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Subclinical hypothyroidism (SCH) in pregnancy is the most common form of thyroid dysfunction in pregnancy, which can affect fetal nervous system development and increase the risk of neurodevelopmental disorders after birth. However, the mechanism of the effect of maternal subclinical hypothyroidism on fetal brain development and behavioral phenotypes is still unclear and requires further study. In this study, we constructed a mouse model of maternal subclinical hypothyroidism by exposing dams to drinking water containing 50 ppm propylthiouracil (PTU) during pregnancy and found that its offspring were accompanied by severe cognitive deficits by behavioral testing. Mechanistically, gestational SCH resulted in the upregulation of protein expression and activity of HDAC1/2/3 in the hippocampus of the offspring. ChIP analysis revealed that H3K9ac on the neurogranin (Ng) promoter was reduced in the hippocampus of the offspring of SCH, with a significant reduction in Ng protein, leading to reduced expression levels of synaptic plasticity markers PSD95 (a membrane-associated protein in the postsynaptic density) and SYN (synaptophysin, a specific marker for presynaptic terminals), and impaired synaptic plasticity. In addition, administration of MS-275 (an HDAC1/2/3-specific inhibitor) to SCH offspring alleviated impaired synaptic plasticity and cognitive dysfunction in offspring. Thus, our study suggests that maternal subclinical hypothyroidism may mediate offspring cognitive dysfunction through the HDAC1/2/3-H3K9ac-Ng pathway. Our study contributes to the understanding of the signaling mechanisms underlying maternal subclinical hypothyroidism-mediated cognitive impairment in the offspring.
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Disfunción Cognitiva , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Hipotiroidismo , Neurogranina , Efectos Tardíos de la Exposición Prenatal , Animales , Neurogranina/metabolismo , Neurogranina/genética , Hipotiroidismo/metabolismo , Femenino , Embarazo , Ratones , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 1/genética , Regulación hacia Abajo , Hipocampo/metabolismo , Masculino , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Ratones Endogámicos C57BL , Plasticidad NeuronalRESUMEN
INTRODUCTION: Ocrelizumab is a CD20-targeting monoclonal antibody used for treatment of multiple sclerosis (MS). Serum and cerebrospinal fluid (CSF) neurofilament light (NFL) chain levels are reduced in MS patients under ocrelizumab treatment indicating a preventive action against neuro-axonal degeneration. Our aim, in this preliminary study, was to explore the impact of ocrelizumab treatment on synaptic integrity through assessment of neurogranin levels. METHODS: Thirteen relapsing-remitting multiple sclerosis (RRMS) patients resistant to first-line immunomodulating agents were enrolled and followed up for 24 months under ocrelizumab treatment. Disease activity was monitored by periodic EDSS, MSSS, and cranial-spinal MRI assessments. No evidence of disease activity (NEDA)-3 was determined, and CSF levels of NFL (marker of neuro-axonal integrity) and neurogranin (marker of synaptic integrity) were measured by ELISA at baseline and 12-month ocrelizumab treatment. RESULTS: Seven RRMS patients, who preserved NEDA-3 status during 24-month follow-up, showed ≥30% NFL level decrease, whereas 6 patients with stable/increased NFL levels displayed relapse, MRI lesion, or disability progression. Although most RRMS patients exhibited increased CSF levels of neurogranin under ocrelizumab treatment, patients with and without neurogranin level increase did not differ in terms of clinical features and NEDA-3 status. Baseline neurogranin levels negatively correlated with baseline EDSS scores. CONCLUSION: Our results confirm that NFL effectively monitors treatment response of RRMS patients under ocrelizumab treatment. Neurogranin does not appear to exhibit a similar benefit in screening of RRMS disease activity. Nevertheless, lower neurogranin levels are associated with increased disability in RRMS indicating a potential disease activity biomarker function.
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INTRODUCTION: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS: Individuals without dementia were classified as A+ (CSF amyloid beta [Aß]42), T+ (CSF phosphorylated tau181), and N+ or N- based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS: Only a few individuals were A+T+Ng-. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng- and A+T+NfL-, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV-, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. HIGHLIGHTS: In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.
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INTRODUCTION: We examined whether the aging suppressor KLOTHO gene's functionally advantageous KL-VS variant (KL-VS heterozygosity [KL-VSHET]) confers resilience against deleterious effects of aging indexed by cerebrospinal fluid (CSF) biomarkers of neuroinflammation (interleukin-6 [IL-6], S100 calcium-binding protein B [S100B], triggering receptor expressed on myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], glial fibrillary acidic protein [GFAP]), neurodegeneration (total α-synuclein [α-Syn], neurofilament light chain protein), and synaptic dysfunction (neurogranin [Ng]). METHODS: This Alzheimer disease risk-enriched cohort consisted of 454 cognitively unimpaired adults (Mage = 61.5 ± 7.75). Covariate-adjusted multivariate regression examined relationships between age (mean-split[age ≥ 62]) and CSF biomarkers (Roche/NeuroToolKit), and whether they differed between KL-VSHET (N = 122) and non-carriers (KL-VSNC; N = 332). RESULTS: Older age was associated with a poorer biomarker profile across all analytes (Ps ≤ 0.03). In age-stratified analyses, KL-VSNC exhibited this same pattern (Ps ≤ 0.05) which was not significant for IL-6, S100B, Ng, and α-Syn (Ps ≥ 0.13) in KL-VSHET. Although age-related differences in GFAP, sTREM2, and YKL-40 were evident for both groups (Ps ≤ 0.01), the effect magnitude was markedly stronger for KL-VSNC. DISCUSSION: Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL-VSHET. HIGHLIGHTS: Older age was associated with poorer profiles across all cerebrospinal fluid biomarkers of neuroinflammation, neurodegeneration, and synaptic dysfunction. KLOTHO KL-VS non-carriers exhibit this same pattern, which is does not significantly differ between younger and older KL-VS heterozygotes for interleukin-6, S100 calcium-binding protein B, neurogranin, and total α-synuclein. Although age-related differences in glial fibrillary acidic protein, triggering receptor expressed on myeloid cells, and chitinase-3-like protein 1 are evident for both KL-VS groups, the magnitude of the effect is markedly stronger for KL-VS non-carriers. Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults are attenuated in KL-VS heterozygotes.
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Envejecimiento , Biomarcadores , Proteína 1 Similar a Quitinasa-3 , Heterocigoto , Proteínas Klotho , Humanos , Femenino , Masculino , Persona de Mediana Edad , Biomarcadores/líquido cefalorraquídeo , Anciano , Envejecimiento/genética , Proteína 1 Similar a Quitinasa-3/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3/genética , Glucuronidasa/genética , Glucuronidasa/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Interleucina-6/genética , Receptores Inmunológicos/genética , Enfermedades Neuroinflamatorias/genética , Enfermedades Neuroinflamatorias/líquido cefalorraquídeo , Subunidad beta de la Proteína de Unión al Calcio S100/líquido cefalorraquídeo , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Estudios de Cohortes , Proteína Ácida Fibrilar de la Glía/líquido cefalorraquídeo , Proteína Ácida Fibrilar de la Glía/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , alfa-Sinucleína/líquido cefalorraquídeo , alfa-Sinucleína/genética , Neurogranina/líquido cefalorraquídeo , Neurogranina/genética , Glicoproteínas de MembranaRESUMEN
Manganese (Mn), a cofactor for various enzyme classes, is an essential trace metal for all organisms. However, overexposure to Mn causes neurotoxicity. Here, we evaluated the effects of exposure to Mn chloride (MnCl2) on viability, morphology, synapse function (based on neurogranin expression) and behavior of zebrafish larvae. MnCl2 exposure from 2.5 h post fertilization led to reduced survival (60%) at 5 days post fertilization. Phenotypical changes affected body length, eye and olfactory organ size, and visual background adaptation. This was accompanied by a decrease in both the fluorescence intensity of neurogranin immunostaining and expression levels of the neurogranin-encoding genes nrgna and nrgnb, suggesting the presence of synaptic alterations. Furthermore, overexposure to MnCl2 resulted in larvae exhibiting postural defects, reduction in motor activity and impaired preference for light environments. Following the removal of MnCl2 from the fish water, zebrafish larvae recovered their pigmentation pattern and normalized their locomotor behavior, indicating that some aspects of Mn neurotoxicity are reversible. In summary, our results demonstrate that Mn overexposure leads to pronounced morphological alterations, changes in neurogranin expression and behavioral impairments in zebrafish larvae.
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Conducta Animal , Larva , Manganeso , Neurogranina , Pez Cebra , Animales , Pez Cebra/metabolismo , Larva/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Neurogranina/metabolismo , Neurogranina/genética , Manganeso/toxicidad , Cloruros/toxicidad , Compuestos de ManganesoRESUMEN
Neurogranin (Ng), a post-synaptic protein involved in memory formation, has been investigated as a biomarker in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD) and ageing. CSF Ng levels are elevated in AD relative to healthy controls and correlate with cognition; however, few studies have focused on Ng abundance in the brain. Synapse loss in the brain correlates closely with cognitive decline in AD making synaptic biomarkers potentially important for tracking disease progression, but the links between synaptic protein changes in CSF and brain remain incompletely understood. In the current study, Ng abundance was examined in post-mortem human brain tissue across AD, healthy ageing (HA), and mid-life (ML) cohorts. Ng levels were quantified in three brain regions associated with cognitive change found during ageing and neurodegenerative diseases, namely the middle temporal gyrus, primary visual cortex and the posterior hippocampus using immunohistochemistry. To support immunohistochemical analysis, total homogenate and biochemically enriched synaptic fractions from available temporal gyrus tissues were examined by immunoblot. Finally, we examined whether Ng is associated with lifetime cognitive ageing. Ng levels were significantly reduced in AD relative to HA and ML cases across all regions. Additionally Ng was significantly reduced in HA in comparison to ML in the primary visual cortex. Immunoblotting confirms reduced Ng levels in AD cases supporting immunohistochemical results. Interestingly, there was also a significant reduction of synapse-associated Ng in our group who had lifetime cognitive decline in comparison to the group with lifetime cognitive resilience indicating loss of neurogranin in remaining synapses during ageing is associated with cognitive decline. Our findings indicate that increases in CSF Ng reflect loss of brain neurogranin and support the use of CSF Ng as a biomarker of AD and potentially of cognitive decline in healthy ageing.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/metabolismo , Neurogranina/líquido cefalorraquídeo , Disfunción Cognitiva/metabolismo , Encéfalo/metabolismo , Biomarcadores/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismoRESUMEN
The rapid increase in urbanization is altering the natural composition of the day-night light ratio. The light/dark cycle regulates animal learning, memory, and mood swings. A study was conducted to examine the effect of different quantity and quality of light at night on the daily clock, learning, memory, cognition, and expression of transcripts in key learning centers. Treatment was similar for experiments one to three. Rats were exposed for 30 days to 12 h light and 12 h dark with a night light of 2 lx (dLAN group), 250 lx (LL), or without night light (LD). In experiment one, after 28 days, blood samples were collected and 2 days later, animals were exposed to constant darkness. In experiment two, after 30 days of treatment, animals were subjected to various tests involving learning, memory, and cognition. In experiment three, after 30 days of treatment, animals were sampled, and transcript levels of brain-derived neurotrophic factor, tyrosine kinase, Growth-Associated Protein 43, Neurogranin, microRNA-132, cAMP Response Element-Binding Protein, Glycogen synthase kinase-3ß, and Tumor necrosis factor α were measured in hippocampus, thalamus, and cortex tissues. In experiment four, animals were exposed to night light of 0.019 W/m2 but of either red (640 nm), green (540 nm), or blue (450 nm) wavelength for 30 days, and similar tests were performed as mentioned in experiment 2. While in experiment five, after 30 days of respective wavelength treatments, all animals were sampled for gene expression studies. Our results show that exposure to dLAN and LL affects the daily clock as reflected by altered melatonin secretion and locomotor activity, compromises the learning, memory, and cognitive ability, and alterations in the expression levels of transcripts in the hypothalamus, cortex, and thalamus. The effect is night light intensity dependent. Further, blue light at night has less drastic effects than green and red light. These results could be of the potential use of framing the policies for the use of light at night.
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Melatonina , MicroARNs , Ratas , Animales , Fotoperiodo , Encéfalo , Cognición , Melatonina/genéticaRESUMEN
INTRODUCTION: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). METHODS: Cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. RESULTS: Biomarkers were correlated with one another. Levels of CSF Aß42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aß42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. DISCUSSION: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3 , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Estudios Longitudinales , Biomarcadores/líquido cefalorraquídeo , Neurogranina/líquido cefalorraquídeoRESUMEN
In addition to amyloid and tau pathology in the central nervous system (CNS), inflammatory processes and synaptic dysfunction are highly important mechanisms involved in the development and progression of dementia diseases. In the present study, we conducted a comparative analysis of selected pro-inflammatory proteins in the CNS with proteins reflecting synaptic damage and core biomarkers in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). To our knowledge, no studies have yet compared CXCL12 and CX3CL1 with markers of synaptic disturbance in cerebrospinal fluid (CSF) in the early stages of dementia. The quantitative assessment of selected proteins in the CSF of patients with MCI, AD, and non-demented controls (CTRL) was performed using immunoassays (single- and multiplex techniques). In this study, increased CSF concentration of CX3CL1 in MCI and AD patients correlated positively with neurogranin (r = 0.74; p < 0.001, and r = 0.40; p = 0.020, respectively), ptau181 (r = 0.49; p = 0.040), and YKL-40 (r = 0.47; p = 0.050) in MCI subjects. In addition, elevated CSF levels of CXCL12 in the AD group were significantly associated with mini-mental state examination score (r = -0.32; p = 0.040). We found significant evidence to support an association between CX3CL1 and neurogranin, already in the early stages of cognitive decline. Furthermore, our findings indicate that CXCL12 might be a useful marker for tract severity of cognitive impairment.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Biomarcadores , Sistema Nervioso Central , Quimiocina CXCL12 , Proteína 1 Similar a Quitinasa-3 , Neurogranina , Quimiocina CX3CL1RESUMEN
Intracellular Ca2+-calmodulin (CaM) signaling plays an important role in Ca2+-CaM-dependent kinase (CaMKII) and calcineurin (CaN)-mediated cardiac biology. While neurogranin (Ng) is known as a major Ca2+-CaM modulator in the brain, its pathophysiological role in cardiac hypertrophy has never been studied before. In the present study, we report that Ng is expressed in the heart and depletion of Ng dysregulates Ca2+ homeostasis and promotes cardiac failure in mice. 10-month-old Ng null mice demonstrate significantly increased heart-to-body weight ratios compared to wild-type. Using histological approaches, we identified that depletion of Ng increases cardiac hypertrophy, fibrosis, and collagen deposition near perivascular areas in the heart tissue of Ng null mice. Ca2+ spark experiments revealed that cardiac myocytes isolated from Ng null mice have decreased spark frequency and width, while the duration of sparks is significantly increased. We also identified that a lack of Ng increases CaMKIIδ signaling and periostin protein expression in these mouse hearts. Overall, we are the first study to explore how Ng expression in the heart plays an important role in Ca2+ homeostasis in cardiac myocytes as well as the pathophysiology of cardiac hypertrophy and fibrosis.
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Calcio , Neurogranina , Animales , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Calmodulina/metabolismo , Cardiomegalia/metabolismo , Fibrosis , Ratones , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Neurogranina/genética , Neurogranina/metabolismoRESUMEN
It is currently unclear how amyloid-ß and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer's disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-ß and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer's disease i.e. in amyloid-ß-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-ß pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-ß and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-ß and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.
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Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Axones/patología , Sinapsis/patología , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Tomografía de Emisión de PositronesRESUMEN
AIM: The aim of this study was to determine the level of serum NGRN in epilepsy patients presenting at the Emergency Department with complaints of an epileptic seizure, and to thus evaluate the utility of this biomarker in the differentiation of epilepsy and PNES patients from each other. MATERIAL METHODS: The study included patients aged >18 years who had experienced an epileptic seizure or were experiencing an epileptic seizure proven with EEG. All patients with brain disease of structural or infectious cause were excluded from the study (dementia, stroke, intracranial mass, meningitis, encephalitis, Creutzfeldt-Jacobs disease, abscess, etc). Patients were also excluded if they had traumatic brain injury or a severe systemic disease such as sepsis, which was thought to impair brain blood flow. The control group was formed of completely healthy volunteers. RESULTS: Evaluation was made of a total of 49 patients, comprising 19 (38.78%) males and 30 (61.22%) females, and a control group of 53 healthy volunteers comprising 28 (52.83%) males and 25 (47.17%) females. The serum neurogranin value was median 184.16 ng/dl (range: 110.1-1172.98) in the patient group and 97.90 ng/dl (range: 73.71-282. 11) in the control group. The serum neurogranin value was determined to be statistically significantly higher in the patient group than in the control group (p < 0.005). CONCLUSION: The differential diagnosis of ES from PNES remains a challenging situation for emergency service physicians. Based on the findings of this study, it can be said that the serum NRGN level is high in patients who have experienced an epileptic seizure. Therefore, this new biomarker can be considered for use in the differential diagnosis of epileptic seizure and PNES.
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Epilepsia , Neurogranina , Adolescente , Biomarcadores , Diagnóstico Diferencial , Electroencefalografía , Epilepsia/diagnóstico , Femenino , Humanos , Masculino , Convulsiones/diagnósticoRESUMEN
Objective: Synaptic degeneration is the pathologic foundation of cognitive decline in the Alzheimer's disease (AD) continuum. We aimed to determine whether cerebrospinal fluid (CSF) synaptic marker neurogranin (Ng) is a disease state or a disease stage biomarker in the AD continuum.Methods: Studies comparing CSF Ng levels among AD, mild cognitive impairment (MCI) and healthy participants were included. Studies were eligible if the correlation between CSF Ng levels and Mini-Mental Status Examination (MMSE) scores was investigated.Results: Twenty-one studies met our inclusion criteria (n = 4515). The magnitude of effect sizes was more apparent in AD (standardized mean difference [SMD] = 1.72; 95% confidence interval [CI] = 1.23-2.22), than in MCI (SMD = 0.82; 95% CI = 0.29-1.34) compared to control populations. These results suggest that CSF Ng can discriminate AD and MCI from control populations, implying that synaptic degeneration worsens as patients progress from MCI to AD. However, there was a very weak correlation between CSF Ng levels and MMSE scores (r = -0.15; 95% CI = -0.21--0.08) among the whole populations, suggesting that an increment of CSF Ng is best considered a biological evidence of disease state in the AD continuum.Conclusion: Our study provides evidence that the synaptic marker CSF Ng can be used as a disease state biomarker for the AD continuum. Because synaptic degeneration is a distinct pathologic event from amyloid deposition and neurofibrillary tangle formation, CSF Ng may provide an important supplementation to the AT(N) biomarker system to reveal the sequence of neuropathology.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Neurogranina/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Biomarcadores/líquido cefalorraquídeo , Péptidos beta-Amiloides , Proteínas tau , Fragmentos de PéptidosRESUMEN
Recently, the synaptic proteins neurogranin (Ng) and α-synuclein (α-Syn) have attracted scientific interest as potential biomarkers for synaptic dysfunction in neurodegenerative diseases. In this study, we measured the CSF Ng and α-Syn concentrations in patients affected by AD (n = 69), non-AD neurodegenerative disorders (n-AD = 50) and non-degenerative disorders (n-ND, n = 98). The concentrations of CSF Ng and α-Syn were significantly higher in AD than in n-AD and n-ND. Moreover, the Aß42/Ng and Aß42/α-Syn ratios showed statistically significant differences between groups and discriminated AD patients from n-AD patients, better than Ng or α-Syn alone. Regression analyses showed an association of higher Ng concentrations with MMSE < 24, pathological Aß 42/40 ratios, pTau, tTau and the ApoEε4 genotype. Aß 42/Ng was associated with MMSE < 24, an AD-related FDG-PET pattern, the ApoEε4 genotype, pathological Aß 42 levels and Aß 42/40 ratios, pTau, and tTau. Moreover, APO-Eε4 carriers showed higher Ng concentrations than non-carriers. Our results support the idea that the Aß 42/Ng ratio is a reliable index of synaptic dysfunction/degeneration able to discriminate AD from other neurological conditions.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Biomarcadores , Fluorodesoxiglucosa F18 , Humanos , Neurogranina/genética , alfa-Sinucleína/genética , Proteínas tauRESUMEN
Synaptic loss and dysfunction are one of the earliest signs of neurodegeneration associated with cognitive decline in Alzheimer's disease (AD) and other neurodegenerative diseases. This study aimed to assess the relationships between biological processes of the synaptic pathology underlying AD, molecular functions, and dynamics of the change concentrations of selected proteins reflecting synaptic and axonal pathology in dementia stages. Neurogranin (Ng), neuronal pentraxin receptor (NPTXR), and Visinin-like protein 1 (VILIP1) concentrations were measured in the cerebrospinal fluid (CSF) of MCI, AD, and non-demented controls (CTRL) using quantitative immunological methods. Gene ontology (GO) enrichment analysis was used for the functional analysis of tested proteins. The CSF Aß42/Ng ratio was significantly different between all the compared groups. The CSF NPTXR/Ng ratio was significantly different between MCI compared to CTRL and AD compared to CTRL. The GO enrichment analysis revealed that two terms (the Biological Process (BP) and Cellular Component (CC) levels) are significantly enriched for NPTXR and Ng but not for VILIP1. Both Ng and NPTXR concentrations in CSF are promising synaptic dysfunction biomarkers for the early diagnosis of the disease. Moreover, both proteins are biochemically associated with classical biomarkers and VILIP-1. Mapping shared molecular and biological functions for the tested proteins by GO enrichment analysis may be beneficial in screening and setting new research targets.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/complicaciones , Biología Computacional , Humanos , Neurocalcina/líquido cefalorraquídeo , Neurogranina/metabolismo , Fragmentos de Péptidos/metabolismo , Proteínas tau/metabolismoRESUMEN
Prion diseases are diagnosed in the symptomatic stage, when the neuronal damage is spread throughout the central nervous system (CNS). The assessment of biological features that allow the detection of asymptomatic cases is needed, and, in this context, scrapie, where pre-symptomatic infected animals can be detected through rectal biopsy, becomes a good study model. Neurogranin (Ng) and neurofilament light chain (NfL) are proteins that reflect synaptic and axonal damage and have been studied as cerebrospinal fluid (CSF) biomarkers in different neurodegenerative disorders. In this study, we evaluated Ng and NfL both at the protein and transcript levels in the CNS of preclinical and clinical scrapie-affected sheep compared with healthy controls and assessed their levels in ovine CSF. The correlation between these proteins and the main neuropathological events in prion diseases, PrPSc deposition and spongiosis, was also assessed. The results show a decrease in Ng and NfL at the protein and gene expression levels as the disease progresses, and significant changes between the control and preclinical animals. On the contrary, the CSF levels of NfL increased throughout the progression of the disease. Negative correlations between neuropathological markers of prion disease and the concentration of the studied proteins were also found. Although further research is needed, these results suggest that Ng and NfL could act as biomarkers for neurodegeneration onset and intensity in preclinical cases of scrapie.
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Enfermedades por Prión , Scrapie , Animales , Biomarcadores/líquido cefalorraquídeo , Filamentos Intermedios , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Neurogranina/líquido cefalorraquídeo , Enfermedades por Prión/líquido cefalorraquídeo , Scrapie/diagnóstico , OvinosRESUMEN
In forensic pathology, traumatic brain injury (TBI) is a frequently encountered cause of death. Unfortunately, the statistic autopsy data, risk investigation about injury patterns, and circumstances of TBI are still sparse. Estimates of survival time post-TBI and postmortem diagnosis of TBI are especially important implications in forensic medicine. Neurogranin (Ng) and myelin basic protein (MBP) represent potential biomarkers of TBI. The present study analyzed retrospectively the forensic autopsy records of TBI cases at a university center of medico-legal investigation from 2008 to 2020. Immunohistochemistry and enzyme-linked immunosorbent assays (ELISA) were used to investigate the expression changes of Ng and MBP in the cortical brain injury adjacent tissues and serum, respectively, from cases of TBI at autopsy with different survival times post-TBI. The results show that the major mechanism of death of TBI is assault, and accident was the major manner of death. Ng and MBP are mainly expressed in the cortical nerve cells and the myelin sheath, respectively. The serum levels of Ng and MBP in each TBI group were higher compared with those in the controls. The brain cortical levels of Ng and MBP decreased at first and then steadily increased with extended survival time post-TBI. The immunopositive ratios and serum concentration of Ng and MBP have shown significant differences among control group and all TBI group (p < 0.001). Collectively, the immunohistochemical analyses of Ng and MBP in human brain tissues may be useful to determine the survival time after TBI, and Ng and MBP level in the human blood specimens could be considered as a postmortem diagnostic tools of TBI in forensic practice.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Humanos , Autopsia , Proteína Básica de Mielina/metabolismo , Neurogranina , Estudios Retrospectivos , BiomarcadoresRESUMEN
Neurogranin (Ng) is a 78 amino acid neuronal protein and a biomarker candidate for Alzheimer's disease (AD). Ng has been suggested to bind to calmodulin and phosphatidic acid via its centrally located IQ domain. Ng is cleaved within this functionally important domain, yielding the majority of fragments identified in cerebrospinal fluid (CSF), suggesting that cleavage of Ng may be a mechanism to regulate its function. Up to now, Ng has been shown to be present in CSF as both C-terminal fragments as well as full-length protein. To obtain an overview of the different molecular forms of Ng present in CSF, we show by size exclusion chromatography (SEC), immunoblotting, immunoprecipitation, and MS that Ng is present in CSF as several molecular forms. Besides monomeric full-length Ng, also higher molecular weight forms of Ng, and C-terminal- and previously not identified N-terminal fragments were observed. We found by immunodepletion that C-terminal peptides contribute on average to ~50% of the total-Ng ELISA signal in CSF samples. There were no differences in the overall C-terminal fragment/total-Ng ratios between samples from AD and control groups. In addition, we found that monomeric Ng and its C-terminal fragments bind to heparin via a heparin-binding motif, which might be of relevance for their export mechanism from neurons. Taken together, this study highlights the presence of several molecular forms of Ng in CSF, comprising monomeric full-length Ng, and N- and C-terminal truncations of Ng, as well as larger forms of still unknown composition.
Asunto(s)
Neurogranina/líquido cefalorraquídeo , Neurogranina/química , Secuencia de Aminoácidos , Química Encefálica , Cromatografía en Gel , Ensayo de Inmunoadsorción Enzimática , Heparina/metabolismo , Humanos , Immunoblotting , Inmunoprecipitación , Espectrometría de Masas , Estructura Molecular , Peso Molecular , Unión Proteica , UltrafiltraciónRESUMEN
BACKGROUND AND AIM: Carbon monoxide poisoning is a toxicological emergency that causes neurological complications. High serum neurogranin can be detected in acute or chronic conditions where brain tissue is damaged. This study aimed to investigate the diagnostic value of serum neurogranin level and its role in demonstrating neurological damage in patients admitted to the emergency department with carbon monoxide poisoning. MATERIALS AND METHODS: The study was conducted prospectively on patients with carbon monoxide poisoning (patient group) and healthy volunteers (control group). Demographic characteristics and serum neurogranin level of all participants and symptoms at admission, neurological examination findings, laboratory results, and Diffusion-Weighted Magnetic Resonance Imaging results of the patient group were recorded. We used an independent sample t-test to compare neurogranin levels and bivariate correlation analysis to compare the relationship between serum neurogranin levels and data belonging to the patient group. RESULTS: Sixty eight participants (patient group, n = 36; control group, n = 32) were included in the study. Serum neurogranin level was significantly higher in patients with carbon monoxide poisoning (0.31 ± 0.16 ng/ml) compared to control group (0.22 ± 0.10 ng/ml) (p = 0.015). The mean Glasgow Coma Scale of the patients with carbon monoxide poisoning was 14.59 ± 0.23, and of Diffusion Weighted Magnetic Resonance Imaging results were completely normal in 94.4% (n = 34). There was no correlation between serum neurogranin level and Diffusion Weighted Magnetic Resonance Imaging results (r = -0.011; p = 0.953). CONCLUSION: Serum neurogranin level may be a new diagnostic biomarker in patients admitted to the emergency department with carbon monoxide poisoning. The high serum neurogranin levels detected in patients with normal diffusion-weighted imaging after carbon monoxide poisoning suggest that there is neurological damage in these patients, even if imaging methods cannot detect it.
Asunto(s)
Biomarcadores/sangre , Intoxicación por Monóxido de Carbono/diagnóstico , Servicio de Urgencia en Hospital , Neurogranina/sangre , Intoxicación por Monóxido de Carbono/diagnóstico por imagen , Estudios de Casos y Controles , Imagen de Difusión por Resonancia Magnética , Femenino , Escala de Coma de Glasgow , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Purpose/aim of the study: Major depressive disorder (MDD) in late life is linked to increased risk of subsequent dementia, but it is still unclear exactly what pathophysiological mechanisms underpin this link. A potential mechanism related to elevated risk of dementia in MDD is increased levels of α-synuclein (α-Syn), a protein found in presynaptic neuronal terminals.Materials and methods: In this study, we examined cerebrospinal fluid (CSF) levels of α-Syn in conjunction with biomarkers of neurodegeneration (amyloid-ß 42, total and phospho tau) and synaptic dysfunction (neurogranin), and measures of memory ability, in 27 cognitively intact older individuals with MDD and 19 controls.Results: Our results show that CSF α-Syn levels did not significantly differ across depressed and control participants, but α-Syn was directly associated with neurogranin levels, and indirectly linked to poorer memory ability.Conclusions: All in all, we found that α-Syn may be implicated in the association between late life MDD and synaptic dysfunction, although further research is needed to confirm these results.