Levels Of Alzheimer Research Articles

Synaptic and extrasynaptic distribution of NMDA receptors in the cortex of Alzheimer's disease patients.

Synaptic and extrasynaptic distribution of N-methyl-D-aspartate receptors (NMDARs) has not been addressed in the brain from Alzheimer´s disease (AD) subjects, despite theircontribution to neurodegeneration. We have developed a protocol to isolate synaptic and extrasynaptic membranes from controls and AD frontal cortex. We characterized the distribution of the NMDAR subunits GluN2B, GluN2A, GluN1, and GluN3A, as well aspost-translational modifications, such as phosphorylation and glycosylation. Lower levels of synaptic GluN2B and GluN2A were found in AD fractions, while extrasynaptic GluN2B and GluN1 levels were significantly higher; GluN3A distribution remained unaffected in AD. We also identified different glycoforms of GluN2B and GluN2A in extrasynaptic membranes. Synaptic Tyr1472 GluN2B phosphorylation was significantly lower in AD fractions. Reduction of synaptic NMDAR subunits, particularly for GluN2B, is likely to contribute to synaptic transmission failure in AD. Additionally, the increment of extrasynaptic NMDAR subunits could favor the activation of excitotoxicity in AD. New protocol to isolate synaptic and extrasynaptic membranes from the human cortex. Low GluN2B and GluN2A levels in Alzheimer´s disease (AD) synaptic membranes. High GluN2B and GluN1 levels in AD extrasynaptic membranes. Specific glycoforms of extrasynaptic GluN2B and GluN2A. Low phosphorylation at Tyr1472 in synaptic GluN2B in AD.

The NRF2 inducer CDDO-2P-Im provokes a reduction in amyloid β levels in Alzheimer's disease model mice.

Alzheimer's disease (AD) is the most common etiology of dementia. The transcription factor NF-E2-related factor 2 (NRF2) induces the expression of genes encoding phase II detoxification and antioxidant genes. NRF2 is regulated by Kelch-like ECH-associated protein 1 (KEAP1), and the KEAP1-NRF2 system is the key regulatory system involved in cytoprotection. To examine whether pharmacological induction of NRF2 expression alleviates AD phenotypes in vivo, we employed two AD mouse models, i.e., App NL-G-F/NL-G-F (AppNLGF) and APPV717I::TAUP301L (APP/TAU) mice. As the synthetic oleanane triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11-dien-28-oyl)] (CDDO)-4(-pyridin-2-yl)-imidazole (CDDO-2P-Im) exhibits strong NRF2-inducing activity, we treated AD model mice with CDDO-2P-Im. We found that Aβ42 levels were markedly greater in the brains of AppNLGF mice than in those of APP/TAU mice. CDDO-2P-Im treatment significantly decreased Aβ42 levels, but not Aβ40 levels, in APP/TAU mice. Consequently, CDDO-2P-Im also decreased the ratio of Aβ42/Aβ40, a vital marker of amyloid plaque formation. LC-MS/MS analyses revealed that CDDO-2P-Im was delivered to the brains of the APP/TAU mice. CDDO-2P-Im induced the expression of detoxification and antioxidant gene targets of NRF2 and elevated reduced glutathione (GSH) levels in the mouse brain. These results support the notion that CDDO-2P-Im ameliorates AD-related pathologic changes.

The relationship between anxiety and levels of Alzheimer's disease plasma biomarkers.

Anxiety is highly prevalent in Alzheimer's disease (AD), correlating with CSF/PET biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/Aβ42 ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration.

Characterization of reduced astrocyte creatine kinase levels in Alzheimer's disease.

The creatine-phosphocreatine cycle serves as a crucial temporary energy buffering system in the brain, regulated by brain creatine kinase (CKB), in maintaining Adenosine triphosphate (ATP)levels. Alzheimer's disease (AD) has been linked to increased CKB oxidation and loss of its regulatory function, although specific pathological processes and affected cell types remain unclear. In our study, cerebral cortex samples from individuals with AD, dementia with Lewy bodies (DLB), and age-matched controls were analyzed using antibody-based methods to quantify CKB levels and assess alterations associated with disease processes. Two independently validated antibodies exclusively labeled astrocytes in the human cerebral cortex. Combining immunofluorescence (IF) and mass spectrometry (MS), we explored CKB availability in AD and DLB cases. IF and Western blot analysis demonstrated a loss of CKB immunoreactivity correlated with increased plaque load, severity of tau pathology, and Lewy body pathology. However, transcriptomics data and targeted MS demonstrated unaltered total CKB levels, suggesting posttranslational modifications (PTMs) affecting antibody binding. This aligns with altered efficiency at proteolytic cleavage sites indicated in the targeted MS experiment. These findings highlight that the proper function of astrocytes, understudied in the brain compared with neurons, is highly affected by PTMs. Reduction in ATP levels within astrocytes can disrupt ATP-dependent processes, such as the glutamate-glutamine cycle. As CKB and the creatine-phosphocreatine cycle are important in securing constant ATP availability, PTMs in CKB, and astrocyte dysfunction may disturb homeostasis, driving excitotoxicity in the AD brain. CKB and its activity could be promising biomarkers for monitoring early-stage energy deficits in AD.

Effect of Hei Xiaoyaosan regulating p38MAPK/Beclin-1/Bcl-2 pathway on autophagy level in Alzheimer's disease model rats

To explore the effect of Hei Xiaoyaosan on autophagy levels in Alzheimer's disease(AD). A total of 100 4-month-old Wistar male rats were randomly selected as a blank group, and 10 rats were taken as a sham operation group and injected with 1 μL of normal saline on both sides of the hippocampus. The other rats were injected with Aβ_(1-42) solution in the hippocampus to replicate the AD model. Fifty successfully modeled rats were selected and randomly divided into the model group, Aricatio group(0.5 mg·kg~(-1)), and high, medium, and low dose groups of Hei Xiaoyaosan(15.30, 7.65, and 3.82 g·kg~(-1)), with 10 rats in each group. The rats were administered by continuous gavage for 42 days. Morris water maze was used to detect the learning and memory ability of rats, and Hoechst staining was used to observe the pathological changes of nerve cells in the hippocampal CA1 region. The mRNA expression of p38MAPK, Beclin-1, and Bcl-2 was detected by RT-qPCR.Western blot was used to detect the expressions of p38MAPK, Beclin-1, Bcl-2, APP, and related proteins. The level of Aβ_(1-42) in the hippocampus was detected by ELISA, and the expression level of LC3Ⅱ in the hippocampus was detected by immunohistochemistry. The experimental results showed that compared with the blank group, the learning and memory ability of rats in the model group decreased(P<0.01). The nuclei in the CA1 region of the hippocampus showed blue bright spots and were closely arranged. The mRNA expression of p38MAPK was up-regulated, and the mRNA expressions of Beclin-1 and Bcl-2 were down-regulated(P<0.01). The expressions of p38MAPK, p-p38MAPK, and APP were increased, while those of Beclin-1, Bcl-2, and p-Bcl-2 were decreased(P<0.01). The expression of Aβ_(1-42) was increased(P<0.01). The relative expression of LC3Ⅱ decreased(P<0.01). Compared with the model group, the learning and memory ability of rats in each administration group was improved(P<0.05 or P<0.01). The nuclei in the CA1 region of the hippocampus gradually became clear, showing light blue. The mRNA expression of p38MAPK was down-regulated(P<0.01), and that of Beclin-1 and Bcl-2 was increased(P<0.05 or P<0.01). The expressions of p38MAPK, p-p38MAPK, and APP were down-regulated, while those of Beclin-1, Bcl-2, and p-Bcl-2 were up-regulated(P<0.05 or P<0.01). The expression of Aβ_(1-42) was decreased(P<0.01). The relative expression of LC3Ⅱ was increased(P<0.01). It can be concluded that Hei Xiaoyaosan can improve the cognitive ability of AD model rats, and its potential mechanism may be related to regulating the p38MAPK/Beclin-1/Bcl-2 signaling pathway, increasing the level of autophagy, and reducing the accumulation of Aβ_(1-42).

Plasma amyloid ® levels in alzheimer’s disease and cognitively normal controls in syrian population

Plasma amyloid ® levels in alzheimer’s disease and cognitively normal controls in syrian population

Corrigendum: Genistein protects hippocampal neurons against injury by regulating calcium/calmodulin dependent protein kinase IV protein levels in Alzheimer's disease model rats.

Corrigendum: Genistein protects hippocampal neurons against injury by regulating calcium/calmodulin dependent protein kinase IV protein levels in Alzheimer's disease model rats.

Cerebrospinal fluid soluble insulin receptor levels in Alzheimer's disease.

Brain insulin resistance and deficiency is a consistent feature of Alzheimer's disease (AD). Insulin resistance can be mediated by the surface expression of the insulin receptor (IR). Cleavage of the IR generates the soluble IR (sIR). We measured the levels of sIR present in cerebrospinal fluid (CSF) from individuals along the AD diagnostic spectrum from two cohorts: Seattle (n=58) and the Consortium for the Early Identification of Alzheimer's Disease-Quebec (CIMA-Q; n=61). We further investigated the brain cellular contribution for sIR using human cell lines. CSF sIR levels were not statistically different in AD. CSF sIR and amyloid beta (Aβ)42 and Aβ40 levels significantly correlated as well as CSF sIR and cognition in the CIMA-Q cohort. Human neurons expressing the amyloid precursor protein "Swedish" mutation generated significantly greater sIR and human astrocytes were also able to release sIR in response to both an inflammatory and insulin stimulus. These data support further investigation into the generation and role of sIR in AD. Cerebrospinal fluid (CSF) soluble insulin receptor (sIR) levels positively correlate with amyloid beta (Aβ)42 and Aβ40.CSF sIR levels negatively correlate with cognitive performance (Montreal Cognitive Assessment score).CSF sIR levels in humans remain similar across Alzheimer's disease diagnostic groups.Neurons derived from humans with the "Swedish" mutation in which Aβ42 is increased generate increased levels of sIR.Human astrocytes can also produce sIR and generation is stimulated by tumor necrosis factor α and insulin.

Data-driven Stochastic Model for Quantifying the Interplay Between Amyloid-beta and Calcium Levels in Alzheimer's Disease.

The abnormal aggregation of extracellular amyloid- in senile plaques resulting in calcium dyshomeostasis is one of the primary symptoms of Alzheimer's disease (AD). Significant research efforts have been devoted in the past to better understand the underlying molecular mechanisms driving deposition and dysregulation. Importantly, synaptic impairments, neuronal loss, and cognitive failure in AD patients are all related to the buildup of intraneuronal accumulation. Moreover, increasing evidence show a feed-forward loop between and levels, i.e. disrupts neuronal levels, which in turn affects the formation of . To better understand this interaction, we report a novel stochastic model where we analyze the positive feedback loop between and using ADNI data. A good therapeutic treatment plan for AD requires precise predictions. Stochastic models offer an appropriate framework for modelling AD since AD studies are observational in nature and involve regular patient visits. The etiology of AD may be described as a multi-state disease process using the approximate Bayesian computation method. So, utilizing ADNI data from 2-year visits for AD patients, we employ this method to investigate the interplay between and levels at various disease development phases. Incorporating the ADNI data in our physics-based Bayesian model, we discovered that a sufficiently large disruption in either metabolism or intracellular homeostasis causes the relative growth rate in both and , which corresponds to the development of AD. The imbalance of ions causes disorders by directly or indirectly affecting a variety of cellular and subcellular processes, and the altered homeostasis may worsen the abnormalities of ion transportation and deposition. This suggests that altering the balance or the balance between and by chelating them may be able to reduce disorders associated with AD and open up new research possibilities for AD therapy.

The Association among Hypothalamic Subnits, Gonadotropic and Sex Hormone Plasmas Levels in Alzheimer's Disease.

This study investigates the sex-specific role of the Hypothalamic-Pituitary-Gonadal axis in Alzheimer's disease progression, utilizing ADNI1 data for 493 individuals, analyzing plasma levels of gonadotropic and sex hormones, and examining neurodegeneration-related brain structures. We assessed plasma levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P4), and testosterone (T), along with volumetric measures of the hippocampus, entorhinal cortex, and hypothalamic subunits, to explore their correlation with Alzheimer's disease markers across different cognitive statuses and sexes. Significant cognitive status effects were observed for all volumetric measures, with a distinct sex-by-cognitive status interaction for hypothalamic volume, indicating a decrease in males but not in females across cognitive impairment stages. Regression analyses showed specific hypothalamic subunit volume related to hormone levels, accounting for up to approximately 40% of the variance (p < 0.05). The findings highlight sex differences in neurodegeneration and hormonal regulation, suggesting potential for personalized treatments and advancing the understanding of Alzheimer's disease etiology.

Whole-body metabolic modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimer’s disease

In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimer's disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilised whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalised whole-body metabolic models. Notably, AD individuals displayed diminished formate microbial secretion in these models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management.

Correlation of Presynaptic and Postsynaptic Proteins with Pathology in Alzheimer's Disease.

Synaptic transmission is essential for nervous system function and the loss of synapses is a known major contributor to dementia. Alzheimer's disease dementia (ADD) is characterized by synaptic loss in the mesial temporal lobe and cerebral neocortex, both of which are brain areas associated with memory and cognition. The association of synaptic loss and ADD was established in the late 1980s, and it has been estimated that 30-50% of neocortical synaptic protein is lost in ADD, but there has not yet been a quantitative profiling of different synaptic proteins in different brain regions in ADD from the same individuals. Very recently, positron emission tomography (PET) imaging of synapses is being developed, accelerating the focus on the role of synaptic loss in ADD and other conditions. In this study, we quantified the densities of two synaptic proteins, the presynaptic protein Synaptosome Associated Protein 25 (SNAP25) and the postsynaptic protein postsynaptic density protein 95 (PSD95) in the human brain, using enzyme-linked immunosorbent assays (ELISA). Protein was extracted from the cingulate gyrus, hippocampus, frontal, primary visual, and entorhinal cortex from cognitively unimpaired controls, subjects with mild cognitive impairment (MCI), and subjects with dementia that have different levels of Alzheimer's pathology. SNAP25 is significantly reduced in ADD when compared to controls in the frontal cortex, visual cortex, and cingulate, while the hippocampus showed a smaller, non-significant reduction, and entorhinal cortex concentrations were not different. In contrast, all brain areas showed lower PSD95 concentrations in ADD when compared to controls without dementia, although in the hippocampus, this failed to reach significance. Interestingly, cognitively unimpaired cases with high levels of AD pathology had higher levels of both synaptic proteins in all brain regions. SNAP25 and PSD95 concentrations significantly correlated with densities of neurofibrillary tangles, amyloid plaques, and Mini Mental State Examination (MMSE) scores. Our results suggest that synaptic transmission is affected by ADD in multiple brain regions. The differences were less marked in the entorhinal cortex and the hippocampus, most likely due to a ceiling effect imposed by the very early development of neurofibrillary tangles in older people in these brain regions.

The relevance between abnormally elevated serum ceramide and cognitive impairment in Alzheimer's disease model mice and its mechanism.

The plasma ceramide levels in Alzheimer's disease (AD) patients are found abnormally elevated, which is related to cognitive decline. This research was aimed to investigate the mechanisms of aberrant elevated ceramides in the pathogenesis of AD. The ICR mice intracerebroventricularly injected with Aβ1-42 and APP/PS1 transgenic mice were employed as AD mice. The cognitive deficiency, impaired episodic and spatial memory were observed without altered spontaneous ability. The serum levels of p-tau and ceramide were evidently elevated. The modified expressions and activities of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) influenced the serum content of p-tau. The levels of ceramide synthesis-related genes including sptlc1, sptlc2, cers2, and cers6 in the liver of AD mice were increased, while the ceramide degradation-related gene asah2 did not significantly change. The regulations of these genes were conducted by activated nuclear factor kappa-B (NF-κB) signaling. NF-κB, promoted by free fatty acid (FFA), also increased the hepatic concentrations of proinflammatory cytokines. The FFA amount was modulated by fatty acid synthesis-related genes acc1 and srebp-1c. Besides, the decreased levels of pre-proopiomelanocortin (pomc) mRNA and increased agouti-related protein (agrp) mRNA were found in the hypothalamus without significant alteration of melanocortin receptor 4 (MC4R) mRNA. The bioinformatic analyses proved the results using GEO datasets and AlzData. Ceramide was positively related to the increased p-tau and impaired cognitive function. The increased generation of ceramide and endoplasmic reticulum stress in the hypothalamus was positively related to fatty acid synthesis and NF-κB signaling via brain-liver axis.

Analysis of apoE levels in Alzheimer’s disease patients and control subjects of APOE ε4 variant carriers and non‐carriers

AbstractBackgroundAlzheimer’s disease (AD) is the most common progressive dementia disease in people over 60 years of age. The pathogenesis of AD is thought to be complex and depends on environmental and genetic factors. The most important genetic factors responsible for AD include variants of the APOE gene, which encodes the protein apolipoprotein E (apoE). There are 2 polymorphisms in the APOE, which presence of three alleles: protective ‐ ε2, neutral ‐ ε3, and pathogenic ‐ ε4. On the other hand, the presence of the ε4 allele is associated with an approximately four times higher risk of developing AD in people with a heterozygous system and a twelve times higher risk in ε4/4ε. Disorders of epigenetic mechanisms affecting the concentration of apoE may participate in the development of AD. Disturbed levels of apoE may impair clearance of Aβ from the brain and exacerbate disease progression. It is not known what level of apoE ensures the removal of Aβ and whether genetic and familial predispositions can regulate the efficiency of protective mechanisms. So far, there is little information on the level of apoE in AD patients and controls who are and are not APOE ε4 carriers.The aim was to analyze genetic variants of the APOE gene and apoE protein concentration in AD patients, control subjects related to AD cases (CR), and controls subjects without a family history of AD (CU), carriers and non‐carriers of the APOE ε4 variant.MethodThe studies were conducted on 156 individuals (AD and controls). The APOE genotype was determined by real‐time PCR. The apoE concentration was determined by the ELISA method.ResultThe highest concentration of apoE was found in CR compared to AD and CU (p&lt;0.001). In both APOE ε4 carriers (p&lt;0.05) and non‐carriers (p&lt;0.001), the highest levels of apoE were found in CR. At the same time, in all tested subjects, carriers of APOE ε4, the level of apoE was lower compared to non‐carriers of this pathogenic variant.ConclusionIt seems that the ε4 pathogenic variant of the APOE gene may lead to the development of AD by regulating the level of apoE.

Time of the day at sampling affects amyloid‐beta levels in CSF and plasma

AbstractBackgroundStudies suggest that cerebrospinal fluid (CSF) levels of Alzheimer’s disease (AD) biomarkers, amyloid‐β (Aβ) and tau, follow a circadian rhythm. However sustained sampling of CSF with indwelling intrathecal catheter used in most of these studies might have affected the observed fluctuations in the biomarker levels.MethodsWe included 38 individuals with either normal (N = 18) or abnormal (N = 20) CSF Aβ42/40 status. CSF and plasma were collected, at the same occasion, at two different visits separated by an average of 53 days with lumbar punctures and venepunctures performed either in the morning or evening. At the first visit, collection was performed in the morning for 17 participants and the order was reversed (evening collection first) for the remaining 21 participants. CSF and plasma samples were analyzed for Aβ42, Aβ40, GFAP, NfL, p‐tau181, p‐tau217 and p‐tau231. CSF samples were also tested for a battery of synaptic and lysosomal proteins.ResultsCSF Aβ42 (mean difference [MD] = 0.208ng/ml; p = 0.043), CSF Aβ40 (MD = 1.85ng/ml; p&lt;0.001), plasma Aβ42 (MD = 1.65pg/ml; p = 0.002) and plasma Aβ40 (MD, 0.011ng/ml, p = 0.003) levels were increased in the evening samples compared with morning samples by 4.2%‐17.0% (Figures 1‐2). However, changes between morning and evening samples were not significant for either CSF or plasma Aβ42/40. Additional proteins in CSF, APP, STX1B, NPTXR and NPTX1, were also found increased in the evening samples (MDrange, 0.087–0.243; p&lt;0.048) by 4.7%‐12.15% (Figure 3). No significant differences were found between morning and evening levels for any of the other biomarkers, including p‐tau’s, NfL and GFAP. There were no significant interactions between time of day at sample collection and either Aβ status or order in which samples were obtained.ConclusionOur findings provide further evidence for diurnal fluctuations in Aβ peptides, which is observed in both CSF and plasma. Additionally, CSF levels of some synaptic proteins followed circadian rhythm. Importantly, CSF and plasma Aβ42/40 ratios remained unaltered, suggesting that increased production or decreased clearance of Aβ peptides during daytime similarly affect the CSF and plasma levels of both Aβ42 and Aβ40. Thus, these ratios are more suitable for implementation as biomarkers of AD as they are not influenced by diurnal fluctuations.

Investigation of tau post‐translational modification based on T217 and T231 in human plasma as new biomarkers

AbstractBackgroundPost‐translational modification (PTM) of human tau protein is of high importance as an indicator for predicting the progress of Alzheimer’s disease (AD). Particularly, phosphorylation and O‐glycosylation on tau have been observed at relatively high levels in Alzheimer’s disease (AD) patients and healthy controls, respectively [1]. Recently, a study reported that an increase in the level of phosphorylation at T217 and T231 was observed in the initial stages of the preclinical Alzheimer’s continuum [2]. Reference: [1] C. Alquezar et al. Frontiers in Neurology, 11 (2021) 595532. [2] Marc Suárez‐Calvet et al. EMBO Molecular Medicine, 12 (2020) e12921.MethodTo investigate the PTM of tau protein in human blood plasma, an electrochemical sensor with 1 µm gap between working and counter electrodes was performed and obtained Taumeter indicating the ratio of phosphorylation and O‐glycosylation on the surface of tau protein, where antibodies for phosphorylated T217 and T231 were used [3]. To explore the clinical association, standardized uptake value ratio (SUVR) of amyloid‐positron emission tomography (PET), mini‐mental state examination (MMSE), and clinical dementia rating scale sum of boxes (CDR‐SB) were also investigated and compared to Taumeters. Reference: [3] Yoon et al. Alzheimer’s &amp; Dementia, 18 (2022) e061465.ResultA total of 43 participants (normal control (NC, n = 15), mild cognitive impairment (MCI, n = 14), and AD (n = 14) were investigated. Taumeters for T217 (p = 0.00423, AUC = 0.82667) and T231 (p = 0.00034, AUC = 0.86222) were obtained and analyzed through one‐way analysis of variance (ANOVA) between NC and AD groups (Figure 2). In regression analysis, Taumeter for T217 (r = 0.23824, p = 0.12394) was more correlated with amyloid‐PET SUVR than Taumeter for T231 (r = 0.28072, p = 0.06824) (Figures 3a‐b). Taumeter for T217 (r = ‐0.51246, p = 0.00044) was also more correlated with MMSE score than Taumeter for T231 (r = ‐0.07186, p = 0.64701) (Figures 3c‐d). Taumeter for T217 (r = 0.57937, p&lt;0.0001) was more correlated with the CDR‐SB score than Taumeter for T231 (r = 0.16254, p = 0.29768) (Figures 3e‐f).ConclusionIn this study, we investigated the correlation between Taumeters for T217 and T231, amyloid‐PET SUVR, MMSE score, and CDR‐SB score. As a result, Taumeter for T217 indicates more strong correlation with analytical results of amyloid‐PET SUVR, MMSE score, and CDR‐SB score than Taumter for T231.

Plasma p‐tau181 levels in Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB)

AbstractBackgroundThe fundamental pathological process in AD involves amyloid(Aβ) deposition and Tau hyperphosphorylation (ptau). Plasma ptau has been proven as more accessible and less invasive biomarker than CSF for the assessment of AD pathological features. DLB is another common cause of dementia in the elderly and has overlapping features with AD. Thus, the detection of Alzheimer’s biomarkers might be useful for distinguishing the underlying pathology of AD from other concurrent pathologic processes. In this study, we compared the plasma levels of p‐tau181 in patients with clinically diagnosed DLB and AD.MethodWe examined EDTA plasma samples of patients assessed at the UBC Hospital Clinic for AD. The cohort was clinically characterized as control (n = 89) if no significant cognitive impairment was found, AD (n = 195) if they fulfill the NIA‐AA criteria (McKhann 2011), and DLB (n = 39) if they fulfill the consensus criteria for DLB (McKeith 2005; McKeith 2017). The samples were analyzed by a p‐tau181‐specific Simoa assay.ResultThe mean age of the cohort is 69.2 ± 10.3 with the control 63.4 ± 8.7, AD 70.1 ±9.9 and DLB 77.8 ± 8. There are 74.2% females in the controls, 52.8% in AD, and 35.9% in DLB.).The patients with DLB were older than the cases of AD and controls (p&lt;0.001) and there was no significant effect of age on plasma ptau‐181 concentrations (p = 0.65). There were more females in the controls and AD groups compared to DLB (p&lt;0.001), however, there was no significant correlation between sex and plasma ptau‐181 (p = 0.24). While the plasma p‐tau181 concentrations of cases with AD (74.1 ± 35.6 pg/ml) were slightly higher than DLB (73.2 ± 44.4 pg/ml), they were not significantly different. However, they were significantly higher than the control group (26.5 ± 23 pg/ml) (p &lt; 0.001).ConclusionIn current study, plasma p‐tau181 levels did not differentiate the DLB group from the AD, but both groups were significantly higher than controls. This suggests that DLB often have co‐existing AD pathology, making their p‐tau measurements like the AD group. Further studies with autopsy‐defined samples will be needed to clarify the role of plasma p‐tau181 in DLB.

CSF 14-3-3β is associated with progressive cognitive decline in Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder characterized pathologically by amyloid-beta plaques, tau tangles and neuronal loss. In clinical practice, the 14-3-3 isoform beta (β) is a biomarker that aids in the diagnosis of sporadic Creutzfeldt-Jakob disease. Recently, a proteomics study found increased CSF 14-3-3β levels in Alzheimer's disease patients, suggesting a potential link between CSF 14-3-3β and Alzheimer's disease. Our present study aimed to further investigate the role of CSF 14-3-3β in Alzheimer's disease by analysing the data of 719 participants with available CSF 14-3-3β measurements from the Alzheimer's Disease Neuroimaging Initiative. Higher CSF 14-3-3β levels were observed in the mild cognitive impairment group compared to the cognitively normal group, with the highest CSF 14-3-3β levels in the Alzheimer's disease dementia group. This study also found significant associations between CSF 14-3-3β levels and CSF biomarkers of p-tau, t-tau, pTau/Aβ42 ratios and GAP-43, as well as other Alzheimer's disease biomarkers such as Aβ-PET. An early increase in CSF 14-3-3β levels was observed prior to Aβ-PET-positive status, and CSF 14-3-3β levels continued to rise after crossing the Aβ-PET positivity threshold before reaching a plateau. The diagnostic accuracy of CSF 14-3-3β (area under the receiver operating characteristic curve = 0.819) was moderate compared to other established Alzheimer's disease biomarkers in distinguishing cognitively normal Aβ pathology-negative individuals from Alzheimer's disease Aβ pathology-positive individuals. Higher baseline CSF 14-3-3β levels were associated with accelerated cognitive decline, reduced hippocampus volumes and declining fluorodeoxyglucose-PET values over a 4-year follow-up period. Patients with mild cognitive impairment and high CSF 14-3-3β levels at baseline had a significantly increased risk [hazard ratio = 2.894 (1.599-5.238), P < 0.001] of progression to Alzheimer's disease dementia during follow-up. These findings indicate that CSF 14-3-3β may be a potential biomarker for Alzheimer's disease and could provide a more comprehensive understanding of the underlying pathological changes of Alzheimer's disease, as well as aid in the diagnosis and monitoring of disease progression.

Correlation of metal ions with specific brain region volumes in neurodegenerative diseases.

There are reports stating that deteriorations in metal homeostasis in neurodegenerative diseases promote abnormal protein accumulation. In this study, the serum metal levels in Alzheimer's disease (AD) and Parkinson's disease (PD) and its relationship with the cortical regions of the brain were investigated. The patients were divided into 3 groups consisting of the AD group, PD group, and healthy control group (n = 15 for each). The volumes of specific brain regions were measured over the participants' 3-dimensional magnetic resonance images, and they were compared across the groups. Copper, zinc, iron, and ferritin levels in the serums were determined, and their correlations with the brain region volumes were examined. The volumes of left hippocampus and right substantia nigra were lower in the AD and PD groups, while the volume of the left nucleus caudatus (CdN) and bilateral insula were lower in the AD group compared to the control group. Serum zinc levels were lower in the AD and PD groups, while the iron level was lower in the PD group in comparison to the control group. In addition, the serum ferritin level was higher in the AD group than in the control group. Serum zinc and copper levels in the AD group were positively correlated with the volumes of the right entorhinal cortex, thalamus, CdN, and insula. Serum zinc and copper levels in the PD group showed a negative correlation with the left nucleus accumbens (NAc), right putamen, and right insula volumes. While the serum ferritin level in the PD group displayed a positive correlation with the bilateral CdN, putamen, and NAc, as well as the right hippocampus and insula volumes, no area was detected that showed a correlation with the serum ferritin level in the AD group. A relationship was determined between the serum metal levels in the AD and PD groups and certain brain cortical regions that showed volumetric changes, which can be important for the early diagnosis of neurodegenerative diseases.

Association of APOE gene with longitudinal changes of CSF amyloid beta and tau levels in Alzheimer's disease: racial differences.

The Apolipoprotein E (APOE) ε4 allele is a risk factor for late-onset Alzheimer's disease (AD). However, no investigation has focused on racial differences in the longitudinal effect of APOE genotypes on CSF amyloid beta (Aβ42) and tau levels in AD. This study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI): 222 participants with AD, 264 with cognitive normal (CN), and 692 with mild cognitive impairment (MCI) at baseline and two years follow-up. We used a linear mixed model to investigate the effect of APOE-ε4-genotypes on longitudinal changes in the amyloid beta and tau levels. Individuals with 1 or 2 APOE ε4 alleles revealed significantly higher t-Tau and p-Tau, but lower amyloid beta Aβ42 compared with individuals without APOE ε4 alleles. Significantly higher levels of log-t-Tau, log-p-Tau, and low levels of log-Aβ42 were observed in the subjects with older age, being female, and the two diagnostic groups (AD and MCI). The higher p-Tau and Aβ42 values are associated with poor Mini-Mental State Examination (MMSE) performance. Non-Hispanic Africa American (AA) and Hispanic participants were associated with decreased log-t-Tau levels (β = - 0.154, p = 0.0112; β = - 0.207, and p = 0.0016, respectively) as compared to those observed in Whites. Furthermore, Hispanic participants were associated with a decreased log-p-Tau level (β = - 0.224, p = 0.0023) compared to those observed in Whites. There were no differences in Aβ42 level for non-Hispanic AA and Hispanic participants compared with White participants. Our study, for the first time, showed that the APOE ε4 allele was associated with these biomarkers, however with differing degrees among racial groups.