Stages Of AD Research Articles

The significance of the Calbindin‐D in Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease is a heterogeneous, progressive, and devastating neurodegenerative disease. In addition to the accumulation of Aβ and tau, neuropathological processes in the early stage of AD are accompanied by calcium dysregulation, which might cause the loss of synapses and then dysfunctions of the neural network. Calbindin‐D is abundant throughout the central nervous system (CNS) and one of the neuronal protective factors, also involved in calcium homeostasis. It has been reported that the depletion of Calbindin‐D in AD transgenic mice brain elicited significant alterations in apoptosis, synaptic transmission, and cytoskeleton organization. Despite of the reduced Calbindin expression in the brains of mice and patients with AD, still the role of this protein in AD‐related dysfunction is tested. To obtain better insights into the pathological significance of the protein we assesed the concentarion of Calbindin‐D in cerebrospinal fluid of patients with AD and non‐demented controls.MethodThe study group included 34 subjects: patients with AD and controls without cognitive impairments. The cerebrospinal fluid (CSF) concentrations of tested proteins were measured with the use of multiplexing technique.ResultThe CSF concentrations of Calbindin‐D were elevated in AD patients in comparison to non‐demented controls. Additionally, the CSF levels of Calbindin‐D positively correlated with tau as well as phTau181, and negatively with MMSE in the whole study group.ConclusionOur preliminary study indicates a potential role of Calbindin‐D in the development of AD, although the question, whether this protein can be useful in clinical practice of dementia requires further examination.

Longitudinal characterization of white matter degeneration in early stages of AD

AbstractBackgroundWhite matter (WM) degeneration in older adults is often characterized unimodally by diffusion tensor imaging (DTI), T1w and T2‐FLAIR MRI. However, approaches integrating multimodal MRI information will be necessary for better understanding WM degeneration in early stages of AD.MethodThis study characterizes the longitudinal changes of WM structure among 66 participants with marked baseline white matter hyperintensity volume (WMHv > 2000 mm3). 42 cognitively normal [CN, 72±7.2y, F = 25] and 24 mild cognitive impairment [MCI, 74±5.7y, F = 14]) adults underwent longitudinal MRI (scan interval: 2.8±0.85 years) within the Wake Forest AD Research Center. DTI metrics were estimated using FMRIB’s Diffusion Toolbox, voxel‐wise volumetric changes of WM (Jacobian Determinant [JD]) were estimated from fractional anisotropy (FA) maps using SPM CAT12, and WMHv were quantified using SPM’s Lesion Segmentation Toolbox. We segmented WM into WMH and normal‐appearing WM (NAWM) to characterize different degeneration patterns by integrating multimodal MRI information. We performed a linear regression analysis of %WMHv change with cognitive status, scan interval, and baseline WMH volume as covariates.ResultDecreased FA and increased mean diffusivity (MD) were observed in WMH regions compared with NAWM. Within WMH, interestingly, volume and FA increased, while MD decreased (p <0.001) during the longitudinal follow‐up (Figs. 1 and 2). Baseline WMHv was not significantly associated with cognitive status, but trended toward higher WMHv in MCI compared to CN (p = 0.07). Adjusted for baseline WMHv, cognitive status was associated with WMHv change (p = 0.036, MCI faster than CN, Fig. 3). While FA (p = 0.99) and MD (p = 0.16) did not change in the NAWM, volumetric change rate (JD) indicated volumetric contraction (p<0.001, Figs. 4 and 5). WMH progresses with time in older adults at risk of AD dementia by occupying neighboring NAWM regions, resulting in relative increases in FA and decreases in MD.ConclusionIn NAWM, WM degeneration can be better characterized by volumetric contraction than white matter microstructural integrity. This observation could implicate that secondary or peripheral WM fibers may reveal more vulnerable tracts in early stages of AD. Further investigation incorporating imaging makers of blood perfusion and metabolism could better explain structural mechanisms of WM degeneration.

0885 Alzheimer’s disease progression risk in Cognitive Normal Older Adults with Obstructive Sleep Apnea using NIA-AA Research Framework

Abstract Introduction We determined risk profiles of strata-specific cognitive-normal (NL) older-adults with obstructive sleep apnea (OSA) characterized by their Aβ, P-Tau & T-tau (ATN) burden, on prospective AD stage-transition Methods Longitudinal study utilizing data from 167 community-dwelling NL older-adults participating in NYU studies on memory, sleep and aging. Subjects had baseline CSF AD-biomarker data and at least two follow-up clinical and neuropsychological data. OSA was defined using AHI4%. Using the NIA-AA Research Framework, data-driven, clinically relevant thresholds for CSF-Aβ42 (≤375pg/ml), P-tau (≥53.7pg/ml) and T-tau (≥367 pg/ml) indicated ATN status respectively. Twenty-four participants with suspected non-AD pathologic change defined as A-T+ were excluded leaving 143 for the analysis. Main outcome was AD stage-transition (i.e., change from Global Deterioration Scale (GDS) 1 or 2 [NL] at baseline to ≥3 [≥ MCI] during follow-up). Logistic mixed-effects models with random intercept and slope were used to assess associations between ATN characterized OSA subjects, and longitudinal AD stage transition, controlling for age-at-baseline, sex, APOE4-status, years-of-education, and their interactions with time. Results Of the 143 participants, 91 (63.8%) were women. The mean (SD) age was 69.6 (7.3) years and follow-up time was 4.73 (3.45) years. Sixteen (11.2%) were OSA+/A+/TN-, and 21 (14.7%) were OSA-/A+/TN-. Ninety-two (64.3%) had normal AD biomarkers (OSA+/A-/T- [n=45] and OSA-/A-/T- [N=47]). To generate strata-specific risks, subjects were combined into groups: (i) OSA subjects with AD pathologic change OSA+/A+/TN [n=25] consisting of OSA+/A+/TN+ [n=9] plus OSA+/A+/TN- [n=16] (ii) non-OSA subjects with AD pathologic change OSA-/A+/TN [n=26]) consisting of OSA-/A+/TN+ [n=5] and OSA-/A+/TN- [n=21] Fourteen subjects (9.8%) transitioned from NL to MCI (i.e., OSA+/A+/TN [6/25], OSA-/A+/TN [3/26], OSA+/A-/TN- [4/45] and OSA-/A-/TN- [3/47]). OSA+/A+/TN subjects were at higher risk of AD stage-transition relative to OSA-/A-/TN- (β = 1.31, 95%CI, 1.02, 1.62); OSA+/A-/TN- (β = 0.89, 95%CI, 0.42, 1.37); and OSA-/A+/TN subjects, (β = 0.71, 95%CI, 0.38, 1.04); P < .01 for all. OSA+/A-/T- vs. OSA-/A-/T- participants did not show differences in cognitive change over time (β = 0.22, 95%CI, -0.15, 0.39, P =.17). Conclusion Among ATN characterized NL older-adults with OSA, those with evidence of AD pathologic change have the greatest risk of developing AD. Support (if any) AASMBTS#231-BS-20, NIAK23AG068534A, AARG-D- 21-848397, BFFA2022033S

Cyclosporine A (CsA) prevents synaptic impairment caused by truncated tau by caspase-3

During Alzheimer's (AD), tau protein suffers from abnormal post-translational modifications, including cleaving by caspase-3. These tau forms affect synaptic plasticity contributing to the cognitive decline observed in the early stages of AD. In addition, caspase-3 cleaved tau (TauC3) impairs mitochondrial dynamics and organelles transport, which are both relevant processes for synapse. We recently showed that the absence of tau expression reverts age-associated cognitive and mitochondrial failure by blocking the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial complex involved in calcium regulation and apoptosis. Therefore, we studied the effects of TauC3 against the dendritic spine and synaptic vesicle formation and the possible role of mPTP in these alterations. We used mature hippocampal mice neurons to express a reporter protein (GFP, mCherry), coupled to full-length human tau protein (GFP-T4, mCherry-T4), and coupled to human tau protein cleaved at D421 by caspase-3 (GFP-T4C3, mCherry-T4C3) and synaptic elements were evaluated.Treatment with cyclosporine A (CsA), an immunosuppressive drug with inhibitory activity on mPTP, prevented ROS increase and mitochondrial depolarization induced by TauC3 in hippocampal neurons. These results were corroborated with immortalized cortical neurons in which ROS increase and ATP loss induced by this tau form were prevented by CsA. Interestingly, TauC3 expression significantly reduced dendritic spine density (filopodia type) and synaptic vesicle number in hippocampal neurons. Also, neurons transfected with TauC3 showed a significant accumulation of synaptophysin protein in their soma. More importantly, all these synaptic alterations were prevented by CsA, suggesting an mPTP role in these negative changes derived from TauC3 expression.

Tau seeds occur before earliest Alzheimer’s changes and are prevalent across neurodegenerative diseases

Tau neurofibrillary tangles are a hallmark of Alzheimer’s disease neuropathological change. However, it remains largely unclear how distinctive Alzheimer’s disease tau seeds (i.e. 3R/4R) correlate with histological indicators of tau accumulation. Furthermore, AD tau co-pathology is thought to influence features and progression of other neurodegenerative diseases including Lewy body disease; yet measurements of different types of tau seeds in the setting of such diseases is an unmet need. Here, we use tau real-time quaking-induced conversion (RT-QuIC) assays to selectively quantitate 3R/4R tau seeds in the frontal lobe which accumulates histologically identifiable tau pathology at late disease stages of AD neuropathologic change. Seed quantitation across a spectrum of neurodegenerative disease cases and controls indicated tau seeding activity can be detected well before accompanying histopathological indication of tau deposits, and even prior to the earliest evidence of Alzheimer’s-related tau accumulation anywhere in the brain. In later stages of AD, 3R/4R tau RT-QuIC measures correlated with immunohistochemical tau burden. In addition, Alzheimer’s tau seeds occur in the vast majority of cases evaluated here inclusive of primary synucleinopathies, frontotemporal lobar degeneration and even controls albeit at multi-log lower levels than Alzheimer’s cases. α-synuclein seeding activity confirmed synucleinopathy cases and further indicated the co-occurrence of α-synuclein seeds in some Alzheimer’s disease and primary tauopathy cases. Our analysis indicates that 3R/4R tau seeds in the mid-frontal lobe correlate with the overall Braak stage and Alzheimer’s disease neuropathologic change, supporting the quantitative predictive value of tau RT-QuIC assays. Our data also indicate 3R/4R tau seeds are elevated in females compared to males at high (≥ IV) Braak stages. This study suggests 3R/4R tau seeds are widespread even prior to the earliest stages of Alzheimer’s disease changes, including in normal, and even young individuals, with prevalence across multiple neurodegenerative diseases to further define disease subtypes.

Development of the "hidden" multi-target-directed ligands by AChE/BuChE for the treatment of Alzheimer's disease.

Accumulation of evidences suggested that excessive amounts of AChE and BuChE in the brain of AD patients at the different stage of AD, which could hydrolyze ACh and accelerated Aβ aggregation. To develop new "hidden" multifunctional agents through AChE/BuChE would be a promising strategy to treat AD. To this end, firstly, a series of chalcone derivatives with chelating property was designed and synthesized. The in vitro results showed that compound 3f indicated significant selective MAO-B inhibitory activity (IC50=0.67μM) and remarkable anti-inflammatory property. It also significantly inhibited self-induced Aβ1-42 aggregation and showed remarkable neuroprotective effects on Aβ25-35-induced PC12cell injury. Furthermore, compound 3f was a selective metal chelator and could inhibit Cu2+-induced Aβ1-42 aggregation. Based on this, the carbamate fragment was introduced to compound 3f to obtain carbamate derivatives. The biological activity results exhibited that compound 4b showed good BBB permeability, good AChE inhibitory potency (IC50=5.3μM), moderate BuChE inhibitory potency (IC50=12.4μM), significant MAO-B inhibitory potency, anti-inflammation potency on LPS-induced BV-2cells and neuroprotective effects on Aβ25-35-induced PC12cell injury. Compared with 3f, compound 4b did not show obvious chelation property. Significantly, compound 4b could be activated by AChE/BuChE following inhibition of AChE/BuChE to liberate an active multifunctional chelator 3f, which was consistent with our original intention. More importantly, compounds 3f and 4b presented favorable ADME properties and good stability in artificial gastrointestinal fluid, blood plasma and rat liver microsomes. The in vivo results suggested that compound 4b (0.0195μg/mL) could significantly improve dyskinesia and reaction capacity of the AlCl3-induced zebrafish AD model by increasing the level of ACh. Together our data suggest that compound 4b was a promising "hidden" multifunctional agent by AChE/BuChE, and this strategy deserved further development for the treatment of AD.

Alzheimers Disease Mechanism in Neuroimmunology Perspective

Among the several neurodegenerative illnesses, one of these is the illness Alzheimer's (AD). it is hard to cure completely for now. To find fresh targets for the therapy of AD, neuroimmunology have been getting attention gradually. Neuroimmunology response, which happened in the central nervous system (CNS), is innate immune response of human. In the AD, microglia activated by damage signals lead to a series of cellular cascade responses. Then, a large number of chemokines and inflammatory cytokines are released by microglial cells. The cytokines have neurotoxic effects on the certain brain areas, causing neuronal degeneration. Since microglia can be activated by tau aggregation in addition to alarm signals, with tau protein aggregation releasing from the degenerative neurons, it provokes a positive feedback mechanism of neuroimmunology in hippocampal area. Microglia mainly play a role of neuroprotective by clearing -amyloid (A) on early stage of AD and have a neurotoxic effects induced by an A-induced phenotypic change on late stage of AD. TREM2 mainly expressed on microglia, it may downregulate the inflammatory response in AD. The review has explained clearly and demonstrated that tau assembly and clearance of A are effective therapeutic targets on AD. In addition, it explained AD nosogenesis from the new view of TREM2 mutations.

Anti-oxidative-initiated cognitive impairment amelioration in Alzheimer's disease model rats through preventive transcutaneous electrical acupoint stimulation

BackgroundAlzheimer's disease (AD) is a chronic and irreversible neurodegenerative disease. Oxidative stress emerges at the early AD stage. As a non-invasive therapy with few adverse reactions, transcutaneous electrical acupoint stimulation (TEAS) combines acupuncture points of traditional Chinese medicine (TCM) and electrical stimulation. This study aimed to investigate the amelioration effects of preventive TEAS treatment (P-TEAS) on cognitive impairment and oxidative stress in AD model rats. MethodsThe AD model was established via subcutaneous injections of D-galactose (D-gal, 120 mg/kg/d) into the back of neck for 9 weeks in Sprague Dawley (SD) rats to simulate the oxidative stress in the early AD stage. On the first day of the 10th week, Aβ1–42 (1 μg/μl) was injected into the CA1 regions of the bilateral hippocampus. P-TEAS was synchronized from the first day of subcutaneous D-gal injections for 9 weeks. ResultsEmpirical measurements showed that P-TEAS can improve the spatial memory ability of AD model rats in the Morris water maze. Superoxide dismutase (SOD) was upregulated in the P-TEAS group. Through the detection of the anti-oxidative stress signaling pathway, namely, Kelch-like ECH-associated protein 1 (Keap1)/ NFE2-related factor 2 (Nrf2), it was found that P-TEAS could promote Nrf2 entering into the nucleus and upregulating the production of protective factors heme oxygenase 1 (HO-1) and NADPH quinone oxidoreductase 1 (NQO1). It was also found that P-TEAS could downregulate the expressions of BCL2-associated X-protein (Bax), caspase 3, and caspase 9 to inhibit neuronal apoptosis. ConclusionsP-TEAS has similar efficacy to electroacupuncture in preventing AD occurrence and development. P-TEAS is a new non-invasive intervention therapy for the prevention of AD.

Interaction between aluminum exposure and ApoEε4 gene on cognitive function of in-service workers.

The occurrence and development of cognitive impairment, the early stage of AD, may be affected both by factors of environmental (aluminum exposure) and genetic (ApoEε4 gene). But whether there is an interaction between the two factors on cognitive function is still unknown. To explore the interaction between the two factors on cognitive function of in-service workers. A total of 1121 in-service workers in a large aluminum factory were investigated in Shanxi Province. Cognitive function was assessed by the Mini-mental State Examination (MMSE), the clock-drawing test (CDT), the Digit Span Test (DST, including DSFT and DSBT), the fuld object memory evaluation (FOM), and the verbal fluency task (VFT). The plasma-Al (p-Al) concentrations were measured by inductively coupled plasma-mass spectrometry (ICP-MS) as an internal exposure indicator, and the participants were divided into four Al exposure groups according to the quartile of p-Al concentrations, namely Q1, Q2, Q3, and Q4. ApoE genotype was determined by Ligase Detection Reaction (LDR). The multiplicative model was fitted using non-conditional logistic regression and additive model was fitted using crossover analysis to analyze the interaction between p-Al concentrations and the ApoEε4 gene. Finally, a dose-response relationship between p-Al concentrations and cognitive impairment was observed, with the p-Al concentrations increased, cognitive function performance gradually becomes worse (Ptrend＜0.05), and the risk of cognitive impairment gradually increases (Ptrend＜0.05), mainly in executive/visuospatial impairment, auditory memory impairment (particularly the working memory impairment). And ApoEε4 gene may be a risk factor for cognitive impairment, while no association between the ApoEε2 gene and cognitive impairment is observed. Additionally, an additive but no multiplicative interaction between p-Al concentrations and ApoEε4 gene is observed, and when the two factors work together, the risk of cognitive impairment further increased, of which 44.2% can be attributed to the interaction effect.

M-Net: An encoder-decoder architecture for medical image analysis using ensemble learning

Only a few of the many subfields of biomedical science study include biomedical engineering, biomedical signal processing, gene analysis, and biomedical image processing. For the investigation and diagnosis of diseases, classification, detection, and recognition have tremendous importance. This work presents a fully automated deep-ensemble architecture, M-Net, for pixel-level semantic segmentation and classification of medical images. The performance of M-Net is evaluated by implementing it on the brain structural Magnetic Resonance Imaging (sMRI) for diagnosing Alzheimer's disease from various sources of datasets. The M-Net system successfully segmented the hippocampus region, vulnerable to damage at the early stage of AD, from the brain sMRI data. The obtained overall accuracy of 99% shows that the proposed deep learning technique is superior to the existing deep semantic segmentation techniques and can reduce the diagnostic time of radiologists.

A Novel Framework for Classification of Different Alzheimer’s Disease Stages Using CNN Model

Background: Alzheimer’s, the predominant formof dementia, is a neurodegenerative brain disorder with no known cure. With the lack of innovative findings to diagnose and treat Alzheimer’s, the number of middle-aged people with dementia is estimated to hike nearly to 13 million by the end of 2050. The estimated cost of Alzheimer’s and other related ailments is USD321 billion in 2022 and can rise above USD1 trillion by the end of 2050. Therefore, the early prediction of such diseases using computer-aided systems is a topic of considerable interest and substantial study among scholars. The major objective is to develop a comprehensive framework for the earliest onset and categorization of different phases of Alzheimer’s. Methods: Experimental work of this novel approach is performed by implementing neural networks (CNN) on MRI image datasets. Five classes of Alzheimer’s disease subjects are multi-classified. We used the transfer learning determinant to reap the benefits of pre-trained health data classification models such as the MobileNet. Results: For the evaluation and comparison of the proposed model, various performance metrics are used. The test results reveal that the CNN architectures method has the following characteristics: appropriate simple structures that mitigate computational burden, memory usage, and overfitting, as well as offering maintainable time. The MobileNet pre-trained model has been fine-tuned and has achieved 96.6 percent accuracy for multi-class AD stage classifications. Other models, such as VGG16 and ResNet50 models, are applied tothe same dataset whileconducting this research, and it is revealed that this model yields better results than other models. Conclusion: The study develops a novel framework for the identification of different AD stages. The main advantage of this novel approach is the creation of lightweight neural networks. MobileNet model is mostly used for mobile applications and was rarely used for medical image analysis; hence, we implemented this model for disease detection andyieldedbetter results than existing models.

Melanocortin receptor agonist NDP-α-MSH improves cognitive deficits and microgliosis but not amyloidosis in advanced stages of AD progression in 5XFAD and 3xTg mice.

Alzheimer's disease (AD) is the most frequent cause of dementia and still lacks effective therapy. Clinical signs of AD include low levels of endogenous melanocortins (MCs) and previous studies have shown that treatment with MC analogs induces neuroprotection in the early stages of AD. We investigated the neuroprotective role of MCs in two transgenic mouse models of severe AD using 5 and 7 month-old (mo) 5XFAD mice and 9 and 12 mo 3xTg mice. These mice were subjected to a chronic stimulation of MC receptors (MCRs) with MC analogue Nle4-D-Phe7-α-melanocyte stimulating hormone (NDP-α-MSH, 340 μg/kg, i.p.). Mouse behavior and ex-vivo histological and biochemical analyses were performed after 50 days of treatment. Our analysis demonstrated an improvement in cognitive abilities of AD mice at late stage of AD progression. We also showed that these protective effects are associated with decreased levels of hyperphosphorylated Tau but not with Aβ burden, that was unaffected in the hippocampus and in the cortex of AD mice. In addition, an age-dependent NDP effect on glial reactivity was observed only in 3xTg mice whereas a global downregulation of p38 mitogen-activated protein kinase was selectively observed in 7 mo 5XFAD and 14 mo 3xTg mice. Our results suggest that MCR stimulation by NDP-α-MSH could represent a promising therapeutic strategy in managing cognitive decline also at late stage of AD, whereas the effects on neuroinflammation may be restricted to specific stages of AD progression.

Validation of the cross-cultural dementia screening test in Alzheimer's disease and Parkinson's disease.

The Cross-Cultural Dementia (CCD) is a new screening tool to evaluate cognitive impairment based on a cross-cultural perspective to reduce the bias of education, and language and cultural differences. We aimed to evaluate the diagnostic properties of the CCD in Spaniards for the assessment of patients with Alzheimer's disease in mild cognitive impairment (AD-MCI) and mild dementia stages (AD-D) and patients with mild cognitive impairment associated with Parkinson's disease (PD-MCI). Sixty participants with AD (50% MCI) and thirty with PD-MCI were enrolled. Each clinical group was compared against a healthy control group (HC) with the same number of participants and no significant differences in age, education, and sex. A comprehensive neuropsychological test battery and CCD were completed. Intergroup comparisons, ROC curves, and cut-off scores were calculated for the study of diagnostic properties. Intergroup differences were found in accordance with the cognitive profile of each clinical condition. Memory measures (Objects test) were especially relevant for the classification between AD and HC. Memory and executive function scores (Sun-Moon and Dots tests) were useful in the case of PD-MCI and HC. Furthermore, CCD described differences in executive functions and speed scores comparing AD-MCI and PD-MCI. Correlations between standardized neuropsychological tests and CCD measures supported the convergent validity of the test. CCD showed good discrimination properties and cut-off scores for dementia and extended its application to a sample of prodromal stages of AD and PD with mild cognitive impairment.

Učestalost Helicobacter pylori infekcije i antibiotska rezistencija kod bolesnika sa akutnim dekompenzacijama jetre

Introduction: Helicobacter pylori (H. pylori) infection is a global healthcare challenge. In its course of infection, Helicobacter pylori infection leads to a systemic increase of post-inflammatory cytokines and can have extra gastric manifestations, affecting the worsening of metabolic and cardiovascular diseases and endangering normal liver function, especially when liver cirrhosis is present. Aim: The aim of this study was to examine the frequency of H. pylori infection in patients with cirrhosis of the liver in stage AD or ACLF. The frequency of antibiotic resistance to clarithromycin and fluoroquinolones was also investigated. Material and methods: A prospective study with 45 patients was conducted which included both sexes. Samples of gastric mucosa were taken from all patients included in the study during the upper endoscopy and were sent to the Institute of Microbiology of the Faculty of Medicine University of Belgrade. A molecular method, Polymerase chain reaction (PCR) was used to detect H. pylori and mutations responsible for resistance to clarithromycin and fluoroquinolones. Results: The presence of H. pylori infection was registered in 15 decompensated patients (33.33%), while 30 (66.67%) were negative. In H. pylori positive patients, PCR detection of genotypes responsible for antibiotic resistance revealed clarithromycin resistance in 11 patients (73.33%), while fluoroquinolone resistance was detected in 7 patients (46.66%). In 6 patients (40.0%), an associated resistance to clarithromycin and fluoroquinolones was found. Conclusion: The H. pylori infection in cirrhotic patients with acute decompensation or ACLF has no significant effect on the severity of the clinical condition, elevated laboratory parameters and survival. Resistance rates to fluoroquinolones and clarithromycin or both antibiotics are high in decompensated patients with cirrhosis. There is a need to increase awareness of the rational use of antibiotics based on further investigations.

A Cognitive Reserve Network That Moderates the Relationship Between Alzheimer’s Disease Pathology and Cognition

AbstractBackgroundThe new consensus definition of cognitive reserve (CR) provides a framework to study individual differences in cognitive functioning relative to aging and disease. CR denotes a property of the brain that allows for better than expected cognitive performance given the degree of age‐related brain changes or disease. More specifically, individual differences in patterns of brain activity during fMRI tasks might explain the differential susceptibility to pathological burden.MethodAccording to the consensus definitions, we sought to identify and quantify CR from fMRI novelty‐contrast maps in a large multi‐centric sample (DELCODE) consisting of 215 participants with SCD, 79 with MCI, 30 with AD dementia, 56 AD relatives and 156 cognitively normal controls (CN). CSF amyloid‐42/40 ratio, CSF p‐tau and hippocampal volume (ATN) were reduced to a single number, representing a (Alzheimer’s) disease progression (DP) score. To identify a CR network, voxel‐wise linear regression models determined where functional task‐activation moderates the relationship between DP and cognition. Finally, task‐related activity within the CR network was extracted to obtain individual fMRI‐based CR scores.ResultThe DP score showed a strong negative quadratic association with baseline memory scores. CR voxels, in which higher or lower activation were associated with better cognition, weakening the effect of DP, were mainly located within the novelty network. They included lateral‐occipital and superior‐parietal regions, lingual and fusiform gyrus, cuneus and small parts of cingulate. While there was no association between the CR score and cognition in CNs, higher CR scores in MCI and AD patients were related to higher PACC5 scores.ConclusionWe established a DP score that collapses the ATN measures into a single number, while retaining its deleterious effect on an individual’s memory score. Furthermore, a newly identified task‐dependent CR network could be used to establish a CR score, which was related to higher PACC5 scores in MCI and AD patients, suggesting a functional compensation mechanism at later stages of AD that is not yet present in CN. Thus, targeted alteration of brain activity might be a promising route to modify cognitive trajectories in MCI and AD patients. Further, detailed examination of individuals with high CR might reveal additional disease‐modifying factors.

The Fractal Geometry of Alzheimer’s disease

AbstractBackgroundHuman brain is the most dynamic and varied system of the body. The brain is composed of neuron and glia. But how do they interact to generate emergent properties like memory, learning, emotion and sleep is little understood. Many such complex systems that exist in non‐linear dynamics are characterized by the fractal nature. The fractal dimension (FD) is a quantitative parameter that has been extensively used to analyze the complexity of structural and functional patterns of the human brain. The fractal dimension (FD) of the human brain quantifies the inherent complexity.MethodA non‐linear analysis called the Fractal Dimension (FD) has been performed to quantify the fractal complexity of AD. Our primary goal is to investigate FD to assess whether it can discriminate between different states of AD. We perform multi‐fractal analysis to discover whether AD and its states belong to class of multi‐fractal object for which a large number of scaling exponents are required to characterize their scaling structures. We plot the multi‐fractal spectra of the fMRI images to compare the width of the scaling exponent for each spectrum.ResultFrom FD analysis, we noticed that the fractal dimension increases with aging the AD, i.e. the complexity and self similarity of brain structure increases. According to our analysis, we have a wide range of exponents for AD fMRI images, which indicates different states of Alzheimer’s disease have multi‐fractal structure.ConclusionAs a result, fractal geometry can be considered as a computational framework to characterize different stages of AD and with further analysis, it can be used as a diagnostic tool to fight against Alzheimer’s disease.

Alzheimer brains: increased soluble amyloid peptides, but decreased lipid rafts

AbstractBackgroundPET imaging studies of AD patients show progressive increases of fibrillar Aβ‐ amyloid. Because current PET ligands underestimate non‐fibrillar forms, we assayed soluble Aβ in AD and controls. To identify mechanisms responsible for soluble Aβ in AD brains, we examined lipid rafts (LR), where APP is enzymatically processed. Frontal cortex was compared with cerebellum, which has minimal AD pathology.MethodPostmortem samples (N=48) were age‐and sex matched for Braak scores. Soluble Aβ was extracted from homogenates of full thickness frontal cortex by isotonic buffer and mild detergent (RIPA; 1% NP40) and centrifuged (10,000g/1h). Supernates were assayed by dot blots with antibodies for Aβ40 and Aβ42 (Biolegend, San Diego, CA). Aβ was assayed as relative fluorescent units per gm brain. LR fractions were isolated from these same brains by kit (Invent Biotechnologies; LR‐039), validated by ultracentrifugal fractionation.ResultCompared with cognitively normal controls (Braak 0‐1), elevations of soluble Aβ40 and Aβ42 were similar for intermediate and later stage AD (Braak 2‐3 and 4‐6). Clinical grade AD had greater increase of soluble Aβ40 (+400%) than Aβ42 (+50%) (p<0.05). LR raft yield per gram AD frontal cortex was 20% below controls (p<0.05), while cerebellar LR did not differ by Braak score. The composition of LR had a similar pattern, with 35% AD decreases of total protein and cholesterol (p<0.05); cerebellar LR again did not differ by Braak score. However, LR 4‐HNE, a marker of oxidative damage, was similarly increased in AD cortex and AD cerebellum.ConclusionThe extensive overlap of soluble Aβ levels in controls with AD contrasts with the PET findings on fibrillar Aβ. These findings further support fibrillar Aβ as a biomarker for AD treatments and show the need for more detailed postmortem analysis of diverse soluble and insoluble Aβ aggregates in relation to PET. The decreased LR in AD frontal cortex is consistent with its extensive neuronal loss, in contrast to the cerebellum. Further studies will examine LR enzymes of APP processing as a source of the increased soluble Aβ in AD, and subcellular clearance processes, which may be impaired in association with the oxidative damage indicated by increased 4‐HNE.

The Cognitive Stress Test (CST): An Innovative Tool to Differentiate Cognitively Unimpaired (CU) Older Adults from those with Pre‐Mild Cognitive Impairment (Pre‐MCI) and Amnestic MCI (aMCI).

AbstractBackgroundThe CST is a novel assessment that was designed to measure cognitive changes during preclinical and prodromal stages of AD, that include aMCI and PreMCI, where deficits do not meet MCI. The CST employs semantically competing word lists to measure the impact of semantic interference, failure to recover from proactive semantic interference (frPSI), and its persistent effects, despite multiple trials. We hypothesized that frPSI deficits on the CST would be persistent in pre‐MCI and aMCI groups when compared to cognitively unimpaired (CU) controls.Method50 aMCI, 31 pre‐MCI, and 69 CU elders were administered the CST. Participants were presented with List A (18 semantically related words: occupations, household items, or transportation methods) for three initial learning trials, followed by three learning trials of List B, a categorically similar wordlist, to examine PSI and frPSI. Retroactive Semantic Interference (RSI) was assessed by using category cues to elicit recall of List A targets, followed by an additional learning trial to examine failure to recover from RSI (frRSI).ResultSignificant differences were observed between all diagnostic groups across CST Cued Recall trials that measure maximum learning, PSI, frPSI, and persistent frPSI. PreMCI and aMCI participants experienced deficits in learning List B despite two additional opportunities; a deficit that was observed even after adjusting for initial learning strength. Older adults with greater risk (preMCI and aMCI) performed similarly on indices that measures PSI, frPSI, and persistent frPSI as compared to controls. There were differences in RSI among CU and aMCI groups yet measuring frRSI did not differentiate groups. aMCI participants made more semantic intrusion errors on recall trials that cued List B words. Pre‐MCI and CU made a similar number of intrusion errors.ConclusionThe CST extends our work by assessing persistent effects of frPSI, which have been shown to predict neurodegenerative progression and have been associated with multiple biomarkers of AD. The finding that persistent frPSI could differentiate CU from preMCI groups is a promising indicator that semantic interference deficits persist in older adults that present a heightened risk for progression to dementia and is worthy of further research.

Differential expression of Mical2 and its activator (Sema3a) in Alzheimer’s disease mouse model

AbstractBackgroundMicals are actin regulatory enzymes which can enhance depolymerization of actin filaments (F‐Actin). Activated Micals catalyze the selective oxidation of methionine residues, Met44 and Met47 within the D‐loop of F‐actin. The oxidation of methionine residues disrupts the interaction between G‐actin monomers, thus facilitating F‐actin depolymerization. Dendritic spines are enriched with filamentous actin (F‐actin) where it regulates the formation, elimination and structural plasticity of spines. Early stage of AD is associated with loss of dendritic spines and F‐actin from synapses, leading to memory deficits. However, the potential mechanism involved in the loss of F‐actin remains largely unknown. Therefore, we aimed to elucidate the role of Micals and semaphorins in actin depolymerization at the synapse of AD mouse model.MethodsTotal RNA was isolated from the cortex, hippocampus and entorhinal cortex of adolescent, young, and middle aged wildtype and APP/PS1 mice as well as from the synaptosomes of respective age groups. The cDNA is synthesized and qRT‐PCR is performed using SYBR green reagents with specific primers to Micals and Semaphorins. Data was analyzed using two tailed non parametric test with a p value of <0.05 signifies the result.ResultsThe mRNA expression levels of Micals and Semaphorins in entorhinal cortex, hippocampus, and cortex of wildtype and APP/PS1 as well as in the synaptosomes of age matched animals were measured by qRT‐PCR. We found that Semaphorin3a showed differential mRNA expression levels in entorhinal cortex of adolescence and young adults of APP/PS1 mice in comparison to wildtype littermate controls. Further, we detected that the synapse specific mRNA levels of Mical 2 and Semaphorin3a are significantly decreased in adolescent APP/PS1 mice in comparison to WT mice. However, we did not detect any significant alteration in the mRNA expression levels of Mical1, Mical3 and Semaphorin3f in APP/PS1 mice at different age groups in comparison to WT littermate controls.ConclusionAltered expression levels of actin regulatory proteins like Micals and Semaphorins at the dendritic spines could play critical roles in Aβ mediated F‐actin depolymerization in Alzheimer's disease pathology.

The case for low‐level BACE1 inhibition for the prevention of AD

AbstractAlzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease‐modifying therapies targeting amyloid‐β plaques in symptomatic stages of AD have only just been approved in the United States. Small‐molecule inhibitors of β‐site amyloid precursor protein (APP)‐cleaving enzyme 1 (BACE1; also known as β‐secretase 1) reduce the production of amyloid‐β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non‐progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this talk, I discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform ‘go‐no‐go’ decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention.