was the marker of cSVD which was more significantly associated with cognitive decline. Similarly, by means of a survival analysis conducted in the complete cohort (n=976) we found that patients with silent brain infarcts were at three-fold increased risk of suffer an incident cardiovascular event within 5 years. On the other hand, ABPM may help to predict the progression of cSVD, although its information should be combined with other variables (e.g., clinical information, blood biomarkers) in order to achieve a clinically significant predictive model. Markers of kidney function (microalbuminuria and estimated glomerular filtration rate) presented a parallel decline with the progression of cSVD and cognitive impairment. Hence, these markers may help to identify patients at risk of progression of cSVD. Moreover, by means of a proteomic study, we proposed several proteins which were correlated with the progression of WMH (MET, MMP9, ASAH-2). Therefore, to study the clinical usefulness of these molecules in future studies, as well as their role in the pathophysiology of WMH, may be of greater interest. Finally, we assessed the burden of hippocampal enlarged perivascular spaces in the sample. We found that these radiological markers were related to other cSVD lesions and to cognitive performance. These results may indicate that hippocampal enlarged perivascular spaces are part of cSVD manifestations. Hence, further research should determine their progression in additional longitudinal studies

Diabetes, Albuminuria and the Kidney-Brain Axis

Cognitive decline and kidney disease are significant public health problems that share similar characteristics and risk factors. The pathophysiology of the kidney-brain axis is not completely understood, and studies analysing the relationship between the biomarkers of kidney damage and cognitive impairment show different results. This article focuses on the epidemiological and clinical aspects concerning the association of albuminuria, a marker for endothelial dysfunction and microvascular disease, and cognitive impairment in patients with chronic kidney disease, diabetic kidney disease and end-stage kidney disease. Most studies show a positive relationship between albuminuria and cognitive impairment in all groups, but evidence in type 2 diabetes (T2D) patients is limited. We briefly discuss the mechanisms underlying these associations, such as damage to the microvascular circulation, leading to hypoperfusion and blood pressure fluctuations, as well as increased inflammation and oxidative stress, both in the brain and in the kidneys. Further clinical and epidemiological studies developed to understand the interplay between the kidneys and brain diseases will hopefully lead to a reduction in cognitive impairment in these patient

Genetics and epigenetics of spontaneous intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a complex and heterogeneous disease, and there is no effective treatment. Spontaneous ICH represents the final manifestation of different types of cerebral small vessel disease, usually categorized as: lobar (mostly related to cerebral amyloid angiopathy) and nonlobar (hypertension-related vasculopathy) ICH. Accurate phenotyping aims to reflect these biological differences in the underlying mechanisms and has been demonstrated to be crucial to the success of genetic studies in this field. This review summarizes how current knowledge on genetics and epigenetics of this devastating stroke subtype are contributing to improve the understanding of ICH pathophysiology and their potential role in developing therapeutic strategies

Epigenetic Clock Explains White Matter Hyperintensity Burden Irrespective of Chronological Age

In this manuscript we studied the relationship between WMH and biological age (B-age) in patients with acute stroke. We included in this study 247 patients with acute stroke recruited at Hospital del Mar having both epigenetic (DNA methylation) and magnetic resonance imaging data. WMH were measured using a semi-automated method. B-age was calculated using two widely used methods: the Hannum and Horvath formulas. We used multiple linear regression models to interrogate the role of B-age on WMH volume after adjusting for chronological age (C-age) and other covariables. Average C-age of the sample was 68.4 (±11.8) and we observed a relatively high median WMH volume (median = 8.8 cm3, Q1–Q3 = 4.05–18.8). After adjusting for potential confounders, we observed a significant effect of B-ageHannum on WMH volume (βHannum = 0.023, p-value = 0.029) independently of C-age, which remained significant (βC-age = 0.021, p-value = 0.036). Finally, we performed a mediation analysis, which allowed us to discover that 42.7% of the effect of C-age on WMH is mediated by B-ageHannum. On the other hand, B-ageHoarvath showed no significant associations with WMH after being adjusted for C-age. In conclusion, we show for the first time that biological age, measured through DNA methylation, contributes substantially to explain WMH volumetric burden irrespective of chronological age