Reduced Glucose Metabolism Research Articles

Aberrant protein O‐GlcNAcylation drives AD‐like neurodegeneration in DS mice

AbstractBackgroundDown syndrome (DS) is related with an increased incidence of Alzheimer’s disease (AD) neuropathology. Among the putative mechanisms leading neurodegeneration, the reduction of cerebral glucose metabolism may trigger brain damage by impacting the hexosamine biosynthetic pathway (HBP). As reported in AD, defective HBP is responsible for flawed protein O‐GlcNAcylation coupled by a mutual inverse increase of protein phosphorylation on Ser/Thr residues, which gives to O‐GlcNAcylation the ability to modulate various pathways involved in AD progression. Previous studies have shown the aberrant O‐GlcNAcylation/phosphorylation ratio of tau and APP in AD brain, confirming dysfunctional O‐GlcNAcylation as a key contributor in the pathogenesis of the disease. Our work aims to unravel, for the first time, the role of protein O‐GlcNAcylation in DS neuropathology along with its possible pharmacological modulation to prevent DS cognitive decline.MethodsWe performed western blot analysis of global O‐GlcNAc levels and total protein Ser/Thr phosphorylation in the hippocampus of 6‐months‐old Ts2Cje, mouse model of DS, compared to age‐matched controls. Furthermore, we measured the activity of enzymes involved in O‐GlcNAcylation cycling (OGT and OGA), as well as the functionality of GFAT1, the rate limiting enzyme of the HBP. Additionally, we determined by immunoprecitation the O‐GlcNAcylation/phosphorylation ratio of AD‐related markers (tau and APP). Finally, we tested the efficacy of an intranasal short‐term treatment with an O‐GlcNAc‐modulating compound.ResultsWe observed an early reduction of total O‐GlcNAcylation levels in young Ts2Cje mice and established its correlation with an increase in total protein phosphorylation. We measured the alteration in OGT and OGA functionality, unrelated with a dysfunctional activity of GFAT1. Moreover, we demonstrated that the reduction of O‐GlcNAcylation/phosphorylation levels affects both tau and APP, actively contributing to DS neuropathology. Lastly, our novel therapeutic strategy was able to increase O‐GlcNAc levels in Ts2Cje mice and restore AD‐related markers, possibly slowing disease progression.ConclusionOur research highlights the pathological role of the altered protein O‐GlcNAcylation profile in DS neurodegeneration and investigates the neuroprotective effects of an O‐GlcNAc‐modulating compound.

The Differential Influence of Immune, Endocytotic, and Lipid Metabolism Genes on Amyloid Deposition and Neurodegeneration in Subjects at Risk of Alzheimer's Disease.

Over 20 single-nucleotide polymorphisms (SNPs) are associated with increased risk of Alzheimer's disease (AD). We categorized these loci into immunity, lipid metabolism, and endocytosis pathways, and associated the polygenic risk scores (PRS) calculated, with AD biomarkers in mild cognitive impairment (MCI) subjects. The aim of this study was to identify associations between pathway-specific PRS and AD biomarkers in patients with MCI and healthy controls. AD biomarkers ([18F]Florbetapir-PET SUVR, FDG-PET SUVR, hippocampal volume, CSF tau and amyloid-β levels) and neurocognitive tests scores were obtained in 258 healthy controls and 451 MCI subjects from the ADNI dataset at baseline and at 24-month follow up. Pathway-related (immunity, lipid metabolism, and endocytosis) and total polygenic risk scores were calculated from 20 SNPs. Multiple linear regression analysis was used to test predictive value of the polygenic risk scores over longitudinal biomarker and cognitive changes. Higher immune risk score was associated with worse cognitive measures and reduced glucose metabolism. Higher lipid risk score was associated with increased amyloid deposition and cortical hypometabolism. Total, immune, and lipid scores were associated with significant changes in cognitive measures, amyloid deposition, and brain metabolism. Polygenic risk scores highlights the influence of specific genes on amyloid-dependent and independent pathways; and these pathways could be differentially influenced by lipid and immune scores respectively.

Pre- and early postnatal enriched environmental experiences prevent neonatal hypoxia-ischemia late neurodegeneration via metabolic and neuroplastic mechanisms.

Prenatal and early postnatal periods are important for brain development and neural function. Neonatal insults such as hypoxia-ischemia (HI) causes prolonged neural and metabolic dysregulation, affecting central nervous system maturation. There is evidence that brain hypometabolism could increase the risk of adult-onset neurodegenerative diseases. However, the impact of non-pharmacologic strategies to attenuate HI-induced brain glucose dysfunction is still underexplored. This study investigated the long-term effects of early environmental enrichment in metabolic, cell, and functional responses after neonatal HI. Thereby, male Wistar rats were divided according to surgical procedure, sham, and HI (performed at postnatal day 3), and the allocation to standard (SC) or enriched condition (EC) during gestation and lactation periods. In-vivo cerebral metabolism was assessed by means of [18 F]-FDG micro-positron emission tomography, and cognitive, biochemical, and histological analyses were performed in adulthood. Our findings reveal that HI causes a reduction in glucose metabolism and glucose transporter levels as well as hyposynchronicity in metabolic brain networks. However, EC during prenatal or early postnatal period attenuated these metabolic disturbances. A positive correlation was observed between [18 F]-FDG values and volume ratios in adulthood, indicating that preserved tissue by EC is metabolically active. EC promotes better cognitive scores, as well as down-regulation of amyloid precursor protein in the parietal cortex and hippocampus of HI animals. Furthermore, growth-associated protein 43 was up-regulated in the cortex of EC animals. Altogether, results presented support that EC during gestation and lactation period can reduce HI-induced impairments that may contribute to functional decline and progressive late neurodegeneration.

In vivo Imaging With 18F-FDG- and 18F-Florbetaben-PET/MRI Detects Pathological Changes in the Brain of the Commonly Used 5XFAD Mouse Model of Alzheimer's Disease.

Imaging biomarkers of Alzheimer's disease (AD) that are able to detect molecular changes in vivo and transgenic animal models mimicking AD pathologies are essential for the evaluation of new therapeutic strategies. Positron-emission tomography (PET) using either 18F-Fluorodeoxyglucose (18F-FDG) or amyloid-tracers is a well-established, non-invasive tool in the clinical diagnostics of AD assessing two major pathological hallmarks. 18F-FDG-PET is able to detect early changes in cerebral glucose metabolism and amyloid-PET shows cerebral amyloid load. However, the suitability of 18F-FDG- and amyloid-PET in the widely used 5XFAD mouse model of AD is unclear as only a few studies on the use of PET biomarkers are available showing some conflicting results. The aim of this study was the evaluation of 18F-FDG-PET and amyloid-PET in 5XFAD mice in comparison to neurological deficits and neuropathological changes. Seven- and 12-month-old male 5XFAD mice showed a significant reduction in brain glucose metabolism in 18F-FDG-PET and amyloid-PET with 18F-Florbetaben demonstrated an increased cerebral amyloid deposition (n = 4–6 per group). Deficits in spatial reference memory were detected in 12-month-old 5XFAD mice in the Morris Water Maze (n = 10–12 per group). Furthermore, an increased plaque load and gliosis could be proven immunohistochemically in 5XFAD mice (n = 4–6 per group). PET biomarkers 18F-FDG and 18F-Florbetaben detected cerebral hypometabolism and increased plaque load even before the onset of severe memory deficits. Therefore, the 5XFAD mouse model of AD is well-suited for in vivo monitoring of AD pathologies and longitudinal testing of new therapeutic approaches.

Usefulness of Brain Positron Emission Tomography with Different Tracers in the Evaluation of Patients with Idiopathic Normal Pressure Hydrocephalous.

Idiopathic normal pressure hydrocephalus (iNPH) is the only form of dementia that can be cured by surgery. Its diagnosis relies on clinical and radiological criteria. Identifying patients who can benefit from surgery is challenging, as other neurological diseases can be concomitant or mimic iNPH. We performed a systematic review on the role of positron emission tomography (PET) in iNPH. We retrieved 35 papers evaluating four main functional aspects with different PET radiotracers: (1) PET with amyloid tracers, revealing Alzheimer’s disease (AD) pathology in 20–57% of suspected iNPH patients, could be useful in predictions of surgical outcome. (2) PET with radiolabeled water as perfusion tracer showed a global decreased cerebral blood flow (CBF) and regional reduction of CBF in basal ganglia in iNPH; preoperative perfusion parameters could predict surgical outcome. (3) PET with 2-Deoxy-2-[18F]fluoroglucose ([18F]FDG ) showed a global reduction of glucose metabolism without a specific cortical pattern and a hypometabolism in basal ganglia; [18F]FDG PET may identify a coexisting neurodegenerative disease, helping in patient selection for surgery; postsurgery increase in glucose metabolism was associated with clinical improvement. (4) Dopaminergic PET imaging showed a postsynaptic D2 receptor reduction and striatal upregulation of D2 receptor after treatment, associated with clinical improvement. Overall, PET imaging could be a useful tool in iNPH diagnoses and treatment response.

Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer\u2019s disease-related inhibitory circuit dysfunction in adults with Down syndrome

BackgroundAlzheimer’s disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging).MethodsThis is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls (n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers; CSF Aβ1–42, CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([18F]-fluorodeoxyglucose positron emission tomography).ResultsCompared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages; aDS (0.6-fold, adj.p < 0.0001), pDS (0.5-fold, adj.p < 0.0001) and dDS (0.3-fold, adj.p < 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj.p < 0.0001). CSF NPTX2 levels were not associated with age (p = 0.6), intellectual disability (p = 0.7) or cognitive performance (all p > 0.07). Low CSF NPTX2 levels were associated with low GluA4 in all clinical groups; controls (r2 = 0.2, p = 0.003), adults with DS (r2 = 0.4, p < 0.0001) and sporadic AD (r2 = 0.4, p < 0.0001). In adults with DS, low CSF NPTX2 levels were associated with low CSF Aβ1–42 (r2 > 0.3, p < 0.006), low CSF t-tau (r2 > 0.3, p < 0.001), increased cortical atrophy (p < 0.05) and reduced glucose metabolism (p < 0.05).ConclusionsLow levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS.

Abstract 5997: Increased connexin 43 expression and gap junction communication correlates with invasion following reduced glucose metabolism in breast cancer cells

Abstract Dysregulation of gap junction intercellular communication (GJIC) is a common feature during cancer progression. GJIC is a means of direct cell-cell communication mediated by regulated membrane channels composed of connexin proteins. This communication is frequently lost between primary tumor cells but may be upregulated at secondary metastatic sites with stromal cells. Control of this process by cancer cells has been shown to facilitate aggressive qualities both in vitro and in vivo. During the process of metastasis, cells encounter numerous metabolic challenges that must be overcome, particularly during growth of primary tumors. In this study, we set out to evaluate if changes to cancer cell metabolism affect GJIC in breast cancer cells. To address this question, we generated a metabolic variant of the MDA-MB-231 cell line conditioned to grow in glucose-limiting conditions. These cells were grown in FBS supplemented RPMI with &amp;lt;0.130mM glucose compared to 2mM in control conditions for more than 4 weeks. Substantial cell death over this time revealed a small population of cells capable of surviving in glucose reduced conditions. Growth of these cells normalized following a period of quiescence and exhibited stable viability and proliferative capacity. Following STR validation, these cells were designated MDA-MB-231LG for their ability to grow in low glucose media. MDA-MB-231LG exhibited a larger and more rounded morphologic appearance with formation of strong cell-cell contacts as demonstrated by scanning electron microscopy in contrast to parental cells which showed a higher degree of membrane overlap. Further comparison of the two cell lines through western blot and immunofluorescence analysis of connexin 43, a major connexin expressed in breast tissue, revealed higher levels in MDA-MB-231LG and increased membrane localization. Using a double label dye transfer technique, the gap junction permeable fluorescent dye calcein showed increased movement from CM-DiI labeled donor cells into neighboring cells in MDA-MB-231LG indicating functional gap junction coupling while MDA-MB-231 had little to no dye movement. To evaluate phenotypic qualities, both cell lines were grown in Matrigel and MDA-MB-231LG displayed increased stellate morphology. Use of a Matrigel invasion chamber assay confirmed the increased invasive qualities with significantly more MDA-MB-231LG invading through the lower portion of the membrane compared to MDA-MB-231 parental cells. Our data demonstrate a clear upregulation of gap junction activity following metabolic adaptation to reduced glucose availability. It also suggests a possible connection between GJIC and invasive qualities in breast cancer cells and may represent an inducible phenotype that occurs in primary tumors when tumor growth limits blood vessel penetration and nutrient availability. Citation Format: Jennifer C. Jones, Amanda M. Miceli, Mary M. Chaudhry, Mallika A. Jai, Romel N. Pancho, Alan Lazzar, Bradley S. Taylor, Vishnupriya Bodempudi, Prarthana P. Jain, Sheeri Hanjra, Alexander E. Urban, Brian Zanotti, Ellen K. Kohlmeir, Thomas M. Bodenstine. Increased connexin 43 expression and gap junction communication correlates with invasion following reduced glucose metabolism in breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5997.

C-Src functionality controls self-renewal and glucose metabolism in MCF7 breast cancer stem cells.

Deregulation of Src kinases is associated with cancer. We previously showed that SrcDN conditional expression in MCF7 cells reduces tumorigenesis and causes tumor regression in mice. However, it remained unclear whether SrcDN affected breast cancer stem cell functionality or it reduced tumor mass. Here, we address this question by isolating an enriched population of Breast Cancer Stem Cells (BCSCs) from MCF7 cells with inducible expression of SrcDN. Induction of SrcDN inhibited self-renewal, and stem-cell marker expression (Nanog, Oct3-4, ALDH1, CD44). Quantitative proteomic analyses of mammospheres from MCF7-Tet-On-SrcDN cells (data are available via ProteomeXchange with identifier PXD017789, project DOI: 10.6019/PXD017789) and subsequent GSEA showed that SrcDN expression inhibited glycolysis. Indeed, induction of SrcDN inhibited expression and activity of hexokinase, pyruvate kinase and lactate dehydrogenase, resulting in diminished glucose consumption and lactate production, which restricted Warburg effect. Thus, c-Src functionality is important for breast cancer stem cell maintenance and renewal, and stem cell transcription factor expression, effects linked to glucose metabolism reduction.

Excessive Astrocytic GABA Causes Cortical Hypometabolism and Impedes Functional Recovery after Subcortical Stroke

Glucose hypometabolism in cortical structures after functional disconnection is frequently reported in patients with white matter diseases such as subcortical stroke. However, the molecular and cellular mechanisms have been poorly elucidated. Here we show, in an animal model of internal capsular infarct, that GABA-synthesizing reactive astrocytes in distant cortical areas cause glucose hypometabolism via tonic inhibition of neighboring neurons. We find that reversal of aberrant astrocytic GABA synthesis, by pharmacological inhibition and astrocyte-specific gene silencing of MAO-B, reverses the reduction in cortical glucose metabolism. Moreover, induction of aberrant astrocytic GABA synthesis by cortical injection of putrescine or adenovirus recapitulates cortical hypometabolism. Furthermore, MAO-B inhibition causes a remarkable recovery from post-stroke motor deficits when combined with a rehabilitation regimen. Collectively, our data indicate that cortical glucose hypometabolism in subcortical stroke is caused by aberrant astrocytic GABA and MAO-B inhibition and that attenuating cortical hypometabolism can be a therapeutic approach in subcortical stroke.

Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium.

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, which while adaptive, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here, we used bacterial lipopolysaccharide (LPS) in female C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 µg/kg) induced hypoglycemia, which was mimicked by interleukin (IL)-1β (25 µg/kg) but not prevented in IL-1RI−/− mice, nor by IL-1 receptor antagonist (IL-1RA; 10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentrations, was mitigated by exogenous glucose (2 g/kg), and was exacerbated by 2-deoxyglucose (2-DG) glycolytic inhibition, despite preventing IL-1β synthesis. Using the ME7 model of chronic neurodegeneration in female mice, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 µg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition selectively in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in CSF in humans during inflammatory trauma-induced delirium. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with acutely altered brain energy metabolism. Collectively, the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.SIGNIFICANCE STATEMENT Acute systemic inflammation alters behavior and produces disproportionate effects, such as delirium, in vulnerable individuals. Delirium has serious short and long-term sequelae but mechanisms remain unclear. Here, we show that both LPS and interleukin (IL)-1β trigger hypoglycemia, reduce CSF glucose, and suppress spontaneous activity. Exogenous glucose mitigates these outcomes. Equivalent hypoglycemia, induced by lipopolysaccharide (LPS) or insulin, was sufficient to trigger cognitive impairment selectively in animals with existing neurodegeneration and glucose also mitigated those impairments. Patient CSF from inflammatory trauma-induced delirium also shows altered brain carbohydrate metabolism. The data suggest that the degenerating brain is exquisitely sensitive to acute behavioral and cognitive consequences of disrupted energy metabolism. Thus “bioenergetic stress” drives systemic inflammation-induced dysfunction. Elucidating this may offer routes to mitigating delirium.

Hypomorphic CAMKK2 in EA.hy926 endothelial cells causes abnormal transferrin trafficking, iron homeostasis and glucose metabolism

We recently reported that loss of calcium/calmodulin-dependent protein kinase kinase-2 (CAMKK2), a serine/threonine kinase activated by intracellular calcium, in mice leads to tissue-specific aberrant turnover of transferrin (TF), a receptor-mediated iron-transporter that supplies iron to tissues. Iron dyshomeostasis is associated with the pathogenesis of several diseases, making TF transport relevant to health. In this study, we used hemizygous CAMKK2 hypomorphic human endothelial cell (EA.hy926) clones to demonstrate that cells with reduced CAMKK2 exhibit increased TF uptake and transcytosis, and decreased intracellular trafficking to subcellular organelles compared to wild-type. The abnormal TF trafficking in CAMKK2 hypomorphic cells correlated with a reduction in intracellular iron content and defective glucose metabolism including glycolysis and mitochondrial respiration. CAMKK2 deficiency also caused reduction in GAPDH and VDAC1 protein level which correlated to defective bioenergetics function. These findings have identified a novel mechanistic link between abnormal calcium signaling, iron dyshomeostasis and metabolic dysfunction involving CAMKK2.

AMBAR, an Encouraging Alzheimer's Trial That Raises Questions.

Grifols' recent Alzheimer Management by Albumin Replacement (“AMBAR”) study investigated the effects of plasmapheresis with albumin replacement, plus intravenous immunoglobulin (IVIG) in some subjects, in patients with mild-to-moderate Alzheimer's disease (AD). AMBAR was a phase IIb trial in the United States and a phase III trial in Europe. There were three treatment groups (plasmapheresis with albumin replacement; plasmapheresis with low dose albumin and IVIG; plasmapheresis with high dose albumin and IVIG) and sham-treated controls. Disease progression in pooled treated patients was 66% less than control subjects based on ADAS-Cog scores (p = 0.06) and 52% less based on ADCS-ADL scores (p = 0.03). Moderate AD patients had 61% less progression, based on both ADAS-Cog and ADCS-ADL scores, than their sham-treated counterparts (p-values 0.05 and 0.002), and their CDR-Sb scores declined 53% less than their sham-treated counterparts. However, ADAS-Cog and ADCS-ADL scores were not significantly different between actively-treated and sham-treated mild AD patients, although CDR-Sb scores improved vs. baseline for treated mild AD patients. Patients administered both IVIG and albumin had less reduction in brain glucose metabolism than sham-treated patients. Questions raised by these findings include: what mechanism(s) contributed to slowing of disease progression? Is this approach as effective in mild AD as in moderate AD? Must IVIG be included in the protocol? Does age, sex, or ApoE genotype influence treatment response? Does the protocol increase the risk for amyloid-related imaging abnormalities? How long does disease progression remain slowed post-treatment? A further study should allow this approach to be optimized.

Bevacizumab combined with apatinib enhances antitumor and anti-angiogenesis effects in a lung cancer model in vitro and in vivo

Angiogenesis is involved in the proliferation and metastasis of solid tumours; hence, it is an attractive therapeutic target. However, most patients who undergo anti-angiogenic drug treatment do not achieve complete tumour regression, resulting in drug resistance. The objective of this research is to explore the therapeutic effect of combining bevacizumab (Bev), an anti-vascular endothelial growth factor (VEGF)-A antibody, with apatinib (Apa), a VEGR receptor (VEGFR)-2-targeting tyrosine kinase inhibitor, in non-small cell lung cancer (NSCLC). In vitro, we assessed the influence which Bev + Apa treatment exerts upon the proliferation as well as apoptosis of Lewis lung carcinoma (LLC) cells in virtue of the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide as assay as well as Annexin V staining, respectively. For in vivo assessment, we established a tumour-bearing mouse model with LLC cells and investigated the anti-angiogenic and antitumor effects of Bev + Apa by 18F-FDG PET/CT imaging, immunohistochemistry and TUNEL staining. Bev + Apa treatment significantly inhibited LLC cell growth and proliferation in a larger scale compared to therapy of either of the only agent. Bev + Apa inhibited tumour growth and extended the median survival time of tumour-bearing mice. Mechanistically, Bev + Apa reduced angiogenesis by inhibiting VEGF and VEGFR-2 expression and reducing glucose metabolism in tumour tissues. Thus, Bev and Apa inhibited tumour angiogenesis synergistically, indicating their potential clinical utility for NSCLC treatment.

Association of cerebrospinal fluid neurogranin levels with cognition and neurodegeneration in Alzheimer's disease.

Accumulating data suggest cerebrospinal fluid (CSF) neurogranin (Ng) as a potential biomarker for cognitive decline and neurodegeneration in Alzheimer disease (AD). To investigate whether the CSF Ng can be used for diagnosis, prognosis, and monitoring of AD, we examined 111 cognitively normal (CN) controls, 193 mild cognitive impairment (MCI) patients and 95 AD patients in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Correlations were tested between baseline CSF Ng levels and baseline core AD biomarkers and longitudinal glucose metabolism, brain atrophy and cognitive decline. We detected that CSF Ng levels increased with disease severity, and correlated with phosphorylated tau and total tau levels within each diagnostic group. High baseline CSF Ng levels correlated with longitudinal reductions in cortical glucose metabolism within each diagnostic group and hippocampal volume within MCI group during follow-up. In addition, high baseline CSF Ng levels correlated with cognitive decline as reflected by decreased cognitive scale scores. The CSF Ng levels predicted future cognitive impairment (adjusted hazard ratio:3.66, 95%CI: 1.74-7.70, P = 0.001) in CN controls. These data demonstrate that CSF Ng offers diagnostic utility for AD and predicts future cognitive impairment in CN individuals and, therefore, may be a useful addition to the current AD biomarkers.

Use of Multimodal Imaging and Clinical Biomarkers in Presymptomatic Carriers of C9orf72 Repeat Expansion

During a time with the potential for novel treatment strategies, early detection of disease manifestations at an individual level in presymptomatic carriers of a hexanucleotide repeat expansion in the C9orf72 gene (preSxC9) is becoming increasingly relevant. To evaluate changes in glucose metabolism before symptom onset of amyotrophic lateral sclerosis or frontotemporal dementia in preSxC9 using simultaneous fluorine 18-labeled fluorodeoxyglucose ([18F]FDG positron emission tomographic (PET) and magnetic resonance imaging as well as the mutation's association with clinical and fluid biomarkers. A prospective, case-control study enrolled 46 participants from November 30, 2015, until December 11, 2018. The study was conducted at the neuromuscular reference center of the University Hospitals Leuven, Leuven, Belgium. Neuroimaging data were spatially normalized and analyzed at the voxel level at a height threshold of P < .001, cluster-level familywise error-corrected threshold of P < .05, and statistical significance was set at P < .05 for the volume-of-interest level analysis, using Benjamini-Hochberg correction for multiple correction. W-score maps were computed using the individuals serving as controls as a reference to quantify the degree of [18F]FDG PET abnormality. The threshold for abnormality on the W-score maps was designated as an absolute W-score greater than or equal to 1.96. Neurofilament levels and performance on cognitive and neurologic examinations were determined. All hypothesis tests were 1-sided. Of the 42 included participants, there were 17 with the preSxC9 mutation (12 women [71%]; mean [SD] age, 51 [9] years) and 25 healthy controls (12 women [48%]; mean [SD] age, 47 [10] years). Compared with control participants, significant clusters of relative hypometabolism were found in frontotemporal regions, basal ganglia, and thalami of preSxC9 participants and relative hypermetabolism in the peri-Rolandic region, superior frontal gyrus, and precuneus cortex. W-score frequency maps revealed reduced glucose metabolism with local maxima in the insular cortices, central opercular cortex, and thalami in up to 82% of preSxC9 participants and increased glucose metabolism in the precentral gyrus and precuneus cortex in up to 71% of preSxC9 participants. Other findings in the preSxC9 group were upper motor neuron involvement in 10 participants (59%), cognitive abnormalities in 5 participants (29%), and elevated neurofilament levels in 3 of 16 individuals (19%) who underwent lumbar puncture. The results suggest that [18F]FDG PET can identify glucose metabolic changes in preSxC9 at an individual level, preceding significantly elevated neurofilament levels and onset of symptoms.

Actions of Alcohol in Brain: Genetics, Metabolomics, GABA Receptors, Proteomics and Glutamate Transporter GLAST/EAAT1.

We present an overview of genetic, metabolomic, proteomic and neurochemical studies done mainly in our laboratories that could improve prediction, mechanistic understanding and possibly extend to diagnostics and treatment of alcoholism and alcohol addiction. Specific polymorphisms in genes encoding for interleukins 2 and 6, catechol-O-methyl transferase (COMT), monaminooxidase B (MAO B) and several other enzymes were identified as associated with altered risks of alcoholism in humans. A polymorphism in the gene for BDNF has been linked to the risk of developing deficiences in colour vision sometimes observed in alcoholics. Metabolomic studies of acute ethanol effects on guinea pig brain cortex in vitro, lead to the identification of specific subtypes of GABA(A) receptors involved in the actions of alcohol at various doses. Acute alcohol affected energy metabolism, oxidation and the production of actaldehyde and acetate; this could have specific consequences not only for the brain energy production/utilization but could influence the cytotoxicity of alcohol and impact the epigenetics (histone acetylation). It is unlikely that brain metabolism of ethanol occurs to any significant degree; the reduction in glucose metabolism following alcohol consumption is due to ethanol effects on receptors, such as α4β3δ GABA(A) receptors. Metabolomics using post-mortem human brain indicated that the catecholaminergic signalling may be preferentially affected by chronic excessive drinking. Changes in the levels of glutathione were consistent with the presence of severe oxidative stress. Proteomics of the post-mortem alcoholic brains identified a large number of proteins, the expression of which was altered by chronic alcohol, with those associated with brain energy metabolism among the most numerous. Neurochemical studies found the increased expression of glutamate transporter GLAST/EAAT1 in brain as one of the largest changes caused by alcoholism. Given that GLAST/EAAT1 is one of the most abundant proteins in the nervous tissue and is intimately associated with the function of the excitatory (glutamatergic) synapses, this may be among the most important effects of chronic alcohol on brain function. It has so far been observed mainly in the prefrontal cortex. We show several experiments suggesting that acute alcohol can translocate GLAST/EAAT1 in astrocytes towards the plasma membrane (and this effect is inhibited by the GABA(B) agonist baclofen) but neither the mechanism nor the specificity (to alcohol) of this phenomenon have been established. Furthermore, as GLAST/EAAT1 is also expressed in testes and sperm (and could also be affected there by chronic alcohol), the levels of GLAST/EAAT1 in sperm could be used as a diagnostic tool in testing the severity of alcoholism in human males. We conclude that the reviewed studies present a unique set of data which could help to predict the risk of developing alcohol dependence (genetics), to improve the understanding of the intoxicating actions of alcohol (metabolomics), to aid in assessing the extent of damage to brain cells caused by chronic excessive drinking (metabolomics and proteomics) and to point to molecular targets that could be used in the treatment and diagnosis of alcoholism and alcohol addiction.

Effect of the Intake of Oyster Mushrooms (Pleurotus ostreatus) on Cardiometabolic Parameters-A Systematic Review of Clinical Trials.

Cardiometabolic diseases are a leading global health challenge. Their incidence as well as progression is strongly affected by diet. Consumption of Pleurotus ostreatus (P. ostreatus), an edible oyster mushroom rich in functional ingredients (e.g., β-glucans), may improve glucose and lipid metabolism, blood pressure, body weight and appetite sensations. Hence, this systematic review aimed to provide an overview on the effects of P. ostreatus intake on cardiometabolic parameters from clinical trials, taking into account risk of bias (RoB). Relevant studies were investigated for details with consideration of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. The Cochrane Collaboration’s tool was used to assess the RoB. In total, eight trials included observed beneficial effects of P. ostreatus intake on glucose metabolism (reduction in fasting and/or 2 h postprandial glucose) and lipids (decrease in total cholesterol, LDL-cholesterol and/or triglycerides), and some found a reduction in blood pressure. In contrast, body weight did not change. Appetite sensations were not assessed. In most studies, the RoB was high or unclear due to methodological weaknesses and/or inadequate reporting. Thus, P. ostreatus intake may improve cardiometabolic health, but evidence for this is low. Hence, further clinical trials with an adequate study design are warranted to validate these suggestions.

Impaired brain glucose metabolism and presynaptic dopaminergic functioning in a mouse model of schizophrenia

BackgroundSchizophrenia is a disease diagnosed by visible signs and symptoms from late adolescence to early adulthood. The etiology of this disease remains unknown. An objective diagnostic approach is required. Here, we used a mouse model that shows schizophrenia-like phenotypes to study brain glucose metabolism and presynaptic dopaminergic functioning by positron emission tomography (PET) and immunohistochemistry. PET scannings were performed on mice after the administration of [18F]-FDG or [18F]-F-DOPA. Glucose metabolism was evaluated in basal conditions and after the induction of a hyperdopaminergic state.ResultsMutant animals show reduced glucose metabolism in prefrontal cortex, amygdala, and nucleus reuniens under the hyperdopaminergic state. They also show reduced [18F]-F-DOPA uptake in prefrontal cortex, substantia nigra reticulata, raphe nucleus, and ventral striatum but increased [18F]-F-DOPA uptake in dorsal striatum. Mutant animals also show reduced tyrosine hydroxylase expression on midbrain neurons.ConclusionsDopamine D2 mutant animals show reduced glucose metabolism and impaired presynaptic dopaminergic functioning, in line with reports from human studies. This mouse line may be a valuable model of schizophrenia, useful to test novel tracers for PET scanning diagnostic.

Report of a Case of Creutzfeldt-Jakob Disease With an Unusual Clinical Presentation.

We describe the clinical features, neuropsychological tests, laboratory, electroencephalography (EEG), magnetic resonance imaging (MRI) and positron emission tomography (PET) findings of a 59-year-old woman who presented to our Centre for cognitive impairment since few months, with language disturbances, particularly anomia, dyscalculia, and memory loss. The clinical and neuropsychological features were non-specific and overlapping with those of other rapidly progressing neurodegenerative disorders. However, brain MRI played a pivotal role in the diagnosis, showing cortical diffusion restriction, particularly in the parietal lobes and posterior cingulum, with sparing of the perirolandic cortex, typical of Creutzfeldt-Jakob disease (CJD). Brain MRI abnormalities were visible since the first evaluation and remained stable at 2 and 6 weeks follow up. Basal ganglia and thalami were never involved. PET showed left lateralized reduced glucose metabolism, with partial overlap with MRI signal abnormalities. Despite MRI were strongly indicative of CJD, clinical, laboratory and EEG findings did not fulfill the diagnostic criteria for CJD which applied at the time of clinical assessment. Indeed, neither myoclonus, visual or cerebellar signs or akinetic mutism were present. Also, the characteristic periodic sharp wave complexes were absent at baseline EEG, and the CSF assay for 14–3–3 was negative. We, therefore, performed a real-time quaking-induced conversion (RT-QuIC) assay on a frozen sample of corticospinal fluid (CSF), which showed a positive result. RT-QuIC is a prion protein conversion assay that has shown high diagnostic sensitivity and specificity for the diagnosis of CJD. RT-QuIC has been recently incorporated in the National CJD Research and Surveillance Unit and Center for Disease Control and Prevention (CDC) diagnostic criteria for CJD. The fatal evolution of the disease brought the patient to death 13 months after symptoms onset. Pathology proved the diagnosis of sporadic CJD, subtype MM/MV 2C.

Association between brain glucose metabolism and cardiac dysfunction in patients with ischemic heart disease undergoing (18)F-FDG PET/CT imaging

Objective: To evaluate the relationship between the brain glucose metabolism and left ventricular function parameters, and to explore the cerebral glucose metabolism reduction regions in patients with ischemic heart disease (IHD). Methods: A total of 110 consecutive IHD patients who underwent gated (99)Tc(m)-sestamibi (MIBI) SPECT/CT myocardial perfusion imaging, gated (18)F-fluorodeoxyglucose (FDG) PET/CT myocardial and brain glucose metabolic imaging within three days in Beijing Anzhen Hospital from April 2016 to October 2017, were enrolled in this study. Left ventricular functional parameters of SPECT/CT and PET/CT including end-diastolic volume (EDV), end-systolic volume (ESV) and left ventricular ejection fraction (LVEF) were analyzed by QGS software. Viable myocardium and myocardial infarction region were determined by 17-segment and 5 score system, and the ratio of viable myocardium and scar myocardium was calculated. According to the range of viable myocardium, the patients were divided into viable myocardium<10% group (n=44), viable myocardium 10%-<20% group (n=36) and viable myocardium≥20% group (n=30). Pearson correlation analysis was used to analyze the correlation between the range of viable myocardium and scar myocardium and the level of cerebral glucose metabolism. Brain glucose metabolism determined by the mean of standardized uptake value (SUV(mean)) was analyzed by SPM. The ratio of SUV(mean) in whole brain and SUV(mean) in cerebellum were calculated, namely taget/background ratio (TBR). Differences in cerebral glucose metabolism among various groups were analyzed by SPM. Results: There were 101 males, and age was (57±10) years in this cohort. The extent of viable myocardium and the extent of scar, LVEF evaluated by SPECT/CT and PET/CT were significantly correlated with TBR (r=0.280, r=-0.329, r=0.188, r=0.215 respectively,all P<0.05). TBR value was significantly lower in viable myocardium<10% group, compared with viable myocardium 10%-<20% group (1.25±0.97 vs. 1.32±0.17, P<0.05) and viable myocardium≥20% group (1.25±0.97 vs. 1.34±0.16, P<0.05). Furthermore, in comparison with viable myocardium≥20% group, the hypo-metabolic regions of viable myocardium<10% group were located in the precuneus, frontal lobe, postcentral gyrus, parietal lobe, temporal lobe, and so on. Conclusions: There is a correlation between impaired left ventricular function and brain glucose metabolism in IHD patients. In IHD patients with low myocardial viability, the level of glucose metabolism in the whole brain is decreased, especially in the brain functional areas related to cognitive function.