Brain Disease Research Articles

Modulation of autophagy by melatonin and its receptors: implications in brain disorders.

Autophagy plays a crucial role in maintaining neuronal homeostasis and function, and its disruption is linked to various brain diseases. Melatonin, an endogenous hormone that primarily acts through MT1 and MT2 receptors, regulates autophagy via multiple pathways. Growing evidence indicates that melatonin's ability to modulate autophagy provides therapeutic and preventive benefits in brain disorders, including neurodegenerative and affective diseases. In this review, we summarize the key mechanisms by which melatonin affects autophagy and explore its therapeutic potential in the treatment of brain disorders.

The emerging role of Never-in-Mitosis A - Related Kinases in the endothelium

The endothelium forms a monolayer, which functions to ensure tissue homeostasis. Barrier hyperpermeability has been associated with lung, brain and eye disease. An emerging body of evidence reports the involvement of Never-in-Mitosis A - Related Kinases in vascular responses, suggesting their value as potential therapeutic targets in endothelial-dependent disorders.

Asynchronous Functional Brain Network Construction with Spatiotemporal Transformer for MCI Classification.

Construction and analysis of functional brain networks (FBNs) with resting-state functional magnetic resonance imaging (rs-fMRI) is a promising method to diagnose functional brain diseases. Nevertheless, the existing methods suffer from several limitations. First, the functional connectivities (FCs) of the FBN are usually measured by the temporal co-activation level between rs-fMRI time series from regions of interest (ROIs). While enjoying simplicity, the existing approach implicitly assumes simultaneous co-activation of all the ROIs, and models only their synchronous dependencies. However, the FCs are not necessarily always synchronous due to the time lag of information flow and cross-time interactions between ROIs. Therefore, it is desirable to model asynchronous FCs. Second, the traditional methods usually construct FBNs at individual level, leading to large variability and degraded diagnosis accuracy when modeling asynchronous FBN. Third, the FBN construction and analysis are conducted in two independent steps without joint alignment for the target diagnosis task. To address the first limitation, this paper proposes an effective sliding-window-based method to model spatiotemporal FCs in Transformer. Regarding the second limitation, we propose to learn common and individual FBNs adaptively with the common FBN as prior knowledge, thus alleviating the variability and enabling the network to focus on the individual disease-specific asynchronous FCs. To address the third limitation, the common and individual asynchronous FBNs are built and analyzed by an integrated network, enabling end-to-end training and improving the flexibility and discriminativity. The effectiveness of the proposed method is consistently demonstrated on three data sets for mild cognitive impairment (MCI) diagnosis.

Augmented cortisol and antiglucocorticoid therapy in mood disorders: the hippocampus as a potential drug target

The pathophysiology of many mood disorders is closely related to abnormal stress response associated with the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and cortisol overproduction. The hippocampus, a key structure of the limbic system responsible for both cognitive and emotional spheres, is selectively vulnerable to excess of glucocorticoids (GCs) inducing neuroinflammation and neurodegeneration. The antiGC therapy of psychiatric diseases, in particular depressive disorders, may be a useful additional treatment. Among other approaches, targeting glucocorticoid receptors, abounded in the hippocampus, is regarded as highly promising. However, though the preclinical data provide fairly firm evidence to the concept of antiGC therapy for stress-related diseases, clinical studies still are at the proof-of-concept stage. Noteworthy, chronic GC excess is associated not only with mood diseases, but also with cognitive decline, metabolic disorders, diabetes. Potentially, antiGC (HPA axis modifying) therapy may alleviate affective symptoms, cognitive disturbances, GC and insulin resistance and adverse side effects of conventional drugs through beneficial effects on the hippocampus mitigating its dysfunction and neurodegeneration, neuroinflammation, and impairment of neurogenesis. Since stress/GC-associated neuroinflammation-mediated pathology of the limbic system and, specifically, the hippocampus, is a general feature typical for many brain diseases, the concept of antiGC therapy may be extended, tested and validated in a wider spectrum of cerebral pathologies.

Exploring the Impact of Sex and Gender in Brain Function: Implications and Considerations.

Sex and gender are crucial variables in understanding brain development and disease. Biological sex is determined by genetic and hormonal factors, whereas gender is a multidimensional construct shaped by social and cultural influences. The interplay of these factors contributes to sex-specific susceptibilities and disease progression in psychiatric and neurological disorders. However, sex and gender are often considered as a single variable, which can lead to biased data analysis and interpretation. This commentary aims to analyze how sex and gender influence brain structure and function, with implications for personalized medicine, research, and the development of gender-sensitive clinical guidelines. Findings from various studies employing neuroimaging techniques and animal models are discussed, as well as the impact of biological sex, gender, environmental, cultural, and social factors on brain development, organization, and behavior. Evidence suggests that sex differences in brain structure and function are not only genetically determined but arealso influenced by gender-related experiences and societal contexts. Importantly, discrepancies between male and female brains are reduced in gender-equal societies. Preclinical studies play a pivotal role in determining the influence of biological sex, independent of gender, in different disease models. The findings underscore the need to consider both sex and gender in research and clinical practice to avoid biases and promote equitable health outcomes. Moving forward, we advocate for gender-sensitive approaches to be integrated into brain research and in clinical guidelines to achieve personalized and precision medicine.

The YTHDF Proteins Shape the Brain Gene Signatures of Alzheimer's Disease.

The gene signatures of Alzheimer's Disease (AD) brains reflect an output of a complex interplay of genetic, epigenetic, epi-transcriptomic, and post-transcriptional regulations. To identify the most significant factor that shapes the AD brain signature, we developed a machine learning model (DEcode-tree) to integrate cellular and molecular factors explaining differential gene expression in AD. Our model indicates that YTHDF proteins, the canonical readers of N6-methyladenosine RNA modification (m6A), are the most influential predictors of the AD brain signature. We then show that protein modules containing YTHDFs are downregulated in human AD brains, and knocking out YTHDFs in iPSC-derived neural cells recapitulates the AD brain gene signature in vitro . Furthermore, eCLIP-seq analysis revealed that YTHDF proteins influence AD signatures through both m6A-dependent and independent pathways. These results indicate the central role of YTHDF proteins in shaping the gene signature of AD brains.

SpliceTransformer predicts tissue-specific splicing linked to human diseases

We present SpliceTransformer (SpTransformer), a deep-learning framework that predicts tissue-specific RNA splicing alterations linked to human diseases based on genomic sequence. SpTransformer outperforms all previous methods on splicing prediction. Application to approximately 1.3 million genetic variants in the ClinVar database reveals that splicing alterations account for 60% of intronic and synonymous pathogenic mutations, and occur at different frequencies across tissue types. Importantly, tissue-specific splicing alterations match their clinical manifestations independent of gene expression variation. We validate the enrichment in three brain disease datasets involving over 164,000 individuals. Additionally, we identify single nucleotide variations that cause brain-specific splicing alterations, and find disease-associated genes harboring these single nucleotide variations with distinct expression patterns involved in diverse biological processes. Finally, SpTransformer analysis of whole exon sequencing data from blood samples of patients with diabetic nephropathy predicts kidney-specific RNA splicing alterations with 83% accuracy, demonstrating the potential to infer disease-causing tissue-specific splicing events. SpTransformer provides a powerful tool to guide biological and clinical interpretations of human diseases.

Paroxysmal sympathetic hyperactivity syndrome after recurrent stroke: A case report

Paroxysmal sympathetic hyperactivity (PSH) is a state of autonomic dysfunction characterized by symptoms such as tachypnea, tachycardia, hypertension, hyperthermia, sweating, and dystonia. It can occur after traumatic brain injury, hypoxic-ischemic encephalopathy, and diseases such as stroke. Hypoxia, extensive axonal damage, and young age are believed to predispose to the development of PSH. These patients may be diagnosed with pulmonary embolism, septicemia, or epileptic seizures. Delays in diagnosis prolong hospital stay. Here, we present an 81-year-old man who developed PSH after a recurrent stroke and our management.

Magnetic Induction Tomography for Brain Tissue Imaging Based on Conductivity Distribution for Parkinson’s Disease Diagnosis

Parkinson's disease is a prevalent neurodegenerative complication defined by the accumulation of alpha synuclein lewy bodies in the brain. Misdiagnosis results widespread of Parkinson’s disease because clinical diagnosis is challenging, underlining a need of a better detection technique, such as non-invasive magnetic induction tomography (MIT) technique. Non-invasive techniques for biological tissues imaging are becoming popular in biomedical engineering field. Therefore, MIT technology as a non-invasive technique has been encouraged in a medical field due to its advancement of technology in diagnosing diseases. The measurement parameters in MIT are passive electromagnetic properties (conductivity, permittivity, permeability) for biological tissue and the most dominant parameter in MIT is conductivity properties. It is uses a phase shift between a primary magnetic field and an induced field caused by a target object's conductivity. As a function of conductivity, the phase shift between the applied and secondary fields is expressed. Thus, the phase shift can be used to characterize the conductivity of a target object. The phase shift between the excitation and induced magnetic fields (EMF and IMF) reflects the change in conductivity in biological tissues. This paper focuses on the virtual simulation by using COMSOL Multi-physics for the design and development of MIT system that emphasizes on single channel magnetic induction tomography for biological tissue (bran tissue) imaging based on conductivity distribution for Parkinson’s disease diagnosis. The develop system employs the use of excitation coils to induce an electromagnetic field (e.m.f) in the brain tissue, which is then measured at the receiving side by sensors. The proposed system is capable of indicating Parkinson’s disease based on conductivity distribution. This method provides the valuable information of the brain abnormality based on differences of conductivities of normal brain and Parkinson’s disease brain tissues.

Elevated peripheral inflammation is associated with choroid plexus enlargement in independent sporadic amyotrophic lateral sclerosis cohorts

BackgroundUsing neuroimaging techniques, growing evidence has suggested that the choroid plexus (CP) volume is enlarged in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Notably, the CP has been suggested to play an important role in inflammation-induced CNS damage under disease conditions. However, to our knowledge, no study has investigated the relationships between peripheral inflammation and CP volume in sporadic ALS patients. Thus, in this study, we aimed to verify CP enlargement and explore its association with peripheral inflammation in vivo in independent ALS cohorts.MethodsBased on structural MRI data, CP volume was measured using Gaussian mixture models and further manually corrected in two independent cohorts of sporadic ALS patients and healthy controls (HCs). Serum inflammatory protein levels were measured using a novel high-sensitivity Olink proximity extension assay (PEA) technique. Xtreme gradient boosting (XGBoost) was used to explore the contribution of peripheral inflammatory factors to CP enlargement. Then, partial correlation analyses were performed.ResultsCP volumes were significantly higher in ALS patients than in HCs in the independent cohorts. Compared with HCs, serum levels of CRP, IL-6, CXCL10, and 35 other inflammatory factors were significantly increased in ALS patients. Using the XGBoost approach, we established a model-based importance of features, and the top three predictors of CP volume in ALS patients were CRP, IL-6, and CXCL10 (with gains of 0.24, 0.18, and 0.15, respectively). Correlation analyses revealed that CRP, IL-6, and CXCL10 were significantly associated with CP volume in ALS patients (r = 0.462 ∼ 0.636, p < 0.001).ConclusionOur study is the first to reveal a consistent and replicable contribution of peripheral inflammation to CP enlargement in vivo in sporadic ALS patients. Given that CP enlargement has been recently detected in other brain diseases, these findings should consider extending to other disease conditions with a peripheral inflammatory component.

Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

Nasal lymphatic obstruction of CSF drainage as a possible cause of Alzheimer's disease and dementia.

Alzheimer's disease, the most common form of dementia among older adults, slowly destroys memory and thinking skills. In recent years, scientists have made tremendous progress in understanding Alzheimer's disease, still, they do not yet fully understand what causes the disease. This article proposes a novel etiology for Alzheimer's disease. Our hypothesis developed from a review of nuclear medicine scans, in which the authors observed a significant increase in nasal turbinate vasodilation and blood pooling in patients with hypertension, sleep apnea, diabetes and/or obesity, all risk factors for Alzheimer's disease. The authors propose that nasal turbinate vasodilation and resultant blood pooling lead to the obstruction of normal nasal lymphatic clearance of cerebrospinal fluid and its waste products from the brain. The nasal turbinate vasodilation, due to increased parasympathetic activity, occurs alongside the well-established increased sympathetic activity of the cardiovascular system as seen in patients with hypertension. The increased parasympathetic activity is likely due to an autonomic imbalance secondary to the increase in worldwide consumption of highly processed food associated with dysregulation of the glucose regulatory system. The authors' hypothesis offers a novel mechanism and a new paradigm for the etiology of Alzheimer's disease and helps explain the rapid worldwide rise in the disease and other dementias which are expected to double in the next 20 years. This new paradigm provides compelling evidence for the modulation of the parasympathetic nervous system as a novel treatment strategy for Alzheimer's disease and other degenerative brain diseases, specifically targeting nasal turbinate lymphatic flow.

Unraveling the Effects of SARS-CoV-2 on Dementia: A Comprehensive Study

Since late 2019, a pandemic caused by SARS-CoV-2, a highly contagious coronavirus, has jeopardized human and public health. Neurodegeneration and structural brain diseases produce dementia, which is developing rapidly. Strong evidence of COVID-19 brain abnormalities as neurotrophic viruses impair neurological systems. Neuron and glial cell degeneration can affect nerve transmission and brain function. Damage to these brain components raises dementia risk. Multiple studies linked SARS-CoV-2 to dementia. This manuscript contains selective data. This study aims to review the findings and suggest strategies to improve SARS-Covid dementia management. The study makes use of medical research databases like Google Scholar, PubMed, Medline, and Embase. Furthermore, information is also collected by recognized health organizations and government agencies. COVID-19 can produce neuropsychological deficits, agitation, confusion, inattention, and disorientation. Thus, SARS can worsen dementia and neurodegeneration. This article summarizes COVID-19's effects on dementia patients from several sources. The focus on existing treatments for affected patients ties the two.

Locust-based genetic classifier for abnormality identification in brain

This study investigates the loctus-based genetic classifier for abnormality identification in the brain. In medical care, clinical professionals have to spend a lot of time extracting, identifying, and segmenting the afflicted region from magnetic resonance brain images. Utilizing computer-aided approaches is crucial to overcome this restriction. Henceforth, this paper proposes an efficient classifier for diagnosing abnormalities in human brain using magnetic resonance images (MRI). The focus is on improving the accuracy and efficiency of medical image segmentation, specifically for brain tumours, to assist clinical professionals in early disease detection. In order to improve the image's quality through noise reduction, the Gaussian filter is employed during the pre-processing stage. The proposed tumour segmentation is based on the Otsu algorithm, and the gray-level co-occurrence matrix (GLCM) is used to extract the relevant features. In this work, the locust-based genetic classifier plays a crucial role in early brain disease identification and pinpointing the precise location of the damaged area. Accuracy, sensitivity, and specificity have been used to analyze and validate the outcomes of the proposed technique. The current study's findings indicate accurate prediction of brain abnormality and have a 98.9% accuracy rate, 97.2% specificity, and 96% sensitivity. The study presents a reliable and efficient method for diagnosing brain abnormalities using MRI. The combination of the proposed approaches significantly enhances the segmentation and classification processes, leading to high diagnostic accuracy. This approach offers practical benefits for clinical professionals by reducing the time and effort required for diagnosing brain abnormalities.

A measles virus collective infectious unit that caused lethal human brain disease includes many locally restricted and few widespread copy-back defective genomes.

During virus replication in cultured cells, copy-back defective viral genomes (cbDVGs) can arise. CbDVGs are powerful inducers of innate immune responses in vitro, but their occurrence and impact on natural infections of human hosts remain poorly defined. We asked whether cbDVGs were generated in the brain of a patient who succumbed to subacute sclerosing panencephalitis (SSPE) about 20 years after acute measles virus (MeV) infection. Previous analyses of 13 brain specimens of this patient indicated that a collective infectious unit (CIU) drove lethal MeV spread. In this study, we identified 276 replication-competent cbDVG species, each present in over 100 copies in the brain. Six species were detected in multiple forebrain locations, implying that they travelled long-distance with the CIU. The cbDVG to full-length genomes ratio was often close to 1 (0.6-1.74). Most cbDVGs were 324-2,000 bases in length, corresponding to 2%-12% of the full-length genome; all are predicted to have complementary terminal sequences. If improperly encapsidated, these sequences have the potential to form double-stranded structures that can induce innate immune responses. To assess this, we examined the transcriptome of all brain specimens. Several interferon and inflammatory response genes were upregulated, but upregulation levels did not correlate with cbDVG levels in the specimens. Thus, the CIU that drove MeV pathogenesis in this brain includes, in addition to two complementary full-length genome populations, many locally restricted and few widespread cbDVG species. The widespread cbDVG species may have been positively selected but how they impacted pathogenesis remains to be determined.IMPORTANCECopy-back defective viral genomes (cbDVGs) can drive virus-host interactions. They can suppress virus replication directly, by competing with full-length genomes, or indirectly by stimulating antiviral immunity. In vitro, cbDVG can slow down infections and promote persistence, but there is limited documentation of their presence in human hosts or of their impact on disease. We had the unique opportunity to analyze the brain of a patient who succumbed to subacute sclerosing panencephalitis, a rare but lethal consequence of measles. We detected more than 270 distinct cbDVG species; most were restricted to one specimen, but several reached all lobes of the forebrain, suggesting positive selection. Our analyses provide the missing knowledge of the diversity of cbDVG in a natural infection of a human host. They also reveal that a collective infectious unit that caused lethal human brain disease includes few widespread cbDVG, in addition to two ubiquitous complementary full-length genome populations.

PET/CT/MRI in Clinical Trials of Alzheimer's Disease.

With the advent of PET imaging in 1976, 2-deoxy-2-[18F]fluoro-D-glucose (FDG)-PET became the preferred method for in vivo investigation of cerebral processes, including regional hypometabolism in Alzheimer's disease. With the emergence of amyloid-PET tracers, [11C]Pittsburgh Compound-B in 2004 and later [18F]florbetapir, [18F]florbetaben, and [18F]flumetamol, amyloid-PET has replaced FDG-PET in Alzheimer's disease anti-amyloid clinical trial treatments to ensure "amyloid positivity" as an entry criterion, and to measure treatment-related decline in cerebral amyloid deposits. MRI has been used to rule out other brain diseases and screen for 'amyloid-related imaging abnormalities' (ARIAs) of two kinds, ARIA-E and ARIA-H, characterized by edema and micro-hemorrhage, respectively, and, to a lesser extent, to measure changes in cerebral volumes. While early immunotherapy trials of Alzheimer's disease showed no clinical effects, newer monoclonal antibody trials reported decreases of 27% to 85% in the cerebral amyloid-PET signal, interpreted by the Food and Drug Administration as amyloid removal expected to result in a reduction in clinical decline. However, due to the lack of diagnostic specificity of amyloid-PET tracers, amyloid positivity cannot prevent the inclusion of non-Alzheimer's patients and even healthy subjects in these clinical trials. Moreover, the "decreasing amyloid accumulation" assessed by amyloid-PET imaging has questionable quantitative value in the presence of treatment-related brain damage (ARIAs). Therefore, future Alzheimer's clinical trials should disregard amyloid-PET imaging and focus instead on assessment of regional brain function by FDG-PET and MRI monitoring of ARIAs and brain volume loss in all trial patients.

Factors Influencing the Central Nervous System (CNS) Distribution of the Ataxia Telangiectasia Mutated and Rad3-Related Inhibitor Elimusertib (BAY1895344): Implications for the Treatment of CNS Tumors.

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro-in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited. SIGNIFICANCE STATEMENT: This study examined the disconnect between the in vitro synergy and in vivo efficacy of elimusertib/temozolomide combination therapy by exploring systemic and central nervous system (CNS) distributional pharmacokinetics. Results indicate that the lack of improvement in in vivo efficacy in glioblastoma (GBM) patient-derived xenograft (PDX) models could be attributed to inadequate exposure of pharmacologically active drug concentrations in the CNS. These observations can guide further exploration of elimusertib for the treatment of GBM or other CNS tumors.

Increased expression of mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to synapse loss in Alzheimer’s disease

BackgroundThe activation of endoplasmic reticulum (ER) stress is an early pathological hallmark of Alzheimer’s disease (AD) brain, but how ER stress contributes to the onset and development of AD remains poorly characterized. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a non-canonical neurotrophic factor and an ER stress inducible protein. Previous studies reported that MANF is increased in the brains of both pre-symptomatic and symptomatic AD patients, but the consequence of the early rise in MANF protein is unknown.MethodsWe examined the expression of MANF in the brain of AD mouse models at different pathological stages. Through behavioral, electrophysiological, and neuropathological analyses, we assessed the level of synaptic dysfunctions in the MANF transgenic mouse model which overexpresses MANF in the brain and in wild type (WT) mice with MANF overexpression in the hippocampus. Using proteomic and transcriptomic screening, we identified and validated the molecular mechanism underlying the effects of MANF on synaptic function.ResultsWe found that increased expression of MANF correlates with synapse loss in the hippocampus of AD mice. The ectopic expression of MANF in mice via transgenic or viral approaches causes synapse loss and defects in learning and memory. We also identified that MANF interacts with ELAV like RNA-binding protein 2 (ELAVL2) and affects its binding to RNA transcripts that are involved in synaptic functions. Increasing or decreasing MANF expression in the hippocampus of AD mice exacerbates or ameliorates the behavioral deficits and synaptic pathology, respectively.ConclusionsOur study established MANF as a mechanistic link between ER stress and synapse loss in AD and hinted at MANF as a therapeutic target in AD treatment.

Experimental peri-implantitis induces neuroinflammation: An exploratory study in rats

PurposeCumulating evidence supports the close association between periodontal diseases, neuroinflammation and neurodegenerative pathologies, except for peri-implantitis (PI). Thus, this study explored the association between experimental PI and neuropathological changes in the rat brain.Materials and methodsAfter bilateral first molars extraction, experimental PI was induced at titanium implants placed in the maxillae by lipopolysaccharide injections and ligature placement. Following 28-weeks of disease progression, the maxillae and brains were retrieved from 6 rats. Healthy brains from 3 rats were used as control. Brains were analyzed by immunohistochemistry to detect signs of neuroinflammation (interleukin (IL)-6 and tumor necrosis factor (TNF)-α)), microglial activation (IBA-1) and astrogliosis (GFAP). To explore signs of neurodegeneration, hematoxylin/eosin and Nissl stainings were used. Also, four different antibodies against amyloid beta (Aβ 1–42) were tested.ResultsChronic PI lesions showed peri-implant bone resorption accompanied by large inflammatory infiltrates. IL-6+ and TNF-α+ cells were found within the CA1 and Dentate Gyrus regions of the hippocampus of the PI-affected group, while almost no immune-positivity was detected in the control (p < 0.05). Detection of activated GFAP+ microglia and IBA-1+ astrocytes surface were significantly higher at the CA areas, and cerebral cortex of the PI-affected group, in comparison with control (p < 0.05). Shrunk neurons with pyknotic nuclei were inconsistently found among the PI-affected group, and these were almost not detected in control. No positive Aβ reactivity was detected in any of the samples.ConclusionChronic experimental PI lesions led to an increased detection of IL-6 and TNF-α, GFAP+ microgliosis and IBA-1+ astrocytosis, and in some cases, neurodegeneration, in the rat brain.

A glycan biomarker predicts cognitive decline in amyloid- and tau-negative patients.

Early detection of Alzheimer's disease is vital for timely treatment. Existing biomarkers for Alzheimer's disease reflect amyloid- and tau-related pathology, but it is unknown whether the disease can be detected before cerebral amyloidosis is observed. N-glycosylation has been suggested as an upstream regulator of both amyloid and tau pathology, and levels of the N-glycan structure bisecting N-acetylglucosamine (GlcNAc) correlate with tau in blood and CSF already at pre-clinical stages of the disease. Therefore, we aimed to evaluate whether bisecting GlcNAc could predict future cognitive decline in patients from a memory clinic cohort, stratified by amyloid/tau status. We included 251 patients (mean age: 65.6 ± 10.6 years, 60.6% female) in the GEDOC cohort, from the Memory Clinic at Karolinska University Hospital, Stockholm, Sweden. Patients were classified as amyloid/tau positive or negative based on CSF biomarkers. Cognitive decline, measured by longitudinal Mini-Mental State Examination scores, was followed for an average of 10.7 ± 4.1 years and modelled using non-linear mixed effects models. Additionally, bisecting GlcNAc levels were measured in hippocampus and cortex with lectin-based immunohistochemistry in 10 Alzheimer's disease and control brains. We found that CSF bisecting GlcNAc levels were elevated in tau-positive individuals compared with tau-negative individuals, but not in amyloid-positive individuals compared with amyloid-negative individuals. In the whole sample, high levels of CSF bisecting GlcNAc predicted earlier cognitive decline. Strikingly, amyloid/tau stratification showed that high CSF bisecting GlcNAc levels predicted earlier cognitive decline in amyloid-negative patients (β = 2.53 ± 0.85 years, P = 0.003) and tau-negative patients (β = 2.43 ± 1.01 years, P = 0.017), but not in amyloid- or tau-positive patients. Finally, histochemical analysis of bisecting GlcNAc showed increased levels in neurons in hippocampus and cortex of Alzheimer's disease compared with control brain (fold change = 1.44-1.49, P < 0.001). In conclusion, high CSF levels of bisecting GlcNAc reflected neuronal pathology and predicted cognitive decline in amyloid- and tau-negative individuals, suggesting that abnormal glycosylation precedes cerebral amyloidosis and tau hyper-phosphorylation in Alzheimer's disease. Bisecting GlcNAc is a promising novel early biomarker for Alzheimer's disease.