- Differentiation of mild cognitive impairment using an entorhinal cortex-based test of virtual reality navigation. [Journal Article]
- BBrain 2019 May 23
- The entorhinal cortex is one of the first regions to exhibit neurodegeneration in Alzheimer's disease, and as such identification of entorhinal cortex dysfunction may aid detection of the disease in …
The entorhinal cortex is one of the first regions to exhibit neurodegeneration in Alzheimer's disease, and as such identification of entorhinal cortex dysfunction may aid detection of the disease in its earliest stages. Extensive evidence demonstrates that the entorhinal cortex is critically implicated in navigation underpinned by the firing of spatially modulated neurons. This study tested the hypothesis that entorhinal-based navigation is impaired in pre-dementia Alzheimer's disease. Forty-five patients with mild cognitive impairment (26 with CSF Alzheimer's disease biomarker data: 12 biomarker-positive and 14 biomarker-negative) and 41 healthy control participants undertook an immersive virtual reality path integration test, as a measure of entorhinal-based navigation. Behavioural performance was correlated with MRI measures of entorhinal cortex volume, and the classification accuracy of the path integration task was compared with a battery of cognitive tests considered sensitive and specific for early Alzheimer's disease. Biomarker-positive patients exhibited larger errors in the navigation task than biomarker-negative patients, whose performance did not significantly differ from controls participants. Path-integration performance correlated with Alzheimer's disease molecular pathology, with levels of CSF amyloid-β and total tau contributing independently to distance error. Path integration errors were negatively correlated with the volumes of the total entorhinal cortex and of its posteromedial subdivision. The path integration task demonstrated higher diagnostic sensitivity and specificity for differentiating biomarker positive versus negative patients (area under the curve = 0.90) than was achieved by the best of the cognitive tests (area under the curve = 0.57). This study demonstrates that an entorhinal cortex-based virtual reality navigation task can differentiate patients with mild cognitive impairment at low and high risk of developing dementia, with classification accuracy superior to reference cognitive tests considered to be highly sensitive to early Alzheimer's disease. This study provides evidence that navigation tasks may aid early diagnosis of Alzheimer's disease, and the basis of this in animal cellular and behavioural studies provides the opportunity to answer the unmet need for translatable outcome measures for comparing treatment effect across preclinical and clinical trial phases of future anti-Alzheimer's drugs.
- Modeling the Effects of Yoga on the Progression of Alzheimer's Disease in a Dish. [Journal Article]
- CTCells Tissues Organs 2019 May 23; :1-9
- Alzheimer's disease (AD) accounts for 80% of all dementia cases, making it the most common form of dementia. Aging serves as the main risk factor for AD, but early onset AD can also occur in individu…
Alzheimer's disease (AD) accounts for 80% of all dementia cases, making it the most common form of dementia. Aging serves as the main risk factor for AD, but early onset AD can also occur in individuals younger than 65 years. AD results from progressive neurodegeneration leading to dysfunctional synaptic transmission in the brain. The cascade hypothesis of AD states that amyloid precursor protein (APP) metabolism becomes impaired either by mutation or an interleukin-mediated stress response to injury, resulting in the splicing of harmful oligomeric forms of amyloid beta (Aβ). These oligomers disrupt extracellular receptor binding, intracellular function, and cellular membrane integrity. Yoga and meditative practices slow the progression of the cognitive decline associated with AD. However, the biological mechanisms underlying this therapeutic effect remain elusive. Here, we investigated the ability of neurotransmitters released during yoga and meditative practices to rescue neurons from synaptic dysfunction in an in vitro Alzheimer's model created by culturing basal forebrain cholinergic neurons with physiologically relevant levels of the I-42 isoform of oligomeric Aβ (OΑβI-42). We found that the neurotransmitters dopamine and histamine produce a cooperative action with serotonin to reverse the loss of choline acetyltransferase (CHaT) by OΑβI-42. The loss of ChaT, the enzyme responsible for processing the cholinergic neurotransmitter acetylcholine, contributes to the synaptic dysfunction experienced during AD. These neurotransmitters inhibit nitric oxide synthesis caused by OΑβI-42, preventing oxidative and nitrosative stress. Serotonin activates an alternate cleavage of APP to produce a fragment with known neurotrophic effects, giving it the unique ability to inhibit the OΑβI-42 production cycle. We hypothesize here that these concerted actions lead to the protection of cholinergic synaptic transmission in AD.
- Tryptophan-related dipeptides in fermented dairy products suppress microglial activation and prevent cognitive decline. [Journal Article]
- AAging (Albany NY) 2019 May 23
- The rapid growth in aging populations has made prevention of age-related memory decline and dementia a high priority. Several epidemiological and clinical studies have concluded that fermented dairy …
The rapid growth in aging populations has made prevention of age-related memory decline and dementia a high priority. Several epidemiological and clinical studies have concluded that fermented dairy products can help prevent cognitive decline; furthermore, intake of Camembert cheese prevents microglial inflammation and Alzheimer's pathology in mouse models. To elucidate the molecular mechanisms underlying the preventive effects of fermented dairy products, we screened peptides from digested milk protein for their potential to regulate the activation of microglia. We identified dipeptides of tryptophan-tyrosine (WY) and tryptophan-methionine that suppressed the microglial inflammatory response and enhanced the phagocytosis of amyloid-β (Aβ). Various fermented dairy products and food materials contain the WY peptide. Orally administered WY peptide was smoothly absorbed into blood, delivered to the brain, and improved the cognitive decline induced by lipopolysaccharide via the suppression of inflammation. Intake of the WY peptide prevented microglial inflammation, hippocampal long-term potential deficit, and memory impairment in aged mice. In an Alzheimer's model using 5×FAD mice, intake of the WY peptide also suppressed microglial inflammation and accumulation of Aβ, which improved cognitive decline. The identified dipeptides regulating microglial activity could potentially be used to prevent cognitive decline and dementia related to inflammation.
- Visuospatial dysfunction in Alzheimer's disease and behavioural variant frontotemporal dementia. [Journal Article]
- JNJ Neurol Sci 2019 Apr 16; 402:74-80
- CONCLUSIONS: Visuospatial measures demonstrate limited ability to distinguish between AD and bvFTD unless disease severity is taken into consideration. Controlling for disease severity reveals a disproportionate visuospatial impairment in AD compared to bvFTD. Development of targeted measures of visuospatial function is required to improve differential diagnosis of these syndromes.
- Influence of different extraction techniques on the chemical profile and biological properties of Anthemis cotula L.: Multifunctional aspects for potential pharmaceutical applications. [Journal Article]
- JPJ Pharm Biomed Anal 2019 May 15; 173:75-85
- The phytochemical composition of different extracts obtained from stinking chamomile (Anthemis cotula L.) was investigated. Ethanol was used as solvent and accelerated solvent extraction (ASE), micro…
The phytochemical composition of different extracts obtained from stinking chamomile (Anthemis cotula L.) was investigated. Ethanol was used as solvent and accelerated solvent extraction (ASE), microwave assisted extraction (MAE), maceration, soxhlet extraction (SE), and ultrasound assisted extraction (UAE) were applied on plant material. Comparison of the phytochemical contents, antioxidant, and enzyme inhibitory properties were performed. The most abundant sesquiterpene in the extracts was anthecotuloide, while the most present phenolics were caffeoyl quinic acid, quercetin, and kaempferol derivatives. UAE extract was the most efficient in the extraction of sesquiterpenoids and polyphenols. Considering the assays on antioxidant activity and enzyme inhibition, ASE extract showed highest phenolic content (62.92 mg gallic acid equivalent/g extract). Likewise, this extract showed highest radical scavenging (103.44 mg trolox equivalent [TE]/g extract and 155.70 mg TE/g extract, for DPPH and ABTS assays respectively) and reducing power potential (435.32 and 317.89 mg TE/g extract, for CUPRAC and FRAP assays, respectively). The different extracts showed similar results in the enzyme inhibition assays suggesting that the extraction methods used have no effect on observed enzyme activities. Novelty of our findings are the inhibitory action of the ethanol extract of A. cotula aerial parts on key enzymes associated with Alzheimer's disease (acetyl cholinesterase, butyryl cholinesterase), type 2 diabetes (α-amylase, α-glucosidase), and skin hyperpigmentation disorders (tyrosinase). Data collected from the present work further appraises the multiple potential biological properties of stinking chamomile suggesting the need for further investigation on its constituents.
- V232M substitution restricts a distinct O-glycosylation of PLD3 and its neuroprotective function. [Journal Article]
- NDNeurobiol Dis 2019 May 20
- The link between Val232Met variant of phospholipase D3 (PLD3) and late-onset Alzheimer's disease (AD) is still obscure. While it may not affect directly the amyloid precursor protein function, PLD3 c…
The link between Val232Met variant of phospholipase D3 (PLD3) and late-onset Alzheimer's disease (AD) is still obscure. While it may not affect directly the amyloid precursor protein function, PLD3 could be regulating multiple cellular compartments. Here, we investigated the function of wild-type human PLD3 (PLD3WT) and the Val232Met variant (PLD3VM) in the presence of β-amyloid (Aβ) in a Drosophila melanogaster model of AD. We expressed PLD3WT in CNS of the Aβ-model flies and monitored its effect on the ER stress, cell apoptosis and recovery the Aβ-induced cognitive impairment. The expression reduced ER stress and neuronal apoptosis, which resulted in normalized antioxidative phospholipids levels and brain protection. A specific O-glycosylation at pT271 in PLD3 is essential for its normal trafficking and cellular localization. The V232 M substitution impairs this O-glycosylation, leading to enlarged lysosomes and plausibly aberrant protein recycling. PLD3VM was less neuroprotective, and while, PLD3WT expression enhances the lysosomal functions, V232 M attenuated PLD3's trafficking to the lysosomes. Thus, the V232 M mutation may affect AD pathogenesis. Further understanding of the mechanistic role of PLD3 in AD could lead to developing novel therapeutic agents.
- A model of brain morphological changes related to aging and Alzheimer's disease from cross-sectional assessments. [Journal Article]
- NNeuroimage 2019 May 20
- In this study we propose a deformation-based framework to jointly model the influence of aging and Alzheimer's disease (AD) on the brain morphological evolution. Our approach combines a spatio-tempor…
In this study we propose a deformation-based framework to jointly model the influence of aging and Alzheimer's disease (AD) on the brain morphological evolution. Our approach combines a spatio-temporal description of both processes into a generative model. A reference morphology is deformed along specific trajectories to match subject specific morphologies. It is used to define two imaging progression markers: 1) a morphological age and 2) a disease score. These markers can be computed regionally in any brain region. The approach is evaluated on brain structural magnetic resonance images (MRI) from the ADNI database. The model is first estimated on a control population using longitudinal data, then, for each testing subject, the markers are computed cross-sectionally for each acquisition. The longitudinal evolution of these markers is then studied in relation with the clinical diagnosis of the subjects and used to generate possible morphological evolutions. In the model, the morphological changes associated with normal aging are mainly found around the ventricles, while the Alzheimer's disease specific changes are located in the temporal lobe and the hippocampal area. The statistical analysis of these markers highlights differences between clinical conditions even though the inter-subject variability is quite high. The model is also generative since it can be used to simulate plausible morphological trajectories associated with the disease. Our method quantifies two interpretable scalar imaging biomarkers assessing respectively the effects of aging and disease on brain morphology, at the individual and population level. These markers confirm the presence of an accelerated apparent aging component in Alzheimer's patients but they also highlight specific morphological changes that can help discriminate clinical conditions even in prodromal stages. More generally, the joint modeling of normal and pathological evolutions shows promising results to describe age-related brain diseases over long time scales.
- Age and Sex Differences in Motivation and Spatial Working Memory in 3xTg-AD Mice in the Hebb-Williams Maze. [Journal Article]
- BBBehav Brain Res 2019 May 20
- The 3xTg-AD mouse model of Alzheimer's disease (AD) has both amyloid beta plaque and tau tangle pathology. However, the results of behavioural testing with these mice have been inconsistent due to ag…
The 3xTg-AD mouse model of Alzheimer's disease (AD) has both amyloid beta plaque and tau tangle pathology. However, the results of behavioural testing with these mice have been inconsistent due to age- and sex-related differences, as well as differences in the difficulty of the tests used to measure cognitive function. In order to better understand the sex- and age-related spatial working memory deficits in the 3xTg-AD mice compared to their B6129S/F2 wildtype controls, we tested 4 and 7-month-old males and females and 13-month-old females in the Hebb-Williams maze. In the acquisition phase, the 3xTg-AD mice performed better than the WT controls, but the females of both genotypes showed motivational deficits; often returning to the start box and failing to eat the food reward, thus taking longer than males to meet the criterion for acquisition. The 3xTg-AD mice showed more working memory deficits than WT mice during the test phase, and the difference increased as the problems increased in difficulty. The results of this study indicate that female 3xTg-AD mice may have motivational deficits in tests using food reward and that the cognitive deficits of the 3xTg-AD mice are not apparent when the tests are too easy; the more difficult the task, the more deficits are shown in the 3xTg-AD mice compared to WT controls. Thus, the inconsistency in previous results may result from differences in motivation and in test difficulty and these must be considered when evaluating cognitive deficits in the 3xTg-AD mice.
- Coffee polyphenols prevent cognitive dysfunction and suppress amyloid β plaques in APP/PS2 transgenic mouse. [Journal Article]
- NRNeurosci Res 2019 May 20
- Epidemiological studies have found that habitual coffee consumption may reduce the risk of Alzheimer's disease. Coffee contains numerous phenolic compounds (coffee polyphenols) such as chlorogenic ac…
Epidemiological studies have found that habitual coffee consumption may reduce the risk of Alzheimer's disease. Coffee contains numerous phenolic compounds (coffee polyphenols) such as chlorogenic acids. However, evidence demonstrating the contribution of chlorogenic acids to the prevention of cognitive dysfunction induced by Alzheimer's disease is limited. The present study investigated the effect of chlorogenic acids on the prevention of cognitive dysfunction in APP/PS2 transgenic mouse model of Alzheimer's disease. Five-week-old APP/PS2 mice were administered a diet supplemented with coffee polyphenols daily for 5 months. The memory and cognitive function of mice was determined using the novel object recognition test, Morris water maze test, and the step-through passive avoidance test. Immunohistochemical analysis revealed that chronic treatment with coffee polyphenols prevented cognitive dysfunction and significantly reduced the amount of amyloid β (Aβ) plaques in the hippocampus. Furthermore, we determined that 5-caffeoylquinic acid, one of the primary coffee polyphenols, did not inhibit Aβ fibrillation; however, degraded Aβ fibrils. In conclusion, our results demonstrate that coffee polyphenols prevent cognitive deficits and reduce Aβ plaque deposition via disaggregation of Aβ in the APP/PS2 mouse.
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- Exploitation vs. exploration-computational temporal and semantic analysis explains semantic verbal fluency impairment in Alzheimer's disease. [Journal Article]
- NNeuropsychologia 2019 May 20
- Impaired Semantic Verbal Fluency (SVF) in dementia due to Alzheimer's Disease (AD) and its precursor Mild Cognitive Impairment (MCI) is well known. Yet, it remains open whether this impairment mirror…
Impaired Semantic Verbal Fluency (SVF) in dementia due to Alzheimer's Disease (AD) and its precursor Mild Cognitive Impairment (MCI) is well known. Yet, it remains open whether this impairment mirrors the breakdown of semantic memory retrieval processes or executive control processes. Therefore, qualitative analysis of the SVF has been proposed but is limited in terms of methodology and feasibility in clinical practice. Consequently, research draws no conclusive picture which of these afore-mentioned processes drives the SVF impairment in AD and MCI. This study uses a qualitative computational approach-combining temporal and semantic information-to investigate exploitation and exploration patterns as indicators for semantic memory retrieval and executive control processes. Audio SVF recordings of 20 controls (C, 66-81 years), 55 MCI (57-94 years) and 20 AD subjects (66-82 years) were assessed while groups were matched according to age and education. All groups produced, on average, the same amount of semantically related items in rapid succession within word clusters. Conversely, towards AD, there was a clear decline in semantic as well as temporal exploration patterns between clusters. Results strongly point towards preserved exploitation-semantic memory retrieval processes-and hampered exploration-executive control processes-in AD and potentially in MCI.