Function In Alzheimer's Disease Research Articles

Serum IL-6, sAXL, and YKL-40 as systemic correlates of reduced brain structure and function in Alzheimer’s disease: results from the DELCODE study

BackgroundNeuroinflammation constitutes a pathological hallmark of Alzheimer’s disease (AD). Still, it remains unresolved if peripheral inflammatory markers can be utilized for research purposes similar to blood-based beta-amyloid and neurodegeneration measures. We investigated experimental inflammation markers in serum and analyzed interrelations towards AD pathology features in a cohort with a focus on at-risk stages of AD.MethodsData of 74 healthy controls (HC), 99 subjective cognitive decline (SCD), 75 mild cognitive impairment (MCI), 23 AD relatives, and 38 AD subjects were obtained from the DELCODE cohort. A panel of 20 serum biomarkers was determined using immunoassays. Analyses were adjusted for age, sex, APOE status, and body mass index and included correlations between serum and CSF marker levels and AD biomarker levels. Group-wise comparisons were based on screening diagnosis and routine AD biomarker-based schematics. Structural imaging data were combined into composite scores representing Braak stage regions and related to serum biomarker levels. The Preclinical Alzheimer’s Cognitive Composite (PACC5) score was used to test for associations between the biomarkers and cognitive performance.ResultsEach experimental marker displayed an individual profile of interrelations to AD biomarkers, imaging, or cognition features. Serum-soluble AXL (sAXL), IL-6, and YKL-40 showed the most striking associations. Soluble AXL was significantly elevated in AD subjects with pathological CSF beta-amyloid/tau profile and negatively related to structural imaging and cognitive function. Serum IL-6 was negatively correlated to structural measures of Braak regions, without associations to corresponding IL-6 CSF levels or other AD features. Serum YKL-40 correlated most consistently to CSF AD biomarker profiles and showed the strongest negative relations to structure, but none to cognitive outcomes.ConclusionsSerum sAXL, IL-6, and YKL-40 relate to different AD features, including the degree of neuropathology and cognitive functioning. This may suggest that peripheral blood signatures correspond to specific stages of the disease. As serum markers did not reflect the corresponding CSF protein levels, our data highlight the need to interpret serum inflammatory markers depending on the respective protein’s specific biology and cellular origin. These marker-specific differences will have to be considered to further define and interpret blood-based inflammatory profiles for AD research.

The effect of hippocampal radiomic features and functional connectivity on the relationship between hippocampal volume and cognitive function in Alzheimer's disease

Hippocampal volume is associated with cognitive function in Alzheimer's disease (AD). Hippocampal radiomic features and resting-state functional connectivity (rs-FC) are promising biomarkers and correlate with AD pathology. However, few studies have been conducted on how hippocampal biomarkers affect the cognition-structure relationship. Therefore, we aimed to investigate the effects of hippocampal radiomic features and resting-state functional connectivity (rs-FC) on this relationship in AD. We enrolled 70 AD patients and 65 healthy controls (HCs). The FreeSurfer software was used to measure hippocampal volume. We selected hippocampal radiomic features to build a model to distinguish AD patients from HCs and used a seed-based approach to calculate the hippocampal rs-FC. Furthermore, we conducted mediation and moderation analyses to investigate the effect of hippocampal radiomic features and rs-FC on the relationship between hippocampal volume and cognition in AD. The results suggested that hippocampal radiomic features mediated the association between bilateral hippocampal volume and cognition in AD. Additionally, patients with AD showed weaker rs-FC between the bilateral hippocampus and right ventral posterior cingulate cortex and stronger rs-FC between the left hippocampus and left insula than HCs. The rs-FC between the hippocampus and insula moderated the relationship between hippocampal volume and cognition in AD, suggesting that this rs-FC could exacerbate or ameliorate the effects of hippocampal volume on cognition and may be essential in improving cognitive function in AD. Our findings may not only expand existing biological knowledge of the interrelationships among hippocampal biomarkers and cognition but also provide potential targets for treatment strategies for AD.

Brain network decoupling with increased serum neurofilament and reduced cognitive function in Alzheimer's disease.

Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer's disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer's disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer's disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer's disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer's disease.

Transcranial Alternating Current Stimulation Improves Memory Function in Alzheimer's Mice by Ameliorating Abnormal Gamma Oscillation.

Transcranial alternating current stimulation (tACS) is considered to have a positive effect on the rehabilitation of Alzheimer's disease (AD) as an intervention method that matches stimulation frequency to neurogenesis frequency. However, when tACS intervention is delivered to a single target, the current received by brain regions outside the target may be insufficient to trigger neural activity, compromising the effectiveness of stimulation. Therefore, it is worth studying how single-target tACS restores gamma-band activity in the whole hippocampal-prefrontal circuit during rehabilitation. We used Sim4Life software to conduct finite element methods (FEM) on the stimulation parameters to ensure that tACS intervened only in the right hippocampus (rHPC) and did not activate the left hippocampus (lHPC) or prefrontal cortex (PFC). We stimulated the rHPC by tACS for 21 days to improve the memory function of AD mice. We simultaneously recorded local field potentials (LFPs) in the rHP, lHPC and PFC and evaluated the neural rehabilitative effect of tACS stimulation with power spectral density (PSD), cross-frequency coupling (CFC) and Granger causality. Compared to the untreated group, the tACS group exhibited an increase in the Granger causality connection and CFC between the rHPC and PFC, a decrease in those between the lHPC and PFC, and enhanced performance on the Y-maze test. These results suggest that tACS may serve as a noninvasive method for Alzheimer's disease rehabilitation by ameliorating abnormal gamma oscillation in the hippocampal-prefrontal circuit.

Study of the possible effect of sacubitril/valsartan combination versus valsartan on the cognitive function in Alzheimer's disease model in rats.

Objectives: Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder. The proportion of elderly individuals at risk for AD and cardiovascular problems increases by raising life expectancy. The present study was designed to investigate the effect of the sacubitril/valsartan combination compared to that of valsartan alone in a rat model of AD. Methods: 72 male adult Wistar rats were divided into seven groups; control untreated rats received saline, control valsartan-treated rats received valsartan orally, control sacubitril/valsartan treated rats received sacubitril/valsartan orally, model rats received aluminum chloride i.p., model valsartan treated rats received aluminum chloride i.p. and valsartan orally and model sacubitril/valsartan treated rats received aluminum chloride i.p. and sacubitril/valsartan combination orally. All previous treatments continued on a daily basis for 6weeks. At the second, fourth, and sixth weeks of the experiment, behavioral changes were evaluated using the Morris water maze and novel object recognition tests, and systolic blood pressure was measured. In the end, rat brain malondialdehyde and amyloid-beta 1-42 levels were measured, and the isolated hippocampus was evaluated histopathologically. Results: Valsartan improved AD symptoms in the aluminum-induced rat model, while the sacubitril/valsartan combination significantly worsened all tested parameters in both control and model rats compared with untreated and valsartan-treated animals. Conclusion: Based on the current study's findings, valsartan did not increase the risk for AD development in control rats and improved AD symptoms in a rat model, while sacubitril/valsartan combination increased the risk of AD in control rats and worsened the condition in a rat model.

Synaptosome microRNAs: emerging synapse players in aging and Alzheimer's disease.

Synaptosome microRNAs: emerging synapse players in aging and Alzheimer's disease.

Supplemental Material for Further Evaluation of Narrative Description as a Measure of Cognitive Function in Alzheimer’s Disease

Supplemental Material for Further Evaluation of Narrative Description as a Measure of Cognitive Function in Alzheimer’s Disease

Treatment of epilepsy using a targeted p38γ kinase gene therapy.

Hyperphosphorylated microtubule-associated protein tau has been implicated in dementia, epilepsy, and other neurological disorders. In contrast, site-specific phosphorylation of tau at threonine 205 (T205) by the kinase p38γ was shown to disengage tau from toxic pathways, serving a neuroprotective function in Alzheimer's disease. Using a viral-mediated gene delivery approach in different mouse models of epilepsy, we show that p38γ activity-enhancing treatment reduces seizure susceptibility, restores neuronal firing patterns, reduces behavioral deficits, and ameliorates epilepsy-induced deaths. Furthermore, we show that p38γ-mediated phosphorylation of tau at T205 is essential for this protection in epilepsy, as a lack of this critical interaction reinstates pathological features and accelerates epilepsy in vivo. Hence, our work provides a scope to harness p38γ as a future therapy applicable to acute neurological conditions.

Poorer dexterity is associated with underlying Alzheimer’s disease brain pathology

AbstractBackgroundThere has been increasing recognition for the decline of motor function in Alzheimer’s disease (AD) progression and its substantial role in disease morbidity. However, less is known about regional pathology burden—including amyloid‐β and tau protein deposition and cortical trophy—and its relationship to motor performance. Here investigate this relationship using standardized motor function assessment tools.MethodParticipants along a control‐to‐impaired continuum were enrolled in the Alzheimer’s Disease Connectome Project and underwent T1‐weighted MRI (N=206), with a subset undergoing [C‐11]PiB (N=61) and [F‐18 ]Flortaucipir PET (N=58) (Table 1) imaging for amyloid and tau pathology, respectively. T1‐weighted scans were processed using Freesurfer to estimate regional cortical thickness. [C‐11]PiB distribution volume ratios (DVR; cerebellar GM reference region) and [F‐18] Flortaucipir standardized uptake value ratios (SUVr; inferior cerebellar GM reference region) were assessed. Regions of interest (ROI) for analysis included the parahippocampal, entorhinal, motor, and frontal regions. Motor function was assessed utilizing NIH toolbox tests including the 2‐minute walking, 9‐hole pegboard dexterity, and dynamometer grip strength assessments. Motor performance was analyzed using participants uncorrected standardized scores. Scores were collected from participant‐reported dominant hand assessments. Multiple linear regression models tested relationships between AD biomarker burden and motor performance while controlling for age and sex of participants.ResultIncreased amyloid‐β (β‐0.42, p‐value: <0.05) and tau (β: ‐0.53, p‐value: <0.05) burden in primary motor cortices were associated with worse dexterity scores independent of age and sex. Grip strength did not show a significant correlation to cortical amyloid‐β (β: ‐0.14, p‐value 0.33) or tau burden (β: 0.23, p‐value: 0.36). Higher cortical thickness in primary motor regions were associated with higher dexterity (β: 0.21, p‐value <0.0001) and 2‐minute walking scores (β: 0.24, p‐value <0.001). When controlling for age and sex, grip strength predicted decreasing cortical thickness (β: 0.01, p‐value: <0.001) (Table 2).ConclusionLower dexterity performance may be driven by elevated AD pathological burden and cortical thinning in cortical motor regions. Further research into motor performance and clinical disease manifestation is needed to determine the diagnostic utility of fine motor assessment as a predictor of motor decline in individuals with Alzheimer’s disease pathology.

Sensory stimulation improves daily functions in Alzheimer’s disease

AbstractBackgroundAbnormal neuronal function in Alzheimer’s disease (AD) is characterized by unbalanced neuronal excitatory‐inhibitory tone, distorted neuronal synchrony, and network oscillations, presumably contributing to the pathogenesis of the disease and accelerating disease progression. The probability that abnormal neuronal activity directly contributes to the pathogenesis of the disease has been recently proposed. It has been demonstrated that induction of synchronized gamma oscillation of neuronal networks by sensory stimulation reverses AD‐related pathological markers in transgenic mice carrying AD‐related human pathological genes. The current study evaluated whether non‐invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for patients in AD spectrum.MethodThe data studied here is from Overture clinical trial (NCT03556280). The study included a treatment group, where participants received daily, 1‐hour, 40Hz gamma visual and auditory stimulation for 6‐months at home, and a placebo group. To assess the treatment efficacy on daily functional abilities, the Alzheimer’s Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL) scale was used. Assessments were made at baseline and every four weeks throughout the study. ADCS‐ADL consists of 23‐items where each item aims to assess different functional abilities. The change in ADCS‐ADL as well as change in each individual item’s score between the treatment group (n = 33) and the placebo group (n‐ = 19) were compared using a mixed model for repeated measures (MMRM).ResultWe observed that treatment group participants were able to maintain their functional abilities while placebo group participants showed a decline as assessed by ADCS‐ADL, p<0.001. Within the instrumental ADCS‐ADL individual items, the most significant differences between the two groups, all favoring treatment group, were observed in: (1) Attentive participation in conversations, p<0.001, and (2) Finding personal belongings, p<0.043.ConclusionOur results suggest that daily, 1‐hour 40Hz gamma sensory stimulation may help prevent functional decline in patients with AD spectrum disorder. Preventing functional loss would help both patients and caregivers. Furthermore, it may reduce the need for institutionalization and reduce healthcare costs. Larger studies are planned to confirm these initial findings on the benefits of gamma sensory stimulation on function.

The Efficacy of Vitamin D Supplementation in Patients With Alzheimer's Disease in Preventing Cognitive Decline: A Systematic Review.

To evaluate the role of vitamin D supplementation in preventing cognitive decline in patients with Alzheimer's disease (AD), five databases such as PubMed, PubMed Central (PMC), Medical Literature Analysis and Retrieval System Online (MEDLINE), ScienceDirect, and Google Scholar were searched for articles relevant to the research question with filters such as English and human studies from 2011 to 2022. Two investigators extracted the data and assessed the quality of the study using the predefined criteria. We identified 24 relevant articles after the critical screening. There were five randomized controlled trials (RCTs), two observational studies, two systematic reviews and meta-analyses, one pilot study, and 14 review articles. Most RCTs showed no significant improvement in vitamin D supplementation except for one study, which reported significant improvement in cognition on taking vitamin D in Alzheimer's disease but was not taken much into consideration as it had a small sample size (n=210) and was for a shorter duration. Another study evidenced significant improvement in Mini-Mental State Examination (MMSE) score when memantine and vitamin D were taken together compared to when memantine and vitamin D were taken independently.Studies have shown that vitamin D deficiency is associated with an increased risk of developing cognitive impairment. But there is no sufficient evidence indicating vitamin D supplementation can improve cognitive function in Alzheimer's disease.

Integrative cross-species analysis of GABAergic neuron cell types and their functions in Alzheimer’s disease

Understanding the phenotypic and functional diversity of cerebral cortical GABAergic neurons requires a comprehensive analysis of key transcriptional signatures and neuronal subtype identity. However, the diversity and conservation of GABAergic neurons across multiple mammals remain unclear. Here, we collected the single-nucleus RNA sequencing (snRNA-seq) datasets of cerebral cortex from human, macaque, mouse, and pig to identify the conserved neuronal cell types across species. After systematic analysis of the heterogeneity of GABAergic neurons, we defined four major conserved GABAergic neuron subclasses (Inc SST, Inc LAMP5, Inc PVALB, and Inc VIP) across species. We characterized the species-enriched subclasses of GABAergic neurons from four mammals, such as Inc Meis2 in mouse. Then, we depicted the genetic regulatory network (GRNs) of GABAergic neuron subclasses, which showed the conserved and species-specific GRNs for GABAergic neuron cell types. Finally, we investigated the GABAergic neuron subclass-specific expression modules of Alzheimer’s disease (AD)-related genes in GABAergic neuron cell types. Overall, our study reveals the conserved and divergent GABAergic neuron subclasses and GRNs across multiple species and unravels the gene expression modules of AD-risk genes in GABAergic neuron subclasses, facilitating the GABAergic neurons research and clinical treatment.

The impacts of curcumin on learning memory function in Alzheimer’s disease under the poly lactic-co-glycolic acid nanoparticle drug carrier

The impacts of curcumin on learning memory function in Alzheimer’s disease under the poly lactic-co-glycolic acid nanoparticle drug carrier

Brain state transition analysis using ultra-fast fMRI differentiates MCI from cognitively normal controls.

PurposeConventional resting-state fMRI studies indicate that many cortical and subcortical regions have altered function in Alzheimer’s disease (AD) but the nature of this alteration has remained unclear. Ultrafast fMRIs with sub-second acquisition times have the potential to improve signal contrast and enable advanced analyses to understand temporal interactions between brain regions as opposed to spatial interactions. In this work, we leverage such fast fMRI acquisitions from Alzheimer’s disease Neuroimaging Initiative to understand temporal differences in the interactions between resting-state networks in 55 older adults with mild cognitive impairment (MCI) and 50 cognitively normal healthy controls.MethodsWe used a sliding window approach followed by k-means clustering. At each window, we computed connectivity i.e., correlations within and across the regions of the default mode, salience, dorsal attention, and frontoparietal network. Visual and somatosensory networks were excluded due to their lack of association with AD. Using the Davies–Bouldin index, we identified clusters of windows with distinct connectivity patterns, also referred to as brain states. The fMRI time courses were converted into time courses depicting brain state transition. From these state time course, we calculated the dwell time for each state i.e., how long a participant spent in each state. We determined how likely a participant transitioned between brain states. Both metrics were compared between MCI participants and controls using a false discovery rate correction of multiple comparisons at a threshold of. 0.05.ResultsWe identified 8 distinct brain states representing connectivity within and between the resting state networks. We identified three transitions that were different between controls and MCI, all involving transitions in connectivity between frontoparietal, dorsal attention, and default mode networks (p<0.04).ConclusionWe show that ultra-fast fMRI paired with dynamic functional connectivity analysis allows us to capture temporal transitions between brain states. Most changes were associated with transitions between the frontoparietal and dorsal attention networks connectivity and their interaction with the default mode network. Although future work needs to validate these findings, the brain networks identified in our work are known to interact with each other and play an important role in cognitive function and memory impairment in AD.

Pharmaceutical Potential of Casein-Derived Tripeptide Met-Lys-Pro: Improvement in Cognitive Impairments and Suppression of Inflammation in APP/PS1 Mice.

Background:Tripeptide Met-Lys-Pro (MKP), a component of casein hydrolysates, has effective angiotensin-converting enzyme (ACE) inhibitory activity. Brain angiotensin II enzyme activates the NADPH oxidase complex via angiotensin II receptor type 1 (AT1) and enhances oxidative stress injury. ACE inhibitors improved cognitive function in Alzheimer’s disease (AD) mouse models and previous clinical trials. Thus, although undetermined, MKP may be effective against pathological amyloid-β (Aβ) accumulation-induced cognitive impairment.Objective:The current study aimed to investigate the potential of MKP as a pharmaceutical against AD by examining MKP’s effect on cognitive function and molecular changes in the brain using double transgenic (APP/PS1) mice.Methods:Experimental procedures were conducted in APP/PS1 mice (n = 38) with a C57BL/6 background. A novel object recognition test was used to evaluate recognition memory. ELISA was used to measure insoluble Aβ40, Aβ42, and TNF-α levels in brain tissue. Immunohistochemical analysis allowed the assessment of glial cell activation in MKP-treated APP/PS1 mice.Results:The novel object recognition test revealed that MKP-treated APP/PS1 mice showed significant improvement in recognition memory. ELISA of brain tissue showed that MKP significantly reduced insoluble Aβ40, Aβ42, and TNF-α levels. Immunohistochemical analysis indicated the suppression of the marker for microglia and reactive astrocytes in MKP-treated APP/PS1 mice.Conclusion:Based on these results, we consider that MKP could ameliorate pathological Aβ accumulation-induced cognitive impairment in APP/PS1 mice. Furthermore, our findings suggest that MKP potentially contributes to preventing cognitive decline in AD.

Cumulative effect of simvastatin, l-arginine, and tetrahydrobiopterin on cerebral blood flow and cognitive function in Alzheimer’s disease

Background and objectivesVascular disease is a known risk factor for Alzheimer’s disease (AD). Endothelial dysfunction has been linked to reduced cerebral blood flow. Endothelial nitric oxide synthase pathway (eNOS) upregulation is known to support endothelial health. This single-center, proof-of-concept study tested whether the use of three medications known to augment the eNOS pathway activity improves cognition and cerebral blood flow (CBF).MethodsSubjects with mild AD or mild cognitive impairment (MCI) were sequentially treated with the HMG-CoA reductase synthesis inhibitor simvastatin (weeks 0–16), l-arginine (weeks 4–16), and tetrahydrobiopterin (weeks 8–16). The primary outcome of interest was the change in CBF as measured by MRI from baseline to week 16. Secondary outcomes included standard assessments of cognition.ResultsA total of 11 subjects were deemed eligible and enrolled. One subject withdrew from the study after enrollment, leaving 10 subjects for data analysis. There was a significant increase in CBF from baseline to week 8 by ~13% in the limbic and ~15% in the cerebral cortex. Secondary outcomes indicated a modest but significant increase in the MMSE from baseline (24.2±3.2) to week 16 (26.0±2.7). Exploratory analysis indicated that subjects with cognitive improvement (reduction of the ADAS-cog 13) had a significant increase in their respective limbic and cortical CBF.ConclusionsTreatment of mild AD/MCI subjects with medications shown to augment the eNOS pathway was well tolerated and associated with modestly increased cerebral blood flow and cognitive improvement.Trial registrationThis study is registered in https://www.clinicaltrials.gov; registration identifier: NCT01439555; date of registration submitted to registry: 09/23/2011; date of first subject enrollment: 11/2011.

The therapeutic potential of TREM2 in cancer

Cancer continues to be a substantial health concern and a leading cause of death in the United States and around the world. Therefore, it is important to continue to explore the potential of novel therapeutic targets and combinatorial therapies. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily that associates with DNAX activation protein (DAP) 12 and DAP10 to propagate signals within the cell. TREM2 has primarily been recognized for its expression on cells in the monocyte-macrophage lineage, with the majority of work focusing on microglial function in Alzheimer’s Disease. However, expansion of TREM2 research into the field of cancer has revealed that epithelial tumor cells as well as intratumoral macrophages and myeloid regulatory cells also express TREM2. In this review, we discuss evidence that TREM2 contributes to tumor suppressing or oncogenic activity when expressed by epithelial tumor cells. In addition, we discuss the immunosuppressive role of TREM2-expressing intratumoral macrophages, and the therapeutic potential of targeting TREM2 in combination with immune checkpoint therapy. Overall, the literature reveals TREM2 could be considered a novel therapeutic target for certain types of cancer.

Kinetics and computational study of butyrylcholinesterase inhibition by methylrosmarinate: relevance to Alzheimer’s disease treatment

Butyrylcholinesterase (BChE) performs a significant function in Alzheimer’s disease progression. Experimental studies have shown that the function of BChE in the attenuation of cholinergic neurotransmission is essentially altered in brains of advanced AD patients. Here, using the complimentary methods of enzyme kinetic studies, molecular modeling and protein-ligand interaction profiling, we sought to reveal the mechanistic and structural features of BChE-methyrosmarinate interactions. Molecular docking simulations revealed that methylrosmarinate dwelled well in the active centre of BChE, where it got involved in stabilizing non-covalent associations with myriad subsites. Enzyme kinetic experiments showed that the Vm and Ks values were 156.20 ± 3.11 U mg−1 protein and 0.13 ± 0.01 μM, respectively. The inhibition studies showed that methylrosmarinate apparently inhibited BChE in a linear mixed manner, with an IC50 value of 10.31 μM and a Ki value of 3.73 ± 1.52 μM. Taken together, the extremely reduced Ki value and the increased number of BChE–methylrosmarinate interactions presuppose that methylrosmarinate is a good inhibitor of BChE, despite the fact that the mechanism for the effect of BChE inhibition on several pathological conditions in vivo remains unexplored.

Association of Enlarged Perivascular Spaces With Amyloid Burden and Cognitive Decline in Alzheimer Disease Continuum.

To investigate the effects of enlarged perivascular space (EPVS) on amyloid burden and cognitive function in Alzheimer disease (AD) continuum. We retrospectively reviewed 208 patients with AD across the cognitive continuum (preclinical, prodromal, and AD dementia) who showed amyloid deposition on 18F-florbetaben PET scans and 82 healthy controls. EPVSs were counted for each patient in the basal ganglia (BG), centrum semiovale (CSO), and hippocampus (HP) on axial T2-weighted images. Patients were then classified according to the number of EPVSs into the EPVS+ (>10 EPVSs) and EPVS- (0-10 EPVSs) groups for the BG and CSO, respectively. In terms of HP-EPVS, equal or more than 7 EPVSs on bilateral hemisphere were regarded as the presence of HP-EPVS. After adjusting for markers of small vessel disease (SVD), multiple linear regression analyses were performed to determine the intergroup differences in global and regional amyloid deposition and cognitive function at the time of diagnosis of AD continuum. A linear mixed model was used to assess the effects of EPVSs on the longitudinal changes in the Mini-Mental State Examination (MMSE) scores. Amyloid burden at the time of diagnosis of AD continuum was not associated with the degree of BG-, CSO-, or HP-EPVS. BG-EPVS affected language and frontal/executive function via SVD markers, and HP-EPVS was associated with general cognition via SVD markers. However, CSO-EPVS was not associated with baseline cognition. A higher number of CSO-EPVS was significantly associated with a more rapid decline in MMSE scores (β = -0.58, standard error = 0.23, p = 0.011) independent of the amyloid burden. In terms of BG and HP, there was no difference between the EPVS+ and EPVS- groups in the rate of longitudinal decreases in MMSE scores. Our findings suggest that BG-, CSO-, and HP-EPVS are not associated with baseline β-amyloid burden or cognitive function independently of SVD at the diagnosis of AD continuum. However, CSO-EPVS appears to be associated with the progression of cognitive decline in an amyloid-independent manner. Further studies are needed to investigate whether CSO-EPVS is a potential therapeutic target in patients with AD continuum.

Synaptosome microRNAs regulate synapse functions in Alzheimer’s disease

MicroRNAs (miRNAs) are found in nerve terminals, synaptic vesicles, and synaptosomes, but it is unclear whether synaptic and cytosolic miRNA populations differ in Alzheimer’s disease (AD) or if synaptosomal miRNAs affect AD synapse activity. To address these questions, we generated synaptosomes and cytosolic fractions from postmortem brains of AD and unaffected control (UC) samples and analyzed them using a global Affymetrix miRNAs microarray platform. A group of miRNAs significantly differed (P < 0.0001) with high fold changes variance (+/− >200-fold) in their expressions in different comparisons: (1) UC synaptosome vs UC cytosol, (2) AD synaptosomes vs AD cytosol, (3) AD cytosol vs UC cytosol, and (4) AD synaptosomes vs UC synaptosomes. MiRNAs data analysis revealed that some potential miRNAs were consistently different across sample groups. These differentially expressed miRNAs were further validated using AD postmortem brains, brains of APP transgenic (Tg2576), Tau transgenic (P301L), and wild-type mice. The miR-501-3p, miR-502-3p, and miR-877-5p were identified as potential synaptosomal miRNAs upregulated with disease progression based on AD Braak stages. Gene Ontology Enrichment and Ingenuity Pathway Analysis of synaptosomal miRNAs showed the involvement of miRNAs in nervous system development, cell junction organization, synapse assembly formation, and function of GABAergic synapse. This is the first description of synaptic versus cytosolic miRNAs in AD and their significance in synapse function.