Neurodegeneration In AD Research Articles

Hybrid virtual screening and molecular dynamics approach for identification of allosteric modulator of EAAT2

EAAT2, a glial protein that clears excess glutamate from synapses, regulates synaptic transmission, and prevents excitotoxicity in neurons is impaired by Aβ induced oxidative stress in neurodegenerative diseases like Alzheimer’s disease. Therefore, compounds that enhance EAAT2 function by reducing oxidative stress and excitotoxicity might be neuroprotective. The current study aimed to identify allosteric activators targeting EAAT2 in the treatment of AD using in-silico. Virtual screening identified promising candidates from the specs database and demonstrated excellent binding affinity with the allosteric pocket of EAAT2. ADMET studies determined the lipophilicity of the compounds and displayed good permeability across the BBB. MM-GBSA analysis further showed higher binding free energy for two compounds. Subsequently, molecular dynamics simulations confirmed the stability of the complex and its binding ability to the allosteric pocket of EAAT2. These findings identified the compound AK-968/15360623 as a promising lead molecule that could enhance EAAT2 function and prevent neurodegeneration in AD.

The KEAP1/PGAM5/AIFM1-Mediated oxeiptosis pathway in Alzheimer’s disease

BackgroundAlzheimer’s Disease (AD) is a neurodegenerative disease with mitochondrial dysfunction and oxidative stress. Oxeiptosis is a cell death pathway sensitive to reactive oxygen species (ROS). This study investigates the role of oxeiptosis pathway and mitochondrial damage in AD. MethodsAn AD model was developed in C57BL/6 mice by injecting Aβ1-42 oligomers into the brain. Cognitive function was tested using the Morris water maze. Exposure of HT22 mouse hippocampal neurons to H2O2 induces oxidative stress. Protein levels of KEAP1, PGAM5 and AIFM1 were analyzed by western blot, and mitochondrial damage was observed with electron microscopy. Cell survival rates were using the CCK8 assay and flow cytometry after knocking down KEAP1, PGAM5 and AIFM1. ResultsThe protein concentrations of KEAP1, PGAM5 and AIFM1 were found to be elevated in the hippocampal tissues of AD mice compared to control group, accompanied by mitochondrial damage in the hippocampal neurons of the AD group. Similarly, in the HT22 oxidative stress model, there was an increase in the protein levels of KEAP1, PGAM5 and AIFM1, along with observed mitochondrial damage. Following individual and combined knockdown of KEAP1, PGAM5 and AIFM1, cell survival rates under oxidative stress conditions were higher compared to H2O2 group, with no significant difference in cell survival rates among the knockdown groups. ConclusionThis research underscores the critical role of the KEAP1/PGAM5/AIFM1-mediated oxeiptosis pathway in neuronal cell death, offering insights into potential therapeutic targets for mitigating neurodegeneration in AD.

A Two-Year Observational Study to Evaluate Conversion Rates from High- and Low-Risk Patients with Amnestic Mild Cognitive Impairment to Probable Alzheimer's Disease in a Real-World Setting.

Predicting conversion to probable Alzheimer&s disease (AD) from amnestic mild cognitive impairment (aMCI) is difficult but important. A nomogram was developed previously for determining the risk of 3-year probable AD conversion in aMCI. To compare the probable AD conversion rates with cognitive and neurodegenerative changes for 2 years from high- and low risk aMCI groups classified using the nomogram. This prospective, multicenter, observational study was conducted in Korea. A total of patients were classified as high- or low-risk aMCI according to the nomogram and followed-up for 2 years to compare the annual conversion rate to probable AD and brain structure changes between the two groups. In total, 176 (high-risk, 85; low-risk, 91) and 160 (high-risk, 77; low-risk, 83) patients completed the 1-year and 2-year follow-up, respectively. The probable AD conversion rate was significantly higher in the high-risk (Year 1, 28.9%; Year 2, 46.1%) versus low-risk group (Year 1, 0.0%; Year 2, 4.9%, both p < 0.0001). Mean changes from baseline in Seoul Neuropsychological Screening Battery-Dementia Version, Clinical Dementia Rating-Sum of Box, and Korean version of the Instrumental Activities of Daily Living scores and cortical atrophy index at Years 1 and 2 were significantly greater in the high-risk group (p < 0.0001). The high-risk aMCI group, as determined by the nomogram, had a higher conversion rate to probable AD and faster cognitive decline and neurodegeneration change than the low-risk group. These real-world results have clinical implications that help clinicians in accurately predicting patient outcomes and facilitating early decision-making.Trial Registration: ClinicalTrials.gov (NCT03448445).

Racial discrimination during middle age predicts higher serum phosphorylated tau and neurofilament light chain levels a decade later: A study of aging black Americans.

Recent evidence suggests that exposure to the stress of racism may increase the risk of dementia for Black Americans. The present study used 17 years of data from a sample of 255 Black Americans to investigate the extent to which exposure to racial discrimination predicts subsequent changes in serum Alzheimer's Disease Research Center (ADRC) biomarkers: serum phosphorylated tau181(p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). We hypothesized that racial discrimination assessed during middle age would predict increases in these serum biomarkers as the participants aged into their 60s. Our findings indicate that exposure to various forms of racial discrimination during a person's 40s and early 50s predicts an 11-year increase in both serum p-tau181 and NfL. Racial discrimination was not associated with subsequent levels of GFAP. These findings suggest that racial discrimination in midlife may contribute to increased AD pathology and neurodegeneration later in life. A 17-year longitudinal study of Black Americans. Assessments of change in serum p-tau181, neurofilament light, and glial fibrillary acidic protein. Exposure to racial discrimination during middle age predicted increases in p-tau181 and neurofilament light. Education was positively related to both p-tau181 and exposure to racial discrimination.

Magnolol extends lifespan and improves age-related neurodegeneration in Caenorhabditis elegans via increase of stress resistance

Magnolol is a naturally occurring polyphenolic compound in many edible plants, which has various biological effects including anti-aging and alleviating neurodegenerative diseases. However, the underlying mechanism on longevity is uncertain. In this study, we investigated the effect of magnolol on the lifespan of Caenorhabditis elegans and explored the mechanism. The results showed that magnolol treatment significantly extended the lifespan of nematode and alleviated senescence-related decline in the nematode model. Meanwhile, magnolol enhanced stress resistance to heat shock, hydrogen peroxide (H2O2), mercuric potassium chloride (MeHgCl) and paraquat (PQ) in nematode. In addition, magnolol reduced reactive oxygen species and malondialdehyde (MDA) levels, and increased superoxide dismutase and catalase (CAT) activities in nematodes. Magnolol also up-regulated gene expression of sod-3, hsp16.2, ctl-3, daf-16, skn-1, hsf-1, sir2.1, etc., down-regulated gene expression of daf-2, and promoted intranuclear translocation of daf-16 in nematodes. The lifespan-extending effect of magnolol were reversed in insulin/IGF signaling (IIS) pathway-related mutant lines, including daf-2, age-1, daf-16, skn-1, hsf-1 and sir-2.1, suggesting that IIS signaling is involved in the modulation of longevity by magnolol. Furthermore, magnolol improved the age-related neurodegeneration in PD and AD C. elegans models. These results indicate that magnolol may enhance lifespan and health span through IIS and sir-2.1 pathways. Thus, the current findings implicate magnolol as a potential candidate to ameliorate the symptoms of aging.

Parkinson's Disease Dementia Patients: Expression of Glia Maturation Factor in the Brain.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disease characterized by the presence of dopaminergic neuronal loss and motor disorders. PD dementia (PDD) is a cognitive disorder that affects many PD patients. We have previously demonstrated the proinflammatory role of the glia maturation factor (GMF) in neuroinflammation and neurodegeneration in AD, PD, traumatic brain injury (TBI), and experimental autoimmune encephalomyelitis (EAE) in human brains and animal models. The purpose of this study was to investigate the expression of the GMF in the human PDD brain. We analyzed the expression pattern of the GMF protein in conjunction with amyloid plaques (APs) and neurofibrillary tangles (NFTs) in the substantia nigra (SN) and striatum of PDD brains using immunostaining. We detected a large number of GMF-positive glial fibrillary acidic protein (GFAP) reactive astrocytes, especially abundant in areas with degenerating dopaminergic neurons within the SN and striatum in PDD. Additionally, we observed excess levels of GMF in glial cells in the vicinity of APs, and NFTs in the SN and striatum of PDD and non-PDD patients. We found that the majority of GMF-positive immunoreactive glial cells were co-localized with GFAP-reactive astrocytes. Our findings suggest that the GMF may be involved in the pathogenesis of PDD.

Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology

BackgroundAlzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aβ) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (fAβ) burden, microglial modulation, and neuroprotection.MethodsWe designed a nanotechnology approach to regulate the SR-mediated intracellular fAβ trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM–NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM–NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines.ResultsAM–NPs interrupted Aβ fibrilization, attenuated fAβ microglial internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM–NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ.ConclusionsThe AM–NP nanotechnology presents a multifactorial strategy to target pathological Aβ aggregation and arrest the fAβ-mediated pathological progression in microglia and neurons.Graphical

Multiple patterns of structural brain change trajectories in AD: MRI deep learning verification with enhanced sequential pattern analysis

AbstractBackgroundOur recently proposed interpretable Ensemble 3DCNN deep learning (DL) technique has allowed the derivation of a P‐score based on brain structural magnetic resonance imaging (sMRI) modelling to predict patterned neurodegeneration in AD (https://doi.org/10.1002/advs.202204717). Sequential association rules with a support rate greater than 18% have been used to define a neurodegenerative progression pattern. To more prudently test the meaningfulness of the patterns found, we further calculated the lift values of the various sequential patterns underlying the suggested longitudinal sMRI changes.MethodThe lift value of an association rule is defined as the rule’s confidence rate divided by the support rate of the rule consequent, i.e., the support rate of the rule divided by the product of the support values of the rule consequent and the rule antecedent. For example, with {L.NAC}→{L.NAC, R.NAC} (https://doi.org/10.1002/advs.202204717), among the 167 AD subjects employed for analyzing neurodegenerative progression patterns, the number (N) of the subjects with at least an sMRI image containing both L.NAC and R.NAC as neurodegenerative regions at all time points examined was firstly calculated. Secondly, among the above‐mentioned 167 AD subjects, the number (M) of the subjects with at least an sMRI image containing only L.NAC as neurodegenerative regions at all time points examined was counted and the time point (P) corresponding to the selected (earlier/earliest) sMRI image was saved. Thirdly, among the above selected M subjects, the number (K) of the subjects with at least an sMRI image containing both L.NAC and R.NAC as neurodegenerative regions at all time points latter than the P was computed. Thus, lift value = (K/M)/(N/167).ResultThe lift values of the fifty sequential association rules reported in the recent paper (https://doi.org/10.1002/advs.202204717) ranged between 1.27 and 2.59(i.e., all &gt; 1; Table 1), further confirming the longitudinal sMRI change patterns in AD.ConclusionThis study analyzing the lift values of the sequential association rules further verified the multiple patterns of longitudinal sMRI trajectories in AD brains, as reported recently. The research demonstrated featured and heterogeneous whole‐brain structural degeneration with AD progression.

Mapping Medial Temporal Lobe Longitudinal Change in Preclinical Alzheimer’s Disease

AbstractBackgroundThe medial temporal lobe (MTL) is a site of early tau pathology and neurodegeneration in AD. In recent work [1], we reported that rates of change in MTL subregion volumes on longitudinal structural T1‐MRI differ significantly between cognitively unimpaired individuals with and without amyloid pathology (A+CU vs A‐CU), suggesting that these measures are effective biomarkers for tracking disease progression in preclinical AD. Here, we develop a specialized pipeline that quantifies pointwise longitudinal change across the MTL, revealing more informative spatial patterns of early neurodegeneration than summary volumetric longitudinal measures.MethodOur pipeline, SkelDBM, combines skeletonization and deformation‐based morphometry to generate maps of annualized rate of atrophy on the skeleton of an MTL template (Figure 1). SkelDBM samples subjects’ atrophy maps along the skeleton of an MTL template, increasing robustness to subject‐to‐template registration errors. We evaluate SkelDBM using a subset of ADNI data studied in [1] (Table 1). Two preclinical AD groups (A+CU and tau‐positive A+CU) are compared to a control group (A‐CU) using general linear models (GLM) with age as nuisance covariate; permutation testing is used to derive statistically significant clusters.ResultThe full A+CU vs A‐CU comparison shows significant differences in rates of change in right anterior hippocampus, right entorhinal cortex, right transentorhinal cortex, and left posterior hippocampus (Figure 2). Limiting the A+CU group to tau‐positive individuals yields more widespread differences, including most of the right anterior MTL cortex and both hippocampi. These patterns align with volumetric longitudinal data reported in [1] but provide a richer characterization of spatial atrophy patterns.ConclusionSkelDBM is sensitive to longitudinal atrophy occurring over relatively short periods (∼2 years) in preclinical AD and characterizes patterns of atrophy more comprehensively than summary volumetric measures. Summary measures are also subject to biases, since larger structures are typically associated with less measurement error and hence may show exaggerated statistical effects compared to smaller structures even when the underlying neurodegeneration rates are the same. Regional maps of longitudinal change may be more robust to this bias and may help discovery of “signature regions” associated with specific pathological drivers of neurodegeneration. [1] Xie et al., Human Brain Mapping, 2020.

Significant dose‐dependent reduction in neurofilament light chain concentration in plasma with oral tau aggregation inhibitor hydromethylthionine mesylate

AbstractBackgroundHydromethylthionine mesylate (HMTM) is a potent oral tau aggregation inhibitor. Recent results from Study TRx‐237‐039 (LUCIDITY) suggest strong effects on cognitive and functional decline and progression of brain atrophy. We investigated the effect of HMTM on change in the plasma biomarker neurofilament light chain (NfL) in LUCIDITY. NfL is a clinically accessible and established biomarker for neurodegeneration that is known to be correlated with measures of clinical decline and brain atrophy in AD and MCI due to AD (MCI‐AD).MethodLUCIDITY is a double‐blind randomised controlled Phase 3 clinical trial comparing change over 12 months in cognitive, functional and brain atrophy outcomes at HMTM doses of 16 mg/day, 8 mg/day and methylthioninium chloride (MTC) at a dose of 4 mg twice weekly as a control in a 4:1:4 randomisation, with a subsequent 12 month blinded open‐label extension phase in which all participants received 16 mg/day.ResultBaseline and 12‐month NfL plasma levels were available as randomised in 161/185 participants receiving HMTM 16 mg/day, 38/48 receiving HMTM 8 mg/day and 136/185 receiving MTC 8 mg/week. The corresponding prespecified analysis model showed a 93% reduction in the change in NfL levels relative to control for HMTM 16 mg/day overall (p = 0.0278). Reduction in NfL change in the MCI‐AD subgroup was significant also at HMTM 8 mg/day (p = 0.0242). In the AD subgroup, there were directional dose‐dependent trends that did not reach statistical significance. Change in NfL level at 12 months was significantly correlated with change in ADAS‐cog11 (p = 0.0038) and whole brain volume (p = 0.0359) over 24 months.ConclusionThese results demonstrate that the orally administered tau aggregation‐inhibitor, HMTM, is able to produce a significant dose‐dependent reduction in neurodegeneration in AD as measured by change in plasma NfL levels.

Using subject‐specific disease progression as an estimation of the disease time to model longitudinal neurodegeneration in AD

AbstractBackgroundWhen patients with clinically probable‐AD get their diagnosis, it is difficult to determine exactly when the disease started. Moreover, not all subjects progress in the same manner and rate. However, clinical measurements such as cognitive scores can help give an estimation of where in the disease trajectory each patient stands. To address the issue of estimating the time of disease onset, we investigated a new technique that leverages cognitive test scores to estimate a latent timeline that models the subject‐specific disease progression.MethodWe used the work of Kühnel et al. (2021) to model the progression of AD using cognitive scores (ADAS13 and MMSE). This method aligns patients along a continuous latent timeline based on their predicted disease progression. Data included the MRI scans of 677 amyloid‐positive subjects from ADNI. Scan resolution was increased to 0.5mm isotropic voxel‐size by super‐sampling (Manjón et al. 2010) before non‐linear registration to an ADNI‐based unbiased template. The resulting deformation fields were used to compute the Jacobian determinant map for each subject and find mean atrophy for different ROIs. we were then able to plot the changes in different regions of the brain across the estimated disease progression timeline and compare slopes for the two methods.ResultAssuming a zero time‐shift for normal subjects, the average time‐shift for the eMCI, lMCI, and AD group was 36.8, 87.5, and 128.8 months respectively. Using the latent time‐shift variable to offset the individual baseline scans, we were able to plot the changes in different regions of the brain across the disease timeline. The results for Hippocampus are shown in figure 1, comparing the estimated timeline to the age as the time‐related axes. We saw much sharper slopes (‐0.01 vol/estimated_time vs ‐0.0025 vol/age) when using the individualized time offset.ConclusionCalendar time is perhaps not a good measure for disease progression. The new method offers an estimation of a latent timeline that models the subject‐specific disease progression and may better model the longitudinal changes in different brain regions, and in turn, would enable us to better compare the magnitude and speed of degeneration across brain regions.

Mapping Medial Temporal Lobe Longitudinal Change in Preclinical Alzheimer’s Disease

AbstractBackgroundThe medial temporal lobe (MTL) is a site of early tau pathology and neurodegeneration in AD. In recent work [1], we reported that rates of change in MTL subregion volumes on longitudinal structural T1‐MRI differ significantly between cognitively unimpaired individuals with and without amyloid pathology (A+CU vs A‐CU), suggesting that these measures are effective biomarkers for tracking disease progression in preclinical AD. Here, we develop a specialized pipeline that quantifies pointwise longitudinal change across the MTL, revealing more informative spatial patterns of early neurodegeneration than summary volumetric longitudinal measures.MethodsOur pipeline, SkelDBM, combines skeletonization and deformation‐based morphometry to generate maps of annualized rate of atrophy on the skeleton of an MTL template (Figure 1). SkelDBM samples subjects’ atrophy maps along the skeleton of an MTL template, increasing robustness to subject‐to‐template registration errors. We evaluate SkelDBM using a subset of ADNI data studied in [1] (Table 1). Two preclinical AD groups (A+CU and tau‐positive A+CU) are compared to a control group (A‐CU) using general linear models (GLM) with age as nuisance covariate; permutation testing is used to derive statistically significant clusters.ResultsThe full A+CU vs A‐CU comparison shows significant differences in rates of change in right anterior hippocampus, right entorhinal cortex, right transentorhinal cortex, and left posterior hippocampus (Figure 2). Limiting the A+CU group to tau‐positive individuals yields more widespread differences, including most of the right anterior MTL cortex and both hippocampi. These patterns align with volumetric longitudinal data reported in [1] but provide a richer characterization of spatial atrophy patterns.ConclusionSkelDBM is sensitive to longitudinal atrophy occurring over relatively short periods (∼2 years) in preclinical AD and characterizes patterns of atrophy more comprehensively than summary volumetric measures. Summary measures are also subject to biases, since larger structures are typically associated with less measurement error and hence may show exaggerated statistical effects compared to smaller structures even when the underlying neurodegeneration rates are the same. Regional maps of longitudinal change may be more robust to this bias and may help discovery of “signature regions” associated with specific pathological drivers of neurodegeneration.[1] Xie et al., Human Brain Mapping, 2020.

GRADUATE I and II: Subgroup analysis and correlations of biomarkers

AbstractBackgroundGantenerumab is a subcutaneous fully human monoclonal antibody targeting aggregated forms of amyloid‐beta. Phase III GRADUATE I (NCT03444870) and II (NCT03443973) trials were designed based on previous key learnings to provide evidence on the benefit:risk profile of subcutaneous gantenerumab in early symptomatic AD. Although primary endpoints were not met, gantenerumab showed treatment effects on amyloid positron emission tomography (PET), volumetric magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) and plasma biomarkers. Correlations of biomarkers with clinical outcomes in the GRADUATE studies were assessed to further evaluate their utility.MethodParticipants aged 50‐90 years with mild cognitive impairment due to AD or mild AD dementia were randomised 1:1 to subcutaneous gantenerumab or placebo. Gantenerumab was up‐titrated over 36 weeks to target dose of 510 mg every 2 weeks. Changes in amyloid centiloid levels were obtained from [18F]Florbetaben or [18F]Flutemetamol PET. Regional changes in tau standardised uptake value ratio were obtained with [18F]GTP1 PET. Whole brain and regional atrophy were assessed via volumetric MRI. Fluid pharmacodynamics biomarkers were measured using Elecsys® immunoassays from Roche Diagnostics.ResultSignificant (but not corrected for multiple testing) treatment effects of gantenerumab on change from baseline to Week 116 were observed for CSF biomarkers (pooled GRADUATE I and II population) including Aβ40 (–10.42%, p = 0.0188), Aβ42 (26.06%, p&lt;0.0001), tTau (–16.49%, p&lt;0.0001), pTau181 (–23.35%; p &lt; 0.0001), NfL (10.76%; p = 0.0159), GFAP (–5.49%; p = 0.0003), and plasma biomarkers including Aβ42 (GRADUATE I: 65.1%, p&lt;0.0001; GRADUATE II: 54.9%, p&lt;0.0001) and pTau181 (GRADUATE I: –17.2%, p&lt;0.0001; GRADUATE II: –15.3%, p&lt;0.0001). Preliminary biomarker analyses showed changes in amyloid PET in gantenerumab‐treated participants had a numerically higher correlation with changes in plasma Aβ42 (R = –0.43), versus pTau181 (R = 0.34) and GFAP (R = 0.16). Biomarker changes in subgroups will also be presented.ConclusionPhase III GRADUATE I and II study results provide evidence of the effect of subcutaneous gantenerumab on biomarkers of AD pathology and neurodegeneration in subgroups.

Cortical gray to white matter signal intensity ratio as a sign of neurodegeneration and cognition independent of β-amyloid in dementia.

Cortical gray to white matter signal intensity ratio (GWR) measured from T1-weighted magnetic resonance (MR) images was associated with neurodegeneration and dementia. We characterized topological patterns of GWR during AD pathogenesis and investigated its association with cognitive decline. The study included a cross-sectional dataset and a longitudinal dataset. The cross-sectional dataset included 60 cognitively healthy controls, 61 mild cognitive impairment (MCI), and 63 patients with dementia. The longitudinal dataset included 26 participants who progressed from cognitively normal to dementia and 26 controls that remained cognitively normal. GWR was compared across the cross-sectional groups, adjusted for amyloid PET. The correlation between GWR and cognition performance was also evaluated. The longitudinal dataset was used to investigate GWR alteration during the AD pathogenesis. Dementia with β-amyloid deposition group exhibited the largest area of increased GWR, followed by MCI with β-amyloid deposition, MCI without β-amyloid deposition, and controls. The spatial pattern of GWR-increased regions was not influenced by β-amyloid deposits. Correlation between regional GWR alteration and cognitive decline was only detected among individuals with β-amyloid deposition. GWR showed positive correlation with tau PET in the left supramarginal, lateral occipital gyrus, and right middle frontal cortex. The longitudinal study showed that GWR increased around the fusiform, inferior/superior temporal lobe, and entorhinal cortex in MCI and progressed to larger cortical regions after progression to AD. The spatial pattern of GWR-increased regions was independent of β-amyloid deposits but overlapped with tauopathy. The GWR can serve as a promising biomarker of neurodegeneration in AD.

Author Response: Predicting Cognitive Decline in Older Adults Using Baseline Metrics of AD Pathologies, Cerebrovascular Disease, and Neurodegeneration.

Author Response: Predicting Cognitive Decline in Older Adults Using Baseline Metrics of AD Pathologies, Cerebrovascular Disease, and Neurodegeneration.

Editors' Note: Predicting Cognitive Decline in Older Adults Using Baseline Metrics of AD Pathologies, Cerebrovascular Disease, and Neurodegeneration.

Editors' Note: Predicting Cognitive Decline in Older Adults Using Baseline Metrics of AD Pathologies, Cerebrovascular Disease, and Neurodegeneration.

Reader Response: Predicting Cognitive Decline in Older Adults Using Baseline Metrics of AD Pathologies, Cerebrovascular Disease, and Neurodegeneration.

Reader Response: Predicting Cognitive Decline in Older Adults Using Baseline Metrics of AD Pathologies, Cerebrovascular Disease, and Neurodegeneration.

Inhibition of IL-6 methylation by Saikosaponin C regulates neuroinflammation to alleviate depression.

Saikosaponin C (SSc) increases the expression of synaptic proteins and has a unexplored role in the prevention of AD and other neurodegeneration in humans. Therefore, we hypothesized that SSc has the potential to relief of depressive symptoms. Here, our study assessed the role of SSc on depression-like behaviors caused by a chronic social defeat stress (CSDS) in mice and explored the underlying mechanisms. Behavioral tests were conducted to verify the efficacy of SSC in treating depression-like behavior in mice. The levels of IL-6, TNF-α and IL-1β in brain tissue and BV2 cells were determined by ELISA. The effect of SSc on dendritic spine density was determined by Golgi staining. The percentage of monocytes in peripheral blood was measured using flow cytometry. The levels of STAT3 and DNMT1 under the influence of SSc were assessed by immunofluorescence. Protein expression of DNMT1, DNMT3a, DNMT3b, p-STAT3 and STAT3 in brain and BV2 cells was studied by Western blot. OE-DNMT1 was induced in the experiment to verify the inhibitory effect of DNMT1 on IL-6 methylation in SSC. Luciferase was used to detect SSC specific fragments affecting IL-6 methylation. SSC treatment significantly alleviated depressive-like behavior, inhibited the levels of inflammatory cytokines including IL-6, IL-1β and TNF-α, increased dendritic spine density and promoted synaptic plasticity in mice. SSC downregulated IL-6, STAT3 and DNMT1 expression in vivo and in vitro. SSC also decreased the percentage of monocytes in peripheral blood and suppressed neuroinflammation in mice. Overexpression of DNMT1 by shRNA abolished the inhibitory effect of SSc on IL-6 methylation. This study showed that SSc reduced IL6 methylation by inhibiting DNMT1 protein, induced a decrease in IL6 expression, promoted synaptic plasticity, and attenuated CSDS-induced depression-like behavior.

Challenges and Opportunities of Metal Chelation Therapy in Trace Metals Overload-Induced Alzheimer's Disease.

Essential trace metals like zinc (Zn), iron (Fe), and copper (Cu) play an important physiological role in the metabolomics and healthy functioning of body organs, including the brain. However, abnormal accumulation of trace metals in the brain and dyshomeostasis in the different regions of the brain have emerged as contributing factors in neuronal degeneration, Aβ aggregation, and Tau formation. The link between these essential trace metal ions and the risk of AD has been widely studied, although the conclusions have been ambiguous. Despite the absence of evidence for any clinical benefit, therapeutic chelation is still hypothesized to be a therapeutic option for AD. Furthermore, the parameters like bioavailability, ability to cross the BBB, and chelation specificity must be taken into consideration while selecting a suitable chelation therapy. The data in this review summarizes that the primary intervention in AD is brain metal homeostasis along with brain metal scavenging. This review evaluates the impact of different trace metals (Cu, Zn, Fe) on normal brain functioning and their association with neurodegeneration in AD. Also, it investigates the therapeutic potential of metal chelators in the management of AD. An extensive literature search was carried out on the "Web of Science, PubMed, Science Direct, and Google Scholar" to investigate the effect of trace elements in neurological impairment and the role of metal chelators in AD. In addition, the current review highlights the advantages and limitations of chelation therapies and the difficulties involved in developing selective metal chelation therapy in AD patients.

Early accumulation of Aβ and Tau is associated with increase in cortical thickness

AbstractBackgroundThere is no consensus in the field regarding the relationship between AD pathologies (Aβ, and Tau) and neurodegeneration. One reason that may contribute to this disagreement is the definition of cut‐point to categorize participants with or without significant pathologies. This approach overlooks an important early stage of pathological accumulation. In this study, we take advantage of Florbetaben/MK6240 PET scans from 61/21 young (&lt;40) and healthy participants to redefined the cut‐point of Aβ/Tau uptake and investigate their association with cortical thickness as a measurement of neurodegeneration.MethodTo capture the early effect of pathologies, we quantify global pathologies by averaging AD‐related regions uptake; global Aβ: frontal, parietal, temporal, anterior and posterior cingulate, and precuneus, global Tau: fusiform, amygdala, parahippocampal, entorhinal, inferior temporal, middle temporal, and medial temporal lobe (MTL) Tau: entorhinal and parahippocampal. We redefied the cut‐point of AD pathologies using 95% percentile of the fitted normal distribution to the young subject's uptakes. Using newly defined cut‐points (1.01&lt;global Aβ&lt;1.25, 0.72&lt;global Tau&lt;1.15, and 0.66&lt;MTL Tau&lt;1.11), we identified 232 older participant (64.79±3.55, 94 males, 229 HC) from 394 healthy control (HC) and 52 with mild cognitive impairment (MCI). To assess the relationship between AD pathologies and neurodegeneration, we run a multiple regression to model cortical thickness at each vertex in the identified elders with global Aβ, and global Tau controlling for age, gender, and Intracranial volume (ICV).ResultEarly and low accumulation of Aβ and Tau were associated with higher cortical thickness in many regions throughout the cerebral cortex. More interestingly, MTL (where the early Tau deposition occurs) was among the regions showing a positive association with Aβ deposition and cortical thickness.ConclusionThese results, provide preliminary evidence that early and low accumulations of AD pathologies are associated with higher cortical thickness. Our results may shed some light on the discrepancies between the existing studies investigating the same relationship. As it has been recently hypothesized, it suggests that the cascade of events in AD may start much earlier than what had been considered in the field and this early accumulation of Aβ and Tau has completely different consequences on brain structure/function.