Alzheimer Type Research Articles

Application of the Semantic Fluency Test in the Screening of Mandarin-Chinese-Speaking Older Adults with Mild Dementia of the Alzheimer Type.

Semantic fluency tests have been widely used as a screening test for dementia of Alzheimer type. However, few studies have explored the application of semantic fluency tests in Mandarin Chinese speakers. This study aimed to explore the feasibility of using different semantic fluency test categories to distinguish between older adults without cognitive impairments and those with dementia of Alzheimer type in Taiwan. A total of 58 healthy older adults and 54 individuals with dementia of Alzheimer type were recruited. Semantic categories of "animals", "fruits", "vegetables", "birds", "means of transportations" and "musical instruments" were administered to participants. The scores from two groups of participants for each category were analyzed. Significant differences in the test scores of each category between two groups of participants were found. The results also revealed that the variables related to whether the participant had dementia, gender, age, and years of schooling significantly influenced the semantic fluency scores for each category. Among all the demographic characteristic of participants, the diagnosis of dementia was the most determining factor. Furthermore, this study proposed optimal cutoff points and calculated the AUC for various test durations (i.e., 30 s, 45 s and 60 s) and semantic categories in the semantic fluency test, which may serve as a reference that would help clinical personnel distinguish between older adults without cognitive impairments and those with dementia of Alzheimer type in Taiwan.

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer’s disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.

The cholesterol depleting agent, (2-Hydroxypropyl)-ß-cyclodextrin, does not affect disease progression in SOD1G93A mice

Objective Previously, we demonstrated that Amyloid Precursor Protein (APP) contributes to pathology in the SOD1G93A mouse model of ALS and that genetic ablation of APP in SOD1G93A mice significantly improved multiple disease parameters, including muscle innervation and motor neuron survival. We also observed elevated levels of potentially neurotoxic Aß peptides that have been implicated in Alzheimer’s Disease (AD) pathogenesis, within motor neurons and astrocytes in SOD1G93A mice. More recently, it has been shown that blocking Aß production improves outcome measures in SOD1G93A mice. The cyclodextrin, (2-Hydroxypropyl)-ß-cyclodextrin (HP-β-CD), has previously been shown to deplete intraneuronal unesterified cholesterol, resulting in effective reduction of Aß production and amelioration of disease progression in mouse models of AD and Niemann Pick Type C (NPC) disease. Here, we tested whether HP-β-CD could also improve phenotypic progression in SOD1G93A mice. Methods Pre-symptomatic male SOD1G93A mice were randomly assigned to the following treatment groups: HP-β-CD (4000mg/kg, n = 9) or vehicle (saline; n = 10), delivered by weekly subcutaneous injection, commencing at 67 days of age. Longitudinal grip-strength and body mass analysis was performed until late-stage disease (120 days of age), followed by in vivo bilateral isometric muscle tension analysis of tibialis anterior (TA) and extensor digitorum longus (EDL) muscles. Results: HP-β-CD administration had no effect on body mass or grip-strength compared to vehicle treated SOD1G93A mice. Similarly, HP-β-CD treatment had no effect on muscle force, contractile properties or motor unit number estimates (MUNE) at late-stage disease in SOD1G93A mice. Conclusion This study shows that HP-β-CD does not confer any therapeutic benefit in SOD1G93A mice. However, the absence of detrimental effects is informative, given the common use of cyclodextrins as complexing agents for other pharmaceutical products, their standalone therapeutic potential and the emerging association between dyslipidaemia and ALS progression.

IMMUNOHISTOCHEMICAL EXPRESSION OF GFAP, GS, AQP4, ALZHEIMER-2-ASTROCYTOSIS AND BRAIN AMMONIA LEVELS IN DECEASED SEPTIC PATIENTS WITHOUT LIVER FAILURE AND THOSE WITH SEPSIS-ASSOCIATED LIVER INJURY

Sepsis-associated liver injury (SALI) induces secondary hepatotoxic brain damage, complementing the mechanisms of sepsis-associated encephalopathy. In these conditions, astrocytes play one of the central roles as being the main homeostatic glia and key cells to metabolize ammonia in the brain.&#x0D; The aim of the study was to determine the ammonia levels and reactive astroglial changes in the brain of deceased septic patients without liver failure and deceased patients with sepsis-associated liver injury.&#x0D; Materials and methods. Sectional material of 40 patients who died from abdominal sepsis was studied. Case histories were analyzed according to the SOFA scale with accent on the brain and liver disfunction confirmation and excluding kidney insufficiency. Septic cases designed two main comparison groups: 1) sepsis without SALI («non-SALI», n = 20); 2) sepsis with SALI («SALI», n = 20). Control group included autopsy material of 30 deceased patients with cardiovascular pathology with no inflammatory, metabolic or toxic comorbidity. In paraffin sections of the postmortem brain cortex, white matter, hippocampus, thalamus, striatum, and cerebellum, it was determined: i) immunohistochemical expression of GFAP, GS, and AQP4; ii) histochemical expression of tissue ammonia with Nessler's reagent according to V. Gutiérrez-de-Juan et al. (2017); iii) Що це за позначення ?numbers of Alzheimer type 2 astrocytes (AA2).&#x0D; Results. In the «non-SALI» group, it is found increased level of all the studied parameters: i) elevated GFAP in six brain regions with the highest growth in the cortex – by 8.46 times; ii) elevated GS in the thalamus and cerebellum (by 1.96 and 1.29 times, respectively); iii) elevated AQP4 in six brain regions with the highest rise in the cortex – by 3 times; iv) elevated histochemical ammonia expression in the thalamus, striatum, and cerebellum (by 1.29, 1.20, and 1.17 times, respectively); v) increased AA2 numbers in the cortex and thalamus (by 2.32 and 1.53 times, respectively). The «SALI» group is characterized by the decreased GFAP expression in six brain regions, with the lowest values in thalamus, striatum, and cerebellum. Herewith, in six brain regions increased levels are typical for: i) GS expression, with maximal aggravation in the cortex and thalamus (by 3.20 and 3.18 times, respectively); ii) AQP4 expression, with maximal increase in thalamus and white matter (by 4.37 and 4.21 times, respectively); iii) histochemical ammonia expression with maximal enhancement in thalamus and cerebellum (by 4.33 and 4.27 times, respectively); iv) severity of AA2-astrocytosis with maximal rates in the cortex and striatum (increase by 3.58 and 3.23 times, respectively).&#x0D; Conclusions. In the brain of deceased septic patients without liver failure, a heterogeneously increased expression of GFAP, AQP4 and GS is observed which is accompanied by a slight increase in the level of tissue ammonia and weak AA2-astrocytosis. In deceased septic patients with sepsis-associated liver injury, a higher level of ammonia in the brain is associated with a significantly reduced level of GFAP, which is accompanied by an enhanced expression of GS and AQP4, as well as more pronounced AA2-astrocytosis, which indicates significant structural and functional remodeling and aggravation of astroglial dystrophy under action of hepatogenic neurointoxicity, which contributes to the disruption of astroglial homeostatic functionality and exacerbates sepsis-associated brain damage.

Multi-Center Validation of Pain Assessment in Advanced Dementia (PAINAD) Scale in Malaysia

The detection of pain in persons with advanced dementia is challenging due to their inability to verbally articulate the pain they are experiencing. Pain Assessment in Advanced Dementia (PAINAD) is an observer-rated pain assessment tool developed based on non-verbal expressions of pain for persons with severe dementia. This study aimed to perform construct validation of PAINAD for pain assessment in persons with severe dementia in Malaysia. This was a prospective cross-sectional study conducted from 27 April 2022 to 28 October 2022 in eight public hospitals in Malaysia. The PAINAD scale was the index test, and the Discomfort Scale—Dementia of the Alzheimer Type (DS-DAT) and Nurse-Reported Pain Scale (NRPS) were the reference tests for construct and concurrent validity assessment. Pain assessment for the study subjects was performed by two raters concurrently at rest and during activity. The PAINAD score was determined by the first rater, whereas the DS-DAT and NRPS were assessed by the second rater, and they were blinded to each other’s findings to prevent bias. PAINAD showed good positive correlations ranging from 0.325 to 0.715 with DS-DAT and NRPS at rest and during activity, with a p-value of &lt;0.05. It also demonstrated statistically significant differences when comparing pain scores at rest and during activity, pre- and post-intervention. In conclusion, the PAINAD scale is a reliable observer-rated pain assessment tool for persons with severe dementia in Malaysia. It is also sensitive to changes in the pain level during activity and at rest, pre- and post-intervention.

Cognitive impairments predict the behavioral and psychological symptoms of dementia.

The purpose of this study was to (1) validate the Thai version of the Neuropsychiatric Inventory Questionnaire (NPI-Q) as a screening tool for behavioral and psychological symptoms of dementia (BPSD), and (2) examine the relationship between cognitive performance and BPSD in an elderly population with amnestic mild cognitive impairment (aMCI) and dementia of Alzheimer's type (DAT). One hundred and twenty participants, comprising 80 aMCI and 40 DAT patients, and their respective caregivers were included in the study. Participants completed the NPI-Q and the Neuropsychiatric Inventory (NPI) within 2 weeks of each other and cognitive performance was primarily assessed using the Montreal Cognitive Assessment (MoCA). The Thai NPI-Q had good validity and reliability. Pure exploratory bifactor analysis revealed that a general factor and a single-group factor (with high loadings on delusions, hallucinations, apathy, and appetite) underpinned the NPI-Q domains. Significant negative correlations between the MoCA total score and the general and single-group NPI-Q scores were found in all subjects (aMCI + DAT combined) and DAT alone, but not in aMCI. Cluster analysis allocated subjects with BPSD (10% of aMCI and 50% of DAT participants) into a distinct "DAT + BPSD" class. The NPI-Q is an appropriate instrument for assessing BPSD and the total score is largely predicted by cognitive deficits. It is plausible that aMCI subjects with severe NPI-Q symptoms (10% of our sample) may have a poorer prognosis and constitute a subgroup of aMCI patients who will likely convert into probable dementia.

PCP4 Promotes Alzheimer's Disease Pathogenesis by Affecting Amyloid-β Protein Precursor Processing.

Down syndrome (DS) is caused by an extra copy of all or part of chromosome 21. The patients with DS develop typical Alzheimer's disease (AD) neuropathology, indicating the role of genes on human chromosome 21 (HSA21) in the pathogenesis of AD. Purkinje cell protein 4 (PCP4), also known as brain-specific protein 19, is a critical gene located on HSA21. However, the role of PCP4 in DS and AD pathogenesis is not clear. To explore the role of PCP4 in amyloid-β protein precursor (AβPP) processing in AD. In this study, we investigated the role of PCP4 in AD progression in vitro and in vivo. In vitro experiments, we overexpressed PCP4 in human Swedish mutant AβPP stable expression or neural cell lines. In vitro experiments, APP23/PS45 double transgenic mice were selected and treated with AAV-PCP4. Multiple topics were detected by western blot, RT-PCR, immunohistochemical and behavioral test. We found that PCP4 expression was altered in AD. PCP4 was overexpressed in APP23/PS45 transgenic mice and PCP4 affected the processing of AβPP. The production of amyloid-β protein (Aβ) was also promoted by PCP4. The upregulation of endogenous AβPP expression and the downregulation of ADAM10 were due to the transcriptional regulation of PCP4. In addition, PCP4 increased Aβ deposition and neural plaque formation in the brain, and exuberated learning and memory impairment in transgenic AD model mice. Our finding reveals that PCP4 contributes to the pathogenesis of AD by affecting AβPP processing and suggests PCP4 as a novel therapeutic target for AD by targeting Aβ pathology.

Ameliorating the Role of Aripiprazole in Memory Deficits Induced by Intracerebroventricular Streptozotocin-Induced Dementia of Alzheimer's Type.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing immense suffering for the patients. Dopamine D2 and 5-hydroxytryptamine receptor 1A (5-HT1A) receptors' activation has been reported to play a crucial role in managing neurological outcomes in the brain and other health disorders. This study aimed to investigate the role of aripiprazole, a dopamine D2 and 5-HT1A selective receptors' activator, in the restoration of memory deficit induced by streptozotocin in mice. The cognitive functions of animals were determined using the Morris water maze. Brain sections were stained with hematoxylin and eosin and Congo red to examine the structural deviations. Brain oxidative stress (thiobarbituric acid reactive substance and glutathione), acetylcholinesterase activity, IL-6, and IL-10 were measured to assess biochemical alterations. Activation of D2 and 5-HT1A with aripiprazole attenuated STZ-induced cognitive deficit, increased brain GSH levels, reduced TBARS levels, AChE activity, IL-6 levels, and IL-10 levels and prevented STZ-induced brain anomalies in mice. Hence, the present study concluded that aripiprazole mitigated STZ-induced memory impairment and can be used as an efficacious therapeutic target for the management of AD.

It's Time to Go Quantum in Medicine.

As the field of medicine grows and expands, new scientific developments hold great promise for improving quality of care, clinical research, and the diagnosis and treatment of diseases. Quantum physics is a promising field that intersects with medicine much more than originally understood. In terms of diagnosing different diseases, incorporating quantum mechanics into the study of medicine can allow for efficient diagnosis before symptoms even arise in a patient. Applying theory-based mathematical structures that describe neuron transmission throughout the brain and mind on a quantum scale can help us to better understand neurological diseases in patients. Quantum theory can even give plausible explanations for subtle DNA changes and even telomere reduction in patients who develop cancer. Utilizing quantum theory in the field of medicine can help in understanding and applying treatments for a multitude of different diseases, such as Alzheimer's disease or diverse types of cancer, and even expand upon efficient and reliable diagnosis in clinical settings. Quantum physics is a pertinent advancing field that may have a significant impact on expanding medical care and treatment in the near future. In this review, the application of quantum physics in medicine is discussed.

The Neurotoxic Effect of β-Amyloid Is Accompanied by Changes in the Mitochondrial Dynamics and Autophagy in Neurons and Brain Endothelial Cells in the Experimental Model of Alzheimer's Disease.

A comparative assessment of the expression of the mitochondrial fission marker Drp1 and the autophagy marker LC3 in neurons and endothelial cells in the hippocampus and entorhinal cortex during progression of cognitive deficit was performed in animals with intrahippocampal administration of β-amyloid. In both brain regions, the expression of Drp1 and LC3 in neuronal and endothelial cells was enhanced. The peak of cognitive impairment corresponded to the maximum expression of Drp1 and LC3 in hippocampal neurons and was preceded by an increase in the number of Drp1+ and LC3+ endothelial cells in this brain region. These data attests to a possible role of aberrant mitochondrial dynamics and autophagy of endothelial cells in the impairment of brain plasticity in the Alzheimer's type neurodegeneration.

The role of Neuropsychological assessment in the Differential Diagnoses of Late-Onset Depression, Dementia, and Mild Cognitive Impairment

Objective: The present study aimed to compare the neuropsychological test parameters of dementia, depression, and MCI patients and determine the disease-specific test characteristics and their relationship with electroencephalography. Methods: Ninety-one patients who were admitted to the neurology outpatient clinic with forgetfulness complaints between October 2019 and March 2022 and whose neuropsychological tests were performed were included in the study. The files of these 91 patients were reviewed retrospectively and their sociodemographic data were recorded. Furthermore, the EEG results which were taken during the patients' evaluation period due to forgetfulness were evaluated. Neuropsychological tests were compared between patients with dementia, MCI and depression. It was also investigated whether there was a relationship between NPT test parameters and EEG in patients with EEG results. Results: The study was completed with 87 patients. Of these 87 patients, 54 were female and 33 were male. Twenty-four patients had depression, 16 MCI, and 47 dementia. All of the dementia patients had Alzheimer's type dementia. When dementia, depression, and MCI groups were compared, the age difference was statistically significant (p=0.001). The mean age of the depression group was 66.5, the MCI group was 73.5, and the dementia group was 77. WMS-I, WMS-II, WMS-III, WMS-IV, similarities test, clock drawing test, trail making test, shape copying, language, and mood evaluation tests were statistically significantly different between the groups. There was no statistically significant difference between the groups regarding gender, education level, dominant hand, and occupation. EEG background activity frequencies were also examined between the groups, and there was no statistically significant difference. Conclusion: In conclusion, when evaluating patients who present with the complaint of forgetfulness, a detailed neuropsychological evaluation must be performed in addition to other diagnostic tests. Sensitive tests should be included to confirm the diagnosis, especially in cases where being in between for the differential diagnosis. Thus, further studies are needed on this subject.

Differential response to donepezil in MRI subtypes of mild cognitive impairment

BackgroundDonepezil is an approved therapy for the treatment of Alzheimer’s disease (AD). Results across clinical trials have been inconsistent, which may be explained by design-methodological issues, the pathophysiological heterogeneity of AD, and diversity of included study participants. We investigated whether response to donepezil differs in mild cognitive impaired (MCI) individuals demonstrating different magnetic resonance imaging (MRI) subtypes.MethodsFrom the Hippocampus Study double-blind, randomized clinical trial, we included 173 MCI individuals (donepezil = 83; placebo = 90) with structural MRI data, at baseline and at clinical follow-up assessments (6–12-month). Efficacy outcomes were the annualized percentage change (APC) in hippocampal, ventricular, and total grey matter volumes, as well as in the AD cortical thickness signature. Participants were classified into MRI subtypes as typical AD, limbic-predominant, hippocampal-sparing, or minimal atrophy at baseline. We primarily applied a subtyping approach based on continuous scale of two subtyping dimensions. We also used the conventional categorical subtyping approach for comparison.ResultsDonepezil-treated MCI individuals showed slower atrophy rates compared to the placebo group, but only if they belonged to the minimal atrophy or hippocampal-sparing subtypes. Importantly, only the continuous subtyping approach, but not the conventional categorical approach, captured this differential response.ConclusionsOur data suggest that individuals with MCI, with hippocampal-sparing or minimal atrophy subtype, may have improved benefit from donepezil, as compared with MCI individuals with typical or limbic-predominant patterns of atrophy. The newly proposed continuous subtyping approach may have advantages compared to the conventional categorical approach. Future research is warranted to demonstrate the potential of subtype stratification for disease prognosis and response to treatment.Trial registrationClinicalTrial.gov NCT00403520. Submission Date: November 21, 2006.

Analysis of emotional prosody as a tool for differential diagnosis of cognitive impairments: a pilot research.

This pilot research was designed to investigate if prosodic features from running spontaneous speech could differentiate dementia of the Alzheimer's type (DAT), vascular dementia (VaD), mild cognitive impairment (MCI), and healthy cognition. The study included acoustic measurements of prosodic features (Study 1) and listeners' perception of emotional prosody differences (Study 2). For Study 1, prerecorded speech samples describing the Cookie Theft picture from 10 individuals with DAT, 5 with VaD, 9 with MCI, and 10 neurologically healthy controls (NHC) were obtained from the DementiaBank. The descriptive narratives by each participant were separated into utterances. These utterances were measured on 22 acoustic features via the Praat software and analyzed statistically using the principal component analysis (PCA), regression, and Mahalanobis distance measures. The analyses on acoustic data revealed a set of five factors and four salient features (i.e., pitch, amplitude, rate, and syllable) that discriminate the four groups. For Study 2, a group of 28 listeners served as judges of emotions expressed by the speakers. After a set of training and practice sessions, they were instructed to indicate the emotions they heard. Regression measures were used to analyze the perceptual data. The perceptual data indicated that the factor underlying pitch measures had the greatest strength for the listeners to separate the groups. The present pilot work showed that using acoustic measures of prosodic features may be a functional method for differentiating among DAT, VaD, MCI, and NHC. Future studies with data collected under a controlled environment using better stimuli are warranted.

Shifting car travel to active modes to improve population health and achieve transport goals: A simulation study

IntroductionBeing physically active has multiple health benefits and contributes to the reduction of co-morbidities and mortality from chronic diseases. Active transport (walking and cycling) contributes to population health by enabling physical activity. We developed a simulation model to measure health impacts of transport scenarios for Melbourne, Australia. Our aim was to demonstrate active transport health impacts and support the materialization of policies for healthy cities and people. The model measures health impacts of increased physical activity from replacing short car trips for any purpose or for commuting under 5 km by walking and cycling. MethodsWe developed a micro-simulation model of physical activity and disease risk in combination with the well-established proportional multi-state life table model. We quantified life course health including health adjusted-life years, life years, new cases of diseases prevented, and deaths prevented for 14 chronic diseases associated with physical inactivity for the adult population of people from Melbourne, Australia in 2017. ResultsOver the life course of the Melbourne adult population of 3.6 million people in 2017, gains in health-adjusted life years ranged from 5,100 (95% Uncertainty Interval (UI) 3,700 to 6,500) for the scenario replacing commute trips by car under 1 km with walking up to 738,800 (95% UI 546,000 to 935,000) when replacing car trips under 2 km with walking and between 2 km and 5 km with cycling. We also estimated benefits in terms of reductions of new cases of diseases and deaths prevented, with the greatest gains for ischemic heart disease, stroke, Alzheimer's and other dementias and type 2 diabetes. ConclusionsWe found that shifting car travel to active modes would accrue important health benefits for the 2017 Melbourne population. Our results support policies and strategies for sustainable transport planning to contribute to reduce the burden from chronic diseases and environmental impact of car-oriented cities.

Crosstalk between Alzheimer's disease and diabetes: a focus on anti-diabetic drugs.

Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM) are two of the most common age-related diseases. There is accumulating evidence of an overlap in the pathophysiological mechanisms of these two diseases. Studies have demonstrated insulin pathway alternation may interact with amyloid-β protein deposition and tau protein phosphorylation, two essential factors in AD. So attention to the use of anti-diabetic drugs in AD treatment has increased in recent years. In vitro, in vivo, and clinical studies have evaluated possible neuroprotective effects of anti-diabetic different medicines in AD, with some promising results. Here we review the evidence on the therapeutic potential of insulin, metformin, Glucagon-like peptide-1 receptor agonist (GLP1R), thiazolidinediones (TZDs), Dipeptidyl Peptidase IV (DPP IV) Inhibitors, Sulfonylureas, Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors, Alpha-glucosidase inhibitors, and Amylin analog against AD. Given that many questions remain unanswered, further studies are required to confirm the positive effects of anti-diabetic drugs in AD treatment. So to date, no particular anti-diabetic drugs can be recommended to treat AD.

Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-β and Prevents Alzheimer's Disease-Type Pathology and Cognitive Deficits.

Deficiencies in the clearance of peripheral amyloid β (Aβ) play a crucial role in the progression of Alzheimer's disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aβ is decreased in AD. However, the exact mechanism of Aβ clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aβ. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβ in vivo and in vitro. Moreover, enhancing blood monocyte Aβ phagocytosis by improving energy metabolism alleviated brain Aβ deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aβ phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.

Determination of Biological Activities of Salvia sclarea L.

Within the last two or three decades the treatment of the neurodegenerative disorders became became the main focus of the researches. In this, our aim was to determine some biological activities of the ethanolic and methanolic extracts of Salvia sclarea L. After obtaining the extracts, first they have been tested for their DPPH radical scavenging activity and then the total phenolic contents of the extracts have been identified. Afterwords, the extracts were evaluated for both their effects on acetylcholinesterase (AChE) and monoamine oxidase-A. These two enzymes are very important enyzmes for their importance in the treatment of neurodegenerative disorders. AChE plays a very crucial role especially in Alzheimer’s Disease. Monoamine oxidases and their inhibitors have also critical value in Alzheimer type dementia and in other neurologic diseases. It has been found that DPPH activity of the methanolic extract was higher than that of ethanolic extracts; while TPC was higher for the ethanolic extract. IC50 values were found for both AChE and MAO-A. For AChE the IC50 values for ethanolic extract and methanolic extract were, 0,27±0,005 mg/mL and 1,19±0,037 mg/mL; respectively. And for MAO-A the IC50 values for ethanolic extract and methanolic extract were 6,53±0,72 microgramg/mL and 3,03±0,05 microgram/mL; respectively.

Decoding the genetic relationship between Alzheimer's disease and type 2 diabetes: potential risk variants and future direction for North Africa.

Alzheimer's disease (AD) and Type 2 diabetes (T2D) are both age-associated diseases. Identification of shared genes could help develop early diagnosis and preventive strategies. Although genetic background plays a crucial role in these diseases, we noticed an underrepresentation tendency of North African populations in omics studies. First, we conducted a comprehensive review of genes and pathways shared between T2D and AD through PubMed. Then, the function of the identified genes and variants was investigated using annotation tools including PolyPhen2, RegulomeDB, and miRdSNP. Pathways enrichment analyses were performed with g:Profiler and EnrichmentMap. Next, we analyzed variant distributions in 16 worldwide populations using PLINK2, R, and STRUCTURE software. Finally, we performed an inter-ethnic comparison based on the minor allele frequency of T2D-AD common variants. A total of 59 eligible papers were included in our study. We found 231 variants and 363 genes shared between T2D and AD. Variant annotation revealed six single nucleotide polymorphisms (SNP) with a high pathogenic score, three SNPs with regulatory effects on the brain, and six SNPs with potential effects on miRNA-binding sites. The miRNAs affected were implicated in T2D, insulin signaling pathways, and AD. Moreover, replicated genes were significantly enriched in pathways related to plasma protein binding, positive regulation of amyloid fibril deposition, microglia activation, and cholesterol metabolism. Multidimensional screening performed based on the 363 shared genes showed that main North African populations are clustered together and are divergent from other worldwide populations. Interestingly, our results showed that 49 SNP associated with T2D and AD were present in North African populations. Among them, 11 variants located in DNM3, CFH, PPARG, ROHA, AGER, CLU, BDNF1, CST9, and PLCG1 genes display significant differences in risk allele frequencies between North African and other populations. Our study highlighted the complexity and the unique molecular architecture of North African populations regarding T2D-AD shared genes. In conclusion, we emphasize the importance of T2D-AD shared genes and ethnicity-specific investigation studies for a better understanding of the link behind these diseases and to develop accurate diagnoses using personalized genetic biomarkers.

Differential expression and differential coexpression analyses revealed altered gene expressions and pathways in atypical Alzheimer’s Disease sub‐cohort brains

AbstractBackgroundIn the Alzheimer’s disease (AD) brain, the hyperphosphorylated tau protein forms neurofibrillary tangles (NFTs), which extent usually matches the dementia severity. However, for some patients, this is not the case. which we name them as asymptomatic AD (AsymAD, heavy NFTs but relatively normal cognition) and Low‐NFT AD (light NFT but severe dementia). We aim to characterize these two subtypes’ transcriptome and proteome, to understand the role of tauopathy in the AD etiology and identify resilient/vulnerable factors contributing to the cognitive decline as well as the potential drug targets for the precision treatment of AD.MethodWe performed differential analyses on both RNA and protein expression data from the atypical groups of two separate datasets ROSMAP and MSBB, using typical AD sub‐cohort as reference. In addition, highly correlated gene/protein co‐expression network modules were mined for each of the four datasets. Enrichment analysis identified biological processes and functions associated with the differentially expressed genes (DEGs) and co‐expressed modules.ResultFive DEG targets were tested in human AsymAD samples and compared with age‐matched controls and typical AD. Using western blot and qRT‐PCR, we confirmed the altered gene expressions in PSCK1 which is related to vesicle trafficking and neuron secretory pathway. Moreover, oppositely regulated pathways were identified for the two subtypes, such as oxidative phosphorylation pathway, neuron CREB signaling, necroptosis signaling pathway. Coexpression analysis also revealed that several coexpressed modules have significant altered expressions in the atypical AD subtypes as compared to typical AD group and are correlated with the disease severeness. For example, the protein modules from both ROSMAP and MSBB, which are enriched with mitochondrial functions and negatively correlated with disease severeness, are significantly elevated in Asym AD group than that of the typical AD or Low‐tau AD group.ConclusionWe have identified several altered pathways and genes that potentially render neuron protection or vulnerability. Identifying key factors in such uncoupling between tauopathy and cognitive impairment will not only improve precision medicine in AD, but also provide insights to prevent or slow down cognitive decline during AD progression. Further validations in Drosophila will elucidate their roles in the pathology or disease progression.

Levels of plasma neurofilament light and pTau‐181 predict for steeper cognitive decline in Typical AD and Hippocampal‐sparing compared to Limbic‐predominant AD subtype

AbstractBackgroundRecent studies suggest plasma neurofilament light (p‐NFL) and phosporylated‐Tau‐181 (p‐pTau181) are valuable biomarkers for detecting faster cognitive decline in patients with Alzheimer’s Disease (AD) dementia. Recently, AD subtyping has been used to subgroup patients into AD phenotypes with possibly different cognitive prognoses. The aim of this study was to investigate the interaction between p‐NFL and p‐pTau‐181 and different AD subtypes to predict decline in episodic memory.MethodIn total, 357 non‐AD (Aß‐) (Cognitive Normal and Mild Cognitive Impairment) and 73 AD subjects (Aß+, according to mainly Amyloid‐PET or ‐CSF) were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Subjects had at least one plasma sample and one MRI scan. The latter was used to subtype AD patients (Risacher et al. 2017). AD subjects were subtyped in Limbic‐predominant (18%), typical AD (67%) and Hippocampal‐sparing (15%) subtypes. The ADNI_MEM composite score was used as proxy for cognition. Linear mixed models were tested to predict cognitive decline up to 4.5 years of follow up (27.7±13.1 months) including the interaction between time, AD subtype and p‐NFL and p‐pTau‐181. Age, gender, education, and ApoE4 status were included in the models. Models were selected incrementally through model comparison (AIC, BIC). The final model included both p‐NFL and p‐pTau‐181.ResultThe AD subtypes did not differ in cognition (‐1±0.6 for the whole group) or age (74±8 ys for the whole group), but in gender. Higher p‐NFL levels in patients with Hippocampal‐sparing and Typical AD subtypes showed faster decline in cognition compared to non‐AD patients (p&lt;0.05, both), while Limbic‐predominant did not. For p‐pTau‐181, the interaction with Limbic‐predominant was significant and the model showed stronger separation of cognitive decline across all AD subtypes than p‐NFL. Combining both biomarkers improved the model but only the interactive effects of pTau‐181 for Hippocampal‐sparing and typical AD subtypes were significant (p&lt;0.05, both).ConclusionIn the Limbic‐predominant AD subtype the levels of the two plasma biomarkers p‐NFL and p‐pTau‐181 did not predict for progressive cognitive decline (episodic memory), suggesting that this AD subtype with late disease onset (contrary to the Hippocampal‐sparing subtype), cannot be early detected with plasma p‐NFL and p‐pTau‐181.