Brain homeostasis depends on mitochondrial efficiency and adequate substrate availability. Guanosine, a naturally occurring purine nucleoside, has emerged as a neuromodulator with neuroprotective properties, however, its impact on mitochondrial bioenergetics across distinct brain regions remains poorly understood. Male Swiss mice (3 months old) were treated with guanosine (8mg/kg) voluntary oral consumption for 26 days. Mitochondrial function was assessed using fluorescent probes (membrane potential and reactive species production), high-resolution respirometry (HRR) for real-time analysis of oxidative phosphorylation (OXPHOS) analysis and enzymatic activity assays in the prefrontal cortex and hippocampus of mice. Behavioral assessments were performed using the open field test and the novel object recognition (NOR) task. Guanosine selectively enhanced mitochondrial membrane potential and significantly increased OXPHOS, maximal electron transfer system (ETS) capacity, and mitochondrial spare capacity in the prefrontal cortex. These functional improvements occurred without alterations in mitochondrial content (citrate synthase activity) or in the activity of respiratory complexes I, II, and IV. In contrast, no significant changes were observed in the hippocampus for any measured parameters, supporting a marked regional difference in bioenergetic response. Behavioral analyses using the novel object recognition (NOR) task indicated no significant effects on cognitive performance. Chronic guanosine administration selectively enhances the bioenergetic efficiency of the prefrontal cortex, while no alterations are observed in the hippocampus. These findings identify guanosine as a differential modulator of brain metabolism and suggest a mechanism involving the enhancement of cortical mitochondrial spare capacity, providing insights relevant to conditions characterized by regional mitochondrial vulnerability, such as neurodegenerative disorders.

Midlife hypertension (HTN) contributes to cognitive decline in Alzheimer's disease (AD). However, the exact effect of late-life HTN on the AD pathology and on cognitive decline is still controversial. Here, we aimed to assess the impact of HTN and AD pathology in cognitively unimpaired (CU) individuals over 65 years of age on longitudinal cognitive decline. We evaluated 637 CU individuals from two independent cohorts (475 CU individuals from the ADNI cohort; and 162 CU individuals from the TRIAD cohort), with a follow-up of up to 6 years. Linear mixed-effects models showed that HTN and Aβ acted together to promote longitudinal cognitive decline, especially memory loss, in a synergistic way, with a dose-dependent association of blood pressure and Aβ pathology. Hence, HTN in late-life confers additional risk for cognitive decline, particularly for memory loss, in CU individuals at risk of developing dementia due to AD and is a potential modifiable risk factor even at older age.

Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer's disease (AD). In this study, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in individuals across the AD spectrum. We examined 101 individuals using positron emission tomography radiotracers to assess Aβ deposition ([18F]AZD4694), tau aggregation ([18F]MK-6240) and microglial activation ([11C]PBR28), along with plasma biomarkers for astrocyte reactivity (GFAP) and tau phosphorylation (p-tau217). We further evaluated 251 individuals with cerebrospinal fluid levels of the microglial marker sTREM2. We found that Aβ pathology was associated with astrocyte reactivity across cortical brain regions only in the presence of microglial activation. The microglia-dependent effects of Aβ on astrocyte reactivity were further related to cognitive impairment through tau phosphorylation and aggregation. Our results suggest that microglial activation plays a key role in Aβ-related astrocyte reactivity, which, in turn, contributes to downstream pathological features of AD.

Purinergic signaling is vital in various cellular processes like neuroinflammation, synaptic transmission, Aβ clearance, and tau phosphorylation regulation. This study aims to examine if SNPs in purinergic signaling genes are associated to A/T(N) status biomarkers in Alzheimer’s Disease through Genome Wide Association Studies. The SNPRelate package was used to analyze SNPs in genes related to purinergic signaling and A/T(N) markers. We included 152 cognitively unimpaired and 359 cognitively impaired individuals from the ADNI cohort. Generalized linear models were applied to investigate associations between independent variables (SNPs, APOE4 status, sex, age, education, and diagnosis), and A/T(N) markers, specifically tau status (CSF/Plasma ptau181), amyloid status (CSF Aβ and AV45-PET ratio of cortical grey matter/whole cerebellum), and neurodegeneration status (average FDG-PET metaROI). We also conducted a voxel-wise linear regression testing the association between [18F]FDG metabolism and SNP carriership, corrected by sex and age. The analysis was corrected for multiple comparisons using the cluster-wise random field theory method (significant t>3.11, p<0.001, df = 495). We identified 13 SNPs in the intronic region of purinergic signaling genes that had a significant association with A/T(N) status biomarkers (Table 1). CSF Aβ levels were associated with polymorphisms in the adenosine deaminase 1 (ADA1) and 2 (ADA2) genes. AV45-PET binding was associated with SNPs in ADA2, ADORA1, and P2×1 genes. CSF ptau181 levels were associated with polymorphisms in the ADORA1, NTPDase-2/CD39L1, and pannexin 1 gene. Increased FDG uptake was associated with a polymorphism in the ADORA2B gene. Finally, a polymorphism in the ADORA1 gene presented a positive association with [18F]FDG metabolism in the parietal lobe white matter (tmax = 3.97, p<0.0001) (Figure 1). Multiple SNPs within genes related to purinergic signaling have been identified to be linked with A/T(N) status markers. These results underscore the significance of purinergic signaling in cellular processes relevant to brain homeostasis, suggesting potential implications for Alzheimer’s disease (AD). Consequently, these findings highlight promising cellular mechanisms underlying the development of dementia.

Resveratrol, a natural polyphenol, has shown promising neuroprotective effects in several in vivo and in vitro experimental models. However, the mechanisms by which resveratrol mediates these effects are not fully understood. Glutamate is the major excitatory neurotransmitter in the brain; however, excessive extracellular glutamate levels can affect neural activity in several neurological diseases. Astrocytes are the glial cells that maintain brain homeostasis and can attenuate excitotoxicity by actively participating in glutamate neurotransmission. This study aimed to investigate the glioprotective effects of resveratrol against glutamate-induced cellular dysfunction in hippocampal slices and primary astrocyte cultures, with a focus on the role of heme-oxygenase 1 (HO-1). Glutamate impaired glutamate uptake activity through a glutamate receptor-dependent mechanism, in addition to altering other important astroglial parameters, including glutamine synthetase activity, glutathione levels and cystine uptake, which were normalized by resveratrol. Resveratrol also prevented glutamate-induced disruption in antioxidant defenses, as well as in trophic and inflammatory functions, including the nuclear factor κB (NFκB) transcriptional activity. Most of the effects of resveratrol, mainly in astrocytes, were dependent on the HO-1 signaling pathway, as they were abrogated when HO-1 was pharmacologically inhibited. Resveratrol also increased HO-1 mRNA expression and its transcriptional regulator, nuclear factor erythroid-derived 2-like 2 (Nrf2). Finally, resveratrol prevented glutamate-induced p21 senescence marker, indicating an anti-aging effect. Therefore, we demonstrated that the activation of the Nrf2/HO-1 system in astrocytes by resveratrol represents an astrocyte-targeted neuroprotective mechanism in neurodegeneration, with glutamate excitotoxicity, oxidative stress, and neuroinflammation as common neurochemical alterations.

COVID-19, identified as the greatest health concern of the century, is associated with vascular inflammation and endothelial activation, resulting in multisystemic damage, including to the central nervous system (CNS). Recent investigations indicate a link between endothelial dysfunction, neurological changes, and the development of the so-called long-COVID. Molecules expressed in the endothelium such as P-selectin, E-selectin, and VEGF-A, increased under inflammatory injury, may be associated with conditions like brain injuries and neurodegenerative diseases. These markers may remain altered in the organism for months after the acute episode of COVID and may be related to long-term neurological disorders. This study aims to identify associations between biomarkers of endothelial dysfunction and brain glucose metabolism in individuals with long-COVID. A total of 39 individuals presenting with long-COVID and 10 healthy controls (HC) underwent brain [ 18 F]FDG-PET imaging. Standardized uptake value ratio maps were generated using the [ 18 F]FDG-PET global mean. Using an ELISA Multiplex assay, we measured P-selectin, E-selectin, and VEGF-A in plasma samples. Voxel-wise linear regressions models accounting for age, gender, and years of education were used to evaluate the association between the interaction biomarker*group and the brain glucose metabolism. The analyses showed that the interaction between P-selectin and group presents positive association clusters in the right isthmus of the corpus callosum, thalamus, and left lingual gyrus (Figure 1). In this model, we also observed negative association clusters in the lingual gyrus bilaterally, the left inferior occipital gyrus, and the flocculonodular lobe (posterior cerebellum) (Figure 2). The linear regression analysis with the interaction between VEGFA or E-selectin and group did not present a significant association with [ 18 F]FDG-PET signal. The results provide preliminary insights into the complex interactions between endothelial dysfunction and cerebral glucose metabolism in long-COVID. The regions presenting significant associations are involved in cognition, memory, sensory and motor function, language and visual processing, indicating a potential widespread brain vascular response. Additional studies are needed for a comprehensive understanding of these relationships in long-COVID.

Allopurinol is a potent xanthine oxidase inhibitor commonly used to treat hyperuricemia and gout. Purines have been implicated in various mechanisms of pain modulation. This study investigated whether xanthine oxidase inhibition by allopurinol could enhance endogenous purinergic activity and produce antinociceptive effects in a neuropathic pain model in mice. Male mice received intraperitoneal injections of allopurinol (50–200 mg/kg) or vehicle (10

Glial reactivity is a key phenomenon in Alzheimer’s disease (AD) and is closely associated with amyloid-β (Aβ) pathology. Although compelling experimental data suggest that microglial activation modulates reactive astrogliosis, it remains to be elucidated whether microglial activation influences the association of Aβ pathology with reactive astrogliosis in the living AD human brain. Here, we tested the association of microglial activation and Aβ pathology with reactive astrogliosis in individuals across the aging and AD clinical spectrum. We studied 101 participants (62 cognitively unimpaired [CU], 26 with mild cognitive impairment [MCI], and 13 with AD dementia) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Individuals had available positron emission tomography (PET) for Aβ ([ 18 F]AZD4694) and microglial activation ([ 11 C]PBR28), as well as magnetic resonance imaging. We further assessed reactive astrogliosis with plasma glial fibrillary acidic protein (GFAP). Linear regression analyses were used to investigate the associations between Aβ, microglial activation and GFAP. Demographic characteristics of the study population are reported in Table 1. Regression analyses revealed a significant positive association between Aβ PET burden and plasma GFAP levels in microglial activation-positive but not in microglial activation-negative individuals (Figure 1A). A significant interaction between continuous values of Aβ PET burden and [ 11 C]PBR28 PET uptake on plasma GFAP levels (Figure 1B) supported that microglial activation affects the association of Aβ pathology with reactive astrogliosis. Analysis of variance further confirmed that the model with the interaction term was the most adequate to describe the association of Aβ PET and microglial activation PET with plasma GFAP ( P = 0.007). In additional analyses investigating the topography of the observed findings, we found that higher Aβ PET burden was associated with higher plasma GFAP levels only in the presence of microglial activation positivity across Aβ-vulnerable cortical brain regions (Figure 1C). Our results suggest that microglial activation impacts Aβ-dependent reactive astrogliosis in the living AD brain. This can help to better understand the complementary roles of glial cells in neurodegenerative diseases, as well as provide insights for the development of novel therapeutic strategies for AD targeting the interplay between Aβ and glial reactivity.

Long COVID is an under-characterized disorder that affects a wide range of individuals after COVID-19 resolution. Long COVID individuals report persistent neurological manifestations, such as anxiety. Understanding its effects in the brain might help uncover the actual burden imposed by the pandemic sequelae and either define or discard long COVID as a risk factor for neurodegenerative diseases. Here, we aim to identify whether there is an association between brain metabolism and anxiety in an underrepresented population. Community-dwelling individuals, above 50 years old, from Porto Alegre, Brazil, were divided into long COVID (n=39) and control groups (n=10) were evaluated with a battery of neuropsychological testing, including the GAD-7 scale of anxiety. Then, they underwent a brain [ 18 F]FDG-PET scan (images normalized by the pons). We conducted a voxel-wise linear regression testing the association between [ 18 F]FDG metabolism and GAD-7, and corrected for education, sex, and age. The analysis was corrected for multiple comparisons using the cluster-wise random field theory method (significant t<-3.34 and t>3.34, p<0.001, df=35). We found that GAD-7 score presented a widespread negative association with [ 18 F]FDG metabolism in multiple gray and white matter regions (Figure 1). Specifically, hippocampus (t max =-3.34, p=0.002), amygdala (t max =-3.82, p=0.0005), cerebellum (t max =-4.28, p=0.0001), and lateral occipitotemporal gyrus (t max =-5.26, p=0.0001) had the most relevant associated clusters in gray matter, while temporal lobe (t max =-3.9, p=0.0004) and frontal lobe (t max =-4.33, p=0.0001) presented the most relevant associated clusters in white matter. Anxiety symptoms are a highly self-reported symptom in long COVID. Here we show that anxiety is widely associated with reduced brain glucose metabolism in crucial areas for the limbic system and cognition, such as the hippocampus and amygdala. The peculiar associations between anxiety and FDG metabolism in white matter may suggest inflammatory responses triggered by long COVID. These data provide new insights into the mechanisms underlying long COVID symptoms in the brain.

AbstractBackgroundLong‐COVID is characterized by persistent symptoms post‐infection with SARS‐CoV‐2. This condition includes neurological manifestations and has been proposed as a potential risk factor for the development of dementia. Individuals presenting with dementia due to Alzheimer's disease have dysfunctional brain metabolism, including metabolic brain network (MBN) hypoconnectivity. However, whether long‐COVID alters brain metabolic architecture remains elusive. Here, we aimed to evaluate the brain metabolic connectivity in a Brazilian cohort of individuals presenting with long‐COVID.Method[18F]FDG‐PET images were acquired from 52 community‐dwelling Brazilians above 50 year old. Standardized uptake value ratio (SUVr) parametric maps were processed to a common 8 mm FWHM and generated using the pons as the reference region (Figure 1). We extracted the mean values of regions of interest using the ICBM152 atlas. [18F]FDG‐PET MBNs were constructed using a novel multiple sampling scheme, which assembles a stable group representative MBN based on bootstrap (n = 2000). Adaptive Synthetic Sampling Approach for Imbalance (ADASYN) was used to account for group imbalance and generated the ADA‐MBNs. Graph measures, including density, global efficiency, average degree, and assortativity coefficient were computed. Data were corrected for multiple comparisons using the False Discovery Rate (FDR) method (p<0.05).Result41 individuals with long‐COVID and 11 healthy controls (HC) were included (Table 1). We observed that long‐COVID individuals present PET hyperconnectivity in both MBN and ADA‐MBN. (Figure 2a‐b). The long‐COVID group presented increased density, global efficiency and average degree whereas assortativity coefficient were reduced in both MBN and ADA‐MBN.ConclusionOur findings showed that individuals with long‐COVID presented a brain metabolic hyperconnectivity, which is supported by increased density and average degree and may indicate a potential compensatory mechanism within the brain. In addition, the increase in global efficiency indicates that the brain of long‐COVID individuals exchanges metabolic information more efficiently, but the decreased assortativity coefficient suggests vertices with different properties connect to each other. Further longitudinal studies should follow these individuals for assessing microstructural and cognitive changes.

Systemic Arterial Hypertension (SAH), distinguished by a persistent elevation of blood pressure, emerges as a risk factor for stroke and Alzheimer’s Disease (AD). Additionally, recent evidence suggests that stroke may adversely affect memory, potentially playing a role in the development of AD. This study aimed to investigate the influence of permanent focal ischemic stroke on memory, as well as on sensorimotor function (asymmetry of the front paws) and cerebral infarct size in adult male spontaneously hypertensive rats (SHR), compared to normotensive Wistar Kyoto (WKY) rats. We assessed the stroke effects on short- and long-term memory through the open field task (7 and 21 days after stroke), on sensorimotor functions through the cylinder test and adhesive removal test (over 42 days after stroke), and on infarction volume through 2,3,5-Triphenyltetrazolium chloride staining (3 and 7 days after stroke). Short-term memory was observed in both naive WKY and naive SHR rats, while SHR naive animals did not exhibit long-term memory. Stroke disrupted short-term memory in both WKY and SHR rats and long-term memory in WKY rats (Fig. 01). In regards to the sensorimotor function, (cylinder test and adhesive removal) WKY rats totally recovered from the stroke-induced asymmetry in the front paws, while SHR rats did not (Fig. 02). Concerning infarction volume, WKY rats showed decreased infarction volume from the third to the seventh day after stroke, while SHR rats did not exhibit this reduction (Fig. 03). These results emphasize the impact of hypertension on memory, as well as on motor outcomes and brain infarct size following stroke, potentially contributing to the risk for AD.

Ischemic stroke (IS) is a risk factor for developing Alzheimer’s disease (AD). In this context, microglial activation is a shared cellular response to these two conditions that can be either beneficial or detrimental. Previous research has established that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) treatment leads to enhanced functional recovery and reduced brain infarct volume in animal IS models. However, current literature findings are unclear when addressing the effects of MSC-EVs treatment on microglial activation. Thus, we aimed to investigate how MSC-EVs treatment alters microglial activation parameters in IS models. The protocol of this systematic review was registered in PROSPERO (CRD42023463152) and followed the PRISMA 2020 statement. We searched EMBASE, PubMed, and Web of Science from database inception to October 2023 for studies with animal or cell culture IS models using MSC-EVs as intervention and measuring microglial activation outcomes compared to control. We performed a random-effects meta-analysis using standardized mean differences (SMD) as the effect measure with the metafor and metaviz packages in R (v4.2.1) (FDR-adjusted p-value<0.05). The database search identified 294 records, from which 27 were included (Fig. 1). Meta-analysis showed that in vivo MSC-EVs treatment resulted in a lower number of total microglia (Iba1+ cells) (SMD = -1.45 [-2.19,-0.71 95%CI] p<0.001, Fig. 2A) and CD16+ microglia (SMD = -1.84 [-2.62,-1.05 95%CI] p<0.001, Fig. 2B), but in a higher number of CD206+ microglia (SMD = 1.95 [1.01,2.88 95%CI] p<0.001, Fig. 2C) in the brain across different IS models and age groups. In microglia cell cultures submitted to oxygen-glucose deprivation, MSC-EVs treatment decreased the levels of TNF-α (SMD = -3.32 [-4.95,-1.69 95%CI] p<0.001, Fig. 3A), IL-1β (SMD = -3.45 [-5.57,-1.32 95%CI] p<0.001, Fig. 3B), and IL-6 (SMD = -2.95 [-4.50,-1.40 95%CI] p<0.001, Fig. 3C) in the culture medium, while increasing the gene expression levels of Arg-1 (SMD = 5.41[3.54,7.29 95%CI] p<0.001, Fig. 3D). We demonstrated that MSC-EVs treatment in IS models reduces the expression of pro-inflammatory microglial activation markers (CD16) and cytokines (TNF-α, IL-1β, IL-6) while increasing the expression of anti-inflammatory markers (CD206, Arg-1). Our results suggest that MSC-EVs treatment modulates microglia towards a pro-resolutive state, potentially contributing to the recovery of damaged brain tissue in IS and, consequently, in AD.

The Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is one of the biggest health concerns of the century. Long COVID is one of the major sequelae from the infection and include persistent neurological manifestations. Brain images study suggest that Long COVID patients present distinct brain metabolic alterations. However, whether brain subtypes of Long COVID exist remains unclear. Here, we aimed to evaluate metabolic patterns in FDG-PET imaging in a Brazilian cohort of individuals presenting with Long COVID. A total of 37 adult Brazilian individuals presenting with Long COVID symptoms were scanned with FDG positron emission tomography (FDG-PET) and its standardized uptake value ratio (SUVr normalized by the whole brain) was obtained. Then, 89 volumes of interest (VOIs) were extracted and used as input features for a principal component analysis (PCA). Average silhouette method was used to determine the optimal number of clusters. K-means clustering was used to split the dataset into a set of K groups. We employed ANCOVA and Tukey tests to compare the groups. Statistical analysis was made in the R environment, significance set at p <0.05. PCA analysis identified three different FDG-PET subtypes: C1 (n=4), C2 (n=6), and C3 (n=27). In the ANCOVA comparison, the regions with the highest increase in the mean regional SUVr were left lingual gyrus for C1 compared to C2 and C3, and corpus callosum for C2 against C3. Conversely, the greatest regional decrease observed were: left caudate nucleus for C1 compared to C2 and right globus pallidus for C1 and C2 compared to C3. These preliminary findings suggest that Long COVID individuals present a predominant metabolic signature (C3) but at least two variants. Our results corroborate that Long COVID is a heterogeneous condition that affects individuals in a different manner. More studies are needed to understand the regional brain vulnerability to Long COVID.

Microglial activation is an early phenomenon in Alzheimer’s disease (AD) that may occur prior to and independently of amyloid-β (Aβ) aggregation. Compelling experimental evidence suggests that the apolipoprotein E ε4 ( APOE ε4) allele may be a culprit of early microglial activation in AD. However, it is unclear whether the APOE ε4 genotype is associated with microglial reactivity in the living human brain. In individuals across the aging and AD spectrum, we tested the hypothesis that APOE ε4 associates with microglial activation. We studied 118 individuals (79 cognitively unimpaired [CU], 23 with mild cognitive impairment [MCI], and 16 with AD dementia) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Individuals had available [ 18 F]AZD4694 Aβ PET, [ 18 F]MK6240 tau PET, [ 11 C]PBR28 microglial activation PET, and magnetic resonance imaging (MRI), as well as APOE genotyping. To increase the reliability of our results, we only included high-affinity binders for the [ 11 C]PBR28 radiotracer. In a subgroup of 42 individuals with longitudinal clinical and MRI data, we further assessed longitudinal hippocampal atrophy and clinical deterioration. Voxel-wise analysis revealed that APOE ε4 carriership was associated with increased [ 11 C]PBR28 uptake mainly in the medial temporal cortex (Figure 1A and B), and this effect of APOE ε4 was independent of Aβ and tau accumulation. Region-wise analyses demonstrated that APOE ε4 carriers presented increased [ 11 C]PBR28 SUVR relative to noncarriers only in Braak I-II regions (Figure 1C), which further supports that APOE ε4-related microglial activation occurs specifically in medial temporal structures. Lastly, we found that [ 11 C]PBR28 uptake in brain regions vulnerable to APOE ε4 effects is associated with subsequent hippocampal atrophy and clinical decline over 2 years (Figure 2). These results support a model in which APOEε4 plays a role in early AD progression by contributing to microglial activation in medial temporal regions. Our findings provide a rationale for the development of novel AD therapies targeting the interplay between ApoE and neuroinflammation.

Fluorodeoxyglucose (FDG)-PET hypometabolism is considered a biomarker of neurodegeneration. However, recent evidence revealed that glial cells contribute to the FDG-PET signal. In this context, microglial changes have been evaluated with 18-kDa translocator protein (TSPO)-PET radiopharmaceuticals. While several studies have concomitantly conducted FDG- and TSPO-PET imaging, their associations remain controversial. We systematically revised multi-tracer preclinical and clinical studies using FDG- and TSPO-PET to investigate neurodegenerative conditions. From 401 studies, 14 preclinical studies, 7 clinical studies and 1 study including both met the inclusion criteria. The preclinical studies included mouse models of amyloid, tau, and neurotoxins, whereas the clinical studies investigated Alzheimer’s disease, Parkinson’s disease and frontotemporal lobar degeneration. Most clinical studies found a negative association between FDG- and TSPO-PET signals, whereas animal studies showed mixed results being highly dependent on the radiotracer used. Our findings support the connection between glial and metabolic changes in the brain while highlighting glial heterogeneity between species and the specificities of TSPO-PET radiotracers. To better understand the dynamic associations between FDG- and TSPO-PET, it is essential to conduct longitudinal studies during the early stages of neurodegenerative disorders, along with the use of novel mouse models that more accurately represent these conditions.

The Zika Virus (ZIKV) is a Flavivirus that caused a recent outbreak worldwide resulting in different neurological outcomes that are still poorly characterized and understood. Concerning this issue, in vitro and in vivo models are being applied to improve the molecular understanding of ZIKV infection. In this work, applying shotgun proteomics we revealed the differential ZIKV infection proteome in Vero cells, a non-neural cell model. A dramatic change resulting from infection was found including the differential expression of several proteins previously associated with brain diseases. The molecular alterations caused by this pathogen were further characterized through bioinformatics such as Gene Ontology and protein-protein interaction network of resulting differential proteome. Our findings identified molecular markers that were differentially expressed during ZIKV infection and had been previously linked to neurological conditions and infections caused by ZIKV and/or SARS-CoV-2. The results presented in this article highlight molecular markers associated with neurological dysfunctions, demonstrating that ZIKV infection can dysregulate neural-specific genes, even in non-neural cells.

Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitively impaired (CI) individuals. We measured amyloid-β (Aβ), phosphorylated tau (pTau181), astrocyte reactivity (GFAP), microglial activation (sTREM2), and synaptic markers (GAP43, neurogranin). CSF GFAP levels were associated with presynaptic and postsynaptic dysfunction, independent of cognitive status or Aβ presence. CSF sTREM2 levels were related to presynaptic markers in cognitively unimpaired and impaired Aβ+ individuals, and to postsynaptic markers in cognitively impaired Aβ+ individuals. Notably, CSF pTau mediated the relationships between GFAP or sTREM2 and synaptic dysfunction. Our findings, validated in two independent cohorts (TRIAD and ADNI), reveal a distinct pattern of glial contribution to synaptic degeneration.

The deposition of β-amyloid (Aβ) plaques is a classical neuropathological feature of Alzheimer’s disease (AD). Currently, it is believed that intermediate products of the Aβ fibrillogenesis process, like the β-amyloid oligomers (AβOs), are the most toxic forms, and are involved in neurodegenerative processes in AD. The evaluation of cerebral glucose metabolism in patients with β-amyloid plaque deposition using [ 18 F]FDG-PET has been used as a marker of neurodegeneration in AD. However, little is understood about AβOs' impact on glucose metabolism prior to Aβ plaques formation. The aim of this study was to evaluate the impact of the intracerebroventricular infusion of AβOs on in vivo glucose metabolism via [ 18 F]FDG-PET. Male Swiss mice (3-month-old, n = 20 per group) were divided into three groups: Vehicle, AβOs 10pmol, and AβOs 100pmol. Vehicle/AβOs were infused into mice’ right ventricle using the freehand technique after brief isoflurane anesthesia. [ 18 F]FDG-PET scans were performed 24h after AβOs infusion. The same animals underwent the Novel Object Recognition (NOR) task 24h after scanning. The images were processed and analyzed using MINC tools. Metabolic networks were built by computing Pearson correlation coefficients based on 2,000 bootstrap samples and FDR corrected (P<0.05). See Fig. 1a, for a experimental design illustration. AβOs induced dose-dependent brain glucose hypometabolism ( Fig. 1b ) and metabolic network disturbances. Voxel-wise percentage change analysis revealed moderate reductions in glucose brain metabolism (5% to 15%) following infusion of 10pmol AβOs, whereas 100 pmol AβOs led to widespread and substantial reductions of up to 25% ( Fig. 1c ). T-statistical voxel-wise analysis indicated statistically significant brain glucose hypometabolism only in the 100pmol group ( Fig. 1d ). The low-dose AβOs (10pmol) induced brain inter-region metabolic hyperconnectivity, while the 100 pmol dose caused hypoconnectivity ( Fig. 1e ). Furthermore, both AβOs infusion groups exhibited impaired recognition memory in the NOR task ( Fig. 1f ). Our results are the first demonstration of AβOs causing in vivo glucose hypometabolism and metabolic network disturbances in the absence of plaques. These findings point to an early impact of AβOs on glucose metabolism, independent of β-amyloid plaque formation. While the molecular pathways underlying this effect require further investigation, they may represent important AD pathophysiological mechanisms and potential targets for therapeutic intervention.

Amyloid-β imaging through positron emission tomography (PET) has significantly transformed Alzheimer’s disease (AD) research. [11C]PiB has been widely used for imaging β-amyloid plaques due to its high affinity and selectivity for amyloid deposits. [18F]AZD4694 is a more recently developed amyloid-PET imaging agent, which structurally resembles PiB and has less non-specific binding in the white matter than other 18F-labeled compounds. The purpose of this study is to compare the in vitro binding properties of the amyloid-PET radiotracers [11C]PiB and [18F]AZD4694 in post-mortem human brain tissue. Total binding was assessed by autoradiography in prefrontal, inferior parietal, posterior cingulate cortices and hippocampal sections of healthy control (HC) and AD autopsy-confirmed brain tissues. Furthermore, the displacement of [18F]AZD4694 by unlabeled PiB was evaluated in the above-mentioned sections of AD brain tissues. For both radiotracers, we found significant differences (p < 0.0001) between HC and AD tissues binding in the prefrontal cortex ([11C]PiB Cohen’s d = 3.424, [18F]AZD4694 Cohen’s d = 5.070), inferior parietal cortex ([11C]PiB Cohen’s d = 3.156, [18F]AZD4694 Cohen’s d = 3.959), posterior cingulate cortex ([11C]PiB Cohen’s d = 1.781, [18F]AZD4694 Cohen’s d = 3.434), and hippocampus ([11C]PiB Cohen’s d = 1.320, [18F]AZD4694 Cohen’s d = 3.696). Higher binding was detected for [18F]AZD4694 compared to [11C]PiB in AD prefrontal, inferior parietal and posterior cingulate cortices, while binding in the hippocampus was comparable for both radioligands. Strong correlations between [18]AZD4694 and [11C]PiB were found in the prefrontal (R = 0.959, p < 0.0001), inferior parietal (R = 0.893, p < 0.0001), posterior cingulate (R = 0.838, p = 0.0006) cortices and hippocampus (R = 0.750, p < 0.0001). Bland–Altman analyses revealed strong agreement between [11C]PiB and [18F]AZD4694 in the prefrontal, inferior parietal, and posterior cingulate cortices, but lower agreement in the hippocampus. Displacement studies confirmed high binding affinity of PiB in all tissues, indicating that both amyloid-PET agents compete for the same binding sites. This head-to-head study provides evidence that while [18F]AZD4694 and [11C]PiB bindings are highly correlated with both tracers competing for the same binding sites, [18F]AZD4694 has a slightly higher effect size when comparing between neuropathologically-confirmed AD and HC brain tissues.