AD Progression Research Articles

Bile acids inform about a sex‐specific resilience phenotype against Alzheimer’s disease implicating a role for the gut microbiome and the exposome

AbstractBackgroundBile acids (BAs) are byproducts of cholesterol metabolism involved in lipid absorption, signaling and energy homeostasis. BA synthesis and metabolism, regulated by human and gut bacteria co‐metabolism, are influenced by the exposome. Our prior studies at a population level illustrated a correlation between altered BA profiles and cognitive and brain imaging changes in MCI and AD. More information is needed to determine if these are causal in sub‐populations, and if their modulation can impact disease course.MethodAbsolute serum levels of 33 primary, secondary, and conjugated BAs were measured on a targeted mass spectrometry‐based platform in 1117 fasted subjects (502 women) drawn from the AD Neuroimaging Initiative (ADNI‐1/GO‐2; AD (N = 180), MCI (N = 607) and CN (N = 330). Analysis centered on adjusted and/or stratified linear models with an interpretative focus emphasizing individual‐level granularity.ResultIn stratified analysis, men but not women showed strong association between levels and ratios of BAs and diagnosis. Inclusion of two (informative) bile acids and their ratios increases AUCs for AD vs control from ∼0.72 to ∼0.82‐0.85 (p<0.001) in APOEε4 genotype‐stratified analyses. Some specific associations were APOEε4 genotype‐dependent; some specific microbiome‐mediated ratios in BAs were associated with AD diagnosis in APOEε4− only and secondary bile acid synthesis was associated with AD diagnosis in APOEε4+ only. Other associations were APOEε4 genotype‐independent ‐ higher ratios of primary BAs to total BAs were associated with reduced AD prevalence. Levels of cholic acid below sharp thresholds 25 or 50 nM (in APOEε4+ and APOEε4−, respectively) at 24 months were associated with 5‐ to 7‐fold increased relative risk of MCI to AD progression, establishing a potential biomarker for a resilience phenotype.ConclusionLeveraging the combined power of ADNI and metabolomics with a focus on granularity and complementarity revealed previously unobserved relationships between BAs, sex, APOEε4 genotype, and AD etiology. These data identify a resilience class and provide a roadmap for stratifying subjects and targeting therapies in a precision medicine approach while gaining deeper insights linking peripheral‐central metabolism influenced by the exposome. BAs are a potential modifiable factor that mediates causal linkages between endogenous and exogenous factors in the susceptibility or resilience against AD.

Synapse dysfunction and astrocyte reactivity are associated independently of amyloid‐β and tau pathologies

AbstractBackgroundBiomarkers of astrocyte reactivity have the potential to improve diagnostic precision, disease monitoring, and treatment efficacy. Glial fibrillary acidic protein (GFAP) protein is expressed in astrocytes, which is important to synaptic plasticity, cell communication, and reactive gliosis.MethodCerebrospinal fluid (CSF) biomarkers were measured in participants of the McGill TRIAD cohort. 75 individuals (>50 years old, 44 cognitively unimpaired (CU), and 31 with cognitive impairment (CI)), had available Aß and tau‐PET. We measured CSF GFAP and synaptic markers (growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptotagmin 1 (SYT1), presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25)). Linear regressions adjusted for age, sex, clinical diagnosis, and Aß/tau‐PET were used to test the associations between astrocyte reactivity and synaptic function.ResultDemographic information is shown in Table 1. We found an association between CSF GFAP and presynaptic markers (GAP‐43: p<0.0001, ß = 0.1076; SYT1: p<0.0001, ß = 0.0024; SNAP‐25 long: p<0.0001, ß = 0.0008) as well as postsynaptic markers (Ng: p<0.05, ß = 0.0066) independently of Aß and tau burden (Figure 1).ConclusionOur biomarker results support experimental literature suggesting that astrocyte reactivity plays a role in downstream synaptic dysfunction independent of the brain levels of Aß and tau tangles pathologies. This supports in vitro literature suggesting that therapeutic interventions targeting astrocyte reactivity can contribute to halting AD progression.

Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer's disease mice.

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

Bone Marrow-Derived GCA+ Immune Cells Drive Alzheimer's Disease Progression.

Alzheimer's disease (AD) is an age-related degenerative disease of the central nervous system (CNS), whereas the role of bone marrow immune cells in the pathogenesis of AD remains unclear. Here, the study reveals that compared to matched healthy individuals, AD patients have higher circulating grancalcin (GCA) levels, which negatively correlate with cognitive function. Bone marrow-derived GCA+ immune cells, which secret abundant GCA and increase during aging, preferentially invaded the hippocampus and cortex of AD mouse model in a C-C Motif Chemokine Receptor 10 (CCR10)-dependent manner. Transplanting GCA+ immune cells or direct stereotaxic injection of recombinant GCA protein intensified amyloid plaque load and aggravated cognitive and memory impairments. In contrast, genetic ablation of GCA in the hematopoietic compartment improves cognitive and memory function. Mechanistically, GCA competitively binds to the low-density lipoprotein receptor-related protein 1 (LRP1) in microglia, thus inhibiting phagocytosis and clearance of Aβ and potentiating neuropathological changes. Importantly, GCA-neutralizing antibody treatment rejuvenated cognitive and memory function and constrained AD progression. Together, the study demonstrates a pathological role of GCA+ immune cells instigating cognitive and memory decline, suggesting that GCA+ immune cells can be a potential target for innovative therapeutic strategies in AD.

Diverse signaling mechanisms and heterogeneity of astrocyte reactivity in Alzheimer's disease.

Alzheimer's disease (AD) affects various brain cell types, including astrocytes, which are the most abundant cell types in the central nervous system (CNS). Astrocytes not only provide homeostatic support to neurons but also actively regulate synaptic signaling and functions and become reactive in response to CNS insults through diverse signaling pathways including the JAK/STAT, NF-κB, and GPCR-elicited pathways. The advent of new technology for transcriptomic profiling at the single-cell level has led to increasing recognition of the highly versatile nature of reactive astrocytes and the context-dependent specificity of astrocyte reactivity. In AD, reactive astrocytes have long been observed in senile plaques and have recently been suggested to play a role in AD pathogenesis and progression. However, the precise contributions of reactive astrocytes to AD remain elusive, and targeting this complex cell population for AD treatment poses significant challenges. In this review, we summarize the current understanding of astrocyte reactivity and its role in AD, with a particular focus on the signaling pathways that promote astrocyte reactivity and the heterogeneity of reactive astrocytes. Furthermore, we explore potential implications for the development of therapeutics for AD. Our objective is to shed light on the complex involvement of astrocytes in AD and offer insights into potential therapeutic targets and strategies for treating and managing this devastating neurodegenerative disorder.

92 Biber Figure Learning Test Outperforms Other Cognitive Measures in Predicting Subjective Cognitive Decline

Objective:Subjective Cognitive Decline (SCD), the perception of deteriorating cognition in the absence of apparent impairment on objective testing, has gained momentum in recent literature as a risk marker for AD. Traditional neuropsychological assessments, while typically inclusive of a word list learning task, often do not include a comparable figure learning task. Growing evidence suggests that nonverbal assessments may be particularly sensitive to the earliest cognitive changes associated with Alzheimer’s disease. The Biber Figure Learning Test (BFLT), a visuospatial analogue to verbal list learning tasks, has been shown to associate with brain-based biomarkers of Alzheimer’s disease (AD; hippocampal volume, amyloid load). This study investigates the utility of the BFLT in capturing SCD above and beyond other cognitive measures sensitive to AD progression.Participants and Methods:50 community-dwelling, cognitively normal individuals (78% White, 16% Black, 6% Other; 92% Non-Hispanic; 64% Female; Education M=17.1, SD=2.1; Age M=72.7, SD=6.2) participated in a study of SCD. All participants performed >-1.5 SD on clinical neuropsychological testing including a word list learning task. SCD was assessed using a 20-item scale querying individuals’ perception of difficulty across a range of memory and non-memory abilities in relation to others of the same age. Participants completed the BFLT, Loewenstein-Acevedo Scales of Semantic Interference and Learning (LASSI-L), Short-Term Memory Binding (STMB), and Face-Name Associative Memory Exam (FNAME), previously established as being sensitive to pre-clinical AD, were examined as predictors of SCD. A multiple regression adjusted for demographics (age, gender, education) was used to investigate the extent to which BFLT Trial 1 (T1) predicted SCD above and beyond these other cognitive measures sensitive to AD progression. Trial 1 of the BFLT was used based on a separate abstract examining which BFLT score was most highly associated with SCD (Kann et al., pending acceptance).Results:Adjusting for demographics, the present model accounts for 42% of the variance in SCD, while Biber T1 alone accounts for 20% and is the only significant individual predictor of SCD (β=-0.55, p=0.004). In contrast, other variables in the model independently accounted for less than 1% to 4% each (age β=-0.23, p=0.15; gender β=-0.15, p=0.34; education β=0.06, p=0.66; LASSI-L β=-0.11, p=0.55; STMB β=-0.03, p=0.85; FNAME β=-0.10, p=0.64).Conclusions:The present study demonstrates the usefulness of the first learning trial of the BFLT as an independent predictor of SCD above and beyond other verbal and nonverbal measures sensitive to AD pathology. It also highlights the value of including even one trial of figure learning (< 5 minutes) in both clinical and research assessments seeking to capture cognitive changes which may be the earliest indicators of a neurodegenerative process. Ongoing longitudinal research is examining the predictive utility of the BFLT for future cognitive decline and transition to Mild Cognitive Impairment. Further research should explore the association between Biber T1, specifically, and neuropathological biomarkers of AD to further establish its utility as a portent of AD.

Evaluating Elements of the Care Partner Experience in Individuals Who Care for People with Alzheimer's Disease Across the Severity Spectrum.

Non-professional care partners play an important and often evolving role in the care of persons living with Alzheimer's disease (PLWAD). We investigated two elements of the care partner experience, namely time and strain incurred by care partners providing care to PLWAD across the severity spectrum. Data gathered from the Alzheimer's Disease Patient and Caregiver Engagement (AD PACE) What Matters Most (WMM) study series were analyzed to determine how much time care partners spent providing care to PLWAD based on where the care recipients lived. Additionally, quantitative assessments of weekly hours providing care and the strain experienced by care partners were conducted using the UsAgainstAlzheimer's A-LIST Insights Series survey, which included the Modified Caregiver Strain Index (MCSI). Finally, a targeted literature review was conducted to contextualize findings and characterize the existing literature landscape. Care partners in the AD PACE WMM studies (n = 139) spent significantly more hours providing care for recipients who lived with someone (mean ± standard deviation [SD], 57.3 ± 44.3h/week) than for recipients who lived alone (26.0 ± 12.0h/week) (P = 0.0096) or lived in assisted living/nursing home (23.6 ± 14.4h/week) (P = 0.0002). In the A-LIST Insights Series survey, care partners provided an overall mean (± SD) 58.1 ± 53.0h of direct care each week, with caregiving hours increasing with increasing severity of AD/AD-related dementias(AD/ADRD). Additionally, care partners for recipients with mild (n = 14), moderate (n = 111), and severe AD/ADRD (n = 91) had overall mean MCSI scores of 9.0 ± 3.8 (range 2-14), 13.3 ± 4.8 (range 4-23), and 17.5 ± 5.3 (range 4-26), respectively, with higher scores suggesting greater care partner strain. Persons living with AD require increasing levels of care along the spectrum of disease, and even individuals with early disease need care from partners. Early interventions that slow progression of AD and programs that improve family function may have beneficial impact on the experiences of care partners for recipients with mild, moderate, or severe AD.

Magnetic resonance spectroscopy in the hippocampus of adult APP/PS1 mice following chronic vitamin D deficiency

Vitamin D (VitD) deficiency can exacerbate AD progression and may cause changes in brain metabolite levels that can be detected by magnetic resonance spectroscopy (MRS). The purpose of this study was to determine whether chronic VitD deficiency in an AD mouse model caused persistent metabolite levels changes in the hippocampus associated with memory performance. Six-month-old APPSwe/PS1ΔE9 (APP/PS1) mice (N = 14 mice/group) were fed either a VitD deficient (VitD-) diet or a control diet. Metabolite level changes in the hippocampus were evaluated by 1H MRS using a 9.4 T MRI. Ventricle volume was assessed by imaging and spatial memory was evaluated using the Barnes maze. All measurements were made at 6, 9, 12, and 15 months of age. At 15 months of age, amyloid plaque load and astrocyte number were evaluated histologically (N = 4 mice/group). Levels of N-acetyl aspartate and creatine were lower in VitD- mice compared to control diet mice at 12 months of age. VitD deficiency did not change ventricle volume. Lactate levels increased over time in VitD- mice and increases from 12 to 15 months were negatively correlated with changes in primary latency to the target hole in the Barns Maze. VitD- mice showed improved spatial memory performance compared to control diet mice. VitD- mice also had more astrocytes in the cortex and hippocampus at 15 months than control diet mice. This study suggests that severe VitD deficiency in APP/PS1 mice may lead to compensatory changes in metabolite and astrocyte levels that contribute to improved performance on spatial memory tasks.

Diagnostic biomarkers and aortic dissection: a systematic review and meta-analysis

BackgroundAortic dissection (AD) is a serious and fatal vascular disease. The earlier the condition of AD patients can be assessed precisely, the more scientifically controlled the patient’s condition will be. Therefore, timely and accurate diagnosis is significant for AD. Blood biomarker testing as a method of liquid biopsy can improve the diagnostic efficiency of AD. This study conducted a systematic review of the current blood diagnostic biomarkers of AD.MethodsThe PubMed, Cochrane Library, Web of Science, and Embase electronic databases were systematically searched from inception to January 1, 2023, using the terms “aortic dissection”, “serum”, “plasma” and “diagnosis”. Stata 12.0 software was used to perform Random effects meta-analysis was performed using Stata 12.0 software to determine the effect sizes and corresponding 95% confidence intervals. Then, a summary receiver operator characteristic (SROC) curve was drawn, and the area under the ROC curve (AUC) was calculated.ResultsD-dimer had the best sensitivity and AUC for AD, with values of 0.96 (95% CI: 0.93–0.98) and 0.95 (95% CI: 0.93–0.97), respectively. The sensitivity and AUC values for D-dimer with a cut-off value of 500 ng/mL were 0.97 (95% CI: 0.95–0.99) and 0.94 (95% CI: 0.92–0.96), respectively. In contrast, microRNA had a better specificity value for AD, at 0.79 (95% CI: 0.73–0.83).ConclusionsD-dimer and microRNA have good accuracy in the diagnosis of AD, but the specificity of D-dimer is worse, and studies of microRNA are insufficient. The combination of different biomarkers can improve the diagnostic accuracy. Other blood biomarkers are related to the pathological progression of AD and can be selected according to pathological progress.

Identification of key lipid metabolism-related genes in Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) represents profound degenerative conditions of the brain that cause significant deterioration in memory and cognitive function. Despite extensive research on the significant contribution of lipid metabolism to AD progression, the precise mechanisms remain incompletely understood. Hence, this study aimed to identify key differentially expressed lipid metabolism-related genes (DELMRGs) in AD progression.MethodsComprehensive analyses were performed to determine key DELMRGs in AD compared to controls in GSE122063 dataset from Gene Expression Omnibus. Additionally, the ssGSEA algorithm was utilized for estimating immune cell levels. Subsequently, correlations between key DELMRGs and each immune cell were calculated specifically in AD samples. The key DELMRGs expression levels were validated via two external datasets. Furthermore, gene set enrichment analysis (GSEA) was utilized for deriving associated pathways of key DELMRGs. Additionally, miRNA-TF regulatory networks of the key DELMRGs were constructed using the miRDB, NetworkAnalyst 3.0, and Cytoscape software. Finally, based on key DELMRGs, AD samples were further segmented into two subclusters via consensus clustering, and immune cell patterns and pathway differences between the two subclusters were examined.ResultsSeventy up-regulated and 100 down-regulated DELMRGs were identified. Subsequently, three key DELMRGs (DLD, PLPP2, and PLAAT4) were determined utilizing three algorithms [(i) LASSO, (ii) SVM-RFE, and (iii) random forest]. Specifically, PLPP2 and PLAAT4 were up-regulated, while DLD exhibited downregulation in AD cerebral cortex tissue. This was validated in two separate external datasets (GSE132903 and GSE33000). The AD group exhibited significantly altered immune cell composition compared to controls. In addition, GSEA identified various pathways commonly associated with three key DELMRGs. Moreover, the regulatory network of miRNA-TF for key DELMRGs was established. Finally, significant differences in immune cell levels and several pathways were identified between the two subclusters.ConclusionThis study identified DLD, PLPP2, and PLAAT4 as key DELMRGs in AD progression, providing novel insights for AD prevention/treatment.

Effects and mechanism of extracts rich in phenylpropanoids-polyacetylenes and polysaccharides from Codonopsis Radix on improving scopolamine-induced memory impairment of mice

Ethnopharmacological relevanceAlzheimer's disease (AD) is a progressive developmental neurodegenerative disease that primarily develops in old age. Memory impairment is an important manifestation of AD. It has been demonstrated that inflammation and oxidative stress are important mediators in the development and progression of AD. Codonopsis Radix (CR) has a long history of consumption, exhibiting lots of beneficial health effects, including anti-ageing, antioxidant, and anti-inflammatory properties. However, studies on the effects of CR on scopolamine-induced amnesia have rarely been reported. Aim of the studyThe aim of this study was to investigate the ameliorative effect of macromolecular portion (polysaccharides, POL) and small molecule portion (fine extract rich in phenylpropanoids-polyacetylenes, EPP) from CR on improving scopolamine-induced memory impairment and to elucidate the potential mechanism of action. Materials and methodsC57BL/6 mice were pretreated with EPP (0.2, 0.4, and 0.6 g/kg), POL (0.3, 0.6, and 0.9 g/kg), and donepezil (5 mg/kg) by gavage for 7 days, followed by intraperitoneal injection of scopolamine (1 mg/kg) to induce memory impairment. The 16S rRNA gene sequencing, histopathological, western blotting, and biochemical analysis (various biochemical markers and protein expressions related to cholinergic system, oxidative stress, and neuroinflammation) were performed to further elucidate the mechanism of action. Moreover, the acetylcholinesterase (AChE) inhibitory activities of POL, EPP, and its main compounds tangshenoside I, lobetyol, lobetyolin, and lobetyolinin were evaluated. ResultsExperiments have confirmed that both POL and EPP from CR could improve scopolamine-induced spatial learning memory deficits. Both of them could regulate cholinergic function by inhibiting AChE and activating choline acetyltransferase (ChAT) activities. They also could enhance antioxidant defense via increasing the activities of superoxide dismutase and glutathione peroxidase, and anti-inflammatory function through suppressing inflammatory factors (nitric oxide, TNF-α, and IL-6) and regulating gut flora. Besides, in vitro experiments demonstrated that four monomeric compounds and EPP, except POL, exhibited inhibition of AChE activity. ConclusionEPP and POL from CR exert a beneficial effect on learning and memory processes in mice with scopolamine-induced memory impairment. CR may be a promising medicine for preventing and improving learning memory.

Neuroimaging and machine learning for studying the pathways from mild cognitive impairment to alzheimer’s disease: a systematic review

BackgroundThis systematic review synthesizes the most recent neuroimaging procedures and machine learning approaches for the prediction of conversion from mild cognitive impairment to Alzheimer’s disease dementia.MethodsWe systematically searched PubMed, SCOPUS, and Web of Science databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) systematic review guidelines.ResultsOur search returned 2572 articles, 56 of which met the criteria for inclusion in the final selection. The multimodality framework and deep learning techniques showed potential for predicting the conversion of MCI to AD dementia.ConclusionFindings of this systematic review identified that the possibility of using neuroimaging data processed by advanced learning algorithms is promising for the prediction of AD progression. We also provided a detailed description of the challenges that researchers are faced along with future research directions. The protocol has been registered in the International Prospective Register of Systematic Reviews– CRD42019133402 and published in the Systematic Reviews journal.

The Objective Dementia Severity Scale Based on MRI with Contrastive Learning: A Whole Brain Neuroimaging Perspective.

In the clinical treatment of Alzheimer's disease, one of the most important tasks is evaluating its severity for diagnosis and therapy. However, traditional testing methods are deficient, such as their susceptibility to subjective factors, incomplete evaluation, low accuracy, or insufficient granularity, resulting in unreliable evaluation scores. To address these issues, we propose an objective dementia severity scale based on MRI (ODSS-MRI) using contrastive learning to automatically evaluate the neurological function of patients. The approach utilizes a deep learning framework and a contrastive learning strategy to mine relevant information from structural magnetic resonance images to obtain the patient's neurological function level score. Given that the model is driven by the patient's whole brain imaging data, but without any possible biased manual intervention or instruction from the physician or patient, it provides a comprehensive and objective evaluation of the patient's neurological function. We conducted experiments on the Alzheimer's disease Neuroimaging Initiative (ADNI) dataset, and the results showed that the proposed ODSS-MRI was correlated with the stages of AD 88.55% better than all existing methods. This demonstrates its efficacy to describe the neurological function changes of patients during AD progression. It also outperformed traditional psychiatric rating scales in discriminating different stages of AD, which is indicative of its superiority for neurological function evaluation.

Distinguishing the Effect of Aging and SIRT1 Manipulation on AD progression with SIRT1 and APP Temporally Regulated Mice Models

Alzheimer’s (AD) is a neurodegenerative disease closely linked to aging. However, mouse models with early onset AD are widely utilized, which may cause data deviations since AD normally occurs in aged subjects. In this work, we devised transgenic mouse models with SIRT1, Aβ42 regulated at the first month after birth and 19th months old via Tet-Off/CREer-LoxP systems. Aging/AD/SIRT1-interacted biomarkers were tracked throughout life. Based on the models, the effects of SIRT1, APP, and aging on AD progression are differentiated through temporal manipulation. The possible results of equal or more significant effects of SIRT1 deficiency on AD progression compared to aging hint the presence of pathology distinctly related to AD, which might lie in induced increased neuron death signals and unprotected mitochondria from blocked P53, triggered by loss of SIRT-1 control over apoptotic factors including P53 and FOXO3a. The data obtained from our work can reveal the magnitude of deviation resulting from using early-onset AD models rather than aging mice, hence serving as a reference to possible bias. The raised pathology about SIRT1 and uncontrolled apoptotic factors could serve as a potential target for AD study.

Neuroprotective Effect of Perillyl alcohol in Experimental Sporadic Alzheimer’s disease

AbstractBackgroundAlzheimer’s is most common neurodegenerative disorder characterized by memory loss due to accumulation of amyloid‐ β fibrils. There are different pathologies that count for AD like neuro‐inflammation. This study highlights the role of oxidative stress and inflammation in progression of AD whereas Perillyl alcohol (POH) shows ant oxidative & anti‐inflammatory properties.Method54 Sprague Dawley ICV‐STZ (3mg/kg) rats (250‐300g, 7‐8 weeks) were treated with three different doses of Perillyl alcohol (25, 50 and 100mg/kg p.o.) for 13 days from 15th to 27th day. Weight measured on 1st and 28th day. Behavioral analysis had done using OFT and MWM.ResultPerillyl alcohol treatment significantly attenuates declined body weight in ICV‐STZ induced dementia in rats, showed significant increase in crossing number, and active time. Dementia induced rats were unable to discriminate familiar and novel objects, which is improved by POH. POH attenuates STZ induced acquisition deficits and retention time, increased MDA and nitrite levels. POH attenuated depleted levels of GSH, Catalase, SOD comparable to standard drug donepezil, POH decreased AChE levels in cortex and hippocampus.ConclusionStudy outcomes demonstrate neuroprotective potential of Perillyl alcohol against ICV‐STZ administration of streptozotocin induced behavioural and biochemical abnormalities. Biventricular STZ infusion produced significant impairment in learning, memory, cholinergic hypo function and elevation in hippocampal oxidative stress in rats. Rats showed poor learning, memory and unable to discriminate between familiar & novel objects in MWM and ORT. POH administration significantly attenuated STZ induced biochemical consequences. Observed beneficial effects of POH include restored cholinergic functions and antioxidant mechanisms.

The QSP model of TREM2 influences on inflammatory state of microglia in Alzheimer’s disease

AbstractBackgroundInflammation is one of the critical components in the development of neurodegenerative diseases. Microglia is the resident of macrophages of the central nervous system. In the AD brain, microglial cells are found in close association with amyloid beta deposits. Histological examination of AD brains as well as cell culture studies have shown that the interaction of microglia with fibrillar amyloid beta leads to their phenotypic activation. It increases the activation of microglia cells and switches them from resting (M0) to activating (M1 or M2) state and the release of cytokines. The role of microglia in AD progression is unclear with conflicting reports regarding their detrimental or protective contribution to the disease. The QSP model was developed to investigate influence of TREM2 on inflammation of microglia.MethodsThe model describes microglia resting state, phagocytosis, TLR, P2×7 and TREM2 receptors, kinases, intracellular signaling pathways, apoptosis of microglia cells, response of microglia to LPS, oligomeric and fibrillar amyloid and cytokines (IL6, IL1b, TNFa), distribution of cytokines from the brain into cerebrospinal fluid and blood.ResultsThe model correctly describes decreased phagocytosis, increased cytokine and pro‐inflammation factors with influence of amyloid beta and TREM2 KO during LPS‐induction. It demonstrates that: 1) TREM KO leads to decrease of phagocytosis [1] 2) Ab influence on TREM2 leads to increase of inflammatory cytokine level [2] 3) Inhibitor of PI3K (LY294002) decreases phagocytosis in signaling pathway (PI3K/FoxO/phagocytosis) [3].ConclusionsThis QSP model can be used to predict the response of microglia to various conditions caused by neurodegenerative diseases and therapies targeting microglial state.[1] – PMID: 30548312[2] – PMID: 33065553[3] – PMID: 28842601

Prevalence and pathological correlates of unawareness of memory impairment in non‐demented individuals with autosomal dominant Alzheimer’s disease: an item‐level investigation of the Memory Complaints Scale

AbstractBackgroundAwareness of memory was previously found to be reduced in the pre‐dementia stages, reaching unawareness/anosognosia 6‐years before dementia onset in individuals who carry the PSEN1 E280A mutation for autosomal dominant Alzheimer’s disease (Vannini et al.,2021). Whether there are potential differences in awareness for specific types of situations involving memory as well as their association with molecular markers of AD disease progression in preclinical AD is unknown. Here, we investigated memory awareness on an item‐level basis as well as its relationship to neocortical amyloid and regional tau levels in non‐demented mutation carriers and non‐carrier family members.MethodA total of 119 Colombian kindred members, 56 carriers (7 mildly impaired) and 63 non‐carriers were included (Table.1). Awareness indexes were calculated using participant and study‐partner discrepancy scores for each of the 15 questions of the Memory Complaint Scale (Spanish version). A score of ≥0 indicates that the participant is aware and <0 unaware. A subset of 67 kindred members (N = 31 carriers, 1 impaired) underwent amyloid (PiB) and tau (FTP) scans. For each question, odds ratio and Fisher’s exact test were used to evaluate prevalence of awareness/unawareness in carriers and non‐carriers. Pearson correlations, corrected for multiple comparisons, were used to assess the associations between awareness and pathology in the mutation carriers.ResultMutation carriers had significantly decreased overall awareness (p = 0.03), increased mean cortical amyloid (p<0.001) and inferior temporal tau (p = 0.001), compared to non‐carriers. Two questions (items 10 and 15), showed significantly lower awareness in the carriers than non‐carriers (both p = 0.002, Table.2). These results remained significant after removing impaired carriers. In carriers, decreased awareness was related to increased tau for 5/15 (33%) questions (Table.3 and Figure.1). No significant associations were found between awareness and amyloid.ConclusionOur results support previous findings that awareness is decreased in pre‐dementia stages of AD and related to tau, and not to amyloid pathology (Gagliardi et al.,2021). Importantly, we found that loss of awareness of specific memory items could differentiate carriers from non‐carriers. These findings support the usefulness of study‐partner‐reported cognitive decline. Individuals who become unaware of cognitive changes may represent a specific risk group to harbor pathology and develop AD dementia.

Impact of white matter hyperintensities on subjective cognitive decline phenotype in a diverse cohort of cognitively normal older adults.

Subjective cognitive decline (SCD) is a preclinical stage of AD. White matter hyperintensities (WMH), an MRI marker of cerebral small vessel disease, associate with AD biomarkers and progression. The impact of WMH on SCD phenotype is unclear. A retrospective, cross-sectional analysis was conducted on a diverse cohort with SCD evaluated at the NYU Alzheimer's Disease Research Center between January 2017 and November 2021 (n=234). The cohort was dichotomized into none-to-mild (n=202) and moderate-to-severe (n=32) WMH. Differences in SCD and neurocognitive assessments were evaluated via Wilcoxon or Fisher exact tests, with p-values adjusted for demographics using multivariable logistic regression. Moderate-to-severe WMH participants reported more difficulty with decision making on the Cognitive Change Index (1.5 SD 0.7 vs. 1.2 SD 0.5, p=0.0187) and worse short-term memory (2.2 SD 0.4 vs. 1.9 SD 0.3, p=0.0049) and higher SCD burden (9.5 SD 1.6 vs. 8.7 SD 1.7, p=0.0411) on the Brief Cognitive Rating Scale. Moderate-to-severe WMH participants scored lower on the Mini-Mental State Examination (28.0 SD 1.6 vs. 28.5 SD 1.9, p=0.0491), and on delayed paragraph (7.2 SD 2.0 vs. 8.8 SD 2.9, p=0.0222) and designs recall (4.5 SD 2.3 vs. 6.1 SD 2.5, p=0.0373) of the Guild Memory Test. In SCD, WMH impact overall symptom severity, specifically in executive and memory domains, as well as objective performance on global and domain-specific tests in verbal memory and visual working/associative memory.

Large‐scale quantitative neuropathological analysis across the spectrum of Alzheimer’s disease neuropathologic change

AbstractBackgroundWhile traditional histologic neuropathological assessment of neurodegenerative disease has tremendous diagnostic value, insights into neurodegeneration’s pathophysiological underpinnings can be significantly enhanced with large‐scale quantitative analyses. As part of the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA‐AD), we present a neuropathology dataset across 84 brains spanning the spectrum of AD neuropathologic change donated by UW Alzheimer’s Disease Research Center and Adult Changes in Thought study participants.MethodHuman brain tissue was collected at rapid autopsy (postmortem interval <12 hours). One hemisphere (randomly selected) was embedded in alginate for uniform coronal slicing (4mm), with alternating slabs fixed in 10% neutral buffered formalin or frozen in a dry ice isopentane slurry. Superior and Middle Temporal Gyrus (MTG) was sampled from fixed slabs and subjected to standard processing, embedding, sectioning (5µm), histochemical (H&E/Luxol fast blue), and immunohistochemical (duplex pTau and pTDP‐43, Aβ and Iba1, and monoplex GFAP, a‐synuclein, and NeuN) labeling. HALO image analysis software (Indica Labs, Albuquerque NM) was used to define and quantify relevant cellular and pathological features within each cortical layer (Figures 1‐3).Result84 individuals were included in these analyses (Table 1).While quantitative metrics of pTau and Aβ aligned with traditional neuropathological measures, they showed substantial variability within discrete diagnostic stages (Figure 4). These findings were robust to quantification (discrete count vs. total area stained) and normalization (total nuclei vs. total area analyzed) methods, and highlight the importance of deploying highly quantitative, continuous measures of pathology in the study of neurodegeneration. This unique resource provides spatially preserved measures of pathologic burden across the spectrum of AD with potential for correlative analysis across pathologies, clinical and biomarker parameters, and omics applications to better support the identification of vulnerable cell types in early stages of AD progression, the principal goal of SEA‐AD.ConclusionHere we present a large‐scale quantitative neuropathology dataset, which enables analysis of pathological proteins and cell types at unprecedented scale and accuracy. Little is known about the interactions of AD‐relevant cell types with pathologic peptides across disease progression. The presented analyses exemplify the potential of this unique publicly‐accessible resource to identify and quantify novel disease‐relevant relationships.

3D bioprinting patient-derived induced pluripotent stem cell models of Alzheimer’s disease using a smart bioink

BackgroundAlzheimer’s disease (AD), a progressive neurodegenerative disorder, is becoming increasingly prevalent as our population ages. It is characterized by the buildup of amyloid beta plaques and neurofibrillary tangles containing hyperphosphorylated-tau. The current treatments for AD do not prevent the long-term progression of the disease and pre-clinical models often do not accurately represent its complexity. Bioprinting combines cells and biomaterials to create 3D structures that replicate the native tissue environment and can be used as a tool in disease modeling or drug screening.MethodsThis work differentiated both healthy and diseased patient–derived human induced pluripotent stems cells (hiPSCs) into neural progenitor cells (NPCs) that were bioprinted using the Aspect RX1 microfluidic printer into dome-shaped constructs. The combination of cells, bioink, and puromorphamine (puro)-releasing microspheres were used to mimic the in vivo environment and direct the differentiation of the NPCs into basal forebrain-resembling cholinergic neurons (BFCN). These tissue models were then characterized for cell viability, immunocytochemistry, and electrophysiology to evaluate their functionality and physiology for use as disease-specific neural models.ResultsTissue models were successfully bioprinted and the cells were viable for analysis after 30- and 45-day cultures. The neuronal and cholinergic markers β-tubulin III (Tuj1), forkhead box G1 (FOXG1), and choline acetyltransferase (ChAT) were identified as well as the AD markers amyloid beta and tau. Further, immature electrical activity was observed when the cells were excited with potassium chloride and acetylcholine.ConclusionsThis work shows the successful development of bioprinted tissue models incorporating patient derived hiPSCs. Such models can potentially be used as a tool to screen promising drug candidates for treating AD. Further, this model could be used to increase the understanding of AD progression. The use of patient derived cells also shows the potential of this model for use in personalized medicine applications.