Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagno...
Amyotrophic lateral sclerosis (ALS) is an invariably fatal neurodegenerative disease with limited... more Amyotrophic lateral sclerosis (ALS) is an invariably fatal neurodegenerative disease with limited therapeutic options. There is an urgent need for novel biomarkers to be used as surrogates for new therapeutic trials and disease monitoring. In this study, we sought to systematically study creatine kinase isoenzyme MB (CK-MB) in a real-world cohort of ALS patients, assess the diagnostic performance, and evaluate its association with other laboratory and clinical parameters. We reviewed data from 194 consecutive patients that included 130 ALS patients and 64 disease control patients (primary lateral sclerosis [PLS], benign fasciculations syndrome [BFS], Huntington’s disease [HD] and Alzheimer’s disease [AD]). CK-MB was elevated in the sera of more than half of all patients with ALS. In patients with spinal-onset ALS, CK-MB levels were significantly higher than in patients with other neurodegenerative diseases. Patients with slower rates of functional decline had a significantly higher ...
Superficial siderosis of the central nervous system (SS-CNS) is a rare condition characterized by... more Superficial siderosis of the central nervous system (SS-CNS) is a rare condition characterized by a hemosiderin accumulation along the subpial surfaces and arises from an intermittent chronic bleeding in the subarachnoid space usually as a result of a chronic subarachnoid hemorrhage by trauma, vascular malformations, CNS tumors, or cerebral amyloid angiopathy (CAA). We present a 61-year-old male with a 12-year history of limb weakness, muscle wasting, cramps, clumsiness, progressive unsteady gait, and fine motor impairments. His medical history included the resection of a left parietal meningioma and a myxopapillary ependymoma near the conus terminalis (L3/4) at the age of 51 years. The clinical examination revealed a motor neuron syndrome with a clear bilateral wasting of the hand muscles, a diffuse atrophy of the shoulder and calf muscles, and a weakness of the arms, fingers, hips, and feet. Deep tendon reflexes were symmetrically briskly hyperactive. Standing and walking were onl...
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by progres... more Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Diagnosis, management and therapeutic trials are hampered by a lack of informative biomarkers. Troponins are components of skeletal and cardiac muscles. Acute elevation of cardiac isoforms of troponin I and T in serum indicates myocardial injury. Case reports suggested that serum levels of cardiac troponin T, but not cardiac troponin I are chronically elevated in myotrophic lateral sclerosis and other neuromuscular disorders. Using standard clinical laboratory methodologies, we studied serum troponin levels in a multicentric cross-sectional cohort of 75 amyotrophic lateral sclerosis patients and 30 Alzheimer’s disease controls and 29 healthy controls (DESCRIBE-ALS cohort) and in a real-world cohort of 179 consecutive patients from our amyotrophic lateral sclerosis clinic at the University Hospital Bonn. We found that serum cardiac troponin T is...
There is growing evidence that promising biomarkers of inflammation in Alzheimer´s disease (AD) a... more There is growing evidence that promising biomarkers of inflammation in Alzheimer´s disease (AD) and other neurodegenerative diseases correlate strongest to levels of tau or neurofilament, indicating an inflammatory response to neuronal damage or death. To test this hypothesis, we investigated three AD candidate markers (ferritin, fatty acid binding protein 3 (FABP‐3), and neurogranin) in interrelation to established AD and inflammatory protein markers. We further aimed to determine if such interrelations would be evident in pathological subjects only or also under non‐pathological circumstances. Cerebrospinal fluid levels of the three proteins were quantified in samples from the University Clinic of Bonn (UKB) Department of Neurodegenerative Diseases & Geriatric Psychiatry, Germany. Data were analyzed based on clinical or biomarker‐defined stratification of subjects with adjustment for covariates age, sex, and APOE status. Levels of ferritin, FABP‐3 and neurogranin were elevated in subjects with pathological levels of t‐tau independent of beta‐amyloid status. The three markers correlated with each other, tau isoforms, age, and those inflammatory markers previously described as related to neurodegeneration, predominantly sTREM2, macrophage migration inhibitory factor, soluble vascular endothelial growth factor receptor, soluble vascular cell adhesion molecule 1 (sVCAM‐1), and C1q. These interrelations existed in subjects with pathological and sub‐pathological tau levels, in particular for FABP‐3 and neurogranin. Relations to ferritin were independent of absolute levels of tau, too, but showed differing trajectories between pathological and non‐pathological subjects. A specific set of inflammatory markers is highly related to markers of neuronal damage such as tau, neurogranin, or FABP‐3. These proteins could be used as readouts of the inflammatory response during the neurodegeneration phase of AD.
IntroductionMultiple immunity biomarkers have been suggested as tracers of neuroinflammation in n... more IntroductionMultiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative–funded project AETIONOMY.MethodsA total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published.ResultsImmunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center‐specific factors.DiscussionImmunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariate...
Arc/Arg3.1, an activity regulated immediate early gene, is essential for learning and memory, syn... more Arc/Arg3.1, an activity regulated immediate early gene, is essential for learning and memory, synaptic plasticity, and maturation of neural networks. It has also been implicated in several neurodevelopmental disorders, including schizophrenia. Here, we used male and female constitutive and conditionalArc/Arg3.1knock-out (KO) mice to investigate the causal relationship betweenArc/Arg3.1deletion and schizophrenia-linked neurophysiological and behavioral phenotypes. Usingin vivolocal field potential recordings, we observed dampened oscillatory activity in the prefrontal cortex (PFC) of the KO and early conditional KO (early-cKO) mice, in whichArc/Arg3.1was deleted perinatally. Whole-cell patch-clamp recordings from neurons in PFC slices revealed altered synaptic properties and reduced network gain in the KO mice as possible mechanisms underlying the oscillation deficits. In contrast, we measured normal oscillatory activity in the PFC of late conditional KO (late-cKO) mice, in whichArc/...
Proceedings of the National Academy of Sciences, 2018
Significance Spatial learning and memory are hippocampal functions that emerge and mature during ... more Significance Spatial learning and memory are hippocampal functions that emerge and mature during early postnatal development. The molecular mechanisms which shape this process are largely unknown. Here, we present evidence that the activity-regulated gene Arc/Arg3.1 is transiently up-regulated in the hippocampus of neonatal mice where it is required for establishing appropriate hippocampal network activity essential for spatial learning. Once established, network activity supports normal spatial learning in the absence of Arc/Arg3.1 while long-term memory storage continues to rely on Arc/Arg3.1 expression throughout life. These results demonstrate that hippocampal networks undergo a critical period of development mediated by Arc/Arg3.1 and open opportunities to investigate normal and pathological neurodevelopment of higher brain functions.
En el Sistema Nervioso Central la expresión de genes dependiente de la actividad sináptica parece... more En el Sistema Nervioso Central la expresión de genes dependiente de la actividad sináptica parece ser un mecanismo importante en diversos procesos como la diferenciación neuronal, el ciclo circadiano, la supervivencia neural, la plasticidad sináptica y la consolidación de la memoria a largo plazo.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagno...
Amyotrophic lateral sclerosis (ALS) is an invariably fatal neurodegenerative disease with limited... more Amyotrophic lateral sclerosis (ALS) is an invariably fatal neurodegenerative disease with limited therapeutic options. There is an urgent need for novel biomarkers to be used as surrogates for new therapeutic trials and disease monitoring. In this study, we sought to systematically study creatine kinase isoenzyme MB (CK-MB) in a real-world cohort of ALS patients, assess the diagnostic performance, and evaluate its association with other laboratory and clinical parameters. We reviewed data from 194 consecutive patients that included 130 ALS patients and 64 disease control patients (primary lateral sclerosis [PLS], benign fasciculations syndrome [BFS], Huntington’s disease [HD] and Alzheimer’s disease [AD]). CK-MB was elevated in the sera of more than half of all patients with ALS. In patients with spinal-onset ALS, CK-MB levels were significantly higher than in patients with other neurodegenerative diseases. Patients with slower rates of functional decline had a significantly higher ...
Superficial siderosis of the central nervous system (SS-CNS) is a rare condition characterized by... more Superficial siderosis of the central nervous system (SS-CNS) is a rare condition characterized by a hemosiderin accumulation along the subpial surfaces and arises from an intermittent chronic bleeding in the subarachnoid space usually as a result of a chronic subarachnoid hemorrhage by trauma, vascular malformations, CNS tumors, or cerebral amyloid angiopathy (CAA). We present a 61-year-old male with a 12-year history of limb weakness, muscle wasting, cramps, clumsiness, progressive unsteady gait, and fine motor impairments. His medical history included the resection of a left parietal meningioma and a myxopapillary ependymoma near the conus terminalis (L3/4) at the age of 51 years. The clinical examination revealed a motor neuron syndrome with a clear bilateral wasting of the hand muscles, a diffuse atrophy of the shoulder and calf muscles, and a weakness of the arms, fingers, hips, and feet. Deep tendon reflexes were symmetrically briskly hyperactive. Standing and walking were onl...
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by progres... more Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Diagnosis, management and therapeutic trials are hampered by a lack of informative biomarkers. Troponins are components of skeletal and cardiac muscles. Acute elevation of cardiac isoforms of troponin I and T in serum indicates myocardial injury. Case reports suggested that serum levels of cardiac troponin T, but not cardiac troponin I are chronically elevated in myotrophic lateral sclerosis and other neuromuscular disorders. Using standard clinical laboratory methodologies, we studied serum troponin levels in a multicentric cross-sectional cohort of 75 amyotrophic lateral sclerosis patients and 30 Alzheimer’s disease controls and 29 healthy controls (DESCRIBE-ALS cohort) and in a real-world cohort of 179 consecutive patients from our amyotrophic lateral sclerosis clinic at the University Hospital Bonn. We found that serum cardiac troponin T is...
There is growing evidence that promising biomarkers of inflammation in Alzheimer´s disease (AD) a... more There is growing evidence that promising biomarkers of inflammation in Alzheimer´s disease (AD) and other neurodegenerative diseases correlate strongest to levels of tau or neurofilament, indicating an inflammatory response to neuronal damage or death. To test this hypothesis, we investigated three AD candidate markers (ferritin, fatty acid binding protein 3 (FABP‐3), and neurogranin) in interrelation to established AD and inflammatory protein markers. We further aimed to determine if such interrelations would be evident in pathological subjects only or also under non‐pathological circumstances. Cerebrospinal fluid levels of the three proteins were quantified in samples from the University Clinic of Bonn (UKB) Department of Neurodegenerative Diseases & Geriatric Psychiatry, Germany. Data were analyzed based on clinical or biomarker‐defined stratification of subjects with adjustment for covariates age, sex, and APOE status. Levels of ferritin, FABP‐3 and neurogranin were elevated in subjects with pathological levels of t‐tau independent of beta‐amyloid status. The three markers correlated with each other, tau isoforms, age, and those inflammatory markers previously described as related to neurodegeneration, predominantly sTREM2, macrophage migration inhibitory factor, soluble vascular endothelial growth factor receptor, soluble vascular cell adhesion molecule 1 (sVCAM‐1), and C1q. These interrelations existed in subjects with pathological and sub‐pathological tau levels, in particular for FABP‐3 and neurogranin. Relations to ferritin were independent of absolute levels of tau, too, but showed differing trajectories between pathological and non‐pathological subjects. A specific set of inflammatory markers is highly related to markers of neuronal damage such as tau, neurogranin, or FABP‐3. These proteins could be used as readouts of the inflammatory response during the neurodegeneration phase of AD.
IntroductionMultiple immunity biomarkers have been suggested as tracers of neuroinflammation in n... more IntroductionMultiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative–funded project AETIONOMY.MethodsA total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published.ResultsImmunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center‐specific factors.DiscussionImmunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariate...
Arc/Arg3.1, an activity regulated immediate early gene, is essential for learning and memory, syn... more Arc/Arg3.1, an activity regulated immediate early gene, is essential for learning and memory, synaptic plasticity, and maturation of neural networks. It has also been implicated in several neurodevelopmental disorders, including schizophrenia. Here, we used male and female constitutive and conditionalArc/Arg3.1knock-out (KO) mice to investigate the causal relationship betweenArc/Arg3.1deletion and schizophrenia-linked neurophysiological and behavioral phenotypes. Usingin vivolocal field potential recordings, we observed dampened oscillatory activity in the prefrontal cortex (PFC) of the KO and early conditional KO (early-cKO) mice, in whichArc/Arg3.1was deleted perinatally. Whole-cell patch-clamp recordings from neurons in PFC slices revealed altered synaptic properties and reduced network gain in the KO mice as possible mechanisms underlying the oscillation deficits. In contrast, we measured normal oscillatory activity in the PFC of late conditional KO (late-cKO) mice, in whichArc/...
Proceedings of the National Academy of Sciences, 2018
Significance Spatial learning and memory are hippocampal functions that emerge and mature during ... more Significance Spatial learning and memory are hippocampal functions that emerge and mature during early postnatal development. The molecular mechanisms which shape this process are largely unknown. Here, we present evidence that the activity-regulated gene Arc/Arg3.1 is transiently up-regulated in the hippocampus of neonatal mice where it is required for establishing appropriate hippocampal network activity essential for spatial learning. Once established, network activity supports normal spatial learning in the absence of Arc/Arg3.1 while long-term memory storage continues to rely on Arc/Arg3.1 expression throughout life. These results demonstrate that hippocampal networks undergo a critical period of development mediated by Arc/Arg3.1 and open opportunities to investigate normal and pathological neurodevelopment of higher brain functions.
En el Sistema Nervioso Central la expresión de genes dependiente de la actividad sináptica parece... more En el Sistema Nervioso Central la expresión de genes dependiente de la actividad sináptica parece ser un mecanismo importante en diversos procesos como la diferenciación neuronal, el ciclo circadiano, la supervivencia neural, la plasticidad sináptica y la consolidación de la memoria a largo plazo.
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Papers by Sergio Castro-Gomez