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24 Feb 2021 at 01:32
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Bibliography on: Alzheimer Disease — Current Literature


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RJR: Recommended Bibliography 24 Feb 2021 at 01:32 Created: 

Alzheimer Disease — Current Literature

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. This bibliography runs a generic query on "Alzheimer" and then restricts the results to papers published in or after 2017.

Created with PubMed® Query: alzheimer[TIAB] and (2017[PDAT] OR [2018[PDAT] OR 2019[PDAT] OR 2020[PDAT] OR 2021[PDAT]) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2021-02-23

Núñez P, Poza J, Gómez C, et al (2021)

Abnormal meta-state activation of dynamic brain networks across the Alzheimer spectrum.

NeuroImage pii:S1053-8119(21)00175-0 [Epub ahead of print].

The characterization of the distinct dynamic functional connectivity (dFC) patterns that activate in the brain during rest can help to understand the underlying time-varying network organization. The presence and behavior of these patterns (known as meta-states) have been widely studied by means of functional magnetic resonance imaging (fMRI). However, modalities with high-temporal resolution, such as electroencephalography (EEG), enable the characterization of fast temporally evolving meta-state sequences. Mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD) have been shown to disrupt spatially localized activation and dFC between different brain regions, but not much is known about how they affect meta-state network topologies and their network dynamics. The main hypothesis of the study was that MCI and dementia due to AD alter normal meta-state sequences by inducing a loss of structure in their patterns and a reduction of their dynamics. Moreover, we expected that patients with MCI would display more flexible behavior compared to patients with dementia due to AD. Thus, the aim of the current study was twofold: (i) to find repeating, distinctly organized network patterns (meta-states) in neural activity; and (ii) to extract information about meta-state fluctuations and how they are influenced by MCI and dementia due to AD. To accomplish these goals, we present a novel methodology to characterize dynamic meta-states and their temporal fluctuations by capturing aspects based on both their discrete activation and the continuous evolution of their individual strength. These properties were extracted from 60-s resting-state EEG recordings from 67 patients with MCI due to AD, 50 patients with dementia due to AD, and 43 cognitively healthy controls. First, the instantaneous amplitude correlation (IAC) was used to estimate instantaneous functional connectivity with a high temporal resolution. We then extracted meta-states by means of graph community detection based on recurrence plots (RPs), both at the individual- and group-level. Subsequently, a diverse set of properties of the continuous and discrete fluctuation patterns of the meta-states was extracted and analyzed. The main novelty of the methodology lies in the usage of Louvain GJA community detection to extract meta-states from IAC-derived RPs and the extended analysis of their discrete and continuous activation. Our findings showed that distinct dynamic functional connectivity meta-states can be found on the EEG time-scale, and that these were not affected by the oscillatory slowing induced by MCI or dementia due to AD. However, both conditions displayed a loss of meta-state modularity, coupled with shorter dwell times and lower complexity of the meta-state sequences. Furthermore, we found evidence that meta-state sequencing is not entirely random; it shows an underlying structure that is partially lost in MCI and dementia due to AD. These results show evidence that AD progression is associated with alterations in meta-state switching, and a degradation of dynamic brain flexibility.

RevDate: 2021-02-23

Haller S, Haacke EM, Thurnher MM, et al (2021)

Susceptibility-weighted Imaging: Technical Essentials and Clinical Neurologic Applications.

Radiology [Epub ahead of print].

Susceptibility-weighted imaging (SWI) evolved from simple two-dimensional T2*-weighted sequences to three-dimensional sequences with improved spatial resolution and enhanced susceptibility contrast. SWI is an MRI sequence sensitive to compounds that distort the local magnetic field (eg, calcium and iron), in which the phase information can differentiate. But the term SWI is colloquially used to denote high-spatial-resolution susceptibility-enhanced sequences across different MRI vendors and sequences even when phase information is not used. The imaging appearance of SWI and related sequences strongly depends on the acquisition technique. Initially, SWI and related sequences were mostly used to improve the depiction of findings already known from standard two-dimensional T2*-weighted neuroimaging: more microbleeds in patients who are aging or with dementia or mild brain trauma; increased conspicuity of superficial siderosis in Alzheimer disease and amyloid angiopathy; and iron deposition in neurodegenerative diseases or abnormal vascular structures, such as capillary telangiectasia. But SWI also helps to identify findings not visible on standard T2*-weighted images: the nigrosome 1 in Parkinson disease and dementia with Lewy bodies, the central vein and peripheral rim signs in multiple sclerosis, the peripheral rim sign in abscesses, arterial signal loss related to thrombus, asymmetrically prominent cortical veins in stroke, and intratumoral susceptibility signals in brain neoplasms.

RevDate: 2021-02-23

Mooko T, Bala A, Tripathy S, et al (2021)

Cannabis Sativa L. Flower and Bud Extracts inhibited In vitro Cholinesterases and b-Secretase Enzymes Activities: Possible Mechanisms of Cannabis use in Alzheimer Disease.

Endocrine, metabolic & immune disorders drug targets pii:EMIDDT-EPUB-114436 [Epub ahead of print].

BACKGROUND: There are anecdotal claims on the use of Cannabis sativa L. in the treatment of Alzheimer's disease, but there is lack of scientific data to support the efficacy and safety of Cannabis sativa L. for Alzheimer's disease.

AIM: The aim of the study was to evaluate the effect of aerial parts of Cannabis sativa L. on the cholinesterases and β-secretase enzyme activity as one of the possible mechanisms of Alzheimer's disease.

METHODS: The phytochemical and heavy metal contents were analysed. The extracts were screened for acetylcholinesterase, butyrylcholinesterase and β-secretase activity. Cytotoxicity of extracts was performed in normal vero and pre-adipocytes cell lines. The extracts were characterized using high performance thin layer chromatography and high-performance liquid chromatography for their chemical fingerprints. Alkaloids, flavonoids and glycosides were present amongst the tested phytochemicals. Cannabidiol concentrations were comparatively high in the hexane and dichloromethane than in dichloromethane: methanol (1:1) and methanol extracts.

RESULTS: Hexane and dichloromethane extracts showed a better inhibitory potential towards cholinesterase activity, while water, hexane, dichloromethane: methanol (1:1) and methanol showed an inhibitory potential towards β-secretase enzyme activity. All extracts showed no cytotoxic effect on pre-adipocytes and vero cells after 24- and 48-hours of exposure.

CONCLUSION: Therefore, this may explain the mechanism through which AD symptoms may be treated and managed by Cannabis sativa L. extracts.

RevDate: 2021-02-22

Brymer KJ, Barnes JR, MP Parsons (2021)

Entering a new era of quantifying glutamate clearance in health and disease.

Journal of neuroscience research [Epub ahead of print].

Glutamate transporter proteins, expressed on both neurons and glia, serve as the main gatekeepers that dictate the spatial and temporal actions of extracellular glutamate. Glutamate is essential to the function of the healthy brain yet paradoxically contributes to the toxicity associated with many neurodegenerative diseases. Rapid transporter-mediated glutamate uptake, primarily occurring at astrocytic processes, tightens the efficiency of excitatory network activity and prevents toxic glutamate build-up in the extracellular space. Glutamate transporter dysfunction is thought to underlie myriad central nervous system (CNS) diseases including Alzheimer and Huntington disease. Over the past few decades, techniques such as biochemical uptake assays and electrophysiological recordings of transporter currents from individual astrocytes have revealed the remarkable ability of the CNS to efficiently clear extracellular glutamate. In more recent years, the rapidly evolving glutamate-sensing "sniffers" now allow researchers to visualize real-time glutamate transients on a millisecond time scale with single synapse spatial resolution in defined cell populations. As we transition to an increased reliance on optical-based methods of glutamate visualization and quantification, it is of utmost importance to understand not only the advantages that glutamate biosensors bring to the table but also the associated caveats and their implications for data interpretation. In this review, we summarize the strengths and limitations of the commonly used methods to quantify glutamate uptake. We then discuss what these techniques, when viewed as a complementary whole, have told us about the brain's ability to regulate glutamate levels, in both health and in the context of neurodegenerative disease.

RevDate: 2021-02-22

Nichols JB, Malek-Ahmadi M, Tariot PN, et al (2021)

Vascular Lesions, APOE ε4, and Tau Pathology in Alzheimer Disease.

Journal of neuropathology and experimental neurology, 80(3):240-246.

We sought to determine the associations among cerebral amyloid angiopathy (CAA), white matter rarefaction (WMR), circle of Willis atherosclerosis (CWA), and total microinfarct number with Braak neurofibrillary stage in postmortem individuals with and without Alzheimer disease (AD). Data from 355 cases of autopsied individuals with Braak stage I-VI who had antemortem consensus diagnoses of cognitively unimpaired (n = 183), amnestic mild cognitive impairment (n = 31), and AD dementia (n = 141) were used. The association between Braak stage and vascular lesions were individually assessed using multivariable linear regression that adjusted for age at death, APOE ε4 carrier status, sex, education, and neuritic plaque density. CAA (p = 0.007) and WMR (p < 0.001) were associated with Braak stage, independent of amyloid load; microinfarct number and CWA showed no association. Analyses of the interactions between APOE ε4 carrier status and vascular lesions found that greater WMR and positive ε4 carrier status were associated with higher Braak stages. These results suggest that CAA and WMR are statistically linked to the severity of AD-related NFT pathology. The statistical link between WMR and NFT load may be strengthened by the presence of APOE ε4 carrier status. An additional finding was that Lewy body pathology was most prevalent in higher Braak stages.

RevDate: 2021-02-22

Poumeaud F, Mircher C, Smith PJ, et al (2021)

Deciphering the links between psychological stress, depression, and neurocognitive decline in patients with Down syndrome.

Neurobiology of stress, 14:100305 pii:S2352-2895(21)00013-8.

The relationships between psychological stress and cognitive functions are still to be defined despite some recent progress. Clinically, we noticed that patients with Down syndrome (DS) may develop rapid neurocognitive decline and Alzheimer's disease (AD) earlier than expected, often shortly after a traumatic life event (bereavement over the leave of a primary caregiver, an assault, modification of lifestyle, or the loss of parents). Of course, individuals with DS are naturally prone to develop AD, given the triplication of chromosome 21. However, the relatively weak intensity of the stressful event and the rapid pace of cognitive decline after stress in these patients have to be noticed. It seems DS patients react to stress in a similar manner normal persons react to a very intense stress, and thereafter develop a state very much alike post-traumatic stress disorders. Unfortunately, only a few studies have studied stress-induced regression in patients with DS. Thus, we reviewed the biochemical events involved in psychological stress and found some possible links with cognitive impairment and AD. Interestingly, these links could probably be also applied to non-DS persons submitted to an intense stress. We believe these links should be further explored as a better understanding of the relationships between stress and cognition could help in many situations including individuals of the general population.

RevDate: 2021-02-22

Fahanik-Babaei J, Baluchnejadmojarad T, M Roghani (2020)

Differential Effect of Amyloid Beta1-40 on Short-term and Long-term Plasticity in Dentate Gyrus of a Rat Model of Alzheimer Disease.

Basic and clinical neuroscience, 11(4):517-524.

Introduction: Synaptic plasticity is inappropriately affected by neurodegenerative diseases, including Alzheimer Disease (AD). In this study, we examined the effect of intrahippocampal amyloid-beta (Aβ1-40) on dentate gyrus Long-term Potentiation (LTP) and presynaptic short-term plasticity in a rat model of AD.

Methods: The experimental groups in this research included the control with no treatment, sham-operated receiving the vehicle (normal saline), and Aβ-lesioned groups. For modeling AD, aggregated Aβ1-40 (10 μg/2 μl on each side) was injected into the hippocampal CA1. Three weeks later, Population Spike (PS) amplitude and slope ratios were determined at different Inter-pulse Intervals (IPI) of 10, 20, 30, and 50 ms as a valid indicator of the short-term presynaptic facilitation and/or depression. In addition, PS amplitude and slope were taken as an index of long-term synaptic plasticity after application of High-frequency Stimulation (HFS) to induce LTP in the medial perforant-dentate gyrus pathway.

Results: No significant differences were noted amongst the experimental groups regarding fEPSP slope and paired-pulse indices as indicators of short-term plasticity. In contrast, fEPSP slope and PS amplitude significantly decreased following the application of HFS in Aβ-injected group. In addition, there was no significant difference between the control and sham-operated groups regarding the mentioned parameters.

Conclusion: Findings of this study clearly demonstrated that microinjection of Aβ1-40 into the CA1 could impair LTP in dentate gyrus but could not modify short-term plasticity.

RevDate: 2021-02-22

Fahimi Truski F, Ghotbeddin Z, Tabandeh MR, et al (2020)

Crocin Treatment after Maternal Hypoxia Attenuates Spatial Memory Impairment and Expression of BACE1 and HIF-1α in Rat Offspring Brain.

Basic and clinical neuroscience, 11(4):499-506.

Introduction: Hypoxia via expression of Hypoxia-Inducible Factor-1 (HIF-1) is an important and effective factor in the onset and progression of memory disorders, such as Alzheimer Disease (AD). The activity of β-secretase (BACE1) is increased in hypoxia conditions. BACE1 triggers a cascade of pathological events resulting in AD. Crocin acts as a memoryimproving agent but its molecular mechanism is not well-known. Therefore, in this study, the effect of crocin on spatial memory, HIF-1α, and BACE1 gene expression was investigated in rat offspring under maternal hypoxia.

Methods: Female pregnant rats on the 20th day of pregnancy were divided into 4 groups, including sham, crocin-treated, hypoxia, and hypoxia group treated with crocin. In the hypoxia groups, pregnant rats were exposed to 7% oxygen and 93% nitrogen intensity for 3 h. In the crocin-treated group, crocin (30 mg/kg) was injected at P14-28 (i.p). At the end, Morris water maze was used to assess spatial memory and real-time polymerase chain reaction was performed to measure the expression of BACE1 and HIF-1α genes in the brain of offspring.

Results: Maternal hypoxia impaired memory compared with the sham group. However, crocin treatment improved cognitive behavior. HIF-1α and BACE1 expressions were upregulated in the brain of offspring in the hypoxia group. Crocin treatment could attenuate the expression of both genes.

Conclusion: According to our results, down-regulation of HIF-1α and BACE1 gene expressions in the brain of rat offspring after crocin treatment can be suggested as a molecular mechanism for crocin to improve spatial memory.

RevDate: 2021-02-22

Jin H, R Wang (2021)

Alzheimer-Associated Neuronal Thread Protein: Research Course and Prospects for the Future.

Journal of Alzheimer's disease : JAD pii:JAD201273 [Epub ahead of print].

Alzheimer's disease (AD) is the leading cause of dementia. With aging societies, the prevalence of AD is increasing dramatically worldwide. The onset of AD is often not identified, and currently no available treatments are capable of stopping the disease process and its effect on cognitive decline. Thus, well-validated biomarkers of the preclinical stages of AD are needed. Alzheimer-associated neuronal thread protein (AD7c-NTP) is a member of the neuronal thread protein family and has a molecular weight of approximately 41 kD. AD7c-NTP has been identified as a biomarker for its specifically elevated levels in putative brain domains, cerebrospinal fluid (CSF), and the urine of AD and mild cognitive impairment (MCI) patients. Since the urine test is non-invasive, easy to perform, and patients accept it more easily than other methods, the urinary AD7c-NTP concentration has been recommended as a practical diagnostic tool for diagnosing AD and MCI. AD7c-NTP has undergone nearly 25 years of research course from its initial discovery to pathological verification, multi-center clinical evaluation, improvement of detection methods, epidemiological investigation, and combined application with other biomarkers. However, as a fluid biomarker, AD7c-NTP can be detected in urine instead of the traditional biomarker sources-CSF or blood, which has made the use of AD7c-NTP as a biomarker controversial. In this article, we review the research course of AD7c-NTP and suggest directions for future research.

RevDate: 2021-02-22

Raj S, Vyas S, Modi M, et al (2021)

Comparative Evaluation of Diffusion Kurtosis Imaging and Diffusion Tensor Imaging in Detecting Cerebral Microstructural Changes in Alzheimer Disease.

Academic radiology pii:S1076-6332(21)00027-1 [Epub ahead of print].

OBJECTIVE: Comparative evaluation of diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) using a whole-brain atlas to comprehensively evaluate microstructural changes in the brain of Alzheimer disease (AzD) patients.

METHODS: Twenty-seven AzD patients and 25 age-matched controls were included. MRI data was analyzed using a whole-brain atlas with inclusion of 98 region of interests. White matter (WM) microstructural changes were assessed by Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), Kurtosis fractional anisotropy (KFA), mean kurtosis (MK), axial kurtosis (AK) and radial kurtosis (RK). Gray matter (GM) integrity was evaluated using KFA, MK, RK, AK and MD. Comparison of the DKI and DTI metrics were done using student t-test (p ≤ 0.001).

RESULTS: In AzD patients widespread increase in MD, AD and RD were found in various WM and GM region of interests. The extent of abnormality for DKI parameters was more limited in both GM and WM regions and revealed reduced kurtosis values except in lentiform nuclei. Both DKI and DTI parameters were sensitive to detect abnormality in WM areas with coherent and complex fiber arrangement. Receiver operating characteristic curve analysis for hippocampal values revealed the highest specificity of 88% for AK <0.6965 and highest sensitivity of 95.2% for MD >1.2659.

CONCLUSION: AzD patients have microstructural changes in both WM and GM and are well-depicted by both DKI and DTI. The alterations in kurtosis parameters, however, are more limited and correlate with areas in the brain primarily involved in cognition.

RevDate: 2021-02-22

Bergeret S, Queneau M, Rodallec M, et al (2021)

Brain Glucose Metabolism in Cerebral Amyloid Angiopathy: An FDG-PET Study.

Stroke [Epub ahead of print].

BACKGROUND AND PURPOSE: The in vivo diagnosis of cerebral amyloid angiopathy (CAA) is currently based on the Boston criteria, which largely rely on hemorrhagic features on brain magnetic resonance imaging. Adding to these criteria 18F-fluoro-deoxy-D-glucose (FDG) positron emission tomography, a widely available imaging modality, might improve their accuracy. Here we tested the hypothesis that FDG uptake is reduced in posterior cortical areas, particularly the primary occipital cortex, which pathologically bear the brunt of vascular Aβ deposition.

METHODS: From a large memory clinic database, we retrospectively included all patients in whom both brain magnetic resonance imaging and FDG positron emission tomography had been obtained as part of routine clinical care and who fulfilled the Boston criteria for probable CAA. None had a history of symptomatic intracerebral hemorrhage. FDG data processing involved (1) spatial normalization to the Montreal Neurology Institute/International Consortium for Brain Mapping 152 space and (2) generation of standardized FDG uptake (relative standardized uptake value; relative to the pons). The relative standardized uptake value data obtained in 13 regions of interest sampling key cortical areas and the cerebellum were compared between the CAA and age-matched control groups using 2 separate healthy subject databases and image-processing pipelines. The presence of significant hypometabolism (2-tailed P<0.05) was assessed for the bilaterally averaged regions-of-interest relative standardized uptake values.

RESULTS: Fourteen patients fulfilling the Boston criteria for probable CAA (≥2 exclusively lobar microbleeds) were identified. Significant hypometabolism (P range, 0.047 to <0.0001) consistently affected the posterior cortical areas, including the superior and inferior parietal, primary visual, lateral occipital, lateral temporal, precuneus, and posterior cingulate regions of interest. The anterior cortical areas were marginally or not significantly hypometabolic, and the cerebellum was spared.

CONCLUSIONS: Supporting our hypothesis, significant glucose hypometabolism predominantly affected posterior cortical regions, including the visual cortex. These findings from a small sample may have diagnostic implications but require replication in larger prospective studies. In addition, whether they generalize to CAA-related symptomatic intracerebral hemorrhage warrants specific studies.

RevDate: 2021-02-21

Liu MN, Liou YJ, Wang WC, et al (2021)

Group Music Intervention Using Percussion Instruments to Reduce Anxiety Among Elderly Male Veterans with Alzheimer Disease.

Medical science monitor : international medical journal of experimental and clinical research, 27:e928714 pii:928714.

BACKGROUND This study aimed to assess the impact of a group music intervention on anxiety and depression of elderly male veterans with dementia. MATERIAL AND METHODS In total, 50 elderly men with Alzheimer disease were randomly divided into intervention and control groups. Patients in the intervention group attended a 60-minute group music session that used percussion instruments with familiar music in the morning once a week for 12 weeks, whereas those in the control group received a rest and reading session at the same intervals and under the same conditions. The Hamilton Anxiety Rating Scale and Geriatric Depression Scale were used to assess anxiety and depression at baseline, week 6, and week 12. The Primary Measures of Music Audiation (PMMA) was used to assess musical aptitude at the baseline. RESULTS A significant reduction in the anxiety level following the 12-week music sessions was observed in the intervention group (P<.001), but there was no significant change in the control group. However, the change in depressive symptoms between the 2 groups was nonsignificant. In the intervention group, when stratifying patients based on music aptitude determined through PMMA assessment, patients with high PMMA scores had significantly reduced anxiety symptoms over time compared with those with low scores. CONCLUSIONS For elderly male veterans with dementia, participating in a group music intervention reduced anxiety symptoms. In patients with high musical aptitude, the treatment effects on anxiety reduction were satisfactory. Measures of music aptitude may provide valuable information regarding patients' response to music intervention.

RevDate: 2021-02-19

Rodrigues-Neves AC, Carecho R, Correia SC, et al (2021)

Retina and Brain Display Early and Differential Molecular and Cellular Changes in the 3xTg-AD Mouse Model of Alzheimer's Disease.

Molecular neurobiology [Epub ahead of print].

The concept 'the retina as a window to the brain' has been increasingly explored in Alzheimer´s disease (AD) in recent years, since some patients present visual alterations before the first symptoms of dementia. The retina is an extension of the brain and can be assessed by noninvasive methods. However, assessing the retina for AD diagnosis is still a matter of debate. Using the triple transgenic mouse model of AD (3xTg-AD; males), this study was undertaken to investigate whether the retina and brain (hippocampus and cortex) undergo similar molecular and cellular changes during the early stages (4 and 8 months) of the pathology, and if the retina can anticipate the alterations occurring in the brain. We assessed amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) levels, barrier integrity, cell death, neurotransmitter levels, and glial changes. Overall, the retina, hippocampus, and cortex of 3xTg-AD are not significantly affected at these early stages. However, we detected a few differential changes in the retina and brain regions, and particularly a different profile in microglia branching in the retina and hippocampus, only at 4 months, where the number and length of the processes decreased in the retina and increased in the hippocampus. In summary, at the early stages of pathology, the retina, hippocampus, and cortex are not significantly affected but already present some molecular and cellular alterations. The retina did not mirror the changes detected in the brain, and these observations should be taking into account when using the retina as a potential diagnostic tool for AD.

RevDate: 2021-02-19

Elkjaer ML, Nawrocki A, Kacprowski T, et al (2021)

CSF proteome in multiple sclerosis subtypes related to brain lesion transcriptomes.

Scientific reports, 11(1):4132.

To identify markers in the CSF of multiple sclerosis (MS) subtypes, we used a two-step proteomic approach: (i) Discovery proteomics compared 169 pooled CSF from MS subtypes and inflammatory/degenerative CNS diseases (NMO spectrum and Alzheimer disease) and healthy controls. (ii) Next, 299 proteins selected by comprehensive statistics were quantified in 170 individual CSF samples. (iii) Genes of the identified proteins were also screened among transcripts in 73 MS brain lesions compared to 25 control brains. F-test based feature selection resulted in 8 proteins differentiating the MS subtypes, and secondary progressive (SP)MS was the most different also from controls. Genes of 7 out these 8 proteins were present in MS brain lesions: GOLM was significantly differentially expressed in active, chronic active, inactive and remyelinating lesions, FRZB in active and chronic active lesions, and SELENBP1 in inactive lesions. Volcano maps of normalized proteins in the different disease groups also indicated the highest amount of altered proteins in SPMS. Apolipoprotein C-I, apolipoprotein A-II, augurin, receptor-type tyrosine-protein phosphatase gamma, and trypsin-1 were upregulated in the CSF of MS subtypes compared to controls. This CSF profile and associated brain lesion spectrum highlight non-inflammatory mechanisms in differentiating CNS diseases and MS subtypes and the uniqueness of SPMS.

RevDate: 2021-02-19

Vasconcelos-Filho FSL, da Rocha-E-Silva RC, Martins JER, et al (2021)

Neuroprotector Effect of Daily 8-Minutes of High-Intensity Interval Training in Rat Aβ1-42 Alzheimer Disease Model.

Current Alzheimer research pii:CAR-EPUB-114346 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is the most common and irreversible neurodegenerative disorder, and amyloid peptide plays a central role in its pathogenesis. Physical training contributes as a beneficial adaptation to AD. However, these effects may be underestimated because much of the literature used fixed training prescription variables (intensity and volume) throughout the protocol. Moreover, researchers poorly understand whether chronic high-intensity interval training (HIIT) exerts similar effects on the brain tissue of individuals with AD.

OBJECTIVE: This study evaluated the effect of 8 minutes of HIIT with incremental overload in an AD model.

METHODS: Forty male Wistar rats were divided into four groups: an untrained Sham group, Sham trained group, Aβ1-42 (Alzheimer's) untrained group, and Aβ1-42 (Alzheimer's) trained group (n=10 rats per group). Animals underwent stereotactic surgery and received a hippocampal injection of Aβ1-42 or a saline solution. Seven days after surgery, two weeks of treadmill adaptation followed by a maximal running test (MRT) was performed. Then, animals were subjected to eight weeks of HIIT. Rats were sacrificed 24 h after the behavioral tests (open field and Morris water maze), hippocampal tissue was extracted to analyze the redox balance and BDNF/TrkB pathway, and neuritic plaques (NP) were detected by evaluating silver impregnation.

RESULTS: The AD trained group presented a physical capacity amelioration every two weeks and locomotor, learning, and memory improvements (p<0.05). These effects were accompanied by increased CAT and SOD levels, followed by decreased lipid peroxidation (p<0.05). Furthermore, increased activation of the BDNF/TrkB (p<0.05) pathway and decreased NP was observed.

CONCLUSIONS: Based on these results, MRT was essential for an excellent chronic training protocol prescription and overload adjustment. Therefore, 8 minutes of HIIT daily for 8 weeks may reduce behavioral deficits by promoting a positive redox balance and increased activity of the BDNF/TrkB pathway that may contribute to NP attenuation.

RevDate: 2021-02-19

Siafaka PI, Mutlu G, NÜ Okur (2021)

Alzheimer's disease and its related Dementia types: A review on their management via nanotechnology based therapeutic strategies.

Current Alzheimer research pii:CAR-EPUB-114345 [Epub ahead of print].

BACKGROUND: Dementia and its related types such as Alzheimer's disease, vascular dementia and mixed dementia belong to brain associated diseases, resulting in long-term progressive memory loss. These diseases are so severe that can affect a person's daily routine. Up to date, treatment of de- mentias is still an unmet challenge due to their complex pathophysiology and unavailable efficient pharmacological approaches. The use of nanotechnology based pharmaceutical products could possibly improve the management of dementia given that nanocarriers could more efficiently deliver drugs to the brain.

OBJECTIVE: The objective of this study is to provide the current nanotechnology based drug delivery systems for the treatment of various dementia types. In addition, the current diagnosis biomarkers for the mentioned dementia types along with their available pharmacological treatment are being dis- cussed.

METHOD: An extensive review of the current nanosystems such as brain drug delivery systems against Alzheimer's disease, vascular dementia and mixed dementia was performed. Moreover, nan- otheranostics as possible imaging markers for such dementias were also reported.

RESULTS: The field of nanotechnology is quite advantageous for targeting dementia given that nanoscale drug delivery systems easily penetrate the blood brain barrier and circulate in the body for prolonged time. These nanoformulations consist of polymeric nanoparticles, solid lipid nanoparticles, nanostruc- tured lipid carriers, microemulsions, nanoemulsions, and liquid crystals. The delivery of the nan- otherapeutics can be achieved via various administration routes such as transdermal, injectable, oral, and more importantly, through the intranasal route. Nonetheless, the nanocarriers are mostly limited to Alzheimer's disease targeting; thus, nanocarriers for other types of dementia should be developed.

CONCLUSION: To conclude, understanding the mechanism of neurodegeneration and reviewing the cur- rent drug delivery systems for Alzheimer's disease and other dementia types are significant for medical and pharmaceutical society to produce efficient therapeutic choices and novel strategies based on mul- tifunctional and biocompatible nanocarriers, which can deliver the drug sufficiently into the brain.

RevDate: 2021-02-19

Chaves S, Várnagy K, MA Santos (2021)

Recent Multi-Target Approaches on the Development of Anti-Alzheimer`s Agents Integrating Metal Chelation Activity.

Current medicinal chemistry pii:CMC-EPUB-114353 [Epub ahead of print].

Alzheimer´s disease (AD) is the most common and severe age-dependent neurodegenerative disorder, worldwide. Notwithstanding the large amount of research dedicated to both the elucidation of this pathology and the development of an effective drug, the multifaceted nature and complexity of the disease are certainly a rationale for the absence of cure so far. Current available drugs are used, mainly, to compensate the decline of the neurotransmitter acetylcholine by acetylcholinesterase (AChE) inhibition, though they only provide temporary symptomatic benefits and cannot stop AD progression. Although the multiple factors that contribute to trigger AD onset and progression are not yet fully understood, several pathological features and underneath pathways have been recognized to contribute to its pathology, such as metal dyshomeostasis, protein misfolding, oxidative stress and neurotransmitter deficiencies, some of them being interconnected. Thus, there is a widespread recent interest in the development of multitarget-directed ligands (MTDLs) for simultaneous interaction with several pathological targets of AD. In this review, a selection of the most recent reports (2016-up to present) on metal chelators of MTDLs with multifunctionalities is presented. These compounds enable the hitting of several AD targets or pathways, such as modulation of specific biometal ions (e.g. Cu, Fe, Zn) and of protein misfolding (β-amyloid and tau protein), anti-oxidant activity and AChE inhibition. The properties found for these hybrids are discussed in comparison with the original reference compounds, some MTDLs being outlined as leading compounds for pursuing future studies in view of efficient potential applications in AD therapy.

RevDate: 2021-02-18

Zhou Y, Flores S, Mansor S, et al (2021)

Spatially constrained kinetic modeling with dual reference tissues improves 18F-flortaucipir PET in studies of Alzheimer disease.

European journal of nuclear medicine and molecular imaging [Epub ahead of print].

PURPOSE: Recent studies have shown that standard compartmental models using plasma input or the cerebellum reference tissue input are generally not reliable for quantifying tau burden in dynamic 18F-flortaucipir PET studies of Alzheimer disease. So far, the optimal reference region for estimating 18F-flortaucipir delivery and specific tau binding has yet to be determined. The objective of the study is to improve 18F-flortaucipir brain tau PET quantification using a spatially constrained kinetic model with dual reference tissues.

METHODS: Participants were classified as either cognitively normal (CN) or cognitively impaired (CI) based on clinical assessment. T1-weighted structural MRI and 105-min dynamic 18F-flortaucipir PET scans were acquired for each participant. Using both a simplified reference tissue model (SRTM2) and Logan plot with either cerebellum gray matter or centrum semiovale (CS) white matter as the reference tissue, we estimated distribution volume ratios (DVRs) and the relative transport rate constant R1 for region of interest-based (ROI) and voxelwise-based analyses. Conventional linear regression (LR) and LR with spatially constrained (LRSC) parametric imaging algorithms were then evaluated. Noise-induced bias in the parametric images was compared to estimates from ROI time activity curve-based kinetic modeling. We finally evaluated standardized uptake value ratios at early phase (SUVREP, 0.7-2.9 min) and late phase (SUVRLP, 80-105 min) to approximate R1 and DVR, respectively.

RESULTS: The percent coefficients of variation of R1 and DVR estimates from SRTM2 with spatially constrained modeling were comparable to those from the Logan plot and SUVRs. The SRTM2 using CS reference tissue with LRSC reduced noise-induced underestimation in the LR generated DVR images to negligible levels (< 1%). Inconsistent overestimation of DVR in the SUVRLP only occurred using the cerebellum reference tissue-based measurements. The CS reference tissue-based DVR and SUVRLP, and cerebellum-based SUVREP and R1 provided higher Cohen's effect size d to detect increased tau deposition and reduced relative tracer transport rate in CI individuals.

CONCLUSION: Using a spatially constrained kinetic model with dual reference tissues significantly improved quantification of relative perfusion and tau binding. Cerebellum and CS are the suggested reference tissues to estimate R1 and DVR, respectively, for dynamic 18F-flortaucipir PET studies. Cerebellum-based SUVREP and CS-based SUVRLP may be used to simplify 18F-flortaucipir PET study.

RevDate: 2021-02-19

Shapira-Lichter I, Oren N, Asvadurian A, et al (2021)

The First Word Recalled Measure - A Potential Addition to Clinical Exams.

Frontiers in neurology, 12:561824.

Characterizing episodic memory abilities is highly important in the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI), and usually includes wordlist learning and recall tasks. Clinical evaluations typically focus on the number of words recalled, ignoring additional information, like serial position. Here, we tested the potential value of two serial positioning measures for clinical diagnosis - how retrieval is initiated, as measured by the first word recalled, and how it proceeds - using data from patients with AD and MCI that completed a wordlist learning and recall task. Our results show that during the early stages of learning, patients with AD are less prone to retrieve the first word from the wordlist, manifested as lower primacy effect in the first word recalled, compared with MCI patients. The first word recalled measure adds to the differentiation between the groups over and above the total number of words learned. Thus, the first word recalled during word list learning and recall tasks may be used as a simple complementary measure to distinguish between MCI and AD during standard neuropsychological evaluations.

RevDate: 2021-02-19

Huynh K, Piguet O, Kwok J, et al (2021)

Clinical and Biological Correlates of White Matter Hyperintensities in Patients with Behavioral-variant Frontotemporal Dementia and Alzheimer Disease.

Neurology pii:WNL.0000000000011638 [Epub ahead of print].

OBJECTIVE: To test the hypothesis that white matter hyperintensities (WMH) in behavioral-variant frontotemporal dementia (bvFTD) and Alzheimer disease (AD) are associated with disease variables such as disease severity, cortical atrophy and cognition, we conducted a cross-sectional brain MRI study with volumetric and voxel-wise analyses.

METHODS: 129 patients (64 bvFTD, 65 AD) and 66 controls underwent high-resolution brain MRI, clinical and neuropsychological examination. Genetic screening was conducted in 124 cases (54 bvFTD, 44 AD, 26 controls) and postmortem pathology was available in 18 cases (13 bvFTD, 5 AD). WMH were extracted using an automated segmentation algorithm, and analyses of total volumes and spatial distribution were conducted. Group differences in total WMH volume and associations with vascular risk and disease severity were examined. Syndrome-specific voxel-wise associations between WMH, cortical atrophy and performance across different cognitive domains were assessed.

RESULTS: Total WMH volumes were larger in bvFTD than AD and controls. In bvFTD, WMH volumes were associated with disease severity but not vascular risk. bvFTD and AD showed distinct spatial patterns of WMH that mirrored characteristic patterns of cortical atrophy. Regional WMH load correlated with worse cognitive performance in discrete cognitive domains. WMH-related cognitive impairments were shared between syndromes, with additional associations found in bvFTD.

CONCLUSION: Increased WMH are common in bvFTD and AD. Our findings suggest that WMH are partly independent of vascular pathology and associated with the neurodegenerative process. WMH occur in processes independent of and related to cortical atrophy. Further, increased WMH in different regions contribute to cognitive deficits.

RevDate: 2021-02-17

Simonato M, Agoston DV, Brooks-Kayal A, et al (2021)

Identification of clinically relevant biomarkers of epileptogenesis - a strategic roadmap.

Nature reviews. Neurology [Epub ahead of print].

Onset of many forms of epilepsy occurs after an initial epileptogenic insult or as a result of an identified genetic defect. Given that the precipitating insult is known, these epilepsies are, in principle, amenable to secondary prevention. However, development of preventive treatments is difficult because only a subset of individuals will develop epilepsy and we cannot currently predict which individuals are at the highest risk. Biomarkers that enable identification of these individuals would facilitate clinical trials of potential anti-epileptogenic treatments, but no such prognostic biomarkers currently exist. Several putative molecular, imaging, electroencephalographic and behavioural biomarkers of epileptogenesis have been identified, but clinical translation has been hampered by fragmented and poorly coordinated efforts, issues with inter-model reproducibility, study design and statistical approaches, and difficulties with validation in patients. These challenges demand a strategic roadmap to facilitate the identification, characterization and clinical validation of biomarkers for epileptogenesis. In this Review, we summarize the state of the art with respect to biomarker research in epileptogenesis and propose a five-phase roadmap, adapted from those developed for cancer and Alzheimer disease, that provides a conceptual structure for biomarker research.

RevDate: 2021-02-16

Henry V, Moszer I, Dameron O, et al (2021)

Converting disease maps into heavyweight ontologies: general methodology and application to Alzheimer's disease.

Database : the journal of biological databases and curation pii:6137817 [Epub ahead of print].

Omics technologies offer great promises for improving our understanding of diseases. The integration and interpretation of such data pose major challenges, calling for adequate knowledge models. Disease maps provide curated knowledge about disorders' pathophysiology at the molecular level adapted to omics measurements. However, the expressiveness of disease maps could be increased to help in avoiding ambiguities and misinterpretations and to reinforce their interoperability with other knowledge resources. Ontology is an adequate framework to overcome this limitation, through their axiomatic definitions and logical reasoning properties. We introduce the Disease Map Ontology (DMO), an ontological upper model based on systems biology terms. We then propose to apply DMO to Alzheimer's disease (AD). Specifically, we use it to drive the conversion of AlzPathway, a disease map devoted to AD, into a formal ontology: Alzheimer DMO. We demonstrate that it allows one to deal with issues related to redundancy, naming, consistency, process classification and pathway relationships. Furthermore, we show that it can store and manage multi-omics data. Finally, we expand the model using elements from other resources, such as clinical features contained in the AD Ontology, resulting in an enriched model called ADMO-plus. The current versions of DMO, ADMO and ADMO-plus are freely available at http://bioportal.bioontology.org/ontologies/ADMO.

RevDate: 2021-02-16

Rentz DM, Papp KV, Mayblyum DV, et al (2021)

Association of Digital Clock Drawing with PET Amyloid and Tau Pathology in Normal Older Adults.

Neurology pii:WNL.0000000000011697 [Epub ahead of print].

OBJECTIVE: To determine whether a digital clock drawing test, DCTclock™, improves upon standard cognitive assessments for discriminating diagnostic groups and for detecting biomarker evidence of amyloid and tau pathology in clinically normal older adults (CN).

METHODS: Participants from the Harvard Aging Brain Study and the Positron Emission Tomography (PET) lab at Massachusetts General Hospital were recruited to undergo the DCTclock drawing test, standard neuropsychological assessments including the Preclinical Alzheimer Cognitive Composite (PACC), and amyloid /tau PET imaging. Receiver operating curve analyses were used to assess diagnostic and biomarker discriminability. Logistic regression and partial correlations were used to assess DCTclock performance in relation to PACC and PET biomarkers.

RESULTS: A total of 300 participants were studied. Among the 264 CN, 143 had amyloid and tau PET imaging (Clinical Dementia Rating=0, Mini Mental State Exam=28.9±1.2). An additional 36 participants with a diagnosis of mild cognitive impairment or early Alzheimer's dementia (CDR=0.5, MMSE=25.2±3.9) were added to assess diagnostic discriminability. DCTclock showed excellent discrimination between diagnostic groups (AUC=0.86). Among CN with biomarkers, the DCTclock summary score and spatial reasoning sub-scores were associated with greater amyloid and tau burden and showed better discrimination (Cohen's d=0.76) between Aβ+/- groups than the PACC (d=0.30).

CONCLUSION: DCTclock discriminates between diagnostic groups and improves upon traditional cognitive tests for detecting biomarkers of amyloid and tau pathology in CN older adults. The validation of such digitized measures has the potential of providing an efficient tool for detecting early cognitive changes along the AD trajectory.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the DCTclock results were associated with amyloid and tau burden in clinically normal older adults.

RevDate: 2021-02-16

Saba M, S Blanchet (2021)

Working memory training in normal and pathological ageing: neurocognitive gains and their impact on daily-living activities.

Geriatrie et psychologie neuropsychiatrie du vieillissement pii:pnv.2020.0908 [Epub ahead of print].

Working memory is one of the cognitive functions that is the most sensitive to the effects of normal and pathological ageing. In older individuals with mild cognitive impairments, working memory deficits are frequent and can precede episodic memory impairments, in addition to having a strong prognostic value of evolution toward an Alzheimer-type dementia. Due to its involvement in numerous cognitive and cognitive-motor tasks, working memory is called upon in a wide range of daily activities. An impaired working memory therefore increases the risk of loss of autonomy. In this review, we present different working memory training programmes. We show how these training programmes are associated with specific effects, and near and far transfer effects on other cognitive functions in older adults without cognitive impairment or with mild cognitive impairment, as well as in patients with dementia. We show that the benefits are confirmed by neuronal modifications, suggesting an improvement in the neuronal efficiency of the processes that are trained or related to them. Finally, we consider the central question of the impact of the cognitive gains made by working memory training on activities of daily living.

RevDate: 2021-02-16

Ulm BS, Borchelt DR, BD Moore (2021)

Remodeling Alzheimer-amyloidosis models by seeding.

Molecular neurodegeneration, 16(1):8.

Alzheimer's disease (AD) is among the most prevalent neurodegenerative diseases, with brain pathology defined by extracellular amyloid beta deposits and intracellular tau aggregates. To aid in research efforts to improve understanding of this disease, transgenic murine models have been developed that replicate aspects of AD pathology. Familial AD is associated with mutations in the amyloid precursor protein and in the presenilins (associated with amyloidosis); transgenic amyloid models feature one or more of these mutant genes. Recent advances in seeding methods provide a means to alter the morphology of resultant amyloid deposits and the age that pathology develops. In this review, we discuss the variety of factors that influence the seeding of amyloid beta pathology, including the source of seed, the time interval after seeding, the nature of the transgenic host, and the preparation of the seeding inoculum.

RevDate: 2021-02-15

Katayama O, Lee S, Bae S, et al (2021)

Lifestyle changes and outcomes of older adults with mild cognitive impairment: A 4-year longitudinal study.

Archives of gerontology and geriatrics, 94:104376 pii:S0167-4943(21)00039-X [Epub ahead of print].

BACKGROUND: Longitudinal studies have shown that mild cognitive impairment (MCI) reverts to normal cognition (NC). However, we could not find any reports on the examination of changes in lifestyle activity patterns in older adults diagnosed with MCI and their outcomes, in a longitudinal study. We determined the changes in lifestyle activity patterns among older adults with MCI.

METHODS: The participants in this study were 769 community-dwelling older adults aged ≥65 years with MCI at baseline. Four years later, participants were categorized into reverters, maintainers, and converters who reverted from MCI to NC, maintained MCI, and had global cognitive impairment or Alzheimer disease, respectively. We used latent class analysis to classify changes in instrumental activities of daily living, and in cognitive, social, and productive activities of the participants. Subsequently, a multinomial logistic regression analysis was performed with reversion status and class membership as the dependent and independent variables, respectively.

RESULTS: The reversion rate of 769 participants was 33.3%. The reverters maintained multidomain lifestyle activities, converters discontinued multidomain lifestyle activities or were inactive, and maintainers maintained productive activities. According to the logistic regression analysis, the activity patterns of those who continued to engage in multidomain lifestyle activities and start activities, were more likely to help in reverting from MCI to NC (P < 0.05).

CONCLUSIONS: Community-dwelling older adults with MCI who continued their multidomain lifestyle activities were more likely to revert to NC. Even if it does not revert to NC, continuing productive activities is important to maintaining MCI without converting.

RevDate: 2021-02-15

Lu M, Pontecorvo MJ, Devous MD, et al (2021)

Aggregated Tau Measured by Visual Interpretation of Flortaucipir Positron Emission Tomography and the Associated Risk of Clinical Progression of Mild Cognitive Impairment and Alzheimer Disease: Results From 2 Phase III Clinical Trials.

JAMA neurology pii:2775982 [Epub ahead of print].

Importance: Flortaucipir positron emission tomography (PET) scans, rated with a novel, US Food and Drug Administration-approved, clinically applicable visual interpretation method, provide valuable information regarding near-term clinical progression of patients with Alzheimer disease (AD) or mild cognitive impairment (MCI).

Objective: To evaluate the association between flortaucipir PET visual interpretation and patients' near-term clinical progression.

Design/Setting/Participants: Two prospective, open-label, longitudinal studies were conducted from December 2014 to September 2019. Study 1 screened 298 patients and enrolled 160 participants who had a flortaucipir scan at baseline visit. Study 2 selected 205 participants from the AMARANTH trial, which was terminated after futility analysis. Out of the 2218 AMARANTH participants, 424 had a flortaucipir scan around randomization, but 219 did not complete 18-month clinical dementia rating (CDR) assessments and thus were excluded. In both studies, all participants were diagnosed as clinically impaired, and they were longitudinally followed up for approximately 18 months after baseline.

Main Outcomes and Measures: Flortaucipir scans were rated as either advanced or nonadvanced AD pattern using a predetermined visual interpretation method. The CDR sum of box (CDR-SB) score was used as primary clinical end point measurement in both studies.

Results: Of the 364 study participants who had readable scans, 48% were female (n = 174 of 364), and the mean (SD) age was 71.8 (8.7) years. Two hundred forty participants were rated as having an advanced AD pattern. At 18 months follow-up, 70% of those with an advanced AD pattern (n = 147 of 210) had 1 point or more increase in CDR-SB, an event predefined as clinically meaningful deterioration. In contrast, only 46% of those with a nonadvanced AD pattern scan (n = 48 of 105) experienced the same event (risk ratio [RR], 1.40; 95% CI, 1.11-1.76; P = .005). The adjusted mean CDR-SB changes were 2.28 and 0.98 for advanced and nonadvanced AD pattern groups, respectively (P < .001). Analyses with other clinical end point assessments, as well as analyses with each individual study's data, consistently indicated a higher risk of clinical deterioration associated with an advanced AD scan pattern.

Conclusions and Relevance: These results suggest that flortaucipir PET scans, when interpreted with an US Food and Drug Administration-approved, clinically applicable visual interpretation method, may provide valuable information regarding the risk of clinical deterioration over 18 months among patients with AD and MCI.

Trial Registration: ClinicalTrials.gov Identifier: NCT02016560 and NCT03901105.

RevDate: 2021-02-15

Ghotbeddin Z, Tabandeh MR, Pourmahdi Borujeni M, et al (2021)

Crocin mitigated cognitive impairment and brain molecular alterations induced by different intensities of prenatal hypoxia in neonatal rats.

Brain and behavior [Epub ahead of print].

INTRODUCTION: Brain hypoxia has important role to the onset and progression of sporadic form of Alzheimer disease via expression of hypoxia-inducible factor-1 (HIF-1). Crocin by anti-amyloidogenic property inhibits β-amyloid formation. However, the molecular mechanism associated with anti-amyloidogenic activity of crocin is unknown. So, the present study was designed to investigate the effect of crocin on cognitive behavior and expression of HIF-1α and β-secretase (BACE1) genes in the brain of neonate rats following different intensities of hypoxia during pregnancy.

MATERIAL AND METHODS: Pregnant female rats were divided into six groups including sham, control crocin treated (CC), hypoxia with three different intensities (H1-H3), and most intense of hypoxic group treated with crocin (H3C) (30 mg/kg; i.p) at P14. Hypoxia induced on the 20th day of pregnancy. Animals in sham and CC were put in hypoxia chamber at the same time of hypoxia group without any hypoxia induction. Morris water maze (MWM) and qRT-PCR were used to evaluate the cognitive behavior and mRNA levels of BACE1 and HIF-1α genes in the brain tissues.

RESULTS: Animal under 7% O2 + 93% N2 condition for 3 hr showed the highest cognitive behavior impairment and upregulated HIF-1α and BACE1 mRNA in brains of offspring (p < .001). Crocin treatment improved memory impairment and attenuated the gene expression of HIF-1α and BACE1 in the brains of neonate rat.

CONCLUSIONS: It was concluded that crocin has beneficial effects on the brain of neonate rats under gestational hypoxia by improvement of memory impairment and molecular alteration related to hypoxia.

RevDate: 2021-02-15

Cezar NOC, Ansai JH, LP de Andrade (2021)

Home-based multimodal exercise program in older people with Alzheimer disease: Randomized controlled trial protocol.

Physiotherapy research international : the journal for researchers and clinicians in physical therapy [Epub ahead of print].

BACKGROUND: At-home physical exercise may be an important intervention strategy for older people with Alzheimer disease (AD) due to the greater adherence and ease for the caregivers.

PURPOSE: Determine the effects home-based multimodal exercise program in older people with AD on muscle strength, balance, functioning, cognition, dual task performance, frailty, and physical activity level.

METHODS: This is a trial with 40 older people with mild and moderate AD, randomized into intervention group (IG) and control group (CG). The participants will be evaluated by blinded examiners at baseline and after 16 weeks of training. The evaluations will investigate functioning (Timed Up and Go test, Direct Assessment of Functional Status, WHO Disability Assessment Schedule, Short Physical Performance Battery, and Activities of Daily Living Questionnaire), muscle strength (manual dynamometer and Sit-to-Stand test), frailty (FRAIL Scale and Edmonton Frail Scale), cognition (Addenbrooke's Cognitive Examination, Trail Making Test, Walking Trail-Making Test, and Frontal Assessment Battery), balance (force platform, Figure-of-Eight Walking Test, Functional Reach Test, Alternate Step Test, and Calf-Raise Senior), dual task (force platform), and physical activity level (Modified Baecke Questionnaire and Life-Space Assessment). The IG will perform 16 weeks of exercise at home that involve functioning, strength, balance, and aerobic endurance in 60-min sessions three times a week. The CG will not undergo any intervention.

CONCLUSION: Improvements in the aspects evaluated are expected in the IG compared to CG. The protocol will provide a theoretical basis for the creation of clinical interventions and health promotion measures for older people with AD.

RevDate: 2021-02-15

Sandusky-Beltran LA, Kovalenko A, Placides DS, et al (2021)

Aberrant AZIN2 and polyamine metabolism precipitates tau neuropathology.

The Journal of clinical investigation, 131(4):.

Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell's response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer's disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD.

RevDate: 2021-02-16

Napolioni V, Scelsi MA, Khan RR, et al (2020)

Recent Consanguinity and Outbred Autozygosity Are Associated With Increased Risk of Late-Onset Alzheimer's Disease.

Frontiers in genetics, 11:629373.

Prior work in late-onset Alzheimer's disease (LOAD) has resulted in discrepant findings as to whether recent consanguinity and outbred autozygosity are associated with LOAD risk. In the current study, we tested the association between consanguinity and outbred autozygosity with LOAD in the largest such analysis to date, in which 20 LOAD GWAS datasets were retrieved through public databases. Our analyses were restricted to eight distinct ethnic groups: African-Caribbean, Ashkenazi-Jewish European, European-Caribbean, French-Canadian, Finnish European, North-Western European, South-Eastern European, and Yoruba African for a total of 21,492 unrelated subjects (11,196 LOAD and 10,296 controls). Recent consanguinity determination was performed using FSuite v1.0.3, according to subjects' ancestral background. The level of autozygosity in the outbred population was assessed by calculating inbreeding estimates based on the proportion (FROH) and the number (NROH) of runs of homozygosity (ROHs). We analyzed all eight ethnic groups using a fixed-effect meta-analysis, which showed a significant association of recent consanguinity with LOAD (N = 21,481; OR = 1.262, P = 3.6 × 10-4), independently of APOE∗4 (N = 21,468, OR = 1.237, P = 0.002), and years of education (N = 9,257; OR = 1.274, P = 0.020). Autozygosity in the outbred population was also associated with an increased risk of LOAD, both for FROH (N = 20,237; OR = 1.204, P = 0.030) and NROH metrics (N = 20,237; OR = 1.019, P = 0.006), independently of APOE∗4 [(FROH, N = 20,225; OR = 1.222, P = 0.029) (NROH, N = 20,225; OR = 1.019, P = 0.007)]. By leveraging the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data, we determined that LOAD subjects do not show an enrichment of rare, risk-enhancing minor homozygote variants compared to the control population. A two-stage recessive GWAS using ADSP data from 201 consanguineous subjects in the discovery phase followed by validation in 10,469 subjects led to the identification of RPH3AL p.A303V (rs117190076) as a rare minor homozygote variant increasing the risk of LOAD [discovery: Genotype Relative Risk (GRR) = 46, P = 2.16 × 10-6; validation: GRR = 1.9, P = 8.0 × 10-4]. These results confirm that recent consanguinity and autozygosity in the outbred population increase risk for LOAD. Subsequent work, with increased samples sizes of consanguineous subjects, should accelerate the discovery of non-additive genetic effects in LOAD.

RevDate: 2021-02-16

Lian TH, Jin Z, Qu YZ, et al (2020)

The Relationship Between Retinal Nerve Fiber Layer Thickness and Clinical Symptoms of Alzheimer's Disease.

Frontiers in aging neuroscience, 12:584244.

Background/Aim: Retinal nerve fiber layer (RNFL) thickness (RT), which can reflect the status of the retinal optic nerve cells, may be affected in patients with Alzheimer's disease (AD). There are few studies on the correlation of RT of patients with AD (AD-RT) with clinical symptoms of various cognitive domains, neuropsychiatric symptoms, and activities of daily living (ADL). This study is to investigate the relationships between RT and the abovementioned clinical symptoms of AD. Methods: A total of 96 patients with AD were included in this study. RT was measured in these patients using optical coherence tomography (OCT). Demographic variables, RT, and clinical symptoms were compared between the normal and the abnormal AD-RT groups. Clinical symptoms, including cognitive symptoms, neuropsychiatric symptoms, and ADL, were evaluated using a series of rating scales. Results: The relationships between RT and cognitive symptoms scores were analyzed in patients with AD. Reduced RT was found in 54.4% of patients with AD. The average RT, RT of the superior 1/2 quadrant, and RT of the inferior 1/2 quadrant of both eyes were all significantly decreased in the abnormal AD-RT group (p < 0.001). Overall cognitive function and performance in multiple cognitive domains, including memory, language, attention, and executive function, were also significantly impaired in the abnormal AD-RT group (p < 0.05). For lower RT value, the global cognitive function and the performance in multiple cognitive domains were worse. ADL was significantly compromised in patients with AD having lower RT values (p < 0.05). Conclusions: Lower RT value appear to be correlated with cognitive impairment, and RT may be an indicator of cognitive decline in patients with AD. Further studies are required to confirm our findings.

RevDate: 2021-02-15

Rasool M, Malik A, Waquar S, et al (2021)

Cellular and molecular mechanisms of Dementia: Decoding the causal link of Diabetes Mellitus in Alzheimer's disease.

CNS & neurological disorders drug targets pii:CNSNDDT-EPUB-114157 [Epub ahead of print].

Dementia and diabetes are the two major disorders that are linked at both biochemical and molecular levels which is due to the existing similarities between pancreatic beta-cells and neuronal cells at the transcription and translational levels. Both diseases have similar causative genes or factors and dementia is one of the advanced complications in about 50-52% of patients with type 2 diabetes mellitus (T2DM). Further, patients with T2DM are at a higher risk of neuronal degeneration and Alzheimer's disease (AD). Dementia, which is most common in AD, is associated with diminished insulin receptors by nearly 80%. The impairment in insulin signaling thus leads to the development of dementia and AD. Biochemical changes in 'tau' protein and amyloid-beta proteins, make them critical players in the formation of plaques in patients with dementia and AD. Here, we decode various cellular and molecular mechanisms associated with the development of dementia in patients with diabetes and AD.

RevDate: 2021-02-15

Liu Y, Chan D, Crawford JD, et al (2021)

The contribution of cerebral vascular neuropathology to mild stage of Alzheimer's dementia using the NACC database.

Current Alzheimer research pii:CAR-EPUB-114182 [Epub ahead of print].

BACKGROUND: The interaction between cerebral vessel disease (CVD) pathology and Alzheimer's disease (AD) pathology in the development of dementia is controversial. We examined the association of cerebral vascular neuropathology and cerebrovascular risk factors with the mild stage of Alzheimer's dementia and cognitive function.

METHODS: This cross-sectional study included men and women aged 60 years or over who had yearly clinical assessments and had agreed to brain autopsy at the time of death, and who contributed to data stored at the National Alzheimer's Coordinating Center (NACC) in the USA. Cognitively normal and impaired subjects with presumptive aetiology of AD, including mild cognitive impairment (ADMCI) and dementia (Alzheimer's dementia), and with complete neuropathological data, were included in our analyses. We used neuropsychological data proximate to death to create summary measures of global cognition and cognitive domains. Systematic neuropathological assessments documenting the severity of cerebral vascular pathology were included. Logistic and linear regression analyses corrected for age at death, sex and Lewy body pathology were used to examine associations of vessel disease with the severity of Alzheimer's disease dementia, and cognitive function, respectively.

RESULTS: No significant relationship was observed between late-life risk factors and Alzheimer's dementia. The severity of arteriosclerosis and presence of global infarcts/lacunes were related to mild Alzheimer's dementia (B=0.423, p<0.001;B=0.366, p=0.026), and the effects were significant after adjusting for neuritic plaques and neurofibrillary tangles (B=0.385, p<0.001;B=0.63, p=0.001). When vascular brain injuries were subdivided into old and acute/subacute types, we found that old microinfarcts and old microbleeds were associated with mild Alzheimer's dementia (B=0.754, p=0.007; B=2.331, p=0.032). The old microinfarcts remained significantly associated with mild Alzheimer's dementia after correcting AD pathologies (B=1.31, p<0.001). In addition, the number of microinfarcts in the cerebral cortex had a significant relation with mild Alzheimer's dementia, whether or not the data were corrected for AD pathologies (B=0.616, p=0.016; B=0.884, p=0.005). Atherosclerosis, arteriosclerosis and white matter rarefaction were found to be significantly associated with faster progression of Alzheimer's dementia (B=0.068, p=0.001; B=0.046, p=0.016, B=0.081, p=0.037), but white matter rarefaction no longer had a significant effect after adjusting for AD pathologies. We also found that the severity of atherosclerosis was related to impairment in processing speed (β=-0.112, p=0.006) and executive function (β=-0.092, p=0.023). Arteriosclerosis was significantly associated with language (β=-0.103, p=0.011) and global cognition (β=-0.098, p=0.016) deficits.

CONCLUSION: Our study found the significant relation of global, old, acute/subacute and regional cerebral vascular pathologies, but not white matter rarefaction, to the onset and severity of Alzheimer's dementia. We also showed that late-life risk factors were found to have no relation with Alzheimer's dementia, and the increased risk of dementia with APOE ε4 is not mediated by CVD. The best interpretation of these findings is that CVD has an additive effect with AD pathologies in the development and progression of what is clinically diagnosed as Alzheimer's dementia, and it is very likely that CVD and AD are to a major degree independent pathologies.

RevDate: 2021-02-15

Garibotto V, Trombella S, Antelmi L, et al (2021)

A Comparison of Two Statistical Mapping Tools for Automated Brain FDG-PET Analysis in Predicting Conversion to Alzheimer's Disease in Subjects with Mild Cognitive Impairment.

Current Alzheimer research pii:CAR-EPUB-114183 [Epub ahead of print].

OBJECTIVE: Automated voxel-based analysis methods are used to detect cortical hypometabolism typical of Alzheimer's Disease (AD) on FDG-PET brain scans. We compared the accuracy of two clinically validated tools for their ability to identify those MCI subjects progressing to AD at follow- up, to evaluate the impact of the analysis method on FDG-PET diagnostic performance.

METHODS: SPMGrid and BRASS (Hermes Medical Solutions, Stockholm, Sweden) were tested on 131 MCI and elderly healthy controls from the EADC PET dataset. The concordance between the tools was tested by correlating the quantitative parameters (z- and t-values), calculated by the two software tools, and by measuring the topographical overlap of the abnormal regions (Dice score). Three independent expert readers blindly assigned a diagnosis based on the two map sets. We used conversion to AD dementia as the gold standard.

RESULTS: The t-map and z-map calculated with SPMGrid and BRASS, respectively, showed a good correlation (R > .50) for the majority of individual cases (128/131) and for the majority of selected regions of interest (ROIs) (98/116 [22]). The overlap of the hypometabolic patterns from the two tools was, however, poor (Dice score .36). The diagnostic performance was comparable, with BRASS showing significantly higher sensitivity (.82 versus .59) and SPMGrid showing higher specificity (.87 versus .52).

CONCLUSION: Despite similar diagnostic performance in predicting conversion to AD in MCI subjects, the two tools showed significant differences, and the maps provided by the tools showed limited overlap. These results underline the urgency for standardization across FDG-PET analysis methods for their use in clinical practice.

RevDate: 2021-02-14

González-Bautista E, de Souto Barreto P, Andrieu S, et al (2021)

What day is today? Cognitive capacity and the risk of incident dementia in the context of integrated care for older people (ICOPE Step 1).

Aging clinical and experimental research [Epub ahead of print].

Based on clinical observations, our objective was to test if the older adults who failed to recall the name of the weekday, or had a higher number of mistakes in the word recall were at higher risk of mild cognitive impairment (MCI) or dementia. Longitudinal data of the Multidomain Alzheimer Preventive Trial (MAPT) was used to retrospectively measure the cognitive capacity according to the ICOPE Step 1 tool. Incident dementia was assessed by two multidisciplinary committees independent from each other. MCI was defined as Clinical Dementia Rating scale CDR = 0.5. Failure to recall the name of the weekday had a three-fold risk of incident dementia in the next 5 years (HRa = 3.11, 95%CI: 1.18-8.17). Having two or three mistakes in the word recall carried a higher risk of incident dementia, (HRa for two mistakes = 3.50, 95% CI: 1.49-8.26; HRa for three mistakes = 4.28, 95% CI: 1.60-11.46), but not MCI. People with impaired cognitive capacity according to the ICOPE Step 1 tool deserve further assessment and a closer follow-up.

RevDate: 2021-02-14

Shimoda W, Murata J, Nakatani A, et al (2021)

Concurrent Validity of the ABC Dementia Scale with Other Standard Scales: A New Comprehensive Instrument for Assessing Dementia in Japan.

Dementia and geriatric cognitive disorders pii:000513485 [Epub ahead of print].

BACKGROUND/AIMS: The ABC Dementia Scale (ABC-DS), a new tool for evaluating dementia, was developed in Japan. The ABC-DS is a comprehensive instrument that can simultaneously evaluate activities of daily living (ADLs), behavioral and psychological symptoms of dementia (BPSD), and cognitive function. The ABC-DS can be administered easily and quickly and can clarify the severity of dementia and its changes over time. While the ABC-DS has been reported to be useful in Alzheimer disease (AD)-type dementia, it has not yet been studied in other types of dementia. The purpose of this study was to reevaluate the standard validity of ABC-DS separately for various dementia types and severities.

METHODS: We evaluated the ABC-DS in outpatients at 1 hospital in Nagasaki Prefecture and patients who use the facility. Domain A, corresponding to ADLs, correlated with Disability Assessment for Dementia (DAD); domain B, corresponding to BPSD, correlated with the Neuropsychiatric Inventory (NPI); domain C, corresponding to cognitive functions, correlated with Mini-Mental State Examination (MMSE); and the total score of the ABC-DS correlated with the Clinical Dementia Rating (CDR).

RESULTS: 102 patients, comprising 38 males and 64 females with an average age of 80.7 ± 8.6 years, were enrolled. AD-type dementia was present in 38 cases, vascular dementia (VaD) in 23, mixed dementia in 23, dementia with Lewy bodies in 6, argyrophilic grain dementia in 9, and mild cognitive impairment in 3. A strong correlation was found between ABC-DS domain scores and their respective reference neuropsychological instruments (domain A and the DAD, domain B and the NPI, domain C and the MMSE, and total score and CDR). The correlation of each ABC-DS domain score with the corresponding standard scale depended on the type and severity of dementia, and we observed moderate or high correlations in AD and VaD patients with moderate and severe dementia.

DISCUSSION: Although the ABC-DS targets AD, it can be used in VaD based on the results of this study. In other types of dementia, the results differed depending on the domain; in some conditions, the ABC-DS may not show sufficient concurrent validity with other standard scales. Also, the ABC-DS is more beneficial for moderate-to-severe dementia, as reported in previous studies. It is highly useful in clinical practice in Japan since there more than half of all patients have moderate-to-severe dementia.

RevDate: 2021-02-13

Cilliers K (2021)

Trace element alterations in Alzheimer's disease: A review.

Clinical anatomy (New York, N.Y.) [Epub ahead of print].

Dyshomeostasis of trace elements have been implicated in the progression of Alzheimer's disease (AD), which is characterized by amyloid-β (Aβ) plaques. Trace elements are particularly associated with the Aβ plaques. Metal-protein attenuating compounds have been developed to inhibit metals from binding to Aβ proteins, which result in Aβ termination, in the hope of improving cognitive functioning. However, there are still some contradicting reports. This review aims to first establish which trace elements are increased or decreased in the brains of Alzheimer's patients, and secondly, to review the effectiveness of clinical trials with metal-protein attenuating compounds for AD. Studies have consistently reported unchanged or increased iron, contradicting reports for zinc, decreased copper, unchanged or decreased manganese, inconsistent results for calcium, and magnesium seems to be unaffected. However, varied results have been reported for all trace elements. Clinical trials using metal-protein attenuating compounds to treat AD have also reported varied results. Copper chelators have repeatedly been used in clinical trials, even though few studies report increased brain copper levels in AD patients. Homeostasis of copper levels is important since copper has a vital role in several enzymes, such as cytochrome c, Cu/Zn superoxide dismutase and ceruloplasmin. Dyshomeostasis of copper levels can lead to increased oxidative stress and neuronal loss. Future studies should assess a variety of trace element levels in moderately and severely affected AD patients since there are contradicting reports. This review thus provides some insight into trace element alterations in the brains of individuals with AD. This article is protected by copyright. All rights reserved.

RevDate: 2021-02-13

Yu E, Liao Z, Fan W, et al (2021)

The Economic Burden of Alzheimer's Disease in Zhejiang Province.

Journal of Alzheimer's disease : JAD pii:JAD201285 [Epub ahead of print].

BACKGROUND: The World Alzheimer Report has described and predicted the economic burden of Alzheimer's disease (AD) patients in detail for four consecutive years. There was a large-scale national survey in China launched by Professor Jianping Jia in 2015, but it did not adequately represent the average economic burden of AD patients in Zhejiang Province.

OBJECTIVE: To investigate the economic burden and main factors influencing Alzheimer's disease (AD) in Zhejiang Province.

METHODS: We recruited 830 patients from 10 cities in Zhejiang Province, evaluated their per capita and total cost related to AD treatment and care in 2017, and analyzed the main factors affecting economic burden from the perspective of demographic characteristics and disease severity.

RESULTS: In 2017, per capita cost of AD was 114,343.7 yuan, while the total cost was 27.53 billion yuan, accounting for 0.77% of Zhejiang Province's GDP (5176.8 billion yuan). Total cost, direct medical cost, and indirect cost have different correlations with age, education level, type of work, marital status, comorbidity, and disease severity.

CONCLUSION: The economic burden of AD in Zhejiang Province is heavy, similar to the national burden, and interventions based on demographic characteristics and disease severity can help reduce it.

RevDate: 2021-02-16

Decker Y, Németh E, Schomburg R, et al (2021)

Decreased pH in the aging brain and Alzheimer's disease.

Neurobiology of aging, 101:40-49 pii:S0197-4580(20)30416-4 [Epub ahead of print].

Using publicly available data sets, we compared pH in the human brain and the cerebrospinal fluid (CSF) of postmortem control and Alzheimer's disease cases. We further investigated the effects of long-term acidosis in vivo in the APP-PS1 mouse model of Alzheimer's disease. We finally examined in vitro whether low pH exposure could modulate the release of proinflammatory cytokines and the uptake of amyloid beta by microglia. In the human brain, pH decreased with aging. Similarly, we observed a reduction of pH in the brain of C57BL/6 mice with age. In addition, independent database analyses revealed that postmortem brain and CSF pH is further reduced in Alzheimer's disease cases compared with controls. Moreover, in vivo experiments showed that low pH CSF infusion increased amyloid beta plaque load in APP-PS1 mice. We further observed that mild acidosis reduced the amyloid beta 42-induced release of tumor necrosis factor-alpha by microglia and their capacity to uptake this peptide. Brain acidosis is associated with aging and might affect pathophysiological processes such as amyloid beta aggregation or inflammation in Alzheimer's disease.

RevDate: 2021-02-12

Ratto F, Franchini F, Musicco M, et al (2021)

A narrative review on the potential of tomato and lycopene for the prevention of Alzheimer's disease and other dementias.

Critical reviews in food science and nutrition [Epub ahead of print].

Oxidative stress is a major factor in aging and is implicated in the pathogenesis of tumors, diabetes mellitus, cardiovascular and neurodegenerative diseases, including Alzheimer Disease (AD). Bioactive constituents of tomato as polyphenols and carotenoids, among which lycopene (LYC) are effective in reducing markers of oxidative stress, and appear to have a protective modulator role on the pathogenetic mechanisms, cognitive symptoms and behavioral manifestations of these diseases in cell cultures and animal models. Epidemiological evidence indicates a consistent association between the intake of tomatoes and reduced cardiovascular and neoplastic risk. LYC deficiency is common in elders and AD patients and it is strongly predictive of mortality and poor cardiovascular (CV) outcomes. Dietary intake of tomatoes seems to be more effective than tomato/LYC supplementation. Limited evidence from human intervention trials suggests that increasing tomato intake, besides improving CV markers, enhances cognitive performances. In this narrative review, we analyze the existing evidence on the beneficial effects of tomatoes on AD-related processes or risk factors. Results support the development of promising nutritional strategies to increase the levels of tomato consumption for the prevention or treatment of AD and other dementias. Extensive well-structured research, however, is mandatory to confirm the neuroprotective effects of tomato/LYC in humans.

RevDate: 2021-02-12

Millman JF, Okamoto S, Teruya T, et al (2021)

Extra-virgin olive oil and the gut-brain axis: influence on gut microbiota, mucosal immunity, and cardiometabolic and cognitive health.

Nutrition reviews pii:6133931 [Epub ahead of print].

Extra-virgin olive oil (EVOO), a popular functional food and major source of fat in the Mediterranean diet, pos sesses a variety of healthful components, including monounsaturated fatty acids and bioactive phenolic compounds that, individually and collectively, exert beneficial effects on cardiometabolic markers of health and act as neuroprotective agents through their anti-inflammatory and antioxidant activities. The gut microbiota and health of the intestinal environment are now considered important factors in the development of obesity, metabolic disease, and even certain neurodegenerative conditions via the gut-brain axis. Recently, data are emerging which demonstrate that the health-promoting benefits of EVOO may also extend to the gut microbiota. In this review, we aimed to examine findings from recent studies regarding the impact of EVOO on gut microbiota and intestinal health and explore how modulations in composition of gut microbiota, production of microbially produced products, and activity and functioning of the mucosal immune system may lead to favorable outcomes in cardiovascular, metabolic, and cognitive health.

RevDate: 2021-02-12

González-Bautista E, de Souto Barreto P, Virecoulon Giudici K, et al (2021)

Frequency of Conditions Associated with Declines in Intrinsic Capacity According to a Screening Tool in the Context of Integrated Care for Older People.

The Journal of frailty & aging, 10(2):94-102.

BACKGROUND: The screening tool of the Integrated Care for Older People (ICOPE Step 1), designed to detect declines in the domains of intrinsic capacity, has been incipiently investigated in older adult populations.

OBJECTIVES: To retrospectively estimate the frequency of priority conditions associated with declines in intrinsic capacity according to an adaptation of the screening tool ICOPE Step 1 among participants of the Multidomain Alzheimer Preventive Trial (MAPT).

DESIGN: A cross-sectional retrospective analysis from the baseline assessment of the MAPT.

SETTING: The data was gathered during a preventive consultation for cardiovascular risk factors in memory clinics in France.

PARTICIPANTS: Seven hundred fifty-nine older adults aged 70-89 years with memory complaints, allocated to the multidomain groups of the MAPT study.

MEASUREMENTS: Five domains of intrinsic capacity (cognition, locomotion, nutrition, sensorial, and psychological) were assessed using a screening tool similar to the ICOPE Step 1 (MAPT Step 1). The frequency of six conditions associated with declines in intrinsic capacity (cognitive decline, limited mobility, malnutrition, visual impairment, hearing loss, and depressive symptoms) was obtained for older adults with memory complaints participating in the MAPT study.

RESULTS: Overall, 89.3% of the participants had one or more conditions associated with declines in intrinsic capacity. The overall frequency of each condition was: 52.2% for cognitive decline, 20.2% for limited mobility, 6.6% for malnutrition, 18.1% for visual impairment, 56.2% for hearing loss, and 39% for depressive symptoms.

CONCLUSION: After being screened with an adaptation of the ICOPE step 1 (MAPT step 1) tool, 9/10 older adults had one or more conditions associated with declines in intrinsic capacity. The relative frequency differs across conditions and could probably be lower in a population without memory complaints. The frequency of screened conditions associated with declines in IC highlights how relevant it is to develop function-centered care modalities to promote healthy aging.

RevDate: 2021-02-13

Imbimbo BP, Lucca U, M Watling (2021)

Can Anti-β-amyloid Monoclonal Antibodies Work in Autosomal Dominant Alzheimer Disease?.

Neurology. Genetics, 7(1):e535.

The dominant theory of Alzheimer disease (AD) has been that amyloid-β (Aβ) accumulation in the brain is the initial cause of the degeneration leading to cognitive and functional deficits. Autosomal dominant Alzheimer disease (ADAD), in which pathologic mutations of the amyloid precursor protein (APP) or presenilins (PSENs) genes are known to cause abnormalities of Aβ metabolism, should thus offer perhaps the best opportunity to test anti-Aβ drugs. Two long-term preventive studies (Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial [DIAN-TU-APT] and Alzheimer Preventive Initiative-ADAD) were set up to evaluate the efficacy of monoclonal anti-Aβ antibodies (solanezumab, gantenerumab, and crenezumab) in carriers of ADAD, but the results of the DIAN-TU-APT study have shown that neither solanezumab nor gantenerumab slowed cognitive decline in 144 subjects with ADAD followed for 4 years, despite one of the drugs (gantenerumab) significantly affected biomarkers relevant to their intended mechanism of action. Surprisingly, solanezumab significantly accelerated cognitive decline of both asymptomatic and symptomatic subjects. These failures further undermine the Aβ hypothesis and could support the suggestion that ADAD is triggered by accumulation of other APP metabolites, rather than Aβ.

RevDate: 2021-02-13

Palumbo D, Stanghellini G, Mucci A, et al (2021)

Autism Rating Scale: A New Tool for Characterizing the Schizophrenia Phenotype.

Frontiers in psychiatry, 12:622359.

Social dysfunctions (SD) are frequently observed in subjects with schizophrenia. Some of these dysfunctions are also observed in other neuropsychiatric disorders such as autism spectrum disorders (ASD), major depression, bipolar disorder, or Alzheimer disease. Recently, a characterization of a specific type of SD in schizophrenia has been proposed, with the concept of dis-sociality, which form the core aspect of "Schizophrenic Autism" (SA). The present study aimed to explore the presence in people with schizophrenia of SA, independent of other autistic traits, which can be often found in schizophrenia and other neurodevelopmental disorders. We used a structured interview-the Autism Rating Scale (ARS), an instrument devised to detect and measure SA. Fifty-one outpatients affected by schizophrenia (26 remitted, SCZ-r) and 28 affected by bipolar disorder type 1, with psychotic features, in the euthymic phase (BD-e) were recruited. Before assessing the specificity for schizophrenia of SA, we tested the internal consistency, the convergent and divergent validity of the ARS in the schizophrenia sample. Specificity was assessed by examining potential differences in ARS scores between SCZ-r and BD-e subjects. ARS showed good internal consistency, as well as convergent and divergent validity. ARS items were more frequently of moderate severity in SCZ-r than in BD-e subjects. This scale can contribute to establish more precise phenomenal boundaries between schizophrenia and bipolar disorder, and opens up the possibility of identifying a different type of SD in schizophrenia, independent of autistic traits and negative symptoms, which might benefit from different treatments.

RevDate: 2021-02-14

Garad M, Edelmann E, V Leßmann (2021)

Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aβ Plaques.

International journal of molecular sciences, 22(3):.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive and irreversible cognitive decline, with no disease-modifying therapy until today. Spike timing-dependent plasticity (STDP) is a Hebbian form of synaptic plasticity, and a strong candidate to underlie learning and memory at the single neuron level. Although several studies reported impaired long-term potentiation (LTP) in the hippocampus in AD mouse models, the impact of amyloid-β (Aβ) pathology on STDP in the hippocampus is not known. Using whole cell patch clamp recordings in CA1 pyramidal neurons of acute transversal hippocampal slices, we investigated timing-dependent (t-) LTP induced by STDP paradigms at Schaffer collateral (SC)-CA1 synapses in slices of 6-month-old adult APP/PS1 AD model mice. Our results show that t-LTP can be induced even in fully developed adult mice with different and even low repeat STDP paradigms. Further, adult APP/PS1 mice displayed intact t-LTP induced by 1 presynaptic EPSP paired with 4 postsynaptic APs (6× 1:4) or 1 presynaptic EPSP paired with 1 postsynaptic AP (100× 1:1) STDP paradigms when the position of Aβ plaques relative to recorded CA1 neurons in the slice were not considered. However, when Aβ plaques were live stained with the fluorescent dye methoxy-X04, we observed that in CA1 neurons with their somata <200 µm away from the border of the nearest Aβ plaque, t-LTP induced by 6× 1:4 stimulation was significantly impaired, while t-LTP was unaltered in CA1 neurons >200 µm away from plaques. Treatment of APP/PS1 mice with the anti-inflammatory drug fingolimod that we previously showed to alleviate synaptic deficits in this AD mouse model did not rescue the impaired t-LTP. Our data reveal that overexpression of APP and PS1 mutations in AD model mice disrupts t-LTP in an Aβ plaque distance-dependent manner, but cannot be improved by fingolimod (FTY720) that has been shown to rescue conventional LTP in CA1 of APP/PS1 mice.

RevDate: 2021-02-11

Liu L, Lauro BM, Wolfe MS, et al (2021)

Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides.

The Journal of biological chemistry pii:S0021-9258(21)00165-4 [Epub ahead of print].

γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer's disease (AD). The biochemical mechanism of how processing by γ-secretase is regulated, especially as regards the interaction between enzyme and substrate, remains largely unknown. Here, mutagenesis reveals that the hydrophilic loop-1 (HL-1) of presenilin-1 (PS1) is critical for both γ-secretase step-wise cleavages (processivity) and its allosteric modulation by heterocyclic γ-modulatory compounds. Systematic mutagenesis of HL-1, including all of its familial AD mutations and additional engineered variants, and quantification of the resultant Aβ products show that HL-1 is necessary for proper sequential γ-secretase processivity. We identify Y106, L113 and Y115 in HL-1 as key targets for heterocyclic γ-secretase modulators (GSMs) to stimulate processing of pathogenic Aβ peptides. Further, we confirm that the GxxxG domain in the APP transmembrane region functions as a critical substrate motif for γ-secretase processivity: a G29A substitution in APP-C99 mimics the beneficial effects of GSMs. Together, these findings provide a molecular basis for the structural regulation of γ-processivity by enzyme and substrate, facilitating the rational design of new GSMs that lower AD-initiating amyloidogenic Aβ peptides.

RevDate: 2021-02-11

Roberts JP, Stokoe SA, Sathler MF, et al (2021)

Selective co-activation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid-induced synaptic dysfunction.

The Journal of biological chemistry pii:S0021-9258(21)00174-5 [Epub ahead of print].

Beta-amyloid (Aβ) has been recognized as an early trigger in the pathogenesis of Alzheimer's disease (AD) leading to synaptic and cognitive impairments. Aβ can alter neuronal signaling through interactions with nicotinic acetylcholine receptors (nAChRs), contributing to synaptic dysfunction in AD. The three major nAChR subtypes in the hippocampus are composed of α7-, α4β2-, and α3β4-nAChRs. Aβ selectively affects α7- and α4β2-nAChRs, but not α3β4-nAChRs in hippocampal neurons, resulting in neuronal hyperexcitation. However, how nAChR subtype selectivity for Aβ affects synaptic function in AD is not completely understood. Here, we showed that Aβ associated with α7- and α4β2-nAChRs but not α3β4-nAChRs. Computational modeling suggested two amino acids in α7-nAChRs, arginine 208 and glutamate 211, were important for the interaction between Aβ and α7-containing nAChRs. These residues are conserved only in the α7 and α4 subunits. We therefore mutated these amino acids in α7-containing nAChRs to mimic the α3 subunit and found that mutant α7-containing receptors were unable to interact with Aβ. Additionally, mutant α3-containing nAChRs mimicking the α7 subunit interact with Aβ. This provides direct molecular evidence for how Aβ selectively interacted with α7- and α4β2-nAChRs, but not α3β4-nAChRs. Selective co-activation of α7- and α4β2-nAChRs also sufficiently reversed Aβ-induced AMPA receptor (AMPAR) dysfunction, including Aβ-induced reduction of AMPAR phosphorylation and surface expression in hippocampal neurons. Moreover, co-stimulation of α7- and α4β2-nAChRs reversed the Aβ-induced disruption of long-term potentiation. These findings support a novel mechanism for Aβ's impact on synaptic function in AD, namely the differential regulation of nAChR subtypes.

RevDate: 2021-02-11

Zhang J, Wang Z, Li Y, et al (2021)

Effects of a Caregiver Training Program on Oral Hygiene of Alzheimer's Patients in Institutional Care.

Journal of the American Medical Directors Association pii:S1525-8610(21)00106-7 [Epub ahead of print].

OBJECTIVES: To investigate the effects of a caregiver training program on the oral hygiene of caregivers and patients with Alzheimer's disease (AD) and to identify program components and parameters for accurate assessment of outcomes.

DESIGN: Single-blinded prospective cohort study.

SETTING AND PARTICIPANTS: Patients with AD and caregivers in nursing homes in the Greater Zhengzhou Area, China.

METHODS: Initially 168 AD patient/caregiver pairs were recruited and randomly assigned to control, limited training, and comprehensive training groups. The mini-mental state examination, global deterioration scale, and Katz activities of daily living scale were conducted for patients with AD. Information on participants' oral hygiene habits and general oral health was collected. The modified Quigley-Hein Plaque Index (PI) and Gingival Index (GI) were used to assess oral hygiene and gingival health. Intervention included (1) an educational video showing the role of dental plaque and the modified Bass technique; and (2) caregivers practicing toothbrushing on themselves and patients with AD under professional guidance. Changes in oral hygiene and correlations between patient PI/GI and caregiver PI/GI were analyzed.

RESULTS: After 6 weeks, complete data for 146 AD patient/caregiver pairs were collected. Before enrollment, most patients with AD had very poor oral hygiene. Compared with controls and limited training, only comprehensive training was able to achieve steady reduction in PI and GI scores in patients with AD, which still fell short of desirable levels (PI: 2.46 ± 0.52, GI: 1.24 ± 0.24, week 6). PI and GI scores in caregivers saw steady improvement only through comprehensive training (PI: 1.41 ± 0.38, GI: 0.88 ± 0.19, week 6). Number of training sessions had the greatest influence on both patient PI and GI scores.

CONCLUSIONS AND IMPLICATIONS: Comprehensive caregiver training on toothbrushing skills is effective in improving the oral hygiene of caregivers and patients with AD in nursing homes. Additional evidence is needed to establish the optimal program structure.

RevDate: 2021-02-11

Saleem U, Akhtar R, Anwar F, et al (2021)

Neuroprotective potential of Malva neglecta is mediated via down-regulation of cholinesterase and modulation of oxidative stress markers.

Metabolic brain disease [Epub ahead of print].

Alzheimer's disease affects daily routine due to loss of memory and decline in cognition. In vitro data showed acetylcholine esterase inhibition activity of Malva neglecta but no in vivo evidence is available. The current study aims to investigate the anti-Alzheimer's activity of Malva neglecta methanolic extract in the AlCl3-induced Alzheimer disease rats' model. Thirty Wistar rats were divided into six groups and respective doses were given orally for 21 days. Behavioural observations were recorded and biochemical analysis was performed on brain homogenate. Improvement in memory and cognition was noted in treated rats as compared to disease control. A dose-dependent decrease (0.530 ± 0.009 at 200 mg/kg, 0.212 ± 0.007 at 400 mg/kg, 0.173 ± 0.005 at 600 mg/kg) in AChE activity was noted in the treatment groups with reference to disease control value (1.572 ± 0.013). This decrease in AChE activity is linked with an increase in acetylcholine in the brain which plays a key role in retaining memory. Oxidative stress biomarkers; GSH (66.77 ± 0.01 at 600 mg/kg), SOD (26.60 ± 0.10 at 600 mg/kg), CAT (21.46 ± 0.01 at 600 mg/kg) levels were increased with a decrease in MDA (103.33 ±0.49 at 600 mg/kg) level in a dose-dependently manner in the treatment groups as compared to disease control respective values. It is concluded that Malva neglecta could ameliorate Alzheimer's symptoms possibly by decreasing AChE activity and oxidative stress.

RevDate: 2021-02-11

Koga S, Ghayal NB, DW Dickson (2021)

Deep Learning-Based Image Classification in Differentiating Tufted Astrocytes, Astrocytic Plaques, and Neuritic Plaques.

Journal of neuropathology and experimental neurology pii:6133134 [Epub ahead of print].

This study aimed to develop a deep learning-based image classification model that can differentiate tufted astrocytes (TA), astrocytic plaques (AP), and neuritic plaques (NP) based on images of tissue sections stained with phospho-tau immunohistochemistry. Phospho-tau-immunostained slides from the motor cortex were scanned at 20× magnification. An automated deep learning platform, Google AutoML, was used to create a model for distinguishing TA in progressive supranuclear palsy (PSP) from AP in corticobasal degeneration (CBD) and NP in Alzheimer disease (AD). A total of 1500 images of representative tau lesions were captured from 35 PSP, 27 CBD, and 33 AD patients. Of those, 1332 images were used for training, and 168 images for cross-validation. We tested the model using 100 additional test images taken from 20 patients of each disease. In cross-validation, precision and recall for each individual lesion type were 100% and 98.0% for TA, 98.5% and 98.5% for AP, and 98.0% and 100% for NP, respectively. In a test set, all images of TA and NP were correctly predicted. Only eleven images of AP were predicted to be TA or NP. Our data indicate the potential usefulness of deep learning-based image classification methods to assist in differential diagnosis of tauopathies.

RevDate: 2021-02-11

Miao H, Chen K, Yan X, et al (2021)

Sugar in Beverage and the Risk of Incident Dementia, Alzheimer's Disease and Stroke: A Prospective Cohort Study.

The journal of prevention of Alzheimer's disease, 8(2):188-193.

BACKGROUND: This study aimed to investigate the association between sugar in beverage and dementia, Alzheimer Disease (AD) dementia and stroke.

METHODS: This prospective cohort study were based on the US community-based Framingham Heart Study (FHS). Sugar in beverage was assessed between 1991 and 1995 (5th exam). Surveillance for incident events including dementia and stroke commenced at examination 9 through 2014 and continued for 15-20 years.

RESULTS: At baseline, a total of 1865 (63%) subjects consumed no sugar in beverage, whereas 525 (18%) subjects consumed it in 1-7 servings/week and 593 (29%) in over 7 servings/week. Over an average follow-up of 19 years in 1384 participants, there were 275 dementia events of which 73 were AD dementia. And 103 of 1831 participants occurred stroke during the follow-up nearly 16 years. After multivariate adjustments, individuals with the highest intakes of sugar in beverage had a higher risk of all dementia, AD dementia and stroke relative to individuals with no intakes, with HRs of 2.80(95%CI 2.24-3.50) for all dementia, 2.55(95%CI 1.55-4.18) for AD dementia, and 2.11(95%CI 1.48-3.00) for stroke. And the same results were shown in the subgroup for individuals with median intakes of sugar in beverage.

CONCLUSION: Higher consumption of sugar in beverage was associated with an increased risk of all dementia, AD dementia and stroke.

RevDate: 2021-02-12

Gazarian K, Ramirez-Garcia L, Tapía Orozco L, et al (2020)

Human Dental Pulp Stem Cells Display a Potential for Modeling Alzheimer Disease-Related Tau Modifications.

Frontiers in neurology, 11:612657.

We present here the first description of tau in human dental pulp stem cells (DPSCs) evidenced by RT-PCR data on expression of the gene MAPT and by immunocytochemical detection of epitopes by 12 anti-tau antibodies. The tau specificity of eight of these antibodies was confirmed by their affinity to neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) postmortem brain samples. We therefore used DPSCs and AD brain samples as a test system for determining the probability of the involvement of tau epitopes in the mechanisms converting tau into NFT in AD. Three antibodies to non-phosphorylated and seven antibodies to phosphorylated epitopes bound tau in both DPSCs and AD NFTs, thus suggesting that their function was not influenced by inducers of formation of NFTs in the AD brain. In contrast, AT100, which recognizes a hyperphosphorylated epitope, did not detect it in the cytoplasm of DPSCs but detected it in AD brain NFTs, demonstrating its AD diagnostic potential. This indicated that the phosphorylation/conformational events required for the creation of this epitope do not occur in normal cytoplasm and are a part of the mechanism (s) leading to NFT in AD brain. TG3 bound tau in the cytoplasm and in mitotic chromosomes but did not find it in nuclei. Collectively, these observations characterize DPSCs as a novel tau-harboring neuronal lineage long-term propagable in vitro cellular system for the normal conformational state of tau sites, detectable by antibodies, with their state in AD NFTs revealing those involved in the pathological processes converting tau into NFTs in the course of AD. With this information, one can model the interaction of tau with inducers and inhibitors of hyperphosphorylation toward NFT-like aggregates to search for drug candidates. Additionally, the clonogenicity of DPSCs provides the option for generation of cell lineages with CRISPR-mutagenized genes of familial AD modeling.

RevDate: 2021-02-13

Yang Y, Zha X, Zhang X, et al (2020)

Dynamics and Concordance Abnormalities Among Indices of Intrinsic Brain Activity in Individuals With Subjective Cognitive Decline: A Temporal Dynamics Resting-State Functional Magnetic Resonance Imaging Analysis.

Frontiers in aging neuroscience, 12:584863.

Individuals with subjective cognitive decline (SCD) are more likely to develop into Alzheimer disease (AD) in the future. Resting-state functional magnetic resonance imaging (rs-fMRI) studies have shown alterations of intrinsic brain activity (IBA) in SCD individuals. However, rs-fMRI studies to date have mainly focused on static characteristics of IBA, with few studies reporting dynamics- and concordance-related changes in IBA indices in SCD individuals. To investigate these aberrant changes, a temporal dynamic analysis of rs-fMRI data was conducted on 94 SCD individuals (71.07 ± 6.18 years, 60 female), 75 (74.36 ± 8.42 years, 35 female) mild cognitive impairment (MCI) patients, and 82 age-, gender-, and education-matched controls (NCs; 73.88 ± 7.40 years, 49 female) from the Alzheimer's Disease Neuroimaging Initiative database. The dynamics and concordance of the rs-fMRI indices were calculated. The results showed that SCD individuals had a lower amplitude of low-frequency fluctuations dynamics in bilateral hippocampus (HP)/parahippocampal gyrus (PHG)/fusiform gyrus (FG) and bilateral cerebellum, a lower fractional amplitude of low-frequency fluctuation dynamics in bilateral precuneus (PreCu) and paracentral lobule, and a lower regional homogeneity dynamics in bilateral cerebellum, vermis, and left FG compared with the other two groups, whereas those in MCI patients were higher (Gaussian random field-corrected, voxel-level P < 0.001, cluster-level P < 0.05). Furthermore, SCD individuals had higher concordance in bilateral HP/PHG/FG, temporal lobe, and left midcingulate cortex than NCs, but those in MCI were lower than those in NCs. No correlation between concordance values and neuropsychological scale scores was found. SCD individuals showed both dynamics and concordance-related alterations in IBA, which indicates a compensatory mechanism in SCD individuals. Temporal dynamics analysis offers a novel approach to capturing brain alterations in individuals with SCD.

RevDate: 2021-02-11

Moor LFE, Vasconcelos TRA, da R Reis R, et al (2021)

Quinoline: an attractive scaffold in drug design.

Mini reviews in medicinal chemistry pii:MRMC-EPUB-114100 [Epub ahead of print].

Quinoline and its derivatives comprise an important group of heterocyclic compounds that exhibits a wide range of pharmacological properties such as antibacterial, antiviral, anticancer, antiparasitic, anti-Alzheimer and anticholesterol. In fact, the quinoline nucleus is found in the structure of many drugs and in rational design in medicinal chemistry for the discovery of novel bioactive molecules. Persistent efforts have been made over the years to develop novel congeners with superior biological activities and minimal potential for undesirable side effects. This review highlights some discoveries on the development of quinoline-based compounds in recent years (2013-2019) focusing on their biological activities, including anticancer, antitubercular, antimalarial, anti-ZIKV, anti-DENV, anti-Leishmania and anti-Alzheimer's disease.

RevDate: 2021-02-11

Kapasi A, Leurgans SE, Arvanitakis Z, et al (2021)

Aβ (Amyloid Beta) and Tau Tangle Pathology Modifies the Association Between Small Vessel Disease and Cortical Microinfarcts.

Stroke [Epub ahead of print].

BACKGROUND AND PURPOSE: There is increasing recognition of the importance of cortical microinfarcts to overall brain health, cognition, and Alzheimer dementia. Cerebral small vessel pathologies are associated with microinfarcts and frequently coexist with Alzheimer disease; however, the extent to which Aβ (amyloid beta) and tau pathology modulates microvascular pathogenesis is not fully understood. Study objective was to examine the relationship of small vessel pathologies, arteriolosclerosis, and cerebral amyloid angiopathy, with cortical microinfarcts in people with differing levels of Aβ or tau tangle burden.

METHODS: Participants were 1489 autopsied older people (mean age at death, 89 years; 67% women) from 1 of 3 ongoing clinical-pathological cohort studies of aging. Neuropathological evaluation identified cortical Aβ and tau tangle burden using immunohistochemistry in 8 brain regions, provided semiquantitative grading of cerebral vessel pathologies, and identified the presence of cortical microinfarcts. Logistic regression models adjusted for demographics and atherosclerosis and examined whether Aβ or tau tangle burden modified relations between small vessel pathologies and cortical microinfarcts.

RESULTS: Cortical microinfarcts were present in 17% of older people, moderate-to-severe cerebral amyloid angiopathy pathology in 36%, and arteriolosclerosis in 34%. In logistic regression models, we found interactions with Aβ and tau tangles, reflecting that the association between arteriolosclerosis and cortical microinfarcts was stronger in the context of greater Aβ (estimate, 0.15; SE=0.07; P=0.02) and tau tangle burden (estimate, 0.13; SE=0.06; P=0.02). Interactions also emerged for cerebral amyloid angiopathy, suggesting that the association between cerebral amyloid angiopathy and cortical microinfarcts is more robust in the presence of higher Aβ (estimate, 0.27; SE=0.07; P<0.001) and tangle burden (estimate, 0.16; SE=0.06; P=0.005).

CONCLUSIONS: These findings suggest that in the presence of elevated Aβ or tangle pathology, small vessel pathologies are associated with greater microvascular tissue injury, highlighting a potential link between neurodegenerative and vascular mechanisms.

RevDate: 2021-02-11

Moore EE, AL Jefferson (2021)

Impact of Cardiovascular Hemodynamics on Cognitive Aging.

Arteriosclerosis, thrombosis, and vascular biology [Epub ahead of print].

It is well known that cardiovascular disease and related vascular risk factors are associated with cognitive decline and worse brain health outcomes among aging adults. Recently, subtle age-related changes in cardiac hemodynamics have been proposed as an emerging risk factor for abnormal brain aging, even in the absence of cardiovascular disease. Changes in cardiac function, vital for determining the total amount of blood available for perfusing the body, and arterial stiffness, important for regulating blood flow delivery, have been associated with compromised brain structure and function among older adults. Such alterations in cardiac output and arterial stiffening may directly affect brain health through blood-brain barrier breakdown or oligemia or may interact with Alzheimer disease and concomitant pathologies common in aging adults to accelerate cognitive decline. This review examines how age-related alterations in cardiovascular integrity contribute to abnormal brain aging, emphasizing that changes in systemic hemodynamics may compromise brain health before or concurrently with the development of neurodegenerative processes that are common in aging.

RevDate: 2021-02-11

Ramirez M, Duran MC, Pabiniak CJ, et al (2021)

Family Caregiver Needs and Preferences for Virtual Training to Manage Behavioral and Psychological Symptoms of Dementia: Interview Study.

JMIR aging, 4(1):e24965 pii:v4i1e24965.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are associated with increased stress, burden, and depression among family caregivers of people with dementia. STAR-Caregivers Virtual Training and Follow-up (STAR-VTF) is adapted from an evidence-based, in-person program that trains family caregivers to manage BPSD. We used a human-centered design approach to obtain feedback from family caregivers about STAR-VTF. The program will be evaluated using a pragmatic randomized trial.

OBJECTIVE: The objective of the study was to understand the needs of family caregivers for improving BPSD management and the extent to which caregivers perceived that STAR-VTF could address those needs.

METHODS: Between July and September 2019, we conducted 15 semistructured interviews with family caregivers of people with dementia who receive care at Kaiser Permanente Washington in the Seattle metropolitan area. We identified participants from electronic health records, primarily based on a prescription for antipsychotic medication for the person with dementia (a proxy for caregivers dealing with BPSD). We showed caregivers low-fidelity prototypes of STAR-VTF online self-directed materials and verbally described potential design elements. We obtained caregiver feedback on these elements, focusing on their needs and preferences and perceived barriers to using STAR-VTF. We used a hybrid approach of inductive and deductive coding and aggregated codes to develop themes.

RESULTS: The idea of a virtual training program for learning to manage BPSD appealed to caregivers. They said health care providers did not provide adequate education in the early disease stages about the personality and behavior symptoms that can affect people with dementia. Caregivers found it unexpected and frustrating when the person with dementia began experiencing BPSD, symptoms they felt unprepared to manage. Accordingly, caregivers expressed a strong desire for the health care organization to offer programs such as STAR-VTF much sooner. Caregivers had already put considerable effort into problem solving challenging behaviors. They anticipated deriving less value from STAR-VTF at that point. Nonetheless, many were interested in the virtual aspect of the training due to the convenience of receiving help from home and the perception that help from a virtual program would be timelier than traditional service modalities (eg, face to face). Given caregivers' limited time, they suggested dividing the STAR-VTF content into chunks to review as time permitted. Caregivers were interested in having a STAR-VTF provider for additional support in managing challenging behaviors. Caregivers reported a preference for having the same coach for the program duration.

CONCLUSIONS: Caregivers we interviewed would likely accept a virtual training program such as STAR-VTF to obtain information about BPSD and receive help managing it. Family caregivers anticipated deriving more value if STAR-VTF was offered earlier in the disease course.

RevDate: 2021-02-10

Gan DRY, Chaudhury H, Mann J, et al (2021)

Dementia-friendly neighbourhood and the built environment: A scoping review.

The Gerontologist pii:6131982 [Epub ahead of print].

BACKGROUND AND OBJECTIVES: There has been a proliferation of research on dementia-friendly communities in recent years, particularly on interpersonal and social aspects. Nonetheless, the neighbourhood built environment remains a co-constituent of the lived experience of people living with dementia (PLWD) that is amenable to interventions for health and well-being in the community. This scoping review presents a narrative synthesis of empirical research on dementia-friendly neighbourhoods, with a focus on the built environment and its associated socio-behavioural aspects. Planning and design principles are distilled to identify research and policy implications.

RESEARCH DESIGN AND METHODS: We reviewed 29 articles identified through a systematic search of AgeLine, PsycINFO, CINAHL, Global Health, MEDLINE, and Scopus. Peer-reviewed articles that employed quantitative and/or qualitative methods in community settings were included.

RESULTS: An equal number of studies focused on behavioural/psychosocial aspects of the built environment and assessment of specific environmental features. The former often used qualitative methods, whereas statistical methods were common in studies on discrete features of the neighbourhood built environment. Few studies focused on rural contexts. Emerging research areas include interactions between dementia risk factors and neighbourhood environments to support primary and secondary prevention.

DISCUSSION AND IMPLICATIONS: The body of literature needs expansion into planning and design fields to foster community participation of PLWD by optimizing environmental stimuli, minimizing environmental barriers, and engaging PLWD in dementia-friendly community initiatives. While evidence has accumulated on landmarks and social participation at the individual level, research at the community- and policy- levels are limited. This requires advanced mixed methods.

RevDate: 2021-02-13

Chen Y, Zhao S, Fan Z, et al (2021)

Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice.

Alzheimer's research & therapy, 13(1):40.

BACKGROUND: The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. Aβ deposition precedes the aggregation of tau pathology and Aβ pathology precipitates tau pathology. Evidence also indicates the reciprocal interactions between amyloid and tau pathology. However, the detailed relationship between amyloid and tau pathology in AD remains elusive. Metformin might have a positive effect on cognitive impairments. However, whether metformin can reduce AD-related pathologies is still unconclusive.

METHODS: Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of 9-month-old APPswe/PS1DE9 (APP/PS1) mice and age-matched wild-type (WT) mice. Metformin was administrated in the drinking water for 2 months. Aβ pathology, tau pathology, plaque-associated microgliosis, and autophagy marker were analyzed by immunohistochemical staining and immunofluorescence analysis 2 months after injection of proteopathic tau seeds. The effects of metformin on both pathologies were explored.

RESULTS: We observed tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau) in the bilateral hippocampi and cortices of tau-injected APP/PS1 mice but not WT mice. Aβ plaques promoted the aggregation of NP tau pathology. Injection of proteopathic tau seeds exacerbated Aβ deposits and decreased the number of microglia around Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Metformin ameliorated the microglial autophagy impairment, increased the number of microglia around Aβ plaques, promoted the phagocytosis of NP tau, and reduced Aβ load and NP tau pathology in APP/PS1 mice.

CONCLUSION: These findings indicate the existence of the crosstalk between amyloid and NP tau pathology. Metformin promoted the phagocytosis of pathological Aβ and tau proteins by enhancing microglial autophagy capability. It reduced Aβ deposits and limited the spreading of NP tau pathology in APP/PS1 mice, which exerts a beneficial effect on both pathologies.

RevDate: 2021-02-10

Barton SM, To E, Rogers BP, et al (2021)

Inhalable Thioflavin S for the Detection of Amyloid Beta Deposits in the Retina.

Molecules (Basel, Switzerland), 26(4): pii:molecules26040835.

We present an integrated delivery technology herein employing the aerosolized method to repurpose thioflavin S for imaging amyloid beta (Abeta) deposits in the retina as a surrogate of Abeta in the brain for early detection of Alzheimer's disease. The data showed that wild type (WT) mice also have Abeta deposits in the retinae, albeit much less than 5XFAD mice. Further, only in 5XFAD mice, significant Abeta deposits were found associated with retinal ganglion cells (RGCs) in whole-mount and cross-section data. Furthermore, the fluorescent signal depicted from thioflavin S corroborates with Abeta immunohistochemistry staining information. Overall, this probe delivery via inhalation method is also applicable to other Abeta-binding molecules, such as Congo red, curcumin, and thioflavin T. The advantage of imaging retinal amyloid deposits compared to the brain counterparts is that the eye is easily accessible by in vivo imaging and it reduces the effort to design a probe that must cross the formidable blood-brain barrier.

RevDate: 2021-02-16

Plagenhoef MR, Callahan PM, Beck WD, et al (2021)

Aged rhesus monkeys: Cognitive performance categorizations and preclinical drug testing.

Neuropharmacology, 187:108489 pii:S0028-3908(21)00043-5 [Epub ahead of print].

Rodent models have facilitated major discoveries in neurobiology, however, the low success rate of novel medications in clinical trials have led to questions about their translational value in neuropsychiatric drug development research. For age-related disorders of cognition such as Alzheimer' disease (AD) there is interest in moving beyond transgenic amyloid-β and/or tau-expressing rodent models and focusing more on natural aging and dissociating "healthy" from "pathological" aging to identify new therapeutic targets and treatments. In complex disorders such as AD, it can also be argued that animals with closer neurobiology to humans (e.g., nonhuman primates) should be employed more often particularly in the later phases of drug development. The purpose of the work described here was to evaluate the cognitive capabilities of rhesus monkeys across a wide range of ages in different delayed response tasks, a computerized delayed match to sample (DMTS) task and a manual delayed match to position (DMTP) task. Based on specific performance criteria and comparisons to younger subjects, the older subjects were generally less proficient, however, some performed as well as young subjects, while other aged subjects were markedly impaired. Accordingly, the older subjects could be categorized as aged "cognitively-unimpaired" or aged "cognitively-impaired" with a third group (aged-other) falling in between. Finally, as a proof of principle, we demonstrated using the DMTP task that aged cognitively-impaired monkeys are sensitive to the pro-cognitive effects of a nicotinic acetylcholine receptor (nAChR) partial agonist, encenicline, suggesting that nAChR ligands remain viable as potential treatments for age-related disorders of cognition.

RevDate: 2021-02-09

Zhuang P, Wu F, Mao L, et al (2021)

Egg and cholesterol consumption and mortality from cardiovascular and different causes in the United States: A population-based cohort study.

PLoS medicine, 18(2):e1003508 pii:PMEDICINE-D-20-04351.

BACKGROUND: Whether consumption of egg and cholesterol is detrimental to cardiovascular health and longevity is highly debated. Data from large-scale cohort studies are scarce. This study aimed to examine the associations of egg and cholesterol intakes with mortality from all causes, cardiovascular disease (CVD), and other causes in a US population.

METHODS AND FINDINGS: Overall, 521,120 participants (aged 50-71 years, mean age = 62.2 years, 41.2% women, and 91.8% non-Hispanic white) were recruited from 6 states and 2 additional cities in the US between 1995 and 1996 and prospectively followed up until the end of 2011. Intakes of whole eggs, egg whites/substitutes, and cholesterol were assessed by a validated food frequency questionnaire. Cause-specific hazard models considering competing risks were used, with the lowest quintile of energy-adjusted intake (per 2,000 kcal per day) as the reference. There were 129,328 deaths including 38,747 deaths from CVD during a median follow-up of 16 years. Whole egg and cholesterol intakes were both positively associated with all-cause, CVD, and cancer mortality. In multivariable-adjusted models, the hazard ratios (95% confidence intervals) associated with each intake of an additional half of a whole egg per day were 1.07 (1.06-1.08) for all-cause mortality, 1.07 (1.06-1.09) for CVD mortality, and 1.07 (1.06-1.09) for cancer mortality. Each intake of an additional 300 mg of dietary cholesterol per day was associated with 19%, 16%, and 24% higher all-cause, CVD, and cancer mortality, respectively. Mediation models estimated that cholesterol intake contributed to 63.2% (95% CI 49.6%-75.0%), 62.3% (95% CI 39.5%-80.7%), and 49.6% (95% CI 31.9%-67.4%) of all-cause, CVD, and cancer mortality associated with whole egg consumption, respectively. Egg white/substitute consumers had lower all-cause mortality and mortality from stroke, cancer, respiratory disease, and Alzheimer disease compared with non-consumers. Hypothetically, replacing half a whole egg with equivalent amounts of egg whites/substitutes, poultry, fish, dairy products, or nuts/legumes was related to lower all-cause, CVD, cancer, and respiratory disease mortality. Study limitations include its observational nature, reliance on participant self-report, and residual confounding despite extensive adjustment for acknowledged dietary and lifestyle risk factors.

CONCLUSIONS: In this study, intakes of eggs and cholesterol were associated with higher all-cause, CVD, and cancer mortality. The increased mortality associated with egg consumption was largely influenced by cholesterol intake. Our findings suggest limiting cholesterol intake and replacing whole eggs with egg whites/substitutes or other alternative protein sources for facilitating cardiovascular health and long-term survival.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00340015.

RevDate: 2021-02-09

Kawas CH, Legdeur N, MM Corrada (2021)

What have we learned from cognition in the oldest-old.

Current opinion in neurology pii:00019052-900000000-98843 [Epub ahead of print].

PURPOSE OF REVIEW: People over 90 are the fastest growing segment of the population with the highest rates of dementia. This review highlights recent findings that provide insight to our understanding of dementia and cognition at all ages.

RECENT FINDINGS: Risk factors for Alzheimer's disease (AD) and dementia differ by age, with some factors, like the development of hypertension, actually becoming protective in the oldest-old. At least half of all dementia in this age group is due to non AD pathologies, including microinfarcts, hippocampal sclerosis and TDP-43. The number of pathologic changes found in the brain is related to both risk and severity of dementia, but many people in this age group appear to be 'resilient' to these pathologies. Resilience to Alzheimer pathology, in part, may be related to absence of other pathologies, and imaging and spinal fluid biomarkers for AD have limited utility in this age group.

SUMMARY: Studies of dementia in the oldest-old are important for our understanding and eventual treatment or prevention of dementia at all ages.

RevDate: 2021-02-09

Ioghen O, Chitoiu L, Gherghiceanu M, et al (2021)

CD36 - a novel molecular target in the neurovascular unit.

The European journal of neuroscience [Epub ahead of print].

CD36 is an integral membrane protein primarily known for its function as a fatty acid transporter, yet also playing other biological roles from lipid metabolism to inflammation modulation. These pleiotropic effects are explained by the existence of multiple different ligands and the extensive distribution in numerous cell types. Moreover, the receptor is related to various pathologies and it may prove to be a good target for prospective therapeutic strategies. In the neurovascular unit (NVU), CD36 is expressed in cells like microglia, microvascular endothelial cells, astrocytes and neurons. In the normal brain, CD36 was proven to be involved in phagocytosis of apoptotic cells, oro-sensory detection of dietary lipids, and fatty acid transport across the blood brain barrier (BBB). CD36 was also acknowledged as a potentially important player in central nervous system (CNS) disorders, such as Alzheimer Disease-associated vascular dysfunction and oxidative stress and the neuroinflammatory response in stroke. Despite continuous efforts, the therapeutic arsenal for such diseases is still scarce and there is an increasing interest in discovering new molecular targets for more specific therapeutic approaches. In this review we summarize the role of CD36 in the normal function of the NVU and in several CNS disorders, focusing on the dysregulation of the NVU and the potential therapeutic modulation.

RevDate: 2021-02-09

Wang Y, Lim YY, He Z, et al (2021)

Dietary phytochemicals that influence gut microbiota: Roles and actions as anti-Alzheimer agents.

Critical reviews in food science and nutrition [Epub ahead of print].

The last decide has witnessed a growing research interest in the role of dietary phytochemicals in influencing the gut microbiota. On the other hand, recent evidence reveals that dietary phytochemicals exhibit properties of preventing and tackling symptoms of Alzheimer's disease, which is a neurodegenerative disease that has also been linked with the status of the gut microbiota over the last decade. Till now, little serious discussions, however, have been made to link recent understanding of Alzheimer's disease, dietary phytochemicals and the gut microbiota together and to review the roles played by phytochemicals in gut dysbiosis induced pathologies of Alzheimer's disease. Deciphering these connections can provide insights into the development and future use of dietary phytochemicals as anti-Alzheimer drug candidates. This review aims at presenting latest evidence in the modulating role of phytochemicals in the gut microbiota and its relevance to Alzheimer's disease and summarizing the mechanisms behind the modulative activities. Limitations of current research in this field and potential directions will also be discussed for future research on dietary phytochemicals as anti-Alzheimer agents.

RevDate: 2021-02-16

Muscari A, Clavarino F, Allegri V, et al (2021)

"2-step MCI-AD": a simple scoring system to predict rapid conversion from mild cognitive impairment to Alzheimer dementia.

Archives of gerontology and geriatrics, 94:104359 pii:S0167-4943(21)00022-4 [Epub ahead of print].

BACKGROUND: Several techniques are available to identify, among patients with mild cognitive impairment (MCI), those at risk of conversion to Alzheimer dementia (CAD). However, simple cost-effective methods to assess the risk are not available yet.

METHODS: This retrospective study included 143 MCI outpatients (76.6±5.2 years, 46.8% women). Baseline variables were common neuropsychological tests (including Mini Mental State Examination-MMSE and Montreal Cognitive Assessment-MoCA), brain CT and 18F-fluorodeoxyglucose (FDG)-PET. Outcome variable was CAD after 1 year.

RESULTS: At follow-up, 31 (21.7%) patients had CAD. In multivariable analysis (OR, 95% CI), female sex (4.7, 1.6-14.0), MoCA-executive component <3 (6.3, 2.1-19.2), left medial temporal atrophy (MTA) ≥3 (5.4, 1.9-15.7) and FDG-PET suggesting CAD (5.4, 1.9-15.7) were associated with CAD (area under ROC curve 0.873). Without FDG-PET, MMSE score <28 remained associated with CAD (6.0, 2.2-16.9). As first step (before FDG-PET execution), we counted 1 point for MMSE <28, executive MoCA <3 and left MTA ≥3. With 2-3 points CAD probability was high (75%) and with 0 points it was low (6.5%). Thus, FDG-PET (second step) might be performed only in patients with 1 point (probability 19.7%, 42.7% of patients). Among them, 35% had a positive FDG-PET, suggesting high risk. Overall, 28.0% of patients were considered at high risk (specificity 83.9%, sensitivity 71.0%, accuracy 81.1%).

CONCLUSION: With a 2-step procedure, less than half of MCI patients might undergo FDG-PET and nearly a quarter of our patients was found to be at high CAD risk, including almost three quarters of future CADs.

RevDate: 2021-02-08

Beattie F, Kerr L, Larkin J, et al (2021)

The components of personal passports for people living with dementia in an acute healthcare setting: An integrative review.

Journal of clinical nursing [Epub ahead of print].

AIM: To explore the components of personal passports for people living with dementia in an acute healthcare setting BACKGROUND: Globally, supporting people with dementia poses a prominent health and social care challenge. Importance for people with dementia in an acute healthcare setting includes social relationships and communication with healthcare staff. A personal passport is an international initiative designed to support the personhood of the person living with dementia.

METHODS: This integrative review is based on the methodology of Whittmore and Knafl (2005). The Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklist were adhered to. A database search of PubMed, MEDLINE, CINHAL, Scopus and EBSCO databases were systematically searched.

RESULTS: This integrative review identified nine research studies on the components of personal passports that met the inclusion and exclusion criteria. A constant comparative method of data analysis identified five key pivotal themes: person-centredness, communication, family/carer involvement, education and leadership.

CONCLUSION: The use of personal passports supports the provision of person-centred care for people living with dementia through enhancing the wellbeing of both the person and their families/caregivers. Relevance to clinical practice Personal passports are an important document and should be determined by the person with dementia, their care needs and the caregiver's role in meeting these needs.

RevDate: 2021-02-08

Tam MT, Dosso JA, JM Robillard (2021)

The Impact of a Global Pandemic on People Living with Dementia and Their Care Partners: Analysis of 417 Lived Experience Reports.

Journal of Alzheimer's disease : JAD pii:JAD201114 [Epub ahead of print].

BACKGROUND: The COVID-19 pandemic is impacting the physical and emotional health of older adults living with dementia and their care partners.

OBJECTIVE: Using a patient-centered approach, we explored the experiences and needs of people living with dementia and their care partners during the COVID-19 pandemic as part of an ongoing evaluation of dementia support services in British Columbia, Canada.

METHODS: A survey instrument was developed around the priorities identified in the context of the COVID-19 and Dementia Task Force convened by the Alzheimer Society of Canada.

RESULTS: A total of 417 surveys were analyzed. Overall, respondents were able to access information that was helpful for maintaining their own health and a period of social distancing. Care partners reported a number of serious concerns, including the inability to visit the person that they care for in long-term or palliative care. Participants also reported that the pandemic increased their levels of stress overall and that they felt lonelier and more isolated than they did before the pandemic. The use of technology was reported as a way to connect socially with their loved ones, with the majority of participants connecting with others at least twice per week.

CONCLUSION: Looking at the complex effects of a global pandemic through the experiences of people living with dementia and their care partners is vital to inform healthcare priorities to restore their quality of life and health and better prepare for the future.

RevDate: 2021-02-12

Vernerová A, Kujovská Krčmová L, Melichar B, et al (2020)

Non-invasive determination of uric acid in human saliva in the diagnosis of serious disorders.

Clinical chemistry and laboratory medicine pii:cclm-2020-1533 [Epub ahead of print].

This review summarizes and critically evaluates the published approaches and recent trends in sample pre-treatment, as well as both separation and non-separation techniques used for the determination of uric acid (UA) in saliva. UA is the final product of purine nucleotide catabolism in humans. UA concentrations in biological fluids such as serum, plasma, and urine represent an important biomarker of diseases including gout, hyperuricemia, or disorders associated with oxidative stress. Previous studies reported correlation between UA concentrations detected in saliva and in the blood. The interest in UA has been increasing during the past 20 years from a single publication in 2000 to 34 papers in 2019 according to MEDLINE search using term "uric acid in saliva". The evaluation of salivary UA levels can contribute to non-invasive diagnosis of many serious diseases. Increased salivary UA concentration is associated with cancer, HIV, gout, and hypertension. In contrast, low UA levels are associated with Alzheimer disease, progression of multiple sclerosis, and mild cognitive impairment.

RevDate: 2021-02-10

Amaral AC, Perez-Nievas BG, Siao Tick Chong M, et al (2021)

Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation.

iScience, 24(2):102058.

It has been suggested that aberrant activation of glycogen synthase kinase-3-beta (GSK-3β) can trigger abnormal tau hyperphosphorylation and aggregation, which ultimately leads to neuronal/synaptic damage and impaired cognition in Alzheimer disease (AD). We examined if isoform-selective partial reduction of GSK-3β can decrease pathological tau changes, including hyperphosphorylation, aggregation, and spreading, in mice with localized human wild-type tau (hTau) expression in the brain. We used adeno-associated viruses (AAVs) to express hTau locally in the entorhinal cortex of wild-type and GSK-3β hemi-knockout (GSK-3β-HK) mice. GSK-3β-HK mice had significantly less accumulation of hyperphosphorylated tau in synapses and showed a significant decrease of tau protein spread between neurons. In primary neuronal cultures from GSK-3β-HK mice, the aggregation of exogenous FTD-mutant tau was also significantly reduced. These results show that a partial decrease of GSK-3β significantly represses tau-initiated neurodegenerative changes in the brain, and therefore is a promising therapeutic target for AD and other tauopathies.

RevDate: 2021-02-10

Li P, Quan W, Wang Z, et al (2020)

AD7c-NTP Impairs Adult Striatal Neurogenesis by Affecting the Biological Function of MeCP2 in APP/PSl Transgenic Mouse Model of Alzheimer's Disease.

Frontiers in aging neuroscience, 12:616614.

The processes by which neural stem cells (NSCs) and neural precursor cells (NPCs) transform into the characteristic lineages observed in Alzheimer's disease (AD) are poorly characterized. Understanding these processes is of critical importance due to the increased prevalence of AD and the lack of effective AD strategies. Here, we used immunohistochemistry and Western blot to find out if MeCP2 was phosphorylated at a specific amino acid residue, Serine 421 (S421), and activated in response to AD-induced damage in amyloid precursor protein (APP)/PSl transgenic mice, altering its nuclear to cytoplasmic shuttling. Epigenetic examinations combined with chromatin immunoprecipitation and methylated DNA immunoprecipitation revealed that the translocation of MeCP2 from the nucleus to cytoplasm led to the loss of lineage-specific gene promoters (such as Gfap, Nestin, and Dcx), decreased transcriptional repression, and the activation of gene expression. Immunofluorescence data demonstrated that neurogenic progenitors with high levels of active phosphorylated MeCP2 at S421 (MeCP2 pS421) possessed a high probability of development into doublecortin (DCX)-expressing cells. AD7c-NTP will control neurogenic progenitor regeneration through its effects on MeCP2 pS421, leading to altered lineage-specific gene expression. This adds to the growing list of biological effects of AD7c-NTP in the brain and highlights MeCP2 as relevant to the plasticity of neural cells in the AD mice striatum.

RevDate: 2021-02-10

Habif M, Do Carmo S, Báez MV, et al (2020)

Early Long-Term Memory Impairment and Changes in the Expression of Synaptic Plasticity-Associated Genes, in the McGill-R-Thy1-APP Rat Model of Alzheimer's-Like Brain Amyloidosis.

Frontiers in aging neuroscience, 12:585873.

Accruing evidence supports the hypothesis that memory deficits in early Alzheimer Disease (AD) might be due to synaptic failure caused by accumulation of intracellular amyloid beta (Aβ) oligomers, then secreted to the extracellular media. Transgenic mouse AD models provide valuable information on AD pathology. However, the failure to translate these findings to humans calls for models that better recapitulate the human pathology. McGill-R-Thy1-APP transgenic (Tg) rat expresses the human amyloid precursor protein (APP751) with the Swedish and Indiana mutations (of familial AD), leading to an AD-like slow-progressing brain amyloid pathology. Therefore, it offers a unique opportunity to investigate learning and memory abilities at early stages of AD, when Aβ accumulation is restricted to the intracellular compartment, prior to plaque deposition. Our goal was to further investigate early deficits in memory, particularly long-term memory in McGill-R-Thy1-APP heterozygous (Tg+/-) rats. Short-term- and long-term habituation to an open field were preserved in 3-, 4-, and 6-month-old (Tg+/-). However, long-term memory of inhibitory avoidance to a foot-shock, novel object-recognition and social approaching behavior were seriously impaired in 4-month-old (Tg+/-) male rats, suggesting that they are unable to either consolidate and/or evoke such associative and discriminative memories with aversive, emotional and spatial components. The long-term memory deficits were accompanied by increased transcript levels of genes relevant to synaptic plasticity, learning and memory processing in the hippocampus, such as Grin2b, Dlg4, Camk2b, and Syn1. Our findings indicate that in addition to the previously well-documented deficits in learning and memory, McGill-R-Thy1-APP rats display particular long-term-memory deficits and deep social behavior alterations at pre-plaque early stages of the pathology. This highlights the importance of Aβ oligomers and emphasizes the validity of the model to study AD-like early processes, with potentially predictive value.

RevDate: 2021-02-10

Wu YY, Lee YS, Liu YL, et al (2021)

Association Study of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Polymorphism With Alzheimer Disease in the Taiwanese Population.

Frontiers in neuroscience, 15:625885.

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are two major alcohol-metabolizing enzymes. Moderate alcohol intake is a protective modified factor in Alzheimer's disease (AD) while heavy alcohol intake and abstinence increased dementia risk. The associations between Alzheimer's disease and alcohol-metabolizing genes are uncertain. This study examined the association of AD with seven ADH/ALDH single-nucleotide polymorphisms (SNPs), ADH1C rs2241894, ADH1B rs1229984, ALDH1B1 rs2073478, ALDH2 rs886205, rs4767944, rs4648328, and rs671. We enrolled 157 AD and 168 age- and sex-matched control subjects in pilot study to examine the association of AD with ADH/ALDH SNPs. Reconstructed ALDH2 haplotypes were performed. We measured plasma level of ADH1C and checked the interaction effect of AD-rs2241894 genotype on plasma ADH1C level. In extension study, we further examined 339 AD and 2,504 healthy control from the Taiwan Biobank. In pilot study, we observed that ADH1C rs2241894 TT genotype was negatively associated with AD in a recessive genetic model (OR = 0.25, 95% CI 0.09-0.75, p < 0.0001) in women. A strong linkage disequilibrium was observed among the four examined SNPs of ALDH2. No haplotype was related to AD. The plasma ADH1C level in AD was higher than that in control. After adjusted by age, sex, hypertension, diabetes mellitus, and alcohol, we found a significant interaction effect of AD-rs2241894 genotype on plasma ADH1C level (p = 0.04). This interaction effect was attributable to the association between AD and plasma ADH1C level (β estimate = 366, 95% CI 92.7∼639.4, p = 0.009). The genetic distribution of ADH1C rs2241894 showed strong ethnic heterogeneity, in which the T allele was the minor allele accounting for 28.5% in our study and 23.6% in East Asians, while it was a major allele in Americans, Europeans, and the global populations. No association was discovered between AD and the five SNPs: rs2241894, rs1229984, rs2073478, rs886205, and rs671 in the extension study. In summary, this study revealed a suggestive association between ADH1C rs2241894 and female AD in the pilot study, but failed to confirm this finding in a population database. Further age-matched and large sample size case-control studies are needed before rs2241894 can be interpreted as a protective genetic factor of AD.

RevDate: 2021-02-07

Donoso A, González J, Muñoz AA, et al (2021)

"Therapeutic uses of natural astaxanthin: An evidence-based review focused on human clinical trials".

Pharmacological research pii:S1043-6618(21)00063-3 [Epub ahead of print].

Astaxanthin is a natural C40 carotenoid with numerous reported biological functions, most of them associated with its antioxidant and anti-inflammatory activity, standing out from other antioxidants as it has shown the highest oxygen radical absorbance capacity (ORAC), 100-500 times higher than ⍺-tocopherol and a 10 times higher free radical inhibitory activity than related antioxidants (α-tocopherol, α-carotene, β -carotene, lutein and lycopene). In vitro and in vivo studies have associated astaxanthin´s unique molecular features with several health benefits, including neuroprotective, cardioprotective and antitumoral properties, suggesting its therapeutic potential for the prevention or co-treatment of dementia, Alzheimer, Parkinson, cardiovascular diseases and cancer. Benefits on skin and eye health promotion have also been reported, highlighting its potential for the prevention of skin photo-aging and the treatment of eye diseases like glaucoma, cataracts and uveitis. In this review, we summarize and discuss the currently available evidence on astaxanthin benefits, with a particular focus on human clinical trials, including a brief description of the potential mechanisms of action responsible for its biological activities.

RevDate: 2021-02-13

Rivas-García L, Quiles JL, Roma-Rodrigues C, et al (2021)

Rosa x hybrida extracts with dual actions: Antiproliferative effects against tumour cells and inhibitor of Alzheimer disease.

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 149:112018 pii:S0278-6915(21)00052-1 [Epub ahead of print].

Edible flowers are being used as a new ingredient in modern gastronomy. Recently, these products have also gained interest as an important source of phenolic compounds with potential for biomedical applications. The present work studied a methanolic extract of Rosa x hybrida in which 35 individual phenolic compounds were identified. The extract has been evaluated for its antiproliferative properties in ovarian carcinoma cells. Results showed that the antiproliferative effect was associated with the induction of autophagy and apoptosis with the concomitant ROS increase probably related to mitochondria dysfunction. These antiproliferative effects might be associated with some components of the extract such as quercetin. The extract did not induce damage in healthy cells and that it was able to improve the wound healing activity. The present study also evaluated the properties of the mentioned extract in vivo in C. elegans. Tests demonstrated a lack of toxicity in the worm model. Promising results have been obtained in transgenic strains of C. elegans that produce human beta amyloid peptide, suggesting the possible utility of the extract from the point of view of Alzheimer disease. Altogether, results suggest that Rosa x hybrida extracts could be a new tool for the development of functional foods.

RevDate: 2021-02-07

Domingues R, Pereira C, Cruz MT, et al (2021)

Therapies for Alzheimer's disease: a metabolic perspective.

Molecular genetics and metabolism pii:S1096-7192(21)00012-3 [Epub ahead of print].

Alzheimer's disease (AD) is one of the most common forms of dementia in the elderly. Currently, there are over 50 million cases of dementia worldwide and it is expected that it will reach 136 million by 2050. AD is described as a neurodegenerative disease that gradually compromises memory and learning capacity. Patients often exhibit brain glucose hypometabolism and are more susceptible to develop type 2 diabetes or insulin resistance in comparison with age-matched controls. This suggests that there is a link between both pathologies. Glucose metabolism and the tricarboxylic acid cycle are tightly related to mitochondrial performance and energy production. Impairment of both these pathways can evoke oxidative damage on mitochondria and key proteins linked to several hallmarks of AD. Glycation is also another type of post-translational modification often reported in AD, which might impair the function of proteins that participate in metabolic pathways thought to be involved in this illness. Despite needing further research, therapies based on insulin treatment, usage of anti-diabetes drugs or some form of dietary intervention, have shown to be promising therapeutic approaches for AD in its early stages of progression and will be unveiled in this paper.

RevDate: 2021-02-07

Thiyagalingam S, Kulinski AE, Thorsteinsdottir B, et al (2021)

Dysphagia in Older Adults.

Mayo Clinic proceedings, 96(2):488-497.

Dysphagia, which is a geriatric syndrome affecting 10% to 33% of older adults, is commonly seen in older adults who have experienced a stroke or neurodegenerative diseases such as Alzheimer or Parkinson disease. Patients diagnosed as having dysphagia can experience malnutrition, pneumonia, and dehydration. Patients can also experience increased rates of mortality and long-term care admission. Providers can identify the specific type of dysphagia for treatment in approximately 80% of patients by asking 5 questions in the patient's history: What happens when you try to swallow? Do you have trouble chewing? Do you have difficulty swallowing solids, liquids, or both? Describe the symptom onset, duration, and frequency? What are the associated symptoms? Providers can then request a videofluoroscopic swallow study or a fiberoptic endoscopic evaluation of swallowing for further evaluation of oropharyngeal dysphagia. If providers are diagnosing esophageal dysphagia, barium esophagraphy or esophagogastroduodenoscopy (EGD) can be used as part of the assessment. Patients can be treated for oropharyngeal dysphagia by using compensatory interventions, including behavioral changes, oral care, dietary modification, or rehabilitative interventions such as exercises and therapeutic oral trials. Providers often address treatment of esophageal dysphagia by managing the underlying etiology, which could include removal of caustic medications or using EGD as a therapeutic modality for esophageal rings. High-quality, large research studies are necessary to further manage the diagnosis and appropriate treatment of this growing geriatric syndrome.

RevDate: 2021-02-07

Hsiao SH, Hwang TJ, Lin FJ, et al (2021)

The Association Between the Use of Cholinesterase Inhibitors and Cardiovascular Events Among Older Patients With Alzheimer Disease.

Mayo Clinic proceedings, 96(2):350-362.

OBJECTIVE: To evaluate the association between the use of cholinesterase inhibitors (ChEIs) and incident cardiovascular events (CVEs) among older patients with Alzheimer disease (AD).

PATIENTS AND METHODS: This retrospective cohort study was conducted with a new-user design and active-comparator design. The data source was the 2005-2014 Full Population file from the Health and Welfare Database in Taiwan. Patients were included if they were aged 50 years or older and had been diagnosed with AD between January 1, 2006, and December 31, 2010. The association between ChEI use and the risk of CVEs was investigated in patients with AD. Among the ChEI users, the risk of CVEs was further compared between patients with different cumulative doses and different ChEI treatment strategies. The propensity score method, which included matching and inverse probability of treatment weighting, was used to balance the potential confounders. A Cox proportional hazards model with competing risks was used to estimate the hazard ratio of CVEs.

RESULTS: The study included 6070 patients with AD. After covariate adjustment, ChEI users had a significantly lower risk of CVEs than nonusers (hazard ratio, 0.57; 95% CI, 0.51 to 0.62). Among ChEI users, patients with a high cumulative dose had a significantly lower risk of CVEs than those with a low cumulative dose (hazard ratio, 0.82; 95% CI, 0.70 to 0.96).

CONCLUSION: The use of ChEIs was associated with a decreased risk of incident CVEs among patients with AD. The cardioprotective effect of ChEIs showed a dose-response relationship.

RevDate: 2021-02-06

Živković L, Bajić V, Čabarkapa-Pirković A, et al (2021)

Strawberry (Fragaria ananassa duch.) Alba extract attenuates DNA damage in lymphocytes of patients with Alzheimer's disease.

Journal of food biochemistry [Epub ahead of print].

Increased levels of oxidative stress and oxidative DNA damage are common features in the pathology of Alzheimer's disease (AD) found in neurons and peripheral cells like peripheral blood lymphocytes (PBL). Natural products such as strawberry cultivar Alba are an important source of bioactive nutrients that could help in lowering both the oxidative stress and DNA damage levels. The objective was to estimate the effects of Alba extract on DNA damage in peripheral blood lymphocytes of sporadic AD (aged 60-84 years) patients, and healthy elderly (aged 69-83 years) and young (aged 21-30 years) individuals in in vitro conditions. Comet assay was used as a sensitive technique for the evaluation of PBL DNA damage levels. Reduction of basal DNA damage level in PBL was shown in the young group after the incubation with Alba extract ranging from 25 to 200 μg/ml, with 100 μg/ml being the most effective concentration. Selected Alba extract of 100 μg/ml was further used for PBL treatment of AD and healthy elderly age matched group, displaying potential to significantly attenuate DNA damage levels in both groups (p < .05). Alba extract displayed biological activity against oxidative DNA damage, suggesting that its functional ingredients may have beneficial health effects. PRACTICAL APPLICATIONS: The data obtained in this preliminary study displayed that strawberry Alba extract is efficient against DNA damage induced by endogenous and exogenous oxidative stress in peripheral blood lymphocytes of Alzheimer`s disease in vitro. An active area of future research of Alba cultivar should be to determine the trials in in vivo systems. Our findings also suggest that Alba cultivar's functional ingredients potentially may have beneficial health effects in AD.

RevDate: 2021-02-10

Coomans EM, Schoonhoven DN, Tuncel H, et al (2021)

In vivo tau pathology is associated with synaptic loss and altered synaptic function.

Alzheimer's research & therapy, 13(1):35.

BACKGROUND: The mechanism of synaptic loss in Alzheimer's disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([18F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB-J PET) and synaptic function (MEG) in Alzheimer's disease.

METHODS: Seven amyloid-positive Alzheimer's disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [18F]flortaucipir PET, dynamic 60-min [11C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [18F]flortaucipir- and [11C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [18F]flortaucipir BPND, [11C]UCB-J BPND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models.

RESULTS: Across subjects, higher regional [18F]flortaucipir uptake was associated with lower [11C]UCB-J uptake. Within subjects, the association between [11C]UCB-J and [18F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [18F]flortaucipir and lower [11C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe.

CONCLUSIONS: These results indicate that in Alzheimer's disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

RevDate: 2021-02-15

Williams M, S Daley (2021)

Innovation in dementia education within undergraduate healthcare programmes: A scoping review.

Nurse education today, 98:104742.

OBJECTIVES: The increase in the number of people living with dementia has resulted in a greater need for healthcare professionals from all disciplines to meet the needs of those living with the condition. This means a workforce which is competent in delivering dementia care which is person-centred, regardless clinical specialism. The aim of scoping review is to provide an overview of the novel education models being used to ensure the future healthcare workforce are able to meet this aspiration.

DATA SOURCES: Online databases PubMed, Web of Science, CINAHL, Medline, PsychInfo, ERIC were used.

REVIEW METHODS: Search terms 'Healthcare Student(s)', 'Dementia or Alzheimer's Education' were used. Inclusion criteria included papers published in English between 2009 and September 2019, with data pertaining to the assessment of dementia knowledge and attitudes among healthcare students. Abstracts were reviewed and identified for inclusion for full-text review. Included studies were assessed using the MMAT (Mixed Methods Appraisal Tool).

RESULTS: 27 studies were included within the review. These were groups into five educational categories; long term experiential (n=5), activity-centered programmes with people with dementia (n=11), interprofessional education (IPE) (n=5), immersive conference style programmes (n=3) and dementia simulation (n=3). Long term experiential and activity centered programmes gave students the greatest increase in perceived confidence, and improvement in dementia attitudes. Programmes were most effective when directly involving people living with dementia.

CONCLUSION: The majority of the education programmes showed a potential benefit in improving either knowledge, confidence, attitude, or all three among healthcare students. This highlights the benefit that novel experiential programmes may have in aiding a culture of positive attitudes among future healthcare professionals who will be treating people with dementia. This review also demonstrates the positive benefit that directly involving people living with dementia within education can have on both student learners.

RevDate: 2021-02-06

Salobrar-García E, López-Cuenca I, Sánchez-Puebla L, et al (2020)

Retinal Thickness Changes Over Time in a Murine AD Model APP NL-F/NL-F .

Frontiers in aging neuroscience, 12:625642.

Background: Alzheimer's disease (AD) may present retinal changes before brain pathology, suggesting the retina as an accessible biomarker of AD. The present work is a diachronic study using spectral domain optical coherence tomography (SD-OCT) to determine the total retinal thickness and retinal nerve fiber layer (RNFL) thickness in an APPNL-F/NL-F mouse model of AD at 6, 9, 12, 15, 17, and 20 months old compared to wild type (WT) animals. Methods: Total retinal thickness and RNFL thickness were determined. The mean total retinal thickness was analyzed following the Early Treatment Diabetic Retinopathy Study sectors. RNFL was measured in six sectors of axonal ring scans around the optic nerve. Results: In the APPNL-F/NL-F group compared to WT animals, the total retinal thickness changes observed were the following: (i) At 6-months-old, a significant thinning in the outer temporal sector was observed; (ii) at 15-months-old a significant thinning in the inner temporal and in the inner and outer inferior retinal sectors was noticed; (iii) at 17-months-old, a significant thickening in the inferior and nasal sectors was found in both inner and outer rings; and (iv) at 20-months-old, a significant thinning in the inner ring of nasal, temporal, and inferior retina and in the outer ring of superior and temporal retina was seen. In RNFL thickness, there was significant thinning in the global analysis and in nasal and inner-temporal sectors at 6 months old. Thinning was also found in the supero-temporal and nasal sectors and global value at 20 months old. Conclusions: In the APPNL-F/NL-F AD model, the retinal thickness showed thinning, possibly produced by neurodegeneration alternating with thickening caused by deposits and neuroinflammation in some areas of the retina. These changes over time are similar to those observed in the human retina and could be a biomarker for AD. The APPNL-F/NL-F AD model may help us better understand the different retinal changes during the progression of AD.

RevDate: 2021-02-05

Marca-Ysabel MV, Rajabli F, Cornejo-Olivas M, et al (2020)

Dissecting the role of Amerindian genetic ancestry and the ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population.

Neurobiology of aging pii:S0197-4580(20)30312-2 [Epub ahead of print].

Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. The apolipoprotein E (ApoE) ε4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic white populations and has a relatively lower effect in African descent populations. Admixture analysis in the African American and Puerto Rican populations showed that the variation in ε4 risk is correlated with the genetic ancestral background local to the ApoE gene. Native American populations are substantially underrepresented in AD genetic studies. The Peruvian population with up to ~80 of Amerindian (AI) ancestry provides a unique opportunity to assess the role of AI ancestry in AD. In this study, we assess the effect of the ApoE ε4 allele on AD in the Peruvian population. A total of 79 AD cases and 128 unrelated cognitive healthy controls from Peruvian population were included in the study. Genome-wide genotyping was performed using the Illumina Global screening array v2.0. Global ancestry and local ancestry analyses were assessed. The effect of the ApoE ε4 allele on AD was tested using a logistic regression model by adjusting for age, gender, and population substructure (first 3 principal components). Results showed that the genetic ancestry surrounding the ApoE gene is predominantly AI (60.6%) and the ε4 allele is significantly associated with increased risk of AD in the Peruvian population (odds ratio = 5.02, confidence interval: 2.3-12.5, p-value = 2e-4). Our results showed that the risk for AD from ApoE ε4 in Peruvians is higher than we have observed in non-Hispanic white populations. Given the high admixture of AI ancestry in the Peruvian population, it suggests that the AI genetic ancestry local to the ApoE gene is contributing to a strong risk for AD in ε4 carriers. Our data also support the findings of an interaction between the genetic risk allele ApoE ε4 and the ancestral backgrounds located around the genomic region of ApoE gene.

RevDate: 2021-02-05

Fragoso-Morales LG, Correa-Basurto J, MC Rosales-Hernández (2021)

Implication of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Its Inhibitors in Alzheimer's Disease Murine Models.

Antioxidants (Basel, Switzerland), 10(2): pii:antiox10020218.

Alzheimer's disease (AD) is one of the main human dementias around the world which is constantly increasing every year due to several factors (age, genetics, environment, etc.) and there are no prevention or treatment options to cure it. AD is characterized by memory loss associated with oxidative stress (OS) in brain cells (neurons, astrocytes, microglia, etc.). OS can be produced by amyloid beta (Aβ) protein aggregation and its interaction with metals, mitochondrial damage and alterations between antioxidants and oxidant enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH oxidase produces reactive oxygen species (ROS) and it is overexpressed in AD, producing large amounts of superoxide anions and hydrogen peroxide which damage brain cells and the vasculature. In addition, it has been reported that NADPH oxidase causes an imbalance of pH which could also influence in the amyloid beta (Aβ) production. Therefore, NADPH oxidase had been proposed as a therapeutic target in AD. However, there are no drugs for AD treatment such as an NADPH oxidase inhibitor despite great efforts made to stabilize the ROS production using antioxidant molecules. So, in this work, we will focus our attention on NADPH oxidase (NOX2 and NOX4) in AD as well as in AD models and later discuss the use of NADPH oxidase inhibitor compounds in AD.

RevDate: 2021-02-16

Lunar Silva I, E Cascales (2021)

Molecular Strategies Underlying Porphyromonas gingivalis Virulence.

Journal of molecular biology, 433(7):166836 pii:S0022-2836(21)00030-9 [Epub ahead of print].

The anaerobic Gram-negative bacterium Porphyromonas gingivalis is considered the keystone of periodontitis diseases, a set of inflammatory conditions that affects the tissues surrounding the teeth. In the recent years, the major virulence factors exploited by P. gingivalis have been identified and characterized, including a cocktail of toxins, mainly proteases called gingipains, which promote gingival tissue invasion. These effectors use the Sec pathway to cross the inner membrane and are then recruited and transported across the outer membrane by the type IX secretion system (T9SS). In P. gingivalis, most secreted effectors are attached to anionic lipopolysaccharides (A-LPS), and hence form a virulence coat at the cell surface. P. gingivalis produces additional virulence factors to evade host immune responses, such as capsular polysaccharide, fimbriae and outer membrane vesicles. In addition to periodontitis, it is proposed that this broad repertoire of virulence factors enable P. gingivalis to be involved in diverse human diseases such as rheumatoid arthritis, and neurodegenerative, Alzheimer, and cardiovascular disorders. Here, we review the major virulence determinants of P. gingivalis and discuss future directions to better understand their mechanisms of action.

RevDate: 2021-02-04

Sion B, M Bégou (2021)

Can chronopharmacology improve the therapeutic management of neurological diseases?.

Fundamental & clinical pharmacology [Epub ahead of print].

The importance of circadian rhythm dysfunctions in the pathophysiology of neurological diseases has been highlighted recently. Chronopharmacology principles imply that tailoring the timing of treatments to the circadian rhythm of individual patients could optimize therapeutic management. According to these principles, chronopharmacology takes into account: the individual differences in patients' clocks, the rhythmic changes in the organism sensitivity to therapeutic and side effects of drugs, and the predictable time variations of disease. This review examines the current literature on chronopharmacology of neurological diseases focusing its scope on epilepsy, Alzheimer and Parkinson diseases, and neuropathic pain, even if other neurological diseases could have been analyzed. While the results of the studies discussed in this review point to a potential therapeutic benefit of chronopharmacology in neurological diseases, the field is still in its infancy. Studies including a sufficiently large number of patients and measuring gold standard markers of the circadian rhythmicity are still needed to evaluate the beneficial effect of administration times over the 24-h day but also of clock modulating drugs.

RevDate: 2021-02-05

Haque A, H Woolery-Lloyd (2021)

Inflammaging in Dermatology: A New Frontier for Research.

Journal of drugs in dermatology : JDD, 20(2):144-149.

As humans age, our ability to manage certain types of inflammation is reduced. As a result, we experience chronic, low-grade inflammation, which has been termed &ldquo;inflammaging&rdquo;. This type of low-level inflammation is driven by a progressive increase in pro- inflammatory systemic cytokines over time. Inflammaging is thought to contribute to many age-related chronic diseases including cardiovascular disease, diabetes, Alzheimer&rsquo;s disease, and even certain cancers. Recent studies suggest that the human microbiome may play a critical role in inflammaging. As the largest organ of the body and home to a significant portion of the human microbiome, the skin may play a unique role in inflammaging. In this review article, we present common dermatological diseases through the lens of inflammaging, look at how our skin may play a role in reducing inflammaging, and highlight the need for further focused research in this area. J Drugs Dermatol. 2021;20(2):144-149. doi:10.36849/JDD.2021.5481.

RevDate: 2021-02-06

Holmer J, Aho V, Eriksdotter M, et al (2021)

Subgingival microbiota in a population with and without cognitive dysfunction.

Journal of oral microbiology, 13(1):1854552.

Aim: The aim of this study was to compare the subgingival microbiota of people with Alzheimer´s disease (AD), mild cognitive impairment (MCI), subjective cognitive decline (SCD) and cognitively healthy individuals. Materials and methods: The study population was recruited from 2013 to 2017 and comprised 132 cases recently diagnosed with AD (n = 46), MCI (n = 40) or SCD (n = 46), and 63 cognitively healthy controls. Subgingival samples were collected, and the microbiotas were characterized by 16S rRNA gene sequencing. Results: The relative abundance of the ten most common genera did not differ between the cases and control groups. However, the microbial richness and evenness were higher in cases than in controls and differed across the four groups. The variables with the greatest influence on the microbial community composition were related to periodontal disease followed by body mass index, study group affiliation and smoking. Ten taxa exhibited significant differences between case participants and controls. Two Operational Taxonomic Units were particularly abundant in AD compared to controls: Slackia exigua, which was also associated with deep periodontal pockets, and a Lachnospiraceae [G-7] bacterium. Conclusion: It is concluded that in individuals with cognitive impairment or AD, the subgingival microbiota exhibits shifts typical of periodontal disease.

RevDate: 2021-02-06

Fifel K, A Videnovic (2020)

Circadian and Sleep Dysfunctions in Neurodegenerative Disorders-An Update.

Frontiers in neuroscience, 14:627330.

Disruptions of sleep and circadian rhythms are among the most debilitating symptoms in patients with neurodegenerative diseases. Their underlying pathophysiology is multilayered and multifactorial. Recent evidence suggests that sleep and circadian disturbances may influence the neurodegenerative processes as well as be their consequence. In this perspective, we provide an update of the current understanding of sleep and circadian dysregulation in Alzheimer's, Parkinson's, and Huntington's diseases.

RevDate: 2021-02-04
CmpDate: 2021-02-04

Košak U, S Gobec (2020)

A Simple and Effective Synthesis of 3- and 4-((Phenylcarbamoyl)oxy)benzoic Acids.

Acta chimica Slovenica, 67(3):940-948.

Phenserine, posiphen, tolserine and cymserine and its derivatives are experimental Alzheimer's disease drugs that contain a phenyl phenylcarbamate moiety that is responsible for their anti-Alzheimer activities. We have developed a simple (3 steps) and effective (overall yields 76-90%) method for preparing 3- and 4-((phenylcarbamoyl)oxy)benzoic acids which can be reacted with amines to produce phenyl phenylcarbamate moiety containing amides as new potential anti-Alzheimer disease drugs. The synthesized carboxylic acids are thus important building blocks with potential use in medicinal chemistry and drug discovery.

RevDate: 2021-02-06

Mangalore S, Mukku SSR, Vankayalapati S, et al (2021)

Shape Profile of Corpus Callosum As a Signature to Phenotype Different Dementia.

Journal of neurosciences in rural practice, 12(1):185-192.

Background Phenotyping dementia is always a complex task for a clinician. There is a need for more practical biomarkers to aid clinicians. Objective The aim of the study is to investigate the shape profile of corpus callosum (CC) in different phenotypes of dementia. Materials and Methods Our study included patients who underwent neuroimaging in our facility as a part of clinical evaluation for dementia referred from Geriatric Clinic (2017-2018). We have analyzed the shape of CC and interpreted the finding using a seven-segment division. Results The sample included MPRAGE images of Alzheimer' dementia (AD) (n = 24), posterior cortical atrophy- Alzheimer' dementia (PCA-AD) (n = 7), behavioral variant of frontotemporal dementia (Bv-FTD) (n = 17), semantic variant frontotemporal dementia (Sv-FTD) (n = 11), progressive nonfluent aphasia (PNFA) (n = 4), Parkinson's disease dementia (PDD) (n = 5), diffuse Lewy body dementia (n = 7), progressive supranuclear palsy (PSP) (n = 3), and corticobasal degeneration (CBD) (n = 3). We found in posterior dementias such as AD and PCA-AD that there was predominant atrophy of splenium of CC. In Bv-FTD, the genu and anterior half of the body of CC was atrophied, whereas in PNFA, PSP, PDD, and CBD there was atrophy of the body of CC giving a dumbbell like profile. Conclusion Our study findings were in agreement with the anatomical cortical regions involved in different phenotypes of dementia. Our preliminary study highlighted potential usefulness of CC in the clinical setting for phenotyping dementia in addition to clinical history and robust biomarkers.

RevDate: 2021-02-06

Carratalá JV, Cisneros A, Hellman E, et al (2021)

Title: insoluble proteins catch heterologous soluble proteins into inclusion bodies by intermolecular interaction of aggregating peptides.

Microbial cell factories, 20(1):30.

BACKGROUND: Protein aggregation is a biological event observed in expression systems in which the recombinant protein is produced under stressful conditions surpassing the homeostasis of the protein quality control system. In addition, protein aggregation is also related to conformational diseases in animals as transmissible prion diseases or non-transmissible neurodegenerative diseases including Alzheimer, Parkinson's disease, amyloidosis and multiple system atrophy among others. At the molecular level, the presence of aggregation-prone domains in protein molecules act as seeding igniters to induce the accumulation of protein molecules in protease-resistant clusters by intermolecular interactions.

RESULTS: In this work we have studied the aggregating-prone performance of a small peptide (L6K2) with additional antimicrobial activity and we have elucidated the relevance of the accompanying scaffold protein to enhance the aggregating profile of the fusion protein. Furthermore, we demonstrated that the fusion of L6K2 to highly soluble recombinant proteins directs the protein to inclusion bodies (IBs) in E. coli through stereospecific interactions in the presence of an insoluble protein displaying the same aggregating-prone peptide (APP).

CONCLUSIONS: These data suggest that the molecular bases of protein aggregation are related to the net balance of protein aggregation potential and not only to the presence of APPs. This is then presented as a generic platform to generate hybrid protein aggregates in microbial cell factories for biopharmaceutical and biotechnological applications.

RevDate: 2021-02-15
CmpDate: 2021-02-15

Ferreira D, Nordberg A, E Westman (2021)

Author Response: Biological Subtypes of Alzheimer Disease: A Systematic Review and Meta-analysis.

Neurology, 96(5):238.

RevDate: 2021-02-15
CmpDate: 2021-02-15

Uleman JF, Melis RJF, MGM Olde Rikkert (2021)

Reader Response: Biological Subtypes of Alzheimer Disease: A Systematic Review and Meta-analysis.

Neurology, 96(5):237-238.

RevDate: 2021-02-12
CmpDate: 2021-02-12

Maesaka JK, Imbriano LJ, Pinkhasov A, et al (2021)

Identification of a Novel Natriuretic Protein in Patients With Cerebral-Renal Salt Wasting-Implications for Enhanced Diagnosis.

The American journal of the medical sciences, 361(2):261-268.

BACKGROUND: The most vexing problem in hyponatremic conditions is to differentiate the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (C-RSW). Both have identical clinical parameters but diametrically opposite therapeutic goals of water- restricting water-logged patients with SIADH or administering salt and water to dehydrated patients with C-RSW. While C-RSW is considered a rare condition, the report of a high prevalence of C-RSW in the general hospital wards creates an urgency to differentiate one syndrome from the other on first encounter. We decided to identify the natriuretic factor (NF) we previously demonstrated in plasma of neurosurgical and Alzheimer diseases (AD) who had findings consistent with C-RSW.

METHODS: We performed the same rat renal clearance studies to determine natriuretic activity (NA) in serum from a patient with a subarachnoid hemorrhage (SAH) and another with AD and demonstrated NA in their sera. The sera were subjected to proteomic and SWATH (Sequential Windowed Acquisition of All) analyses which identified increased levels of haptoglobin related protein (Hpr) without signal peptide (Hpr-WSP).

RESULTS: Recombinant Hpr with His tag at the N terminus had no NA. Hpr-WSP had a robust NA in a dose-dependent manner when injected into rats. Serum after recovery from C-RSW in the SAH patient had no NA.

CONCLUSIONS: Hpr-WSP may be the NF in C-RSW which should be developed as a biomarker to differentiate C-RSW from SIADH on first encounter, introduces a new syndrome of C-RSW in AD and can serve as a proximal diuretic to treat congestive heart failure.

RevDate: 2021-02-10

Bekdash RA (2021)

The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer's Disease.

International journal of molecular sciences, 22(3):.

Neurodegenerative diseases are a major public health problem worldwide with a wide spectrum of symptoms and physiological effects. It has been long reported that the dysregulation of the cholinergic system and the adrenergic system are linked to the etiology of Alzheimer's disease. Cholinergic neurons are widely distributed in brain regions that play a role in cognitive functions and normal cholinergic signaling related to learning and memory is dependent on acetylcholine. The Locus Coeruleus norepinephrine (LC-NE) is the main noradrenergic nucleus that projects and supplies norepinephrine to different brain regions. Norepinephrine has been shown to be neuroprotective against neurodegeneration and plays a role in behavior and cognition. Cholinergic and adrenergic signaling are dysregulated in Alzheimer's disease. The degeneration of cholinergic neurons in nucleus basalis of Meynert in the basal forebrain and the degeneration of LC-NE neurons were reported in Alzheimer's disease. The aim of this review is to describe current literature on the role of the cholinergic system and the adrenergic system (LC-NE) in the pathology of Alzheimer's disease and potential therapeutic implications.

RevDate: 2021-02-07

Koenig LN, McCue LM, Grant E, et al (2021)

Lack of association between acute stroke, post-stroke dementia, race, and β-amyloid status.

NeuroImage. Clinical, 29:102553 pii:S2213-1582(20)30390-9 [Epub ahead of print].

INTRODUCTION: Stroke and Alzheimer disease share risk factors and often co-occur, and both have been reported to have a higher prevalence in African Americans as compared to non-Hispanic whites. However, their interaction has not been established. The objective of this study was to determine if preclinical Alzheimer disease is a risk factor for stroke and post-stroke dementia and whether racial differences moderate this relationship.

METHODS: This case-control study was analyzed in 2019 using retrospective data from 2007 to 2013. Participants were adults age 65 and older with and without acute ischemic stroke. Recruitment included word of mouth and referrals in Saint Louis, MO, with stroke participants recruited from acutely hospitalized patients and non-stroke participants from community living older adults who were research volunteers. Our assessment included radiologic reads of infarcts, microbleeds, and white matter hyperintensitites (WMH); a Pittsburgh Compound B PET measure of cortical β-amyloid binding; quantitative measures of hippocampal and WMH volume; longitudinal Mini Mental State Examination (MMSE) scores; and Clinical Dementia Rating (CDR) 1 year post-stroke.

RESULTS: A total of 243 participants were enrolled, 81 of which had a recent ischemic stroke. Participants had a mean age of 75, 57% were women, and 52% were African American. Cortical amyloid did not differ significantly by race, stroke status, or CDR post-stroke. There were racial differences in MMSE scores at baseline (mean 26.8 for African Americans, 27.9 for non-Hispanic whites, p = 0.03), but not longitudinally. African Americans were more likely to have microbleeds (32.8% vs 22.6%, p = 0.04), and within the acute stroke group, African Americans were more likely to have small infarcts (75.6% vs 56.8%, p = 0.049).

CONCLUSION: Preclinical Alzheimer disease did not show evidence of being a risk factor for stroke nor predictive of post-stroke dementia. We did not observe racial differences in β-amyloid levels. However, even after controlling for several vascular risk factors, African Americans with clinical stroke presentations had greater levels of vascular pathology on MRI.

RevDate: 2021-02-06

Pereira AKDS, Santos IA, da Silva WW, et al (2021)

Memantine hydrochloride: a drug to be repurposed against Chikungunya virus?.

Pharmacological reports : PR [Epub ahead of print].

BACKGROUND: Chikungunya fever is an endemic disease caused by the Chikungunya virus (CHIKV) to which there is no vaccine or effective antiviral drug treatment so far. Our study aimed to evaluate the potential anti-CHIKV activity of memantine hydrochloride (mtnH), a drug from the class of the aminoadamantanes approved for the treatment of Alzheimer´s disease, as a possible drug to be repurposed to the treatment of Chikungunya fever.

METHODS: MtnH antiviral activity against CHIKV was determined by infecting BHK-21 cells with CHIKV-nanoluc, a virus carrying the marker nanoluciferase reporter, in the presence or absence of mtnH at concentrations ranging from 500 to 1.45 µM. The effective concentration of 50% inhibition (EC50) was calculated. Cell viability assay (determination of CC50) was also performed employing BHK-21 cells. Mutagenic assays were performed by the Salmonella Typhimurium/microsome assay (Ames test).

RESULTS: MtnH presented a CC50 of 248.4 ± 31.9 µM and an EC50 of 32.4 ± 4 µM against CHIKV in vitro. The calculated selectivity index (SI) was 7.67. MtnH did not induce genetic mutation in Salmonella strains with or without an external metabolizing system.

CONCLUSION: With the data herein presented, it is possible to hypothesize mtnH as a viable candidate to be repurposed as an anti-CHIKV drug. Clinical assays are, therefore, encouraged due to the promising in vitro results. The drug memantine hydrochloride is herein personified with a doubt: as a prior regulated drug against Alzheimer, could it follow the path against Chikungunya virus too?

RevDate: 2021-02-06

Piña-Escudero SD, López L, Sriram S, et al (2020)

Neurodegenerative Disease and the Experience of Homelessness.

Frontiers in neurology, 11:562218.

Introduction: Today, half of the American homeless population is older than 50 years of age. This shift in age distribution among people experiencing homelessness has challenged our long-held views of the causes of homelessness. Age-related neurological diseases, especially neurodegenerative diseases of the brain (NDDB), may play a role eliciting homelessness in a significant proportion of vulnerable older adults. This article aims to explore relationships between homelessness and NDDB in a cohort of research participants enrolled in observational studies on NDDB at an academic center. Methods: We reviewed charts of the Memory and Aging Center (MAC) of the University of California, San Francisco's database searching for research participants with NDDB that had direct relationship to homelessness. We reviewed all research visits conducted between 2004 and 2018 (N = 5,300). Research participants who had any relationship to homelessness were included in this analysis. NDDB was diagnosed via comprehensive neurological, functional, neuropsychological, and biomarker assessments. Non-parametric tests were used for analysis. Thirteen participants were found to have a direct relationship with homelessness. Seven were female and the median of education was 16 (IR: 12.0-19.5) years. Participants were divided into two groups: Those who experienced homelessness while symptomatic from a NDDB but before formal diagnosis (n = 5, Group 1); and participants with formally diagnosed NDDB who exhibited a new propensity toward homelessness (n = 8, Group 2). Compared to Group 2, participants in Group 1 were younger (p = 0.021) and showed similar results in the neuropsychological evaluation. In both groups, the most prevalent diagnosis was frontotemporal dementia. In Group 1, the majority of participants became homeless in the setting of a fragile socioeconomic situation and informants believed that NDDB contributed or caused their homeless state. In Group 2, a new propensity toward homelessness became manifest in different ways and it stood out that all of these participants were well-supported by family and friends during their illness. Conclusions and Relevance: This case series highlights the role that NDDB may have in precipitating homelessness among vulnerable older adults, particularly in the setting of challenging socioeconomic circumstances and unsupportive living environments. Social ramifications of these findings, particularly pertaining to challenges around rehousing these individuals is discussed.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

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