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04 Jun 2020 at 01:32
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Bibliography on: Alzheimer Disease — Current Literature


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RJR: Recommended Bibliography 04 Jun 2020 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]) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2020-06-03

Hane CA, Nori VS, Crown WH, et al (2020)

Predicting Onset of Dementia Using Clinical Notes and Machine Learning: Case-Control Study.

JMIR medical informatics, 8(6):e17819 pii:v8i6e17819.

BACKGROUND: Clinical trials need efficient tools to assist in recruiting patients at risk of Alzheimer disease and related dementias (ADRD). Early detection can also assist patients with financial planning for long-term care. Clinical notes are an important, underutilized source of information in machine learning models because of the cost of collection and complexity of analysis.

OBJECTIVE: This study aimed to investigate the use of deidentified clinical notes from multiple hospital systems collected over 10 years to augment retrospective machine learning models of the risk of developing ADRD.

METHODS: We used 2 years of data to predict the future outcome of ADRD onset. Clinical notes are provided in a deidentified format with specific terms and sentiments. Terms in clinical notes are embedded into a 100-dimensional vector space to identify clusters of related terms and abbreviations that differ across hospital systems and individual clinicians.

RESULTS: When using clinical notes, the area under the curve (AUC) improved from 0.85 to 0.94, and positive predictive value (PPV) increased from 45.07% (25,245/56,018) to 68.32% (14,153/20,717) in the model at disease onset. Models with clinical notes improved in both AUC and PPV in years 3-6 when notes' volume was largest; results are mixed in years 7 and 8 with the smallest cohorts.

CONCLUSIONS: Although clinical notes helped in the short term, the presence of ADRD symptomatic terms years earlier than onset adds evidence to other studies that clinicians undercode diagnoses of ADRD. De-identified clinical notes increase the accuracy of risk models. Clinical notes collected across multiple hospital systems via natural language processing can be merged using postprocessing techniques to aid model accuracy.

RevDate: 2020-06-03

Allegri RF, Chrem Méndez P, Calandri I, et al (2020)

Prognostic value of ATN Alzheimer biomarkers: 60-month follow-up results from the Argentine Alzheimer's Disease Neuroimaging Initiative.

Alzheimer's & dementia (Amsterdam, Netherlands), 12(1):e12026 pii:DAD212026.

Purpose: To describe results of the Amyloid, Tau, Neurodegeneration (ATN) research framework classification in the Argentine-Alzheimer's Disease Neuroimaging Initiative (arg-ADNI) cohort.

Methods: Twenty-three patients with mild cognitive impairment (MCI), 12 dementia of Alzheimer's type (DAT), and 14 normal controls were studied following the ADNI2 protocol. Patients were categorized according to presence or absence of the biomarkers for amyloid beta (Aβ; A: amyloid positron emission tomography [PET] scan or cerebrospinal fluid [CSF] Aβ42), tau (T: CSF phosphorylated-tau), and neurodegeneration (N: CSF total-tau, fluorodeoxyglucose [FDG]-PET scan, or structural magnetic resonance imaging [MRI] scan).

Results: A+T+N+ biomarker profile was identified at baseline in 91% of mild dementia patients, 20% of early MCI patients, 46% of late MCI patients, and 14% of control subjects. Suspected non-AD pathophysiology (SNAP, A-T-N+) was found in 8% of mild dementia, 20% of early MCI, 15% of late MCI, and 7% of control subjects. Conversion rates to dementia after 5-year follow-up were 85% in A+T+N+ MCI patients and 50% in A-T-N+ patients.

Conclusions: We present initial 5-year follow-up results of a regional ADNI based on AD biomarkers and the ATN classification.

RevDate: 2020-06-03

Bewicz-Binkowska D, Zgorzynska E, Dziedzic B, et al (2019)

Docosahexaenoic Acid (DHA) Inhibits FADS2 Expression in Astrocytes but Increases Survival of Neurons Co-cultured with DHA-enriched Astrocytes.

International journal of molecular and cellular medicine, 8(3):232-240.

Docosahexaenoic acid (DHA), the most abundant n-3 polyunsaturated fatty acid (n-3PUFA) in the brain, has attracted great importance for a variety of neuronal functions such as signal transduction through plasma membranes, neuronal plasticity, and neuroprotection. Astrocytes that provide structural, functional, and metabolic support for neurons, express ∆6- desaturase encoded by FADS2 gene that can be, next to the plasma DHA pool, additional source of DHA in the brain. Furthermore, the genetic variations of FADS gene cluster has been found in children with developmental disorders, and are associated with cognitive functions. Since, the regulation of DHA biosynthesis in astrocytes remains poorly studied the aim of this study was to determine the effect of palmitic acid (PA), α-linolenic acid (ALA) or docosahexaenoic acid (DHA), on the transcription of FADS2 gene in astrocytes and survival of neurons challenged with oxidative compounds after co-culture with astrocytes exposed to DHA. The lipid profile in cell membranes after incubation with fatty acids was determined by gas chromatography, and FADS2 expression was analyzed using real-time PCR. The viability of neurons cocultured with PUFA-enriched astrocytes was investigated by flow cytometry after staining cells with annexin V-FITC and PI. The results showed that DHA suppressed (P <0.01), PA stimulated (P <0.01), while ALA did not change the FADS2 gene expression after 24 h incubation of astrocytes with fatty acids. Although FADS2 mRNA was down-regulated by DHA, its level in astrocytic membranes significantly increased (P <0.01). Astrocytes with DHA-enriched membrane phospholipids markedly enhanced neuronal resistance to cytotoxic compounds and neuronal survival. These results suggest that beneficial effects of supplementation with n-3 PUFA in Alzheimer disease and in psychiatric disorders is caused, in part, by increased efficacy of DHA-enriched astrocytes to protect neurons under adverse conditions in the brain.

RevDate: 2020-06-03

Gao F, Zhang J, Ni T, et al (2020)

Herpud1 deficiency could reduce amyloid-β40 expression and thereby suppress homocysteine-induced atherosclerosis by blocking the JNK/AP1 pathway.

Journal of physiology and biochemistry pii:10.1007/s13105-020-00741-5 [Epub ahead of print].

Homocysteine (Hcy) is considered an independent risk factor for various cardiovascular diseases including atherosclerosis which is associated with lipid metabolism, inflammation, and oxidative stress. Results from our previous study suggested that Hcy-induced atherosclerosis could be reversed by Herpud1 knockout which inhibits vascular smooth muscle cell (VSMC) phenotype switching. Here, we aim to investigate more precise mechanisms behind the improvement in Hcy-induced atherosclerosis. Amyloid-β40 (Aβ40), a vital protein in Alzheimer disease (AD), has been regarded as an important component in the atherosclerosis program in recent years due to the biological similarity between AD and atherosclerosis. Thus, we determined to assess the value of Aβ40 in a Herpud1 knockout Hcy-induced atherosclerosis mouse model by measuring Aβ40 expression in tissue and biomarkers of lipid metabolism, inflammation, and oxidative stress in serum. Additionally, since endothelial dysfunction plays a prominent role in atherosclerosis, we tested human umbilical vein endothelial cell (HUVEC) function following Herpud1 silencing in vitro and evaluated JNK/AP1 signaling activation in our models because of its close relationship with Aβ40. As a result, our animal models showed that Herpud1 knockout reduced Aβ40 expression, inflammation, and oxidative stress levels other than lipid metabolism and alleviated atherosclerosis via JNK/AP1 signaling inhibition. Similarly, our cell experiments implied that Hcy-induced Aβ40 elevation and HUVEC dysfunction involving cell proliferation and apoptosis could be restored by Herpud1 silence through restraining JNK/AP1 pathway. Collectively, our study demonstrates that Herpud1 deficiency could reduce Aβ40 expression, thereby suppressing Hcy-induced atherosclerosis by blocking the JNK/AP1 pathway. This may provide novel potential targets for atherosclerosis prevention or treatment.

RevDate: 2020-06-03

Jung M, Ko W, Muhwava W, et al (2020)

Mind the gaps: age and cause specific mortality and life expectancy in the older population of South Korea and Japan.

BMC public health, 20(1):819 pii:10.1186/s12889-020-08978-x.

BACKGROUND: Recent life expectancy gains in high-income Asia-pacific countries have been largely the result of postponement of death from non-communicable diseases in old age, causing rapid demographic ageing. This study compared and quantified age- and cause-specific contributions to changes in old-age life expectancy in two high-income Asia-pacific countries with ageing populations, South Korea and Japan.

METHODS: This study used Pollard's actuarial method of decomposing life expectancy to compare age- and cause-specific contributions to changes in old-age life expectancy between South Korea and Japan during 1997 and 2017.

RESULTS: South Korea experienced rapid population ageing, and the gaps in life expectancy at 60 years old between South Korea and Japan were reduced by 2.47 years during 1997 and 2017. Decomposition analysis showed that mortality reductions from non-communicable diseases in South Korea were the leading causes of death contributing to the decreased gaps in old-age life expectancy between the two countries. More specifically, mortality reductions from cardiovascular diseases (stroke, ischaemic and hypertensive heart disease) and cancers (stomach, liver, lung, pancreatic cancers) in South Korea contributed to the decreased gap by 1.34 and 0.41 years, respectively. However, increased mortality from Alzheimer and dementia, lower respiratory tract disease, self-harm and falls in South Korea widened the gaps by 0.41 years.

CONCLUSIONS: Age- and cause- specific contributions to changes in old-age life expectancy can differ between high-income Asia-pacific countries. Although the gaps in old-age life expectancy between high-income Asia-pacific countries are primarily attributed to mortality changes in non-communicable diseases, these countries should also identify potential emerging threats of communicable diseases and injuries along with demographic ageing in pursuit of healthy life years in old age.

RevDate: 2020-06-03

Park D, Choi EK, Cho TH, et al (2020)

Human Neural Stem Cells Encoding ChAT Gene Restore Cognitive Function via Acetylcholine Synthesis, Aβ Elimination, and Neuroregeneration in APPswe/PS1dE9 Mice.

International journal of molecular sciences, 21(11): pii:ijms21113958.

In Alzheimer disease (AD) patients, degeneration of the cholinergic system utilizing acetylcholine for memory acquisition is observed. Since AD therapy using acetylcholinesterase (AChE) inhibitors are only palliative for memory deficits without slowing or reversing disease progress, there is a need for effective therapies, and stem cell-based therapeutic approaches targeting AD should fulfill this requirement. We established a human neural stem cell (NSC) line encoding choline acetyltransferase (ChAT) gene, an acetylcholine-synthesizing enzyme. APPswe/PS1dE9 AD model mice transplanted with the F3.ChAT NSCs exhibited improved cognitive function and physical activity. Transplanted F3.ChAT NSCs in the AD mice differentiated into neurons and astrocytes, produced ChAT protein, increased the ACh level, and improved the learning and memory function. F3.ChAT cell transplantation reduced Aβ deposits by recovering microglial function; i.e., the down-regulation of β-secretase and inflammatory cytokines and up-regulation of Aβ-degrading enzyme neprilysin. F3.ChAT cells restored growth factors (GFs) and neurotrophic factors (NFs), and they induced the proliferation of NSCs in the host brain. These findings indicate that NSCs overexpressing ChAT can ameliorate complex cognitive and physical deficits of AD animals by releasing ACh, reducing Aβ deposit, and promoting neuroregeneration by the production of GFs/NFs. It is suggested that NSCs overexpressing ChAT could be a candidate for cell therapy in advanced AD therapy.

RevDate: 2020-05-31

de Oliveira FF, Chen ES, Smith MC, et al (2020)

Selected LDLR and APOE Polymorphisms Affect Cognitive and Functional Response to Lipophilic Statins in Alzheimer's Disease.

Journal of molecular neuroscience : MN pii:10.1007/s12031-020-01588-7 [Epub ahead of print].

Effects of statins over clinical changes in Alzheimer's disease (AD) are usually non-significant, but epistatic interactions between genetic variants involved in cholesterol metabolism could be important for such effects. We aimed to investigate whether LDLR single-nucleotide polymorphisms rs11669576 (LDLR8), rs5930 (LDLR10), and rs5925 (LDLR13) are associated with cognitive and functional changes in AD, while also considering APOE haplotypes and lipid-lowering treatment with lipophilic statins for stratification. Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and caregiver burden, with prospective neurotranslational correlations documented for 1 year. For 179 patients, minor allele frequencies were 0.078 for rs11669576-A (14.5% heterozygotes), 0.346 for rs5930-A (42.5% heterozygotes), and 0.444 for rs5925-C (56.4% heterozygotes), all in Hardy-Weinberg equilibrium; 134 patients had hypercholesterolemia, and 133 used lipophilic statins. Carriers of rs11669576-G had faster cognitive decline, while functional decline was slower for carriers of rs11669576-A who used lipophilic statins. APOE-ε4 carriers who also carried rs5930-AA had improved caregiver burden, while carriers of haplotypes that included rs5930-AG had worse cognitive and functional outcomes, though carriers of the A allele of rs5930 had better cognitive and functional response to lipophilic statins. APOE-ε4 non-carriers who carried rs5925-TT had slower cognitive decline, while lipophilic statins protected carriers of the other genotypes. We preliminarily conclude that reportedly protective variants of LDLR and APOE against risk of AD also slowed cognitive decline, regardless of cholesterol variations, while therapy with lipophilic statins might benefit carriers of specific genetic variants.

RevDate: 2020-06-02

Korhonen T, Katisko K, Cajanus A, et al (2020)

Comparison of Prodromal Symptoms of Patients with Behavioral Variant Frontotemporal Dementia and Alzheimer Disease.

Dementia and geriatric cognitive disorders pii:000507544 [Epub ahead of print].

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) is the most common clinical subtype of frontotemporal lobar degeneration. bvFTD is often characterized by changes in behavior and personality, frequently leading to psychiatric misdiagnoses. On the other hand, substantial clinical overlap with other neurodegenerative diseases, such as Alzheimer disease (AD), further complicates the diagnostics.

OBJECTIVE: Our aim was to identify the main differences in early symptoms of bvFTD and AD in the prodromal stages of the diseases. In addition, patients with bvFTD were analyzed separately according to whether they carry the C9orf72repeat expansion or not.

METHODS: Patient records of bvFTD (n = 75) and AD (n = 83) patients were analyzed retrospectively for memory and neuropsychiatric symptoms, sleeping disorders, and somatic complaints before the setting of the accurate diagnosis.

RESULTS: A total of 84% of bvFTD patients (n = 63) and 98.8% of AD patients (n = 82) reported subjective memory disturbances in the prodromal phases of the disease. bvFTD patients presented significantly more often with sleeping disorders, headache, inexplicable collapses, transient loss of consciousness, somatization, delusions, and hallucinations, suicidality, changes in oral behaviors, and urinary problems. In addition, poor financial judgement was frequently detected in patients with prodromal bvFTD. Aberrant sensations in the nose and throat without any physical explanation, regarded as somatizations, emerged only in bvFTD patients with the C9orf72 repeat expansion.

CONCLUSIONS: Subjective reporting of impaired episodic memory is a poor indicator in differentiating bvFTD from AD. Sleeping disturbances, delusions, hallucinations, and unexplained somatic complaints in a patient with cognitive disturbances should prompt the clinicians to consider bvFTD as a possible diagnostic option behind these symptoms. The spectrum of symptoms in the prodromal stages of bvFTD may be more diverse than the latest criteria suggest.

RevDate: 2020-06-02

Patel DV, Patel NR, Kanhed AM, et al (2020)

Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents.

Bioorganic chemistry, 101:103977 pii:S0045-2068(20)31113-5 [Epub ahead of print].

Molecules capable of engaging with multiple targets associated with pathological condition of Alzheimer's disease have proved to be potential anti-Alzheimer's agents. In our goal to develop multitarget-directed ligands for the treatment of Alzheimer's disease, a novel series of carbazole-based stilbene derivatives were designed by the fusion of carbazole ring with stilbene scaffold. The designed compounds were synthesized and evaluated for their anti-AD activities including cholinesterase inhibition, Aβ aggregation inhibition, antioxidant and metal chelation properties. Amongst them, (E)-1-(4-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea (50) appeared to be the best candidate with good inhibitory activities against AChE (IC50 value of 2.64 μM) and BuChE (IC50 value of 1.29 μM), and significant inhibition of self-mediated Aβ1-42 aggregation (51.29% at 25 μM concentration). The metal chelation study showed that compound (50) possessed specific copper ion chelating property. Additionally, compound (50) exhibited moderate antioxidant activity. To understand the binding mode of 50, molecular docking studies were performed, and the results indicated strong non-covalent interactions of 50 with the enzymes in the active sites of AChE, BuChE as well as of the Aβ1-42 peptide. Additionally, it showed promising in silico ADMET properties. Putting together, these findings evidently showed compound (50) as a potential multitarget-directed ligand in the course of developing novel anti-AD drugs.

RevDate: 2020-06-02

Lorenzoni R, Davies S, Cordenonsi LM, et al (2020)

Lipid-core nanocapsules containing simvastatin improve the cognitive impairment induced by obesity and hypercholesterolemia in adult rats.

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences pii:S0928-0987(20)30186-X [Epub ahead of print].

The development of cognitive impairment may be related to high levels of plasma cholesterol and obesity. Simvastatin (SV) and lovastatin (LV) are drugs that can potentially be used for the treatment of cognitive deficit. This study aimed to develop and characterize lipid-core nanocapsules (LNC) containing SV (SV-LNC) or LV (LV-LNC), evaluating the effects of SV-LNC in an animal model of cognitive deficit. The formulations SV-LNC and LV-LNC presented a particle average size around 200 nm, a low-polydispersity index, and negative zeta potential. Analysis of differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy showed that there is no reaction among LNC components: LV was crystallized in the suspensions, and SV was molecularly dispersed. The encapsulation efficiency of the SV was high (98.9 ± 1.4%), while that of the LV was low (21.5 ± 1.5%), and because of this, just SV-LNC was used in the preclinical studies. Animals fed with a hyperlipidic diet (HD) developed obesity, hypercholesterolemia, and cognitive impairment, which was corroborated by the brain lesions indicated by histological analysis of some of the animals that received the high-fat diet. We observed that free simvastatin (CS3) was able to reduce the enzymatic activity of pyruvate kinase, an important enzyme for brain energy homeostasis, without affecting the memory of the animals that received a standard diet. However, it failed to improve the cognitive damage caused by a diet high in cholesterol and saturated fats. On the other hand, when simvastatin is "camouflaged" in the lipid-core nanocapsules (HNS3), this cognitive impairment improves. Thus, SV-LNC is a promising alternative therapy for the treatment of cognitive impairment.

RevDate: 2020-06-02

Di Lorenzo F, Motta C, Casula EP, et al (2020)

LTP-like cortical plasticity predicts conversion to dementia in patients with memory impairment.

Brain stimulation pii:S1935-861X(20)30112-1 [Epub ahead of print].

BACKGROUND: New diagnostic criteria consider Alzheimer's disease (AD) as a clinico-biological entity identifiable in vivo on the presence of specific patterns of CSF biomarkers.

OBJECTIVE: Here we used transcranial magnetic stimulation to investigate the mechanisms of cortical plasticity and sensory-motor integration in patients with hippocampal-type memory impairment admitted for the first time in the memory clinic stratified according to CSF biomarkers profile.

METHODS: Seventy-three patients were recruited and divided in three groups according to the new diagnostic criteria: 1) Mild Cognitive Impaired (MCI) patients (n=21); Prodromal AD (PROAD) patients (n=24); AD with manifest dementia (ADD) patients (n=28). At time of recruitment all patients underwent CSF sampling for diagnostic purposes. Repetitive and paired-pulse transcranial magnetic stimulation protocols were performed to investigate LTP-like and LTD-like cortical plasticity, short intracortical inhibition (SICI) and short afferent inhibition (SAI). Patients were the followed up during three years to monitor the clinical progression or the conversion to dementia.

RESULTS: MCI patients showed a moderate but significant impairment of LTP-like cortical plasticity, while ADD and PROAD groups showed a more severe loss of LTP-like cortical plasticity. No differences were observed for LTD-like cortical plasticity, SICI and SAI protocols. Kaplan-Meyer analyses showed that PROAD and MCI patients converting to dementia had weaker LTP-like plasticity at time of first evaluation.

CONCLUSION: LTP-like cortical plasticity could be a novel biomarker to predict the clinical progression to dementia in patients at with memory impairment at prodromal stages of AD identifiable with the new diagnostic criteria based on CSF biomarkers.

RevDate: 2020-06-02

Inglet S, Winter B, Yost SE, et al (2020)

Clinical Data for the Use of Cannabis-Based Treatments: A Comprehensive Review of the Literature.

The Annals of pharmacotherapy [Epub ahead of print].

Objective: To compile and synthesize the available literature describing medical cannabis use across various disease states. Data Sources: PubMed, EBSCO, and Google Scholar searches were conducted using MeSH and/or keywords. Study Selection and Data Extraction: Studies were included if they described the use of cannabis-based products and medications in the treatment of a predefined list of disease states in humans and were published in English. The extraction period had no historical limit and spanned through April 2019. Data Synthesis: Evidence was compiled and summarized for the following medical conditions: Alzheimer disease, amyotrophic lateral sclerosis, autism, cancer and cancer-associated adverse effects, seizure disorders, human immunodeficiency virus, inflammatory bowel disease, multiple sclerosis (MS), nausea, pain, posttraumatic stress disorder, and hospice care. Relevance to Patient Care and Clinical Practice: Based on identified data, the most robust evidence suggests that medical cannabis may be effective in the treatment of chemotherapy-induced nausea and vomiting, seizure disorders, MS-related spasticity, and pain (excluding diabetic neuropathy). Overall, the evidence is inconsistent and generally limited by poor quality. The large variation in cannabis-based products evaluated in studies limits the ability to make direct comparisons. Regardless of the product, a gradual dose titration was utilized in most studies. Cannabis-based therapies were typically well tolerated, with the most common adverse effects being dizziness, somnolence, dry mouth, nausea, and euphoria. Conclusions: As more states authorize medical cannabis use, there is an increasing need for high-quality clinical evidence describing its efficacy and safety. This review is intended to serve as a reference for clinicians, so that the risks and realistic benefits of medical cannabis are better understood.

RevDate: 2020-06-02

Gelpi E, Rahimi J, Klotz S, et al (2020)

The autophagic marker p62 highlights Alzheimer type II astrocytes in metabolic/hepatic encephalopathy.

Neuropathology : official journal of the Japanese Society of Neuropathology [Epub ahead of print].

Metabolic/hepatic encephalopathy is neuropathologically characterized by the presence of Alzheimer type II astrocytes (AA II) with large and clear nuclear morphology. To date, there is no good immunohistochemical marker to better identify these cells. Here, we assessed cases of hepatic encephalopathy of different etiologies by immunohistochemistry using an anti-p62 antibody. We observed peripheral or diffuse nuclear staining of variable intensity in AA II in all cases but not in normal controls or reactive astrocytes. We conclude that p62 is a useful immunohistochemical marker for the identification of AA II and may be helpful for the neuropathological diagnosis of metabolic/hepatic encephalopathy in difficult or equivocal cases.

RevDate: 2020-06-02

Molaei A, Hatami H, Dehghan G, et al (2020)

Synergistic effects of quercetin and regular exercise on the recovery of spatial memory and reduction of parameters of oxidative stress in animal model of Alzheimer's disease.

EXCLI journal, 19:596-612 pii:Doc596.

It has widely been reported that the brain in Alzheimer's disease (AD) is affected by increased oxidative stress, and this may have a role in the pathogenesis of this disorder. Quercetin, a polyphenol extensively found in nature, has recently been considered. Also, physical activities have a paradoxical effect on brain function in older adults. Therefore, this study aimed at investigating the synergic effects of quercetin (as chemical treatment) and exercise (as physical treatment) on AD-induced learning and memory impairment. Fifty-six adult male Wistar rats were randomly assigned into one of the following eight groups (n=7): The Control, Sham (saline), AD (intracerebroventricular administration of streptozotocin (STZ)), AD+80 mg/kg Quercetin (STZ+Q80), Quercetin vehicle (1 % Ethanol)+STZ, Exercise pretreatment (EX)+STZ, Off the treadmill+STZ, and EX+Q80+STZ. Quercetin administration was done intraperitoneally for 21 days after STZ injection. The rats ran on the treadmill for one hour a day for 60 days at a speed of 20-22 m/min. After the treatment, the spatial memory and levels of oxidative stress parameters were evaluated. The results showed that STZ caused spatial memory impairment and increased oxidative stress in the hippocampus. Exercise pretreatment or Quercetin injection improved the spatial memory impairment and oxidative stress caused by STZ injection. However, the combination of quercetin and exercise pretreatment was more effective. It can be concluded that the combined exercise pretreatment and Quercetin injection affected the antioxidant defense system and improved STZ-induced memory impairment.

RevDate: 2020-06-02

Sachs BC, Steenland K, Zhao L, et al (2020)

Expanded Demographic Norms for Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set.

Alzheimer disease and associated disorders [Epub ahead of print].

BACKGROUND: Norms for the Uniform Data Set Version 3 Neuropsychological Battery are available for cognitively normal individuals based on age, education, and sex; however, these norms do not include race. We provide expanded norms for African Americans and whites.

METHODS: Data from 32 Alzheimer's Disease Centers (ADCs) and ADC affiliated cohorts with global Clinical Dementia Rating Scale (CDR) Dementia Staging Instrument scores of 0 were included. Descriptive statistics for each test were calculated by age, sex, race, and education. Multiple linear regressions were conducted to estimate the effect of each demographic variable; squared semipartial correlation coefficients measured the relative importance of variables.

RESULTS: There were 8313 participants (16% African American) with complete demographic information, ranging from 6600 to 7885 depending on the test. Lower scores were found for older and less educated groups, and African Americans versus whites. Education was the strongest predictor for most tests, followed in order by age, race, and sex. Quadratic terms were significant for age and education, indicating some nonlinearity, but did not substantially increase R.

CONCLUSIONS: Although race-based norms represent incomplete proxies for other sociocultural variables, the appropriate application of these norms is important given the potential to improve diagnostic accuracy and to reduce misclassification bias in cognitive disorders of aging such as Alzheimer disease.

RevDate: 2020-06-02

Ban JY, Park HK, SK Kim (2020)

Effect of Glycyrrhizic Acid on Scopolamine-Induced Cognitive Impairment in Mice.

International neurourology journal, 24(Suppl 1):S48-55.

PURPOSE: Cognitive impairment is one of the main symptoms of Alzheimer disease and other dementias. Glycyrrhiza uralensis is a natural product that has a protective effect against cognitive impairment. In this study, we investigated whether glycyrrhizic acid, among the main bioactive components of Glycyrrhiza uralensis, has a neuroprotective effect on scopolamine-induced cognitive impairment.

METHODS: Twenty-week-old male Institute of Cancer Research mice were used in this study. The scopolamine-induced cognitive impairment mice model was used. Glycyrrhizic acid was orally administered to mice once daily for 21 days, while scopolamine (1 mg/kg) treatment was delivered 30 minutes before behavioral tests. Donepezil (2 mg/kg) was used as a positive drug control. To evaluate the effect of glycyrrhizic acid, the following assessments were performed on hippocampal tissue: Y-maze test, acetylcholinesterase activity, antioxidant enzymes' activity (superoxide dismutase, catalase). Western blotting for phosphor-extracellular signal-regulated kinase, P38, and c-Jun NH2-terminal kinase was conducted.

RESULTS: We found that glycyrrhizic acid administration significantly improved scopolamine-induced cognitive impairment in the Y-maze test. The acetylcholinesterase activity, superoxide dismutase, and catalase activity in the glycyrrhizic acid-treated group showed a significant reversal of cognitive impairment compared with the scopolamine-treated group.

CONCLUSION: Our results suggest that glycyrrhizic acid has a neuroprotective effect on cognitive function in scopolamine-induced cognitive impairment.

RevDate: 2020-06-02

Sohn JH, Lee SH, Kwon YS, et al (2020)

The impact of tamsulosin on cognition in Alzheimer disease with benign prostate hyperplasia: A study using the Hallym Smart Clinical Data Warehouse.

Medicine, 99(22):e20240.

Studies suggest that the use of alpha-blockers increases the risk of dementia in patients with benign prostate hyperplasia (BPH). Due to study limitations, the relationship between the use of alpha-blockers, such as tamsulosin, and the risk of dementia is still unclear. However, alpha1-adrenoreceptors are also present in the brain, so there is potential for adverse effects on cognitive function. Therefore, we investigated possible associations between the use of alpha-blockers and aggravation of cognitive decline in dementia patients using a clinical data analytic solution called the Smart Clinical Data Warehouse (CDW).We retrospectively investigated clinical data using the Smart CDW of Hallym University Medical Center from 2009 to 2019. We enrolled patients with probable Alzheimer disease (AD) who had completed the Mini-Mental State Examination (MMSE) at least twice during follow-up, and who had BPH. We compared the difference in MMSE scores between patients who took tamsulosin for >1000 days and those who did not take any alpha-blocker. We tested the effect of tamsulosin on cognitive decline in patients with AD, using propensity score-matched logistic regression analysis.Eligible cases were included in the tamsulosin (n = 68) or no-medication (n = 153) groups. After propensity score matching, clinical characteristics such as educational attainment and vascular risk factors were similar in the tamsulosin and no-medication groups. The MMSE scores did not differ significantly between the tamsulosin and no-medication groups (P = .470).The results suggest that tamsulosin for BPH is not associated with worsening of the cognitive decline in patients with AD.

RevDate: 2020-06-01

Chiu WT, Lee TY, Chan L, et al (2020)

Deep cerebral microbleeds are associated with poor cholinesterase inhibitor treatment response in people with Alzheimer disease.

Clinical neurology and neurosurgery, 195:105959 pii:S0303-8467(20)30302-4 [Epub ahead of print].

OBJECTIVES: Cholinesterase inhibitors (ChEIs) are the most effective treatment for Alzheimer disease (AD), but the response to treatment varies. Vascular lesions are associated with the pathogenesis of AD, and cerebral microbleeds (CMBs) are an indicator of hemorrhagic vascular pathology, which can be detected through susceptibility-weighted magnetic resonance imaging (SWMRI). This study investigated the association between CMBs and ChEI treatment response in patients with AD.

PATIENTS AND METHODS: We reviewed the medical records of 112 Taiwanese people with mild to moderate AD and at least 2 years of ChEI treatment between 2009 and 2016. Their baseline CMBs were quantified using the Microbleed Anatomical Rating Scale on SWMRI. Cognitive function of the patients was assessed using the Mini-Mental State Examination (MMSE) and Cognitive Abilities Screening Instrument (CASI). Student t test and multivariable logistic regression were used to analyze the association between cognitive decline and CMBs.

RESULTS: The mean age of the study population was 76.0 ± 8.0 years. In total, 79 out of 112 patients were women. The presence of deep, but not lobar CMBs at baseline was associated with a significant cognitive decline according to the MMSE and CASI, particularly in long-term memory, attention, orientation, mental manipulation, and verbal fluency. Among deep CMBs, those in the basal ganglia and thalamus were significantly associated with cognitive decline.

CONCLUSIONS: Deep CMBs, particularly those in the basal ganglia and thalamus, but not lobar CMBs, are associated with poor response to ChEI treatment in people with AD. This can serve as a biomarker for predicting ChEI treatment response.

RevDate: 2020-06-01

Saranya V, Mary PV, Vijayakumar S, et al (2020)

The hazardous effects of the environmental toxic gases on amyloid beta-peptide aggregation: A theoretical perspective.

Biophysical chemistry, 263:106394 pii:S0301-4622(20)30102-2 [Epub ahead of print].

Alzheimer's disease (AD) is one of the leading causes of dementia in elderly people. It has been well documented that the exposure to environmental toxins such as CO, CO2, SO2 and NO2 that are present in the air is considered as a hallmark for the progression of Alzheimer's disease. However, their actual mechanism by which environmental toxin triggers the aggregation of Aβ42 peptide at the molecular and atomic levels remain unknown. In this study, molecular dynamics simulation was carried out to study the aggregation mechanism of the Aβ42 peptide due to its interaction of toxic gas (CO, CO2, SO2 and NO2). During the 400 ns simulation, all the Aβ42 interacted toxic gas (CO, CO2, SO2, and NO2) complexes have smaller Root Mean Square Deviation values when compared to the Aβ42 peptide, which shows that the interaction of toxic gases (CO, CO2, SO2, and NO2) would increase the Aβ42 peptide structural stability. The radius of gyration analysis also supports that Aβ42 interacted CO2 and SO2 complexes have the minimum value in the range of 0.95 nm and 1.5 nm. It is accounted that the Aβ42 interacted CO2 and SO2 complexes have a greater compact structure in comparison to Aβ42 interacted CO and NO2 complexes. Furthermore, all the Aβ42 interacted toxic gas (CO, CO2, SO2, and NO2) complexes exhibited an enhanced secondary structural probability for coil and turn regions with a reduced α-helix probability, which indicates that the interaction of toxic gases may enhance the toxicity and aggregation of Aβ42.

RevDate: 2020-06-01

Kartalou GI, Endres T, Lessmann V, et al (2020)

Golgi-Cox impregnation combined with fluorescence staining of amyloid plaques reveals local spine loss in an Alzheimer mouse model.

Journal of neuroscience methods pii:S0165-0270(20)30220-X [Epub ahead of print].

BACKGROUND: Spine loss is a hallmark of Alzheimer´s and other neurodegenerative diseases, and testing candidate therapeutic drugs needs quantitative analysis of dendritic spine densities. Golgi-Cox impregnation of neurons is a classical method to visualize dendritic spines in diseased brains. Importantly, at early disease stages spine loss occurs locally in the vicinity of amyloid plaques, and concomitant fluorescence labeling of amyloid plaques is required to detect local spine damage.

NEW METHOD: Because Golgi-Cox impregnation is done on unsectioned brains, whereas fluorescence staining is performed on sectioned material, the combination is technically challenging. We have now developed a novel combination of Golgi-Cox impregnation with methoxy-X04 fluorescence labeling of plaques that is performed on unsectioned brains.

RESULTS: We used this new combination method to quantify dendritic spine densities in mouse hippocampal CA1 pyramidal neurons. Comparison of neurons from wildtype and APP/PS1 mice revealed local spine loss in the vicinity of amyloid plaques in both male and female APP/PS1 mice. Comparison with existing method: Golgi-Cox impregnation of neurons combined with methoxy-X04 staining of amyloid plaques is a highly reliable, easy-to-use method for permanent visualization of spines as compared to the technically more sophisticated and less stable fluorescence imaging of spines.

CONCLUSION: Our novel combination method will be highly useful for testing potential therapeutic drugs in Alzheimer mouse models.

RevDate: 2020-06-01

Hu M, Shu X, Wu X, et al (2020)

Neuropsychiatric symptoms as prognostic makers for the elderly with mild cognitive impairment: a meta-analysis.

Journal of affective disorders, 271:185-192.

BACKGROUND: Although several neuropsychiatric symptoms (NPSs) have been demonstrated to have value in the prediction of the progression of mild cognitive impairment (MCI) to dementia, these symptoms are less studied for the prediction of the transition from normal cognition (NC) to MCI.

METHODS: Prospective cohort studies were included if they reported on at least one NPS at baseline and had MCI as the outcome.

RESULTS: We obtained 13 cohort studies with a total population of 33,066. Depression was the most common neuropsychiatric symptom and could significantly predict transition to MCI (RR = 1.49, 95% CI: 1.13-1.86). However, depression was more capable of predicting amnestic MCI (RR=1.43, 95% CI: 1.04-1.83) than non-aMCI (RR= 0.96, 95% CI 95% CI: 0.60-1.33). Subgroup analysis suggested that the association between depression and MCI changed with depression severity, depression criteria, apolipoprotein-E-adjusted status, age, the percentage of females, and follow-up times, but some data were too sparse for a reliable estimate. Regarding other NPSs, there were insufficient data to assess their effect on the development of MCI. However, apathy, anxiety, sleep disturbances, irritability, and agitation might be risk factors for the prediction of NC-MCI transition with strong predictive value.

CONCLUSIONS: Depression was associated with an approximately 1.5-fold sincreased risk of the progression to MCI in the population with normal cognition. Other NPSs with underlying predictive value deserve more attention.

RevDate: 2020-06-01

Larsson SC, Gill D, Mason AM, et al (2020)

Lipoprotein(a) in Alzheimer, Atherosclerotic, Cerebrovascular, Thrombotic, and Valvular Disease: Mendelian Randomization Investigation.

Circulation, 141(22):1826-1828.

RevDate: 2020-06-01

Dermody G, Whitehead L, Wilson G, et al (2020)

The Role of Virtual Reality in Improving Health Outcomes for Community-Dwelling Older Adults: Systematic Review.

Journal of medical Internet research, 22(6):e17331 pii:v22i6e17331.

BACKGROUND: Virtual reality (VR) delivered through immersive headsets creates an opportunity to deliver interventions to improve physical, mental, and psychosocial health outcomes. VR app studies with older adults have primarily focused on rehabilitation and physical function including gait, balance, fall prevention, pain management, and cognition. Several systematic reviews have previously been conducted, but much of the extant literature is focused on rehabilitation or other institutional settings, and little is known about the effectiveness of VR apps using immersive headsets to target health outcomes among community-dwelling older adults.

OBJECTIVE: The objective of this review was to evaluate the effectiveness of VR apps delivered using commercially available immersive headsets to improve physical, mental, or psychosocial health outcomes in community-dwelling older adults.

METHODS: Peer-reviewed publications that included community-dwelling older adults aged ≥60 years residing in residential aged care settings and nursing homes were included. This systematic review was conducted in accordance with the Joanna Briggs Institute (JBI) methodology for systematic reviews of effectiveness evidence. The title of this review was registered with JBI, and the systematic review protocol was registered with the International Prospective Register of Systematic Reviews.

RESULTS: In total, 7 studies that specifically included community-dwelling older adults were included in this review. VR apps using a head-mounted display led to improvements in a number of health outcomes, including pain management, posture, cognitive functioning specifically related to Alzheimer disease, and a decreased risk of falls. A total of 6 studies reported a statistically significant difference post VR intervention, and 1 study reported an improvement in cognitive function to reduce navigational errors. Only one study reported on the usability and acceptability of the interventions delivered through VR. While one study used a distraction mechanism for pain management, none of the studies used gaming technology to promote enjoyment.

CONCLUSIONS: Interventions to improve health outcomes through VR have demonstrated potential; however, the ability to synthesize findings by primary outcome for the older adult population is not possible. A number of factors, especially related to frailty, usability, and acceptability, also need to be explored before more substantial recommendations on the effectiveness of VR interventions for older adults can be made.

TRIAL REGISTRATION: PROSPERO CRD42019143504; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=143504.

RevDate: 2020-06-01

Macron C, Lavigne R, Núñez Galindo A, et al (2020)

Exploration of human cerebrospinal fluid: A large proteome dataset revealed by trapped ion mobility time-of-flight mass spectrometry.

Data in brief, 31:105704 pii:105704.

Cerebrospinal fluid (CSF) is a biofluid in direct contact with the brain and as such constitutes a sample of choice in neurological disorder research, including neurodegenerative diseases such as Alzheimer or Parkinson. Human CSF has still been less studied using proteomic technologies compared to other biological fluids such as blood plasma or serum. In this work, a pool of "normal" human CSF samples was analysed using a shotgun proteomic workflow that combined removal of highly abundant proteins by immunoaffinity depletion and isoelectric focussing fractionation of tryptic peptides to alleviate the complexity of the biofluid. The resulting 24 fractions were analysed using liquid chromatography coupled to a high-resolution and high-accuracy timsTOF Pro mass spectrometer. This state-of-the-art mass spectrometry-based proteomic workflow allowed the identification of 3'174 proteins in CSF. The dataset reported herein completes the pool of the most comprehensive human CSF proteomes obtained so far. An overview of the identified proteins is provided based on gene ontology annotation. Mass and tandem mass spectra are made available as a possible starting point for further studies exploring the human CSF proteome.

RevDate: 2020-06-01

Nikbakht F, Khadem Y, Haghani S, et al (2019)

Protective Role of Apigenin Against Aβ 25-35 Toxicity Via Inhibition of Mitochondrial Cytochrome c Release.

Basic and clinical neuroscience, 10(6):557-566.

Introduction: Cognitive dysfunction is the most common problem of patients with Alzheimer Disease (AD). The pathological mechanism of cognitive impairment in AD may contribute to neuronal loss, synaptic dysfunction, and alteration in neurotransmitters receptors. Mitochondrial synapses dysfunction due to the accumulation of Amyloid Beta (Aβ) is one of the earliest pathological features of AD. The flavone apigenin has been reported to play some protective roles in AD through the anti-oxidative and anti-inflammatory properties. This study aimed at investigating the effects of apigenin on spatial working memory and neural protection by restoring mitochondrial dysfunction and inhibition of caspase 9.

Methods: Intracerebroventricular (ICV) microinjection of Aβ 25-35 was used for AD modeling. Working memory was assessed 21 days later using the Y maze test. Neuronal loss was detected in the hilar area of the hippocampus using Nissl and Fluoro-jade B staining, whereas immunohistochemistry was used to illustrate cytochrome c positive cells and caspase 9.

Results: The results revealed that apigenin significantly ameliorated spatial working memory. It also significantly reduced the number of degenerative neurons in the hilus area. Apigenin almost completely blocked the release of cytochrome c and caspase 9 in hilus.

Conclusion: Apigenin may improve the spatial working memory deficits and neuronal degeneration through the amelioration of the mitochondrial dysfunction.

RevDate: 2020-06-01

Amiri S, Azadmanesh K, Dehghan Shasaltaneh M, et al (2019)

Protein Kinase Cɛ in the Platelet and Hippocampal Tissue as a Diagnostic Biological Marker in Alzheimer Disease.

Basic and clinical neuroscience, 10(6):545-556.

Introduction: Alzheimer Disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory and other cognitive functions. Protein Kinase Cɛ (PKCɛ) is an isoform that most effectively suppresses Amyloid Beta (Aβ) production and synaptic loss.

Methods: In this study, spatial learning and memory for treated rats were evaluated by the Morris water maze test. The activity (total PKC), mRNA expression, and protein level of PKCɛ in the platelet and hippocampal tissue were evaluated using immunosorbent assay, real-time qPCR, and western blotting analysis, respectively.

Results: The traveled distance was significantly prolonged, and escape latency significantly increased in Aβ-treated groups. PKC activity assay showed that there was a remarkable difference between the Aβ-treated and sham-operated groups on days 10 and 30 in the hippocampus and also day 30 in platelet after the injection of Aβ. A significant effect in PKC activity was observed between days 0 and 10, days 0 and 30, as well as days 5 and 30. Aβ significantly downregulated the PKCɛ mRNA expression in the hippocampus of rats on day 30; however, no significant difference was observed in platelet. Western blot analysis demonstrated that Aβ significantly reduced PKCɛ protein expression in the hippocampus of treated groups on day 30.

Conclusion: The expression level of PKCɛ was downregulated following the injection of Aβ in the hippocampus, but no significant difference was observed between the AD and sham groups in platelet that may be due to the low concentration of PKCɛ or duration of Aβ exposure in the rat brain.

RevDate: 2020-06-01

Williams A, Gow A, Kilpatrick S, et al (2020)

Astrocyte lesions in cerebral cortex and cerebellum of dogs with congenital ortosystemic shunting.

Journal of veterinary science, 21(3):e44.

BACKGROUND: Congenital portosystemic shunt (cPSS) is one of the most common congenital disorders diagnosed in dogs. Hepatic encephalopathy (HE) is a frequent complication in dogs with a cPSS and is a major cause of morbidity and mortality. Despite HE been a major cause of morbidity in dogs with a cPSS, little is known about the cellular changes that occur in the central nervous system of dogs with a cPSS.

OBJECTIVES: The objective of this study was to characterise the histological changes in the cerebral cortex and cerebellum of dogs with cPSS with particular emphasis on astrocyte morphology.

METHODS: Eight dogs with a confirmed cPSS were included in the study.

RESULTS: Six dogs had substantial numbers of Alzheimer type II astrocytes and all cases had increased immunoreactivity for glial fibrillary acidic protein in the cerebral cortex, even if there were minimal other morphological changes.

CONCLUSIONS: This study demonstrates that dogs with a cPSS have marked cellular changes in the cerebral cortex and cerebellum. The cellular changes that occur in the cerebral cortex and cerebellum of dogs with spontaneously arising HE are similar to changes which occur in humans with HE, further validating dogs with a cPSS as a good model for human HE.

RevDate: 2020-05-30

Saffari PM, Alijanpour S, Takzaree N, et al (2020)

Metformin loaded phosphatidylserine nanoliposomes improve memory deficit and reduce neuroinflammation in streptozotocin-induced Alzheimer's disease model.

Life sciences pii:S0024-3205(20)30611-1 [Epub ahead of print].

Alzheimer's disease (AD) is closely associated with neuroinflammation development in the brain. Co-delivery of metformin (MET) with phosphatidylserine liposomes neuroprotectant may be beneficial in ameliorating AD-related symptoms like memory impairment and inflammation. Therefore, we aimed to prepare metformin containing phosphatidylserine nanoliposomes formulation (MET-PSL) and to evaluate its effect on rats subjected to AD. Alzheimer's disease model was induced by bilateral intracerebroventricular injection of streptozotocin (3 mg/kg) into rat brains using the stereotactic technique. MET-PSL, MET, and PSL alone were administered intraperitoneally to AD-induced animals and factors including learning and memory storage in addition to cytokine and tissue inflammatory changes were evaluated after a 22-day experiment period. The learning and memory parameters significantly (P < 0.05) improved in AD-rats treated with MET-PSL. Moreover, MET-PSL administration significantly (P < 0.05) decreased cytokine levels of IL1-β, TNF-α, and TGF-β in hippocampal tissues of rats with AD. Histological results indicated a considerable reduction in inflammatory and necrotic neural cells along with significantly (P < 0.05) increased neurogenesis in MET-PSL-treated rats. Furthermore, our results showed that MET-PSL formulation could potentially act better than the free form of MET and PSL alone in the recovery process of rats with AD. In general, our data suggest that combination therapy of metformin-loaded phosphatidylserine liposomes may enhance the therapeutic performance in AD patients of a clinical study.

RevDate: 2020-05-30

Soyal SM, Kwik M, Kalev O, et al (2020)

A TOMM40/APOE allele encoding APOE-E3 predicts high likelihood of late-onset Alzheimer's disease in autopsy cases.

Molecular genetics & genomic medicine [Epub ahead of print].

BACKGROUND: The APOE-ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE-ε4 are at variance.

METHODS: We investigated associations of AD with haplotypes defined by three TOMM40 and two APOE single nucleotide polymorphisms in 73 and 71 autopsy cases with intermediate and high likelihood of AD (defined by BRAAK stages
RESULTS: We observed eight haplotypes with a frequency >0.02. The two haplotypes encoding APOE-E4 showed strong associations with AD that did not differ between intermediate and high likelihood AD. In contrast, a TOMM40 haplotype encoding APOE-E3 was identified as risk haplotype of high- (p = .0186), but not intermediate likelihood AD (p = .7530). Furthermore, the variant allele of rs2075650 located in intron 2 of TOMM40, increased the risk of high-, but not intermediate likelihood AD on the APOE-ε3/ε3 background (p = .0230).

CONCLUSION: The striking association of TOMM40 only with high likelihood AD may explain some contrasting results for TOMM40 in clinical studies and may reflect an association with more advanced disease and/or suggest a role of TOMM40 in the pathogenesis of neurofibrillary tangles.

RevDate: 2020-05-29

Quiroz YT, Zetterberg H, Reiman EM, et al (2020)

Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study.

The Lancet. Neurology, 19(6):513-521.

BACKGROUND: Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred.

METHODS: In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer's disease Colombian kindred aged 8-75 years with no other neurological or health conditions were recruited from the Alzheimer's Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers.

FINDINGS: We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0·0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset.

INTERPRETATION: Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies.

FUNDING: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Banner Alzheimer's Foundation, COLCIENCIAS, the Torsten Söderberg Foundation, the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, and the Swedish state under the ALF-agreement.

RevDate: 2020-05-29

Akbarialiabad H, Dahroud MD, Khazaei MM, et al (2020)

Green Tea, A medicinal food with promising neurological benefits.

Current neuropharmacology pii:CN-EPUB-106982 [Epub ahead of print].

Neurological disorders and their sequelae, as of the widespread and critical humans complications, affect the body's nervous systems, organ functions, and behaviors. According to WHO, neurological disorders are currently predicted to affect more than one billion people globally. It is well-established that complementary medicine is one of the high accepted interventions that could have been considered for the management of neurological ailments. The current review aimed to compile a frame from all the crucial data reporting the investigation on the conspicuous intervention of green tea (made of Camellia sinensis) and related lead compounds (especially l-theanine, epigallocatechin-3-gallate, epicatechin-3-gallate, epicatechin, and epigallocatechin) for their neurological activities, mechanisms of action, and clinical properties. According to the documents, green tea exhibits antidepressant, anti-neurodegenerative (e.g., anti-Parkinson and anti-Alzheimer), as well as neuroprotective effects. Chief among them, for offering novel work, it is worth focusing on several related assessments with great attention to more extensive standardized clinical trials, and subsequently more in-depth pharmacokinetic studies to safely introduce this beneficial medicinal food as a neuro-effective agent.

RevDate: 2020-05-29

Revi M (2020)

Alzheimer's Disease Therapeutic Approaches.

Advances in experimental medicine and biology, 1195:105-116.

Alzheimer's disease (AD) was first described and diagnosed by Dr. Alois Alzheimer in 1906 (Hippius and Neundorfer, Dialogues Clin Neurosc 5:101-108, 2003). According to World Health Organization (WHO), AD is the most common cause of dementia, accounting for as many as 60-70% of senile dementia cases and affecting 47.5 million people worldwide (data from 2015) (Dementia Fact Sheet No 362. http://who.int/mediacentre/factsheets/fs362/en/). The median survival time after the onset of dementia ranges from 3.3 to 11.7 years (Todd et al. Int J Geriatr Psychiatry 28:1109-1124, 2013). AD is characterized as a severe, chronic, incurable, and progressive neurodegenerative disorder, associated with memory loss and cognition impairment accompanied by abnormal behavior and personality changes (Godyn et al. Pharmacol Rep 68:127-138, 2016). AD is characterized by neuronal death, which usually correlates with the appearance of key neuropathological changes, including acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of β-amyloid (Aβ plaques), intracellular neurofibrillary tangles by hyperphosphorylated tau protein deposits, neuroinflammation, and widespread neuronal loss (Godyn et al. Pharmacol Rep 68:127-138, 2016; Graham et al. Annu Rev. Med 68:413-430, 2017). The discovery of the degeneration of cholinergic neurons and the reduction of acetylcholine levels in postmortem studies of patients resulted in the use of drugs that leads to the increase of acetylcholine levels in brain (Dubois et al. Lacet Neurol 13:614-629, 2014). At present there is no preventative or curative treatment that interferes with the development of the disease. However, in recent years progress was made in the development of cholinergic drugs which have a positive effect on disease progression. Nowadays, specific drugs that can inhibit the enzyme that degrades acetylcholine are used. The development of new effective drugs involves a difficult and time-consuming process, accompanied by a very high failure rate. In the absence of effective therapies, the estimated number of people with dementia will reach 115 to 131, five million by 2050 (Dubois et al. Lacet Neurol 13:614-629, 2014; Cummings et al. Alzheimers Res Ther 6:37, 2014). Novel therapies and new targets required for developing more effective drugs for the treatment of AD patients are urgently needed.

RevDate: 2020-05-29

Xristina F, Demeter K, John G, et al (2020)

The Role of the Family in the Care of Alzheimer Patients.

Advances in experimental medicine and biology, 1196:103-107.

According to the World Health Organisation (WHO 2002), people's life expectancy worldwide is continuously growing, and on the one hand, that is one of the greatest triumphs of humanity to date. But at the same time, it is also one of the most important challenges as the aging of the population raises economic and social requirements in all countries.

RevDate: 2020-05-29

Ghatak S, Dolatabadi N, Gao R, et al (2020)

NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models.

Molecular psychiatry pii:10.1038/s41380-020-0776-7 [Epub ahead of print].

Beginning at early stages, human Alzheimer's disease (AD) brains manifest hyperexcitability, contributing to subsequent extensive synapse loss, which has been linked to cognitive dysfunction. No current therapy for AD is disease-modifying. Part of the problem with AD drug discovery is that transgenic mouse models have been poor predictors of potential human treatment. While it is undoubtedly important to test drugs in these animal models, additional evidence for drug efficacy in a human context might improve our chances of success. Accordingly, in order to test drugs in a human context, we have developed a platform of physiological assays using patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) experiments on human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids. We compare hiPSCs bearing familial AD mutations vs. their wild-type (WT) isogenic controls in order to characterize the aberrant electrical activity in such a human context. Here, we show that these AD neuronal cultures and organoids manifest increased spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity. Importantly, the dual-allosteric NMDAR antagonist NitroSynapsin, but not the FDA-approved drug memantine, abrogated this hyperactivity. We propose a novel model of synaptic plasticity in which aberrant neural networks are rebalanced by NitroSynapsin. We propose that hiPSC models may be useful for screening drugs to treat hyperexcitability and related synaptic damage in AD.

RevDate: 2020-05-29

Gourley D, Pasha EP, Kaur SS, et al (2020)

Association of Dementia and Vascular Risk Scores With Cortical Thickness and Cognition in Low-risk Middle-aged Adults.

Alzheimer disease and associated disorders [Epub ahead of print].

BACKGROUND: Increased risk for the future development of Alzheimer disease begins as early as midlife. Algorithm-based scores, such as the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) dementia risk score, and the Framingham general cardiovascular disease (CVD) risk score, have been used to determine future risk for the development of cognitive decline and dementia. We evaluated the association between neuroimaging and cognitive measures with the 2 risk scores in middle-aged, cognitively intact adults (49±6 y).

METHODS: In a cohort of 132 participants collected in 2014, magnetic resonance imaging was used to determine measures of cortical thickness in a priori regions of interest and a neuropsychological battery to assess memory and executive function.

RESULTS: The CAIDE dementia risk score was significantly and inversely associated with the cortical thickness of the parahippocampal (r=-0.266; P=0.002) and superior frontal gyrus (r=-0.261; P=0.002) despite a considerable percentage of individuals (99.3%) at low risk for CVD. There was a significant negative association between CAIDE and memory (r=-0.251; P=0.003). Framingham general CVD score was not associated with brain structure or cognitive function.

CONCLUSIONS: These results indicate that the CAIDE dementia risk score is associated with cortical thickness and cognitive function at midlife in a low-risk population. These data provide insight into subclinical structural and functional changes occurring during midlife associated with future risk for the development of dementia.

RevDate: 2020-05-29

Gandhi P, Klatt BN, Y Agrawal (2020)

Physical and Vestibular Physical Therapy Referrals in People With Alzheimer Disease.

Alzheimer disease and associated disorders [Epub ahead of print].

People with Alzheimer disease (AD) are at increased risk of falls and disproportionately burdened with vestibular impairment compared with healthy older adults. Although physical therapy (PT) and vestibular physical therapy (VPT) are effective rehabilitation interventions in improving balance and fall risk, referral patterns for these services in the AD population are understudied. A retrospective chart review was conducted of patients seen for primary AD care at a tertiary AD referral center to investigate the frequency of rehabilitation referrals. Of the 801 people with AD seen for AD care in 1 year, 48 individuals (6.0%) were referred to PT and 5 individuals (0.6%) to VPT. People with AD appear to receive very infrequent PT and VPT referrals, despite the potentially large number of people with AD who could benefit from PT and VPT services to improve their balance and vestibular function.

RevDate: 2020-05-29

Gotoh N, Saito Y, Hata S, et al (2020)

Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of Alcadein α-deficient mice.

The Journal of biological chemistry pii:RA119.012386 [Epub ahead of print].

Alzheimer's disease (AD) is a very common neurodegenerative disorder, chiefly caused by increased production of neurotoxic amyloid-β (Aβ) peptide generated from proteolytic cleavage of amyloid β protein precursor (APP). Except for familial AD arising from mutations in the APP and presenilins (PSENs) genes, the molecular mechanisms regulating the amyloidogenic processing of APP are largely unclear. Alcadein α/calsyntenin1 (ALCα/CLSTN1) is a neuronal type I transmembrane protein that forms a complex with APP, mediated by the neuronal adaptor protein X11-like (X11L or MINT2). Formation of the ALCα-X11L-APP tripartite complex suppresses Aβ generation in vitro, and X11L-deficient mice exhibit enhanced amyloidogenic processing of endogenous APP. However, the role of ALCα in APP metabolism in vivo remains unclear. Here, by generating ALCα-deficient mice and using immunohistochemistry, immunoblotting, and co-immunoprecipitation analyses, we verified the role of ALCα in the suppression of amyloidogenic processing of endogenous APP in vivo We observed that ALCα deficiency attenuates the association of X11L with APP, significantly enhances amyloidogenic β-site cleavage of APP especially in endosomes, and increases the generation of endogenous Aβ in the brain. Furthermore, we noted amyloid plaque formation in the brains of human APP-transgenic mice in an ALCα-deficient background. These results unveil a potential role of ALCα in protecting cerebral neurons from Aβ-dependent pathogenicity in AD.

RevDate: 2020-05-28

Amici M, Lee Y, Pope RJP, et al (2020)

GSK-3β regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIα.

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

Deregulation of GSK-3β is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. To understand how GSK-3β becomes dysregulated in these conditions it is important to understand its physiological functions in the central nervous system. In this context, GSK-3β plays a role in the induction of NMDA receptor-dependent long-term depression (LTD) and several substrates for GSK-3β have been identified in this form of synaptic plasticity, including KLC-2, PSD-95 and tau. Stabilization of NMDA receptors at synapses has also been shown to involve GSK-3β, but the substrates involved are currently unknown. Recent work has identified phosphatidylinositol 4 kinase type IIα (PI4KIIα) as a neuronal GSK-3β substrate that can potentially regulate the surface expression of AMPA receptors. In the present study, we investigated the synaptic role of PI4KIIα in organotypic rat hippocampal slices. We found that knockdown of PI4KIIα has no effect on synaptic AMPA receptor-mediated synaptic transmission but substantially reduces NMDA receptor-mediated synaptic transmission. Furthermore, the ability of the selective GSK-3β inhibitor, CT99021, to reduce the amplitude of NMDA receptor-mediated currents was occluded in shRNA-PI4KIIα transfected neurons. The effects of knocking down PI4KIIα were fully rescued by a shRNA-resistant wild type construct, but not by a mutant construct that cannot be phosphorylated by GSK-3β. These data suggest that GSK-3β phosphorylates PI4KIIα to stabilize NMDA receptors at the synapse.

RevDate: 2020-05-28

Maier F, Spottke A, Bach JP, et al (2020)

Bupropion for the Treatment of Apathy in Alzheimer Disease: A Randomized Clinical Trial.

JAMA network open, 3(5):e206027 pii:2766381.

Importance: Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed.

Objective: To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type.

This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019.

Interventions: Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study.

Main Outcomes and Measures: Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks.

Results: A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups.

Conclusions and Relevance: Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood.

Trial Registration: EU Clinical Trials Register Identifier: 2007-005352-17.

RevDate: 2020-05-28

Wesselman LMP, Schild AK, Hooghiemstra AM, et al (2020)

Targeting Lifestyle Behavior to Improve Brain Health: User-Experiences of an Online Program for Individuals with Subjective Cognitive Decline.

The journal of prevention of Alzheimer's disease, 7(3):184-194.

BACKGROUND: Online programs targeting lifestyle have the potential to benefit brain health. We aimed to develop such a program for individuals with subjective cognitive decline (SCD). These individuals were reported to be at increased risk for dementia, and report both an intrinsic need for brain health information and motivation to participate in prevention strategies. Co-creation and user-evaluation benefits the adherence to and acceptance of online programs. Previously, we developed a prototype of the online program in co-creation with the users .

OBJECTIVES: We now aimed to evaluate the user-experiences of our online lifestyle program for brain health.

DESIGN: 30-day user test; multi-method.

SETTING: Participants were recruited in a memory clinic and (online) research registries in the Netherlands (Alzheimer Center Amsterdam) and Germany (Center for memory disorders, Cologne).

PARTICIPANTS: Individuals with SCD (N=137, 65±9y, 57% female).

MEASUREMENTS: We assessed user-experiences quantitatively with rating daily advices and usefulness, satisfaction and ease of use questionnaires as well as qualitatively using telephone interviews.

RESULTS: Quantitative data showed that daily advices were rated moderately useful (3.5 ±1.5, range 1-5 points). Participants (n=101, 78%) gave moderate ratings on the programs' usability (3.7±1.3, max 7), ease of learning (3.6±1.9) and satisfaction (4.0±1.5), and marginal ratings on the overall usability (63.7±19.0, max 100). Qualitative data collected during telephone interviews showed that participants highly appreciated the content of the program. They elaborated that lower ratings of the program were mainly due to technical issues that hindered a smooth walk through. Participants reported that the program increased awareness of lifestyle factors related to brain health.

CONCLUSIONS: Overall user-experience of the online lifestyle program was moderate to positive. Qualitative data showed that content was appreciated and that flawless, easy access technique is essential. The heterogeneity in ratings of program content and in program use highlights the need for personalization. These findings support the use of online self-applied lifestyle programs when aiming to reach large groups of motivated at-risk individuals for brain health promotion.

RevDate: 2020-05-27

Thomas NWD, Beattie Z, Marcoe J, et al (2020)

An Ecologically Valid, Longitudinal, and Unbiased Assessment of Treatment Efficacy in Alzheimer Disease (the EVALUATE-AD Trial): Proof-of-Concept Study.

JMIR research protocols, 9(5):e17603 pii:v9i5e17603.

BACKGROUND: The current clinical trial assessment methodology relies on a combination of self-report measures, cognitive and physical function tests, and biomarkers. This methodology is limited by recall bias and recency effects in self-reporting and by assessments that are brief, episodic, and clinic based. Continuous monitoring of ecologically valid measures of cognition and daily functioning in the community may provide a more sensitive method to detect subtle, progressive changes in patients with cognitive impairment and dementia.

OBJECTIVE: This study aimed to present an alternative trial approach using a home-based sensing and computing system to detect changes related to common treatments employed in Alzheimer disease (AD). This paper introduces an ongoing study that aims to determine the feasibility of capturing sensor-based data at home and to compare the sensor-based outcomes with conventional outcomes. We describe the methodology used in the assessment protocol and present preliminary results of feasibility measures and examples of data related to medication-taking behavior, activity levels, and sleep.

METHODS: The EVALUATE-AD (Ecologically Valid, Ambient, Longitudinal and Unbiased Assessment of Treatment Efficacy in Alzheimer's Disease) trial is a longitudinal naturalistic observational cohort study recruiting 30 patients and 30 spouse coresident care partners. Participants are monitored continuously using a home-based sensing and computing system for up to 24 months. Outcome measures of the automated system are compared with conventional clinical outcome measures in AD. Acceptance of the home system and protocol are assessed by rates of dropout and protocol adherence. After completion of the study monitoring period, a composite model using multiple functional outcome measures will be created that represents a behavioral-activity signature of initiating or discontinuing AD-related medications, such as cholinesterase inhibitors, memantine, or antidepressants.

RESULTS: The home-based sensing and computing system has been well accepted by individuals with cognitive impairment and their care partners. Participants showed good adherence to the completion of a weekly web-based health survey. Daily activity, medication adherence, and total time in bed could be derived from algorithms using data from the sensing and computing system. The mean monitoring time for current participants was 14.6 months. Medication adherence, as measured with an electronic pillbox, was 77% for participants taking AD-related medications.

CONCLUSIONS: Continuous, home-based assessment provides a novel approach to test the impact of new or existing dementia treatments generating objective, clinically meaningful measures related to cognition and everyday functioning. Combining this approach with the current clinical trial methodology may ultimately reduce trial durations, sample size needs, and reliance on a clinic-based assessment.


RevDate: 2020-05-27

Kalovyrna N, Apokotou O, Boulekou S, et al (2020)

A 3'UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice.

Scientific reports, 10(1):8670 pii:10.1038/s41598-020-65378-2.

Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine, involved in Alzheimer's disease pathogenesis. Anti-TNF-α therapeutic approaches currently used in autoimmune diseases have been proposed as a therapeutic strategy in AD. We have previously examined the role of TNF-α and anti-TNF-α drugs in AD, using 5XFAD mice, and we have found a significant role for peripheral TNF-α in brain inflammation. Here we investigated the role of mouse TNF-α on the AD-like phenotype of 5XFAD mice using a knock-in mouse with deletion of the 3'UTR of the endogenous TNF-α (TNFΔARE/+) that develops rheumatoid arthritis and Crohn's disease. 5XFAD/TNFΔARE/+ mice showed significantly decreased amyloid deposition. Interestingly, microglia but not astrocytes were activated in 5XFAD/ TNFΔARE/+ brains. This microglial activation was associated with increased infiltrating peripheral leukocytes and perivascular macrophages and synaptic degeneration. APP levels and APP processing enzymes involved in Aβ production remained unchanged, suggesting that the reduced amyloid burden can be attributed to the increased microglial and perivascular macrophage activation caused by TNF-α. Peripheral TNF-α levels were increased while brain TNF-α remained the same. These data provide further evidence for peripheral TNF-α as a mediator of inflammation between the periphery and the brain.

RevDate: 2020-05-27

Yin J, Reiman EM, Beach TG, et al (2020)

Effect of ApoE isoforms on mitochondria in Alzheimer disease.

Neurology pii:WNL.0000000000009582 [Epub ahead of print].

OBJECTIVE: To test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD.

METHODS: We obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25).

RESULTS: Levels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance.

CONCLUSION: ApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.

RevDate: 2020-05-27

Obrenovich M, Jaworski H, Tadimalla T, et al (2020)

The Role of the Microbiota-Gut-Brain Axis and Antibiotics in ALS and Neurodegenerative Diseases.

Microorganisms, 8(5): pii:microorganisms8050784.

: The human gut hosts a wide and diverse ecosystem of microorganisms termed the microbiota, which line the walls of the digestive tract and colon where they co-metabolize digestible and indigestible food to contribute a plethora of biochemical compounds with diverse biological functions. The influence gut microbes have on neurological processes is largely yet unexplored. However, recent data regarding the so-called leaky gut, leaky brain syndrome suggests a potential link between the gut microbiota, inflammation and host co-metabolism that may affect neuropathology both locally and distally from sites where microorganisms are found. The focus of this manuscript is to draw connection between the microbiota-gut-brain (MGB) axis, antibiotics and the use of "BUGS AS DRUGS" for neurodegenerative diseases, their treatment, diagnoses and management and to compare the effect of current and past pharmaceuticals and antibiotics for alternative mechanisms of action for brain and neuronal disorders, such as Alzheimer disease (AD), Amyotrophic Lateral Sclerosis (ALS), mood disorders, schizophrenia, autism spectrum disorders and others. It is a paradigm shift to suggest these diseases can be largely affected by unknown aspects of the microbiota. Therefore, a future exists for applying microbial, chemobiotic and chemotherapeutic approaches to enhance translational and personalized medical outcomes. Microbial modifying applications, such as CRISPR technology and recombinant DNA technology, among others, echo a theme in shifting paradigms, which involve the gut microbiota (GM) and mycobiota and will lead to potential gut-driven treatments for refractory neurologic diseases.

RevDate: 2020-05-27

Mahomoodally MF, Picot-Allain MCN, Zengin G, et al (2020)

Phytochemical Analysis, Network Pharmacology and in Silico Investigations on Anacamptis pyramidalis Tuber Extracts.

Molecules (Basel, Switzerland), 25(10): pii:molecules25102422.

Anacamptis pyramidalis (L.) Rich. forms part of the Orchidaceae family that is highlyvalued for its horticultural as well as therapeutic benefits. The present study set out to investigatethe inhibitory activity of A. pyramidalis tubers against key biological targets for the management oftype 2 diabetes, Alzheimer disease, and skin hyperpigmentation. In addition, the antioxidantpotential of the extracts was also assessed using multiple methods. The detailed phytochemicalprofiles of the extracts were determined using high-performance liquid chromatography. Based onqualitative phytochemical fingerprint, a network pharmacology analysis was conducted as well.Parishin was identified from the water extract only, whereas gastrodin and caffeic acid derivativeswere present in the methanol extract. The methanol extract exhibited high inhibitory activityagainst tyrosinase (69.69 mg kojic acid equivalent/g extract), α-amylase (15.76 mg acarboseequivalent/g extract), and α-glucosidase (20.07 mg acarbose equivalent/g extract). Similarly, themethanol extract showed highest antioxidant potential (22.12, 44.23, 45.56, and 29.38 mg Troloxequivalent/g extract, for 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), CUPric Reducing Antioxidant Capacity (CUPRAC),and Ferric Reducing Antioxidant Power (FRAP) assays, respectively). Finally, the results ofnetwork pharmacology analysis, besides corroborating traditional uses of plant extracts in themanagement of cold and flu, confirmed a direct involvement of identified phytochemicals in theobserved enzyme inhibitory effects, especially against tyrosinase, α-amylase, and α-glucosidase.Furthermore, based on the results of both colorimetric assays and network pharmacology analysis&nbsp;related to the activity of A. pyramidalis extracts and identified phytocompounds on enzymesinvolved in type 2 diabetes, a docking study was conducted in order to investigate the putativeinteractions of oxo-dihydroxy octadecenoic acid trihydroxy octadecenoic acid against aldosereductase, peroxisome proliferator-activated receptor (PPAR)-α, dipeptidyl peptidase (DPP)-IV,and α-glucosidase. Docking analysis suggested the inhibitory activity of these compounds againstthe aforementioned enzymes, with a better inhibitory profile shown by oxo-dihydroxyoctadecenoic acid. Overall, the present findings supported the rationale for the use of A.pyramidalis as source of bioactive metabolites and highlight, today more than ever, for the strongnecessity of linkage strategy between wild resource valorization and conservation policy.

RevDate: 2020-05-26

Nabil-Adam A, Shreadah MA, El Moneam NMA, et al (2020)

Various In Vitro Bioactivities of Secondary Metabolites Isolated from the Sponge Hyrtios aff. Erectus from the Red Sea Coast of Egypt.

Turkish journal of pharmaceutical sciences, 17(2):127-135.

Objectives: The present study revealed the presence of bioactive constituents in Hyrtios aff. erectus sponge (HES) extract collected from the Red Sea using skin and scuba diving.

Materials and Methods: Cytotoxicity was tested against hepatocellular carcinoma cell lines as a prescreening test.

Results: The HES extract had high contents of total phenolic compounds (0.061 mg/g), flavonoids (0.2839 mg/g), and carotenoids (1.976 mg/g). Moreover, the HES extract showed high antioxidant capacity with 93.0% and 99% at 1 mg using 2.2'-Diphenyl-α-picrylhydrazyl and 2.2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), respectively. Cytotoxic activity against cancerous cell lines showed that the HES extract could inhibit cell growth effectively with IC50=47.5 μg/mL. Furthermore, anticancer activity using protein tyrosine kinase and sphingosine kinase 1 inhibitor screening assays resulted in 71.66% and 85.21% inhibition activity, respectively. The anti-inflammatory assays showed that the inhibition activity against cyclooxygenase (COX1), COX2, interleukin-6, and tumor necrosis factor-α was 71.82%, 81.13%, 80.89%, and 59.74%, respectively. At the same time, the anti-Alzheimer results using acetylcholine inhibition assay showed high activity at 1 mg with 83.51%. Additionally, the antiviral activity using the reverse transcriptase inhibition assay was 91.70%.

Conclusion: This marine sponge isolated from the Red Sea showed tremendous activity against many diseases and it is considered an excellent source for bioactive pharmaceutical compounds.

RevDate: 2020-05-26

Hwang TW, Kim EJ, Kim D, et al (2020)

Fat-1 expression enhance hippocampal memory in scopolamine-induced amnesia.

The Journal of nutritional biochemistry, 82:108394 pii:S0955-2863(19)30715-6 [Epub ahead of print].

Omega-3 polyunsaturated fatty acids (PUFA) are critical for optimal brain health and are involved in psychiatric and neurological ailments. Here, we report the effects of higher endogenous omega-3 PUFA on memory impairment in the hippocampus by studying mice with transgenic expression of the fat-1 gene that converts omega-6 to omega-3 PUFA. We performed Y-maze and passive avoidance tests to evaluate the memory function of fat-1 mice treated with scopolamine. Fat-1 mice showed induced alternation in the Y-maze test and increased latency in the passive avoidance test. The effects of scopolamine on hippocampal neurogenesis were confirmed by increases in the number of Ki-67- and DCX-positive cells in the fat-1 mice. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein levels, and lower scopolamine-induced apoptosis based on the cleaved-caspase 3 protein level in fat-1 mice. These findings suggest that higher endogenous omega-3 PUFA prevented granular cell loss, increased BDNF signaling, and decreased apoptosis signaling in scopolamine-treated fat-1 mice. These processes may underlie granular cell survival and suggest potential therapeutic targets for memory impairment.

RevDate: 2020-05-26

Sil S, Hu G, Liao K, et al (2020)

HIV-1 Tat-mediated astrocytic amyloidosis involves the HIF-1α/lncRNA BACE1-AS axis.

PLoS biology, 18(5):e3000660 pii:PBIOLOGY-D-19-02913 [Epub ahead of print].

Increased life expectancy of patients diagnosed with HIV in the current era of antiretroviral therapy is unfortunately accompanied with the prevalence of HIV-associated neurocognitive disorders (HANDs) and risk of comorbidities such as Alzheimer-like pathology. HIV-1 transactivator of transcription (Tat) protein has been shown to induce the production of toxic neuronal amyloid protein and also enhance neurotoxicity. The contribution of astrocytes in Tat-mediated amyloidosis remains an enigma. We report here, in simian immunodeficiency virus (SIV)+ rhesus macaques and patients diagnosed with HIV, brain region-specific up-regulation of amyloid precursor protein (APP) and Aβ (40 and 42) in astrocytes. In addition, we find increased expression of β-site cleaving enzyme (BACE1), APP, and Aβ in human primary astrocytes (HPAs) exposed to Tat. Mechanisms involved up-regulation of hypoxia-inducible factor (HIF-1α), its translocation and binding to the long noncoding RNA (lncRNA) BACE1-antisense transcript (BACE1-AS), resulting, in turn, in the formation of the BACE1-AS/BACE1 RNA complex, subsequently leading to increased BACE1 protein, and activity and generation of Aβ-42. Gene silencing approaches confirmed the regulatory role of HIF-1α in BACE1-AS/BACE1 in Tat-mediated amyloidosis. This is the first report implicating the role of the HIF-1α/lncRNABACE1-AS/BACE1 axis in Tat-mediated induction of astrocytic amyloidosis, which could be targeted as adjunctive therapies for HAND-associated Alzheimer-like comorbidity.

RevDate: 2020-05-26

Yu L, Schneider JA, Kapasi A, et al (2020)

Limbic-predominant Age-related TDP-43 Encephalopathy and Distinct Longitudinal Profiles of Domain-specific Literacy.

Alzheimer disease and associated disorders [Epub ahead of print].

PURPOSE: Emerging evidence suggests that limbic-predominant age-related TAR DNA-binding protein-43 (TDP-43) encephalopathy impacts domain-specific literacy, a complex ability not assessed in traditional cognitive evaluations. We examined longitudinal profiles of financial and health literacy in relation to limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC).

PARTICIPANTS: A total of 275 community-dwelling older persons who had completed annual literacy assessments, died and undergone brain autopsy.

METHODS: Financial and health literacy was assessed using a 32-item instrument. Latent class mixed effects models identified groups of individuals with distinct longitudinal literacy profiles. Regression models examined group differences in 9 common age-related neuropathologies assessed via uniform structured neuropathologic evaluations.

RESULTS: Two distinct literacy profiles emerged. The first group (N=121, 44%) had higher level of literacy at baseline, slower decline and less variabilities over time. The second group (N=154, 56%) had lower level of literacy at baseline, faster decline, and greater variabilities. Individuals from the latter group were older, with fewer years of education and more female. They also had higher burdens of Alzheimer disease and LATE-NC. The group association with Alzheimer disease was attenuated and no longer significant after controlling for cognition. By contrast, the association with LATE-NC persisted.

CONCLUSION: Limbic-predominant age-related TDP-43 encephalopathy is uniquely associated with distinct longitudinal profiles of financial and health literacy in old age.

RevDate: 2020-05-26

Yonezawa K, Kusumoto Y, Kanchi N, et al (2020)

Recent trends in mental illness and omega-3 fatty acids.

Journal of neural transmission (Vienna, Austria : 1996) pii:10.1007/s00702-020-02212-z [Epub ahead of print].

Although it is clear that nutrition affects physical and metabolic functions in humans, the importance of nutrition in mental illness has often been overlooked. Following a report by Hibbeln (Lancet 351:1213, 1998) published in The Lancet, which suggested that depression rates and fish consumption were inversely correlated, the relationships between a variety of nutritional/epidemiological treatments and neuropsychiatric disorders have received increased attention. In particular, many studies have been conducted on the omega-3 fatty acid mechanism of action in pathophysiological aspects of various neuropsychiatric disorders. Furthermore, many clinical studies have also been conducted on the effects of omega-3 replacement therapy. Therefore, this article reports recent trends in, and perspectives on, the use of omega-3 fatty acids to treat the five psychiatric disorders: schizophrenia (a delusion of the psychotic zone), depression and other mood disorders, attention deficit hyperactivity disorder (a developmental disorder), post-traumatic stress disorder (psychological trauma after the disaster), and Alzheimer-type dementia.

RevDate: 2020-05-25

Abo-Youssef AM, Khallaf WA, Khattab MM, et al (2020)

The anti-Alzheimer effect of telmisartan in a hyperglycemic ovariectomized rat model; role of central angiotensin and estrogen receptors.

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association pii:S0278-6915(20)30331-8 [Epub ahead of print].

The central renin angiotensin system (RAS) is implicated in Alzheimer's disease (AD). Here, induction of experimental AD simulation was performed by D-galactose (D-Gal) injection to ovariectomized (OVX) rats fed on high fat high fructose diet (HFFD). Telmisartan administration to OVX/HFFD/D-Gal rats lowered the expression of hippocampal angiotensin 1 and 2 receptors and glucose transporter 2 in addition to lowering of the peripheral and central glucose levels. Furthermore, it improved cognitive impairment and suppressed hippocampal amyloidogenic markers including amyloid-beta level, phosphorylated tau protein and beta site amyloid precursor protein cleaving enzyme 1 expression, while elevated levels of insulin degrading enzyme and recovered permeability of blood brain barrier (BBB). In addition, it inhibited hippocampal oxido-nitrosative stress as well as neuroinflammatory and apoptotic biomarkers. Telmisartan improved memory and cognitive impairment as shown in the behavioral Morris water maze, Y-maze, novel object recognition and open field tests in addition to amelioration of depressive like behavior as shown in forced swimming test. Histopathological examination of brain and immune expression of glial fibrillary acidic protein were also improved together with astrogliosis improvement. In conclusion, telmisartan improved memory and cognitive impairment, recovered amyloidogenesis-hyperglycemic axis, astrogliosis, integrity of BBB, memory deficit and oxidonitrosative stress induced in OVX/HFFD/D-Gal rats.

RevDate: 2020-05-25

Hossain MI, Marcus JM, Lee JH, et al (2020)

Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective.

Autophagy [Epub ahead of print].

Stroke is a leading cause of death and disability. The pathophysiological mechanisms associated with stroke are very complex and not fully understood. Lysosomal function has a vital physiological function in the maintenance of cellular homeostasis. In neurons, CTSD (cathepsin D) is an essential protease involved in the regulation of proteolytic activity of the lysosomes. Loss of CTSD leads to lysosomal dysfunction and accumulation of different cellular proteins implicated in neurodegenerative diseases. In cerebral ischemia, the role of CTSD and lysosomal function is not clearly defined. We used oxygen-glucose deprivation (OGD) in mouse cortical neurons and the middle cerebral artery occlusion (MCAO) model of stroke to assess the role of CTSD in stroke pathophysiology. Our results show a time-dependent decrease in CTSD protein levels and activity in the mouse brain after stroke and neurons following OGD, with concurrent defects in lysosomal function. We found that shRNA-mediated knockdown of CTSD in neurons is sufficient to cause lysosomal dysfunction. CTSD knockdown further aggravates lysosomal dysfunction and cell death in OGD-exposed neurons. Restoration of CTSD protein levels via lentiviral transduction increases CTSD activity in neurons and, thus, renders resistance to OGD-mediated defects in lysosomal function and cell death. This study indicates that CTSD-dependent lysosomal function is critical for maintaining neuronal survival in cerebral ischemia; thus, strategies focused on maintaining CTSD function in neurons are potentially novel therapeutic approaches to prevent neuronal death in stroke.

ABBREVIATIONS: 3-MA: 3-methyladenine; ACTB: actin beta; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; CQ: chloroquine; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; FTD: frontotemporal dementia, HD: Huntington disease; LAMP1: lysosomal associated membrane protein 1; LSD: lysosomal storage disease; MCAO: middle cerebral artery occlusion; OGD: oxygen glucose deprivation; OGR: oxygen glucose resupply; PD: Parkinson disease; SQSMT1: sequestosome 1; TCA: trichloroacetic acid; TTC: triphenyl tetrazolium chloride.

RevDate: 2020-05-25

Huwait EA, Baghallab IM, Glabe CG, et al (2020)

Identification of amyloid antibodies for Alzheimer disease - immunotherapy.

Archives of physiology and biochemistry [Epub ahead of print].

The current study identified the specific antibodies that recognise amyloid protein for Alzheimer disease - immunotherapy. The immune-selection of random sequences from a phage display library and sequencing to obtain the random 12 amino acids peptide library for each antibody, and then we analysed these peptides for unique and common sequences, relation to Aβ42 sequence and shape and pattern of the amino acid reaction to the antibody to predict the epitopes. Data obtained for 4G8 showed that, the sequence segment related to the putative epitope of 4G8 was LVFFAED. Nine of the ten top sequences contain the sequence RHD corresponding to the Aβ sequence from residues 5-7. Peptide 7 has the sequence IRYDTGSYHIH, which has a RYD. It was concluded that, 4G8 and 6E10 can tolerate the binding the sequences that explain it is able to recognise amyloid aggregates.

RevDate: 2020-05-25

Sohara K, Kiriyama T, Mizumura S, et al (2020)

Diagnostic utility and characteristics of CT-based attenuation correction in brain perfusion SPECT/CT in predicting the exacerbation of Alzheimer changes from mild cognitive impairment utilizing voxel-based statistical analysis in comparison with Chang's method.

Annals of nuclear medicine pii:10.1007/s12149-020-01477-4 [Epub ahead of print].

OBJECTIVE: We examined the diagnostic value of brain perfusion single-photon emission computed tomography (SPECT) using voxel-based statistical analysis with CT-based attenuation correction (CT-AC) by comparing it to that with Chang's AC in mild cognitive impairment (MCI) patients and attempted to locate brain areas that are good indicators predicting the progression of MCI.

METHODS: Twenty-six individuals matched for age, educational background and initial Mini-Mental State Examination (MMSE) score of more than 24 underwent SPECT with N-isopropyl-4-[123I]iodoamphetamine and were assigned to 2 groups: the stable MCI (S-MCI) group comprising 11 subjects who maintained their MMSE score (mean 27.0) during at least a 1-year follow-up period (mean 37.2 months) and the progressive MCI (P-MCI) group comprising 15 subjects whose MMSE scores decreased by 3 or more points (from 26.4 to 21.4, mean). The diagnostic values of the two AC methods for discriminating P-MCI from S-MCI were compared using voxel-based statistical analysis in the lobe (Level 2) and lobule/gyrus levels (Level 3).

RESULTS: Receiver operating characteristic analysis revealed that the area under the curve (AUC) was higher with CT-AC than with Chang's AC in the left temporal and limbic lobes in Level 2. In Level 3, the AUC in the left middle temporal gyrus was higher with CT-AC (0.852) than with Chang's AC (0.827). There were differences between the gyri/lobules that showed higher AUCs with CT-AC and those that showed higher AUCs with Chang's AC. When the gyri with the 4 highest AUCs were combined, AUC (0.897) and accuracy (84.6%) were better with CT-AC than with Chang's AC (0.806 and 80.8%). Surprisingly, the AUCs in the posterior cingulate gyrus and precuneus, excluding the AUC in the right precuneus with Chang's AC (0.715), were no more than 0.70 and less useful.

CONCLUSIONS: CT-AC may allow brain perfusion SPECT to reflect more exact neuropathic changes in MCI that would cause progression of early AD. CT-AC in conjunction with voxel-based statistical analysis could possess higher diagnostic accuracy for exacerbation of disease implying early Alzheimer changes in MCI patients, with decreases in cerebral perfusion in the left temporal and limbic lobes representing good indicators.

RevDate: 2020-05-25

Patel C, Pande S, S Acharya (2020)

Potentiation of anti-Alzheimer activity of curcumin by probiotic Lactobacillus rhamnosus UBLR-58 against scopolamine-induced memory impairment in mice.

Naunyn-Schmiedeberg's archives of pharmacology pii:10.1007/s00210-020-01904-3 [Epub ahead of print].

Curcumin, a major component of Indian saffron through clinical studies, revealed its neuroprotective effect in neurodegenerative diseases. However, it has not been utilized alone orally due to its low bioavailability. There are certain strategies to overcome the drawbacks such as poor absorption and low aqueous solubility. Many strategies are utilized to increase the systemic availability of curcumin. Among them, the steady intestinal and liver metabolism of curcumin by a curcumin adjuvant (enzyme inhibitor/inducer) is an important and less engrossed strategy for improving the overall systemic bioavailability of curcumin. Here, we assess the effect of probiotic Lactobacillus rhamnosus as a curcumin adjuvant (potentiate the effect of curcumin) in scopolamine-induced dementia in mice. To induce amnesia, scopolamine was used in a mouse model (1 mg/kg, daily for 10 days i.p.). After execution of behavioural tests (Morris water maze test), brains and liver were isolated for further neurochemical and histopathology examination. Our results showed a significant increase in antioxidant enzyme levels in curcumin with a probiotic group compared with curcumin alone. Besides, histopathology study results showed less neuronal damage of curcumin with probiotics as compared with the curcumin and scopolamine alone groups. Additionally, curcumin with probiotics improved memory and cognitive functions in the behavioural study with the significance of p ≤ 0.0001. In conclusion, curcumin with probiotics has greater activity as compared with curcumin alone and reverses the hallmarks of Alzheimer's disease (AD).

RevDate: 2020-05-25

Quntanilla RA, C Tapia-Monsalves (2020)

The role of mitochondrial impairment on Alzheimer´s disease neurodegeneration: the Tau connection.

Current neuropharmacology pii:CN-EPUB-106892 [Epub ahead of print].

Accumulative evidence has shown that mitochondrial dysfunction plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial impairment actively contributes to the synaptic and cognitive failure that characterizes AD. The presence of soluble pathological forms of tau like hyperphosphorylated at Ser396 and Ser404 and cleaved at Asp421 by caspase 3, negatively impacts mitochondrial bioenergetics, transport, and morphology in neurons. These adverse effects against mitochondria health will contribute to the synaptic impairment and cognitive decline showed in AD. Current studies suggest that mitochondrial failure induced by pathological tau forms are likely the result of the opening of the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial mega-channel that is activated by increases in calcium and is associated with mitochondrial stress and apoptosis. This structure is composed of different proteins, where CypD is considered to be the primary mediator of mPTP activation. Also, new studies suggest that mPTP contributes to A pathology and oxidative stress in AD. Further, inhibition of mPTP through the reduction of CypD expression prevents cognitive and synaptic impairment in AD mouse models. More importantly, tau protein contributes to the physiological regulation of mitochondria through the opening/interaction with mPTP in hippocampal neurons. Therefore, in this paper, we will discuss evidence that suggests an important role of pathological forms of tau against mitochondrial health. Also, we will discuss the possible role of mPTP in the mitochondrial impairment produced by the presence of tau pathology and its impact on synaptic function present in AD.

RevDate: 2020-05-23

Chen S, J Jia (2020)

Tenuifolin Attenuates Amyloid-β42-Induced Neuroinflammation in Microglia Through the NF-κB Signaling Pathway.

Journal of Alzheimer's disease : JAD pii:JAD200077 [Epub ahead of print].

BACKGROUND: Inflammation and oxidative stress are believed to play an important role in the pathogenesis of Alzheimer's disease (AD). Tenuifolin (TEN) is a natural neuroprotective compound extracted from Polygala tenuifolia Willd, which may improve cognitive symptoms.

OBJECTIVE: This study was designed to evaluate the protective effect of TEN on inflammatory and oxidative stress induced by amyloid-β (Aβ)42 oligomers in BV2 cells, and to explore the underlying mechanisms.

METHODS: We conducted cell viability assays to estimate drug toxicity and drug effects on cells. Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays were performed to detect the release of inflammatory factors. Nitric oxide (NO) assays were used to measure the degree of oxidative stress. Western blot and immunofluorescence analysis were used to explore the influence of TEN on the nuclear factor-κB (NF-κB) pathway.

RESULTS: Pretreatment of BV2 microglial cells with TEN inhibited the release of tumor necrosis factor-α, interleukin-6, and interleukin-1β, alleviated NO-induced oxidative stress by inhibiting the expression of inducible nitric oxide synthase and cyclo-oxygenase-2, and protected SH-SY5Y cells from the toxicity induced by the medium conditioned by BV2 cells previously exposed to Aβ42 oligomers. Moreover, TEN suppressed upstream activators of NF-κB, as well as NF-κB translocation to the nucleus in BV2 microglial cells.

CONCLUSION: This study demonstrates that TEN can protect SH-SY5Y cells from Aβ42 oligomer-induced microglia-mediated inflammation, and oxidative stress by downregulating the NF-κB signaling pathway.

RevDate: 2020-05-22

Smith TO, Mistry D, Lee H, et al (2020)

Moderators of Cognitive Outcomes from an Exercise Program in People with Mild to Moderate Dementia.

Journal of the American Geriatrics Society [Epub ahead of print].

BACKGROUND/OBJECTIVES: Our aim was to estimate whether baseline participant variables were able to moderate the effect of an exercise intervention on cognition in patients with mild to moderate dementia.

DESIGN: Subgroup analysis of a multicenter pragmatic randomized controlled trial.

SETTING: Community-based gym/rehabilitation centers.

PARTICIPANTS: A total of 494 community-dwelling participants with mild to moderate dementia.

INTERVENTION: Participants were randomized to a moderate- to high-intensity aerobic and strength exercise program or a usual care control group. Experimental group participants attended twice weekly 60- to 90-minute gym sessions for 4 months. Participants were prescribed home exercises for an additional hour per week during the supervised period and 150 minutes each week after the supervised period.

MEASUREMENTS: Multilevel regression model analyses were undertaken to identify individual moderators of cognitive function measured through the Alzheimer Disease Assessment Scale-Cognitive Subscale score at 12 months.

RESULTS: When tested for a formal interaction effect, only cognitive function assessed by the baseline number cancellation test demonstrated a statistically significant interaction effect (-2.7 points; 95% confidence interval = -5.14 to -0.21).

CONCLUSION: People with worse number cancellation test scores may experience greater progression of cognitive decline in response to a moderate- to high-intensity exercise program. Further analyses to examine whether these findings can be replicated in planned sufficiently powered analyses are indicated.

RevDate: 2020-05-22

Hardman RJ, Meyer D, Kennedy G, et al (2020)

Findings of a Pilot Study Investigating the Effects of Mediterranean Diet and Aerobic Exercise on Cognition in Cognitively Healthy Older People Living Independently within Aged-Care Facilities: The Lifestyle Intervention in Independent Living Aged Care (LIILAC) Study.

Current developments in nutrition, 4(5):nzaa077 pii:nzaa077.

Background: Cognitive decline and Alzheimer disease are more prevalent in our aging population. Modifiable risk factors, such as diet and sedentary lifestyle, have been proposed as key to potentially ameliorating cognitive decline. Both exercise and Mediterranean diet (MedDiet) have been linked to reduced levels of cardiovascular disease and other comorbidities. Higher levels of exercise and MedDiet adherence may prove to be cognitively protective, both individually and synergistically.

Objectives: The aim was to investigate the effect of a 6-mo program of MedDiet, exercise, and a combination of both, on cognition, mood, and general health in older persons living independently in aged-care communities.

Methods: The Lifestyle Intervention in Independent Living Aged Care (LIILAC) Study (ACTRN12614001133628) involved 102 participants, aged 60-90 y, who were randomly assigned to 1 of 4 intervention groups. Change in overall memory performance was assessed as the primary outcome. Additionally, changes in cognitive task performance, as well as mood, wellness, cardiovascular function, and blood biomarkers, were investigated.

Results: While there was no significant change in overall memory performance, there was a significant improvement in spatial working memory performance in the combined exercise and diet group, relative to controls. This combined intervention group also showed an overall improvement in their emotional state, as assessed by the Depression Anxiety Stress Scale, as did the exercise-only group.

Conclusions: This research indicates that diet and exercise programs have the potential to improve aspects of cognition and mood in an aging population. However, given the lower than optimal sample size and lack of resources to reinforce the interventions during the trial, further larger randomized controlled trials are required to substantiate whether the introduction of diet and exercise programs into independent-living facilities is a viable method to preserve cognitive health in older people. This trial was registered at www.ANZCTR.org.au ACTRN 12614001133628 (LIILAC Study).

RevDate: 2020-05-22

Törnquist M, Cukalevski R, Weininger U, et al (2020)

Ultrastructural evidence for self-replication of Alzheimer-associated Aβ42 amyloid along the sides of fibrils.

Proceedings of the National Academy of Sciences of the United States of America pii:1918481117 [Epub ahead of print].

The nucleation of Alzheimer-associated Aβ peptide monomers can be catalyzed by preexisting Aβ fibrils. This leads to autocatalytic amplification of aggregate mass and underlies self-replication and generation of toxic oligomers associated with several neurodegenerative diseases. However, the nature of the interactions between the monomeric species and the fibrils during this key process, and indeed the ultrastructural localization of the interaction sites have remained elusive. Here we used NMR and optical spectroscopy to identify conditions that enable the capture of transient species during the aggregation and secondary nucleation of the Aβ42 peptide. Cryo-electron microscopy (cryo-EM) images show that new aggregates protrude from the entire length of the progenitor fibril. These protrusions are morphologically distinct from the well-ordered fibrils dominating at the end of the aggregation process. The data provide direct evidence that self-replication through secondary nucleation occurs along the sides of fibrils, which become heavily decorated under the current solution conditions (14 µM Aβ42, 20 mM sodium phosphate, 200 µM EDTA, pH 6.8).

RevDate: 2020-05-22

Nowrangi MA (2020)

Neuropsychiatric Aspects of Alzheimer Dementia: From Mechanism to Treatment.

The Psychiatric clinics of North America, 43(2):383-397.

Developing disease-modifying treatments for Alzheimer dementia requires innovative approaches to identify novel biological targets during the course of the disease. Treatment development for the neuropsychiatric symptoms of Alzheimer may benefit from a mechanistic approach to treatment. There has been progress in identifying mild forms of behavioral impairment along the Alzheimer spectrum that may lead to additional insights into progression to dementia as well as the fundamental mechanisms of the symptoms. Developing therapies for complex neurobehavioral syndromes may require the translation of mechanistic insights into therapy, which may both improve the symptoms and delay progression to dementia in certain patients.

RevDate: 2020-05-21

Vicario A, GH Cerezo (2020)

[The cognitive-behavioural impact of hypertension].

Hipertension y riesgo vascular pii:S1889-1837(20)30037-4 [Epub ahead of print].

Arterial hypertension is considered the main modifiable vascular risk factor that causes silent damage to brain vessels. This vascular brain injury could be the common nucleus that justifies the cognitive (cognitive impairment, dementia and Alzheimer's disease) and behavioural symptoms (late-life depression) of target organ damage mediated-hypertension. Incomplete knowledge about the complex pathophysiology that links hypertension with cognitive-behavioural changes is overlooking brain involvement and underestimating cardio and cerebrovascular risk. The confluence of cognitive impairment, depression and arterial hypertension in elderly adults, warns of the need for a comprehensive evaluation to plan treatment, improve prognosis and contribute to reducing the risk of dementia and its incidence.

RevDate: 2020-05-21

Aldaz P, Garjón J, Beitia G, et al (2020)

Association between benzodiazepine use and development of dementia.

Medicina clinica pii:S0025-7753(20)30191-3 [Epub ahead of print].

OBJECTIVE: To evaluate the association between use of benzodiazepines and incident dementia.

METHODS: Analytical prospective nested case-control study for which the Spanish database for pharmacoepidemiological research in primary care (BIFAP) of the Spanish Agency of Medicines and Medical Devices (AEMPS) was used. A total of 15,212 subjects diagnosed with dementia of the Alzheimer type and 62,397 controls were identified. Exposure was retrieved retrospectively with a 3-year lag time before the index date. Adjusted odd ratios (OR) were calculated.

RESULTS: Benzodiazepines use increased the risk of suffering Alzheimer's disease (OR=1.05, 95% CI, 1.01-1.10). No statistical differences were shown between short-acting and long-acting drugs. The risk is more evident with longer exposure times.

CONCLUSIONS: There seems to be a weak association between benzodiazepine use and the development of dementia, the risk increases with greater exposure.

RevDate: 2020-05-20

Peters C, Bascuñán D, Burgos CF, et al (2020)

Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's disease.

Neurobiology of disease pii:S0969-9961(20)30213-8 [Epub ahead of print].

INTRODUCTION: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in elderly people. Existent therapies are directed at alleviating some symptoms, but are not effective in altering the course of the disease.

METHODS: Based on our previous study that showed that an Aβ-interacting small peptide protected against the toxic effects of amyloid-beta peptide (Aβ), we carried out an array of in silico, in vitro, and in vivo assays to identify a molecule having neuroprotective properties.

RESULTS: In silico studies showed that the molecule, referred to as M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine), was able to interact with the Aβ peptide. Additionally, in vitro assays showed that M30 blocked Aβ aggregation, association to the plasma membrane, synaptotoxicity, intracellular calcium, and cellular toxicity, while in vivo experiments demonstrated that M30 induced a neuroprotective effect by decreasing the toxicity of Aβ in the dentate gyrus of the hippocampus and improving the alteration in spatial memory in behavior assays.

DISCUSSION: Therefore, we propose that this new small molecule could be a useful candidate for the additional development of a treatment against AD since it appears to block multiple steps in the amyloid cascade. Overall, since there are no drugs that effectively block the progression of AD, this approach represents an innovative strategy.

SIGNIFICANCE: Currently, there is no effective treatment for AD and the expectations to develop an effective therapy are low. Using in silico, in vitro, and in vivo experiments, we identified a new compound that is able to inhibit Aβ-induced neurotoxicity, specifically aggregation, association to neurons, synaptic toxicity, calcium dyshomeostasis and memory impairment induced by Aβ. Because Aβ toxicity is central to AD progression, the inhibition mediated by this new molecule might be useful as a therapeutic tool.

RevDate: 2020-05-20

Muñoz P, Ardiles ÁO, Pérez B, et al (2020)

Redox modifications in synaptic components as biomarkers of cognitive status, in brain aging and disease.

Mechanisms of ageing and development pii:S0047-6374(20)30046-4 [Epub ahead of print].

Aging is a natural process that includes several changes that gradually make organisms degenerate and die. Harman's theory proposes that aging is a consequence of the progressive accumulation of oxidative modifications mediated by reactive oxygen/nitrogen species, which plays an essential role in the development and progression of many neurodegenerative diseases. This review will focus on how abnormal redox modifications induced by age impair the functionality of neuronal redox-sensitive proteins involved in axonal elongation and guidance, synaptic plasticity, and intercellular communication. We will discuss post-transcriptional regulation of gene expression by microRNAs as a mechanism that controls the neuronal redox state. Finally, we will discuss how some brain-permeant antioxidants from the diet have a beneficial effect on cognition. Taken together, the evidence revised here indicates that oxidative-driven modifications of specific proteins and changes in microRNA expression may be useful biomarkers for aging and neurodegenerative diseases. Also, some specific antioxidant therapies have undoubtedly beneficial neuroprotective effects when administered in the correct doses, in the ideal formulation combination, and during the appropriate therapeutic window. The use of some antioxidants is, therefore, still poorly explored for the treatment of neurodegenerative diseases such as Alzheimer's disease.

RevDate: 2020-05-20

Wagner F, Duering M, Gesierich BG, et al (2020)

Gray Matter Covariance Networks as Classifiers and Predictors of Cognitive Function in Alzheimer's Disease.

Frontiers in psychiatry, 11:360.

The study of shared variation in gray matter morphology may define neurodegenerative diseases beyond what can be detected from the isolated assessment of regional brain volumes. We, therefore, aimed to (1) identify SCNs (structural covariance networks) that discriminate between Alzheimer's disease (AD) patients and healthy controls (HC), (2) investigate their diagnostic accuracy in comparison and above established markers, and (3) determine if they are associated with cognitive abilities. We applied a random forest algorithm to identify discriminating networks from a set of 20 SCNs. The algorithm was trained on a main sample of 104 AD patients and 104 age-matched HC and was then validated in an independent sample of 28 AD patients and 28 controls from another center. Only two of the 20 SCNs contributed significantly to the discrimination between AD and controls. These were a temporal and a secondary somatosensory SCN. Their diagnostic accuracy was 74% in the original cohort and 80% in the independent samples. The diagnostic accuracy of SCNs was comparable with that of conventional volumetric MRI markers including whole brain volume and hippocampal volume. SCN did not significantly increase diagnostic accuracy beyond that of conventional MRI markers. We found the temporal SCN to be associated with verbal memory at baseline. No other associations with cognitive functions were seen. SCNs failed to predict the course of cognitive decline over an average of 18 months. We conclude that SCNs have diagnostic potential, but the diagnostic information gain beyond conventional MRI markers is limited.

RevDate: 2020-05-20

Chen Y, Lu Y, Lee RJ, et al (2020)

Nano Encapsulated Curcumin: And Its Potential for Biomedical Applications.

International journal of nanomedicine, 15:3099-3120 pii:210320.

Curcumin, a yellow-colored polyphenol extracted from the rhizome of turmeric root, is commonly used as a spice and nutritional supplement. It exhibits many pharmacological activities such as anti-inflammatory, anti-bacterial, anti-cancer, anti-Alzheimer, and anti-fungal. However, the therapeutic application of curcumin is limited by its extremely low solubility in aqueous buffer, instability in body fluids, and rapid metabolism. Nano delivery system has shown excellent potential to improve the solubility, biocompatibility and therapeutic effect of curcumin. In this review, we focus on the recent development of nano encapsulated curcumin and its potential for biomedical applications.

RevDate: 2020-05-19

Barthet G, C Mulle (2020)

Presynaptic failure in Alzheimer's disease.

Progress in neurobiology pii:S0301-0082(20)30056-3 [Epub ahead of print].

Synaptic loss is the best correlate of cognitive deficits in Alzheimer's disease (AD). Extensive experimental evidence also indicates alterations of synaptic properties at the early stages of disease progression, before synapse loss and neuronal degeneration. A majority of studies in mouse models of AD have focused on post-synaptic mechanisms, including impairment of long-term plasticity, spine structure and glutamate receptor-mediated transmission. Here we review the literature indicating that the synaptic pathology in AD includes a strong presynaptic component. We describe the evidence indicating presynaptic physiological functions of the major molecular players in AD. These include the amyloid precursor protein (APP) and the two presenilin (PS) paralogs PS1 or PS2, genetically linked to the early-onset form of AD, in addition to tau which accumulates in a pathological form in the AD brain. Three main mechanisms participating in presynaptic functions are highlighted. APP fragments bind to presynaptic receptors (e.g. nAChRs and GABAB receptors), presenilins control Ca2+ homeostasis and Ca2+-sensors, and tau regulates the localization of presynaptic molecules and synaptic vesicles. We then discuss how impairment of these presynaptic physiological functions can explain or forecast the hallmarks of synaptic impairment and associated dysfunction of neuronal circuits in AD. Beyond the physiological roles of the AD-related proteins, studies in AD brains also support preferential presynaptic alteration. This review features presynaptic failure as a strong component of pathological mechanisms in AD.

RevDate: 2020-05-19

Guo Y, Yang F, Hu F, et al (2020)

Correction: Existing Mobile Phone Apps for Self-Care Management of People With Alzheimer Disease and Related Dementias: Systematic Analysis.

JMIR aging, 3(1):e18754 pii:v3i1e18754.

[This corrects the article DOI: 10.2196/15290.].

RevDate: 2020-05-19

Barbaresko J, Lellmann AW, Schmidt A, et al (2020)

Dietary Factors and Neurodegenerative Disorders: An Umbrella Review of Meta-Analyses of Prospective Studies.

Advances in nutrition (Bethesda, Md.) pii:5840643 [Epub ahead of print].

Diet has been hypothesized to be associated with neurodegenerative disorders. The aim was to conduct an umbrella review to summarize and evaluate the current evidence of prospective associations between any dietary factors and the incidence of neurodegenerative disorders. We conducted a systematic search in PubMed, Embase, and the Cochrane library up to November 2019 to identify systematic reviews with meta-analyses of prospective studies investigating the association between dietary factors (dietary patterns, foods and beverages, nutrients, and phytochemicals) and neurodegenerative disorders (cognitive decline, cognitive impairment, Alzheimer disease, all-cause dementia, and Parkinson disease). Summary risk ratios (SRRs) and 95% CIs were recalculated using a random effects model. We evaluated the risk of bias of identified meta-analyses and the quality of evidence for all associations. In total, 20 meta-analyses including 98 SRRs were identified. All original meta-analyses were rated as being at high risk of bias. Methodological concerns related mainly to the inappropriate synthesis, assessment, and discussion of the risk of bias of primary studies. For the recalculated meta-analyses, quality of evidence was moderate for inverse associations between higher adherence to the Mediterranean diet (SRR: 0.63; 95% CI: 0.48, 0.82; n = 4 primary studies) and higher fish intake (SRR: 0.72; 95% CI: 0.59, 0.89; n = 6) and Alzheimer disease, as well as for tea consumption and all-cause dementia (SRR: 0.74; 95% CI: 0.63, 0.88; n = 2) and Parkinson disease (SRR per 2 cups/d: 0.69; 95% CI: 0.54, 0.87; n = 5). This umbrella review provides a comprehensive overview of the available evidence on dietary factors and neurodegenerative disorders. The results indicate that the Mediterranean diet, fish, and tea could be inversely associated with neurodegenerative disorders. However, the quality of evidence was generally low, suggesting that further studies are likely to change the overall estimates. Thus, more well-conducted research, also investigating other dietary factors in association with neurodegenerative disorders, is warranted.

RevDate: 2020-05-19

Sasayama D, Hattori K, Yokota Y, et al (2020)

Increased apolipoprotein E and decreased TNF-α in the cerebrospinal fluid of nondemented APOE-ε4 carriers.

Neuropsychopharmacology reports [Epub ahead of print].

AIM: The ε4 allele of apolipoprotein E gene (APOE) is a well-known risk factor of late-onset Alzheimer's disease. However, little is known why this variant confers a risk for Alzheimer's disease. The aim of this study was to examine the influence of the APOE genotype on cerebrospinal fluid (CSF) protein levels.

METHODS: The present study performed a secondary analysis on our previously generated database to compare the CSF levels of 1128 proteins between APOE-ε4 carriers (28 subjects) and noncarriers (104 subjects). All subjects were physically healthy Japanese individuals without dementia.

RESULTS: CSF levels of apoE2, apoE3, and apoE4 were significantly higher (all nominal P < 10 × 10-5 , false discovery rate < 0.001) and those of tumor necrosis factor-α (TNF-α) were significantly lower (nominal P = 1.39 × 10-6 , false discovery rate < 0.001) in APOE-ε4 carriers than in noncarriers. No significant correlation was observed between the CSF levels of TNF-α and any of the apoE proteins.

CONCLUSIONS: Our findings indicate the possible roles of apoE and TNF-α in the pathogenesis of APOE-ε4-associated Alzheimer's disease.

RevDate: 2020-05-19

Niaz K, Shah SZA, Khan F, et al (2020)

Ochratoxin A-induced genotoxic and epigenetic mechanisms lead to Alzheimer disease: its modulation with strategies.

Environmental science and pollution research international pii:10.1007/s11356-020-08991-y [Epub ahead of print].

Ochratoxin A (OTA) is a naturally occurring mycotoxin mostly found in food items including grains and coffee beans. It induces DNA single-strand breaks and has been considered to be carcinogenic. It is recognized as a serious threat to reproductive health both in males and females. OTA is highly nephrotoxic and carcinogenic, and its potency changes evidently between species and sexes. There is a close association between OTA, mutagenicity, carcinogenicity, and genotoxicity, but the underlying mechanisms are not clear. Reports regarding genotoxic effects in relation to OTA which leads to the induction of DNA adduct formation, protein synthesis inhibition, perturbation of cellular energy production, initiation of oxidative stress, induction of apoptosis, influences on mitosis, induction of cell cycle arrest, and interference with cytokine pathways. All these mechanisms are associated with nephrotoxicity, hepatotoxicity, teratotoxicity, immunological toxicity, and neurotoxicity. OTA administration activates various mechanisms such as p38 MAPK, JNKs, and ERKs dysfunctions, BDNF disruption, TH overexpression, caspase-3 and 9 activation, and ERK-1/2 phosphorylation which ultimately lead to Alzheimer disease (AD) progression. The current review will focus on OTA in terms of recent discoveries in the field of molecular biology. The main aim is to investigate the underlying mechanisms of OTA in regard to genotoxicity and epigenetic modulations that lead to AD. Also, we will highlight the strategies for the purpose of attenuating the hazards posed by OTA exposure.

RevDate: 2020-05-19

Xiong C, Ye B, Mihailidis A, et al (2020)

Sex and gender differences in technology needs and preferences among informal caregivers of persons with dementia.

BMC geriatrics, 20(1):176 pii:10.1186/s12877-020-01548-1.

BACKGROUND: Dementia is a major public health concern associated with significant caregiver demands and there are technologies available to assist with caregiving. However, there is a paucity of information on caregiver needs and preferences for these technologies, particularly from a sex and gender perspective. To address this gap in research, the objectives of this study are to examine (1) the knowledge of technology, (2) perceived usefulness of technology, (3) feature preferences when installing and using technology and (4) sex and gender influences on technology needs and preferences among family caregivers of persons with dementia (PWD) across North America.

METHODS: A secondary analysis was conducted on an existing cross-sectional survey with family caregivers of PWDs. Respondents were recruited through the Alzheimer Society of Canada, the Victorian Order of Nurses and Adult Day Programs and other Canadian health care provision institutes. Descriptive statistics, bivariate and multivariate analyses were used to describe the study sample, uncover differences between male and female caregivers and examine sex and gender influences on caregivers' technology needs and preferences.

RESULTS: A total of 381 eligible responses were received over a nine month data collection period. The majority of respondents did not know much about and never used any technologies to assist with caregiving. "Being easy to install", "easy to learn how to use" and "cost" were identified as the most important features when purchasing and setting up technology, while "reliability" was identified as the most important feature when using technology. Most respondents were willing to pay up to $500 to acquire individual technologies. Controlling for other socio-demographic variables, female respondents were more likely to have some or more knowledge about technology for caregiving while male respondents were more willing to pay higher amounts for these technologies compared to their female counterparts.

CONCLUSIONS: As one of the first studies of its kind, our findings represent a step towards the incorporation of sex and gender considerations such as cost and reliability in technology design and promotion for caregivers. Future efforts are warranted to establish an in-depth understanding of sex and gender influences in relation to other social and environmental factors.

RevDate: 2020-05-19

Giesers NK, O Wirths (2020)

Loss of Hippocampal Calretinin and Parvalbumin Interneurons in the 5XFAD Mouse Model of Alzheimer's Disease.

ASN neuro, 12:1759091420925356.

The deposition of amyloid-β peptides in the form of extracellular plaques and neuronal degeneration belong to the hallmark features of Alzheimer's disease (AD). In addition, impaired calcium homeostasis and altered levels in calcium-binding proteins seem to be associated with the disease process. In this study, calretinin- (CR) and parvalbumin- (PV) positive gamma-aminobutyric acid-producing (GABAergic) interneurons were quantified in different hippocampal subfields of 12-month-old wild-type mice, as well as in the transgenic AD mouse models 5XFAD and Tg4-42. While, in comparison with wild-type mice, CR-positive interneurons were mainly reduced in the CA1 and CA2/3 regions in plaque-bearing 5XFAD mice, PV-positive interneurons were reduced in all analyzed subfields including the dentate gyrus. No reduction in CR- and PV-positive interneuron numbers was detected in the non-plaque-forming Tg4-42 mouse, although this model has been previously demonstrated to harbor a massive loss of CA1 pyramidal neurons. These results provide information about hippocampal interneuron numbers in two relevant AD mouse models, suggesting that interneuron loss in this brain region may be related to extracellular amyloid burden.

RevDate: 2020-05-18

Yliranta A, M Jehkonen (2020)

Limb and face apraxias in frontotemporal dementia: A systematic scoping review.

Cortex; a journal devoted to the study of the nervous system and behavior pii:S0010-9452(20)30135-0 [Epub ahead of print].

PURPOSE: To investigate the literature for frequencies, profiles and neural correlates of limb and face apraxias in frontotemporal dementia (FTD).

METHOD: The search conducted in Ovid Medline, PsycINFO and Scopus yielded 487 non-duplicate records, and 43 were included in the final analysis.

RESULTS: Apraxias are evident in diverse forms in all clinical variants of FTD within the first four years of the disease. Face apraxia and productive limb apraxia co-occur in the behavioural and nonfluent variants. The logopenic variant resembles Alzheimer's disease in terms of pronounced parietal limb apraxia and absence of face apraxia. The semantic variant exhibits conceptual praxis deficits together with relatively preserved imitation skills. Concerning the genetic variants of FTD, productive limb apraxia is common among carriers of the progranulin gene mutation, and subtle gestural alterations have been documented among carriers of the chromosome 9 open reading frame 72 gene mutation before the expected disease onset. The data on neural correlations suggest that the breakdown of praxis results from bilateral cortical and subcortical damage in FTD and that Alzheimer-type pathology of the cerebrospinal fluid increases the severity of limb apraxia in all of the variants. Face apraxia correlates with degeneration of the medial and superior frontal cortices.

CONCLUSIONS: Each of the clinical variants of FTD exhibits a characteristic profile of apraxias that may support early differentiation between the variants and from Alzheimer's disease. However, the screening procedures developed for stroke populations seem insufficient, and a multifaceted assessment tool is needed. Although valid and practical tests already exist for dementia populations, a concise selection of test items that covers all of the critical domains is called for.

RevDate: 2020-05-18

Wahle T, Sofranko A, Dekkers S, et al (2020)

Evaluation of neurological effects of cerium dioxide nanoparticles doped with different amounts of zirconium following inhalation exposure in mouse models of Alzheimer's and vascular disease.

Neurochemistry international pii:S0197-0186(20)30146-7 [Epub ahead of print].

Increasing evidence from toxicological and epidemiological studies indicates that the brain is an important target for ambient (ultrafine) particles. Disturbance of redox-homeostasis and inflammation in the brain are proposed as possible mechanisms that can contribute to neurotoxic and neurodegenerative effects. Whether and how engineered nanoparticles (NPs) may cause neurotoxicity and promote neurodegenerative diseases such as Alzheimer´s disease (AD) is largely unstudied. We have assessed the neurological effects of subacute inhalation exposures (4 mg/m3 for 3 h/day, 5 days/week for 4 weeks) to cerium dioxide (CeO2) NPs doped with different amounts of zirconium (Zr, 0%, 27% and 78%), to address the influence of particle redox-activity in the 5xFAD transgenic mouse model of AD. Four weeks post-exposure, effects on behaviour were evaluated and brain tissues were analysed for amyloid-β plaque formation and reactive microglia (Iba-1 staining). Behaviour was also evaluated in concurrently exposed non-transgenic C57BL/6J littermates, as well as in Western diet-fed apolipoprotein E-deficient (ApoE-/-) mice as a model of vascular disease. Markers of inflammation and oxidative stress were evaluated in brain cortex. The brains of the NP-exposed 5xFAD mice revealed no accelerated amyloid-β plaque formation. No significant treatment-related behaviour impairments were observed in the healthy C57BL/6J mice. In the 5xFAD and ApoE-/- models, the NP inhalation exposures did not affect the alternation score in the X-maze indicating absence of spatial working memory deficits. However, following inhalation exposure to the 78% Zr-doped CeO2 NPs changes in forced motor performance (string suspension) and exploratory motor activity (X-maze) were observed in ApoE-/- and 5xFAD mice, respectively. Exposure to the 78% doped NPs also caused increased cortical expression of glial fibrillary acidic protein (GFAP) in the C57BL/6J mice. No significant treatment-related changes neuroinflammation and oxidative stress were observed in the 5xFAD and ApoE-/- mice. Our study findings reveal that subacute inhalation exposure to CeO2 NPs does not accelerate the AD-like phenotype of the 5xFAD model. Further investigation is warranted to unravel whether the redox-activity dependent effects on motor activity as observed in the mouse models of AD and vascular disease result from specific neurotoxic effects of these NPs.

RevDate: 2020-05-18

Xue M, Sun FR, Ou YN, et al (2020)

Association of cerebrospinal fluid neurogranin levels with cognition and neurodegeneration in Alzheimer's disease.

Aging, 12: pii:103211 [Epub ahead of print].

Accumulating data suggest cerebrospinal fluid (CSF) neurogranin (Ng) as a potential biomarker for cognitive decline and neurodegeneration in Alzheimer disease (AD). To investigate whether the CSF Ng can be used for diagnosis, prognosis, and monitoring of AD, we examined 111 cognitively normal (CN) controls, 193 mild cognitive impairment (MCI) patients and 95 AD patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Correlations were tested between baseline CSF Ng levels and baseline core AD biomarkers and longitudinal glucose metabolism, brain atrophy and cognitive decline. We detected that CSF Ng levels increased with disease severity, and correlated with phosphorylated tau and total tau levels within each diagnostic group. High baseline CSF Ng levels correlated with longitudinal reductions in cortical glucose metabolism within each diagnostic group and hippocampal volume within MCI group during follow-up. In addition, high baseline CSF Ng levels correlated with cognitive decline as reflected by decreased cognitive scale scores. The CSF Ng levels predicted future cognitive impairment (adjusted hazard ratio:3.66, 95%CI: 1.74-7.70, P = 0.001) in CN controls. These data demonstrate that CSF Ng offers diagnostic utility for AD and predicts future cognitive impairment in CN individuals and, therefore, may be a useful addition to the current AD biomarkers.

RevDate: 2020-05-18

Puente-Castro A, Fernandez-Blanco E, Pazos A, et al (2020)

Automatic assessment of Alzheimer's disease diagnosis based on deep learning techniques.

Computers in biology and medicine, 120:103764.

Early detection is crucial to prevent the progression of Alzheimer's disease (AD). Thus, specialists can begin preventive treatment as soon as possible. They demand fast and precise assessment in the diagnosis of AD in the earliest and hardest to detect stages. The main objective of this work is to develop a system that automatically detects the presence of the disease in sagittal magnetic resonance images (MRI), which are not generally used. Sagittal MRIs from ADNI and OASIS data sets were employed. Experiments were conducted using Transfer Learning (TL) techniques in order to achieve more accurate results. There are two main conclusions to be drawn from this work: first, the damages related to AD and its stages can be distinguished in sagittal MRI and, second, the results obtained using DL models with sagittal MRIs are similar to the state-of-the-art, which uses the horizontal-plane MRI. Although sagittal-plane MRIs are not commonly used, this work proved that they were, at least, as effective as MRI from other planes at identifying AD in early stages. This could pave the way for further research. Finally, one should bear in mind that in certain fields, obtaining the examples for a data set can be very expensive. This study proved that DL models could be built in these fields, whereas TL is an essential tool for completing the task with fewer examples.

RevDate: 2020-05-18

Yu X, Li Y, X Mu (2020)

Effect of Quercetin on PC12 Alzheimer's Disease Cell Model Induced by Aβ25-35 and Its Mechanism Based on Sirtuin1/Nrf2/HO-1 Pathway.

BioMed research international, 2020:8210578.

Objective: This study is aimed at studying the effect of quercetin on the Alzheimer disease cell model induced by Aβ25-35 in PC12 cells and its mechanism of action.

Methods: The AD cell model was established by Aβ25-35. Quercetin was used at different concentrations (0, 10, 20, 40, and 80 μmol/L). The morphology of cells was observed, and the effect on cell survival rate was detected by the MTT method. Cell proliferation was detected by the SRB method. The contents of LDH, SOD, MDA, GSH-Px, AChE, CAT, and T-AOC were detected by kits. The expression of sirtuin1/Nrf2/HO-1 was detected by RT-qPCR and Western blot.

Results: PC12 cells in the control group grew quickly and adhered well to the wall, most of which had extended long axons and easily grew into clusters. In the model group, cells were significantly damaged and the number of cells was significantly reduced. It was found that PC12 cells were swollen, rounded, protruding, and retracting, with reduced adherent function and floating phenomenon. Quercetin could increase the survival rate and proliferation rate of PC12 cells; reduce the levels of LDH, AChE, MDA, and HO-1 protein; and increase the levels of SOD, GSH-Px, CAT, T-AOC, sirtuin1, and Nrf2 protein.

Conclusion: Quercetin can increase the survival rate of PC12 injured by Aβ25-35, promote cell proliferation, and antagonize the toxicity of Aβ; it also has certain neuroprotective effects. Therefore, quercetin is expected to become a drug for the treatment of AD.

RevDate: 2020-05-17

Amariglio RE, Buckley RF, Rabin JS, et al (2020)

Examining Cognitive Decline Across Black and White Participants in the Harvard Aging Brain Study.

Journal of Alzheimer's disease : JAD pii:JAD191291 [Epub ahead of print].

BACKGROUND: Black Americans are approximately twice as likely to develop dementia as compared to White Americans and the magnitude of this disparity is often attributed to a variety of factors that include psychosocial and vascular risk factors. However, less is known about the potential contribution of Alzheimer's disease pathological differences.

OBJECTIVE: To examine potential differences incross-sectional and longitudinal cognitive performance in black and white participants who were clinically normal at baseline.

METHODS: 296 participants (48 African-American/black participants) underwent MRI and amyloid PET at baseline. Linear mixed models were used to examine the main effects of race, years of education, reading ability, Framingham Heart Study cardiovascular risk score (FHS-CVD), white matter hyperintensities (WMH), and amyloid (Aβ) burden on the Preclinical Alzheimer Cognitive Composite-5 (PACC5).

RESULTS: Lower levels of educationalattainment and reading ability were found for blacks compared to whites. By contrast, no differences in FHS-CVD, WMH, or Aβ were found by racial group. Baseline differences in PACC5 score were attenuated after adjusting for educationalfactors, vascular factors, and Aβ, but remained lower for blacks compared to whites (β= -0.24, p = 0.014). Further, blacks demonstrated a faster rate of PACC5 decline longitudinally compared to whites (β = -0.055, p = 0.025) after adjusting for covariates.

CONCLUSION: Accounting for educationalfactors, vascular factors, and Aβ burden diminished, but did not eliminate, racial differences in PACC5 performance longitudinally. Understanding potential differences in longitudinal cognitive outcomes by race may be important for upcoming secondary prevention trials.

RevDate: 2020-05-17

Hallett M, de Haan W, Deco G, et al (2020)

Human brain connectivity: Clinical applications for clinical neurophysiology.

Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, 131(7):1621-1651 pii:S1388-2457(20)30137-1 [Epub ahead of print].

This manuscript is the second part of a two-part description of the current status of understanding of the network function of the brain in health and disease. We start with the concept that brain function can be understood only by understanding its networks, how and why information flows in the brain. The first manuscript dealt with methods for network analysis, and the current manuscript focuses on the use of these methods to understand a wide variety of neurological and psychiatric disorders. Disorders considered are neurodegenerative disorders, such as Alzheimer disease and amyotrophic lateral sclerosis, stroke, movement disorders, including essential tremor, Parkinson disease, dystonia and apraxia, epilepsy, psychiatric disorders such as schizophrenia, and phantom limb pain. This state-of-the-art review makes clear the value of networks and brain models for understanding symptoms and signs of disease and can serve as a foundation for further work.

RevDate: 2020-05-16

Ricci M, Todino V, Magarelli M, et al (2020)

Spect-neuropsychology correlations in very mild Alzheimer's disease and amnesic mild cognitive impairment.

Archives of gerontology and geriatrics, 89:104085 pii:S0167-4943(20)30079-0 [Epub ahead of print].

BACKGROUND: The purpose of this study was to explore the clinical and brain functional abnormalities in patients with mild Alzheimer's Disease (AD) and patients with amnesic Mild Cognitive Impairment (aMCI).

METHODS: we used resting spect-neuropsychology correlations method.

RESULTS: We found that parieto-temporal associative cortex, mainly involving the inferior parietal lobule, posterior cingulate and middle temporal gyrus, is compromised early in AD. These results suggest that the dysfunction in these areas contributes to cognitive decline in the storage of verbal information, drawing abilities and non-verbal abstract reasoning in AD. The aMCI group showed hypoperfusion primarily involving the frontal areas bilaterally, and this correlated with the impairment in free delayed recall on a verbal memory task.

CONCLUSION: Our results underlie the clinical differences between AD and aMCI patients that might reflect the involvement of different degenerative mechanisms in these groups.

RevDate: 2020-05-16

Mai N, Wu Y, Zhong X, et al (2020)

Determining the effects of LLD and MCI on brain decline according to machine learning and a structural covariance network analysis.

Journal of psychiatric research, 126:43-54 pii:S0022-3956(20)30180-1 [Epub ahead of print].

BACKGROUND: Late-life depression (LLD) and mild cognitive impairment (MCI) are risk factors for Alzheimer disease (AD). However, the interactive effect between LLD and MCI in the progression to AD remains unknown. The purpose of this research is to clarify whether this interaction exists and determined the characteristics of the structural change patterns in LLD and MCI.

METHOD: To address this question, a total 225 participants (91 with intact cognitive function (IC), 34 with MCI, 35 with LLD-IC, 47 with LLD-MCI and 18 with AD) were recruited for the current study and their T1 scanning were acquired. Machine learning was applied to estimate the brain's age gap according to grey matter information (thickness and volume was calculated based on the Human Connectome Project Multi-Modal Parcellation version 1.0 and the Desikan atlas). A structural covariance network (SCN) was constructed based on grey matter volume. Rich-club analysis, global network properties and the Jaccard distance were utilized to describe the topological features in each cohort. Their cognitive functions (executive function, processing speed and memory) were evaluated by a full-scale battery of neuropsychological tests.

RESULT: The interactive effect between LLD and MCI was detected through the brain age gap. The estimated age was positively correlated with processing speed and memory in LLD and non-LLD subjects. In the SCN analysis, the rich-club coefficient and global network properties were disrupted in the MCI group, but remained normal in the LLD-IC, LLD-MCI and AD groups. There was a significant discrepancy in brain structural change patterns between the AD and other cohorts by the Jaccard distance.

CONCLUSION: The application of machine learning reflects that synergies between LLD and MCI could increase the risk of developing AD. According to the SCN, the structural coordination was disrupted in MCI and was kept normal in the other cohorts, while the discrepancies in brain structural change patterns appeared in AD. Overall, the brain age gap could be a potential predictor of AD, and the Jaccard distance has the potential to be a new type of SCN analysis indicator.

RevDate: 2020-05-16

Garnier-Crussard A, Taki A, Bonnefoy M, et al (2020)

Cerebral amyloid angiopathy with focal presentation-about 3 cases.

Neuroradiology pii:10.1007/s00234-020-02450-8 [Epub ahead of print].

Cerebral amyloid angiopathy (CAA) is a common cerebrovascular disease involved in ischemic and hemorrhagic strokes, and its progression is correlated to cognitive decline. In vivo diagnosis of CAA is guided by the modified Boston criteria, with the presence of multiple intracerebral hemorrhage or cerebral microbleeds (CMB), or single hemorrhage and cortical superficial siderosis. The diagnosis of CAA is highly dependent on the quality of imaging and the advent of susceptibility-weighted imaging (SWI) sequences has improved sensitivity of MRI to detect hemosiderin deposition and CMB, hallmarks of CAA. We report here 3 clinical cases of patients with Alzheimer's disease and a focal form (i.e., not disseminated) of probable CAA, diagnosed with SWI sequences. Focal CAA may require closer attention and could offer keys in the understanding of both Alzheimer's disease and CAA pathogenesis.

RevDate: 2020-05-16

Holm H, Nägga K, Nilsson ED, et al (2020)

High circulating levels of midregional proenkephalin A predict vascular dementia: a population-based prospective study.

Scientific reports, 10(1):8027 pii:10.1038/s41598-020-64998-y.

Midregional Pro-enkephalin A (MR-PENK A) and N-terminal Protachykinin A (NT-PTA) have been associated with vascular dementia. However, the longitudinal relationship between these biomarkers and incident dementia has not been fully investigated. In the population-based Malmö Preventive Project, circulating levels of MR-PENK A and NT-PTA were determined in a random sample of 5,323 study participants (mean age: 69 ± 6 years) who were followed-up over a period of 4.6 ± 1.6 years. The study sample included 369 patients (7%) who were diagnosed in the same period with dementia. We analyzed relationship of MR-PENK A and NT-PTA with the risk of developing dementia by using multivariable-adjusted Cox regression models adjusted for traditional risk factors. Increased plasma levels of MR-PENK A were associated with higher risk of incident vascular dementia whereas no associations were found with all-cause or Alzheimer dementia. The risk of vascular dementia was mainly conferred by the highest quartile of MR-PENK as compared with lower quartiles. Elevated levels of NT-PTA yielded significant association with all-cause dementia or dementia subtypes. Elevated plasma concentration of MR-PENK A independently predicts vascular dementia in the general population. MR-PENK A may be used as an additional tool for identifying vascular subtype in ambiguous dementia cases.

RevDate: 2020-05-16

Barthel H, Seibyl J, Lammertsma AA, et al (2020)

Exploiting the Full Potential of Beta-Amyloid and Tau PET Imaging for Drug Efficacy Testing.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine pii:jnumed.119.228346 [Epub ahead of print].

RevDate: 2020-05-16

Catalán-García M, García-García FJ, Moreno-Lozano PJ, et al (2020)

Mitochondrial Dysfunction: A Common Hallmark Underlying Comorbidity between sIBM and Other Degenerative and Age-Related Diseases.

Journal of clinical medicine, 9(5): pii:jcm9051446.

Sporadic inclusion body myositis (sIBM) is an inflammatory myopathy associated, among others, with mitochondrial dysfunction. Similar molecular features are found in Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM), underlying potential comorbidity. This study aims to evaluate common clinical and molecular hallmarks among sIBM, AD, and T2DM. Comorbidity with AD was assessed in n = 14 sIBM patients by performing neuropsychological and cognitive tests, cranial magnetic resonance imaging, AD cerebrospinal fluid biomarkers (levels of amyloid beta, total tau, and phosphorylated tau at threonine-181), and genetic apolipoprotein E genotyping. In the same sIBM cohort, comorbidity with T2DM was assessed by collecting anthropometric measures and performing an oral glucose tolerance test and insulin determinations. Results were compared to the standard population and other myositis (n = 7 dermatomyositis and n = 7 polymyositis). Mitochondrial contribution into disease was tested by measurement of oxidative/anaerobic and oxidant/antioxidant balances, respiration fluxes, and enzymatic activities in sIBM fibroblasts subjected to different glucose levels. Comorbidity of sIBM with AD was not detected. Clinically, sIBM patients showed signs of misbalanced glucose homeostasis, similar to other myositis. Such misbalance was further confirmed at the molecular level by the metabolic inability of sIBM fibroblasts to adapt to different glucose conditions. Under the standard condition, sIBM fibroblasts showed decreased respiration (0.71 ± 0.08 vs. 1.06 ± 0.04 nmols O2/min; p = 0.024) and increased anaerobic metabolism (5.76 ± 0.52 vs. 3.79 ± 0.35 mM lactate; p = 0.052). Moreover, when glucose conditions were changed, sIBM fibroblasts presented decreased fold change in mitochondrial enzymatic activities (-12.13 ± 21.86 vs. 199.22 ± 62.52 cytochrome c oxidase/citrate synthase ratio; p = 0.017) and increased oxidative stress per mitochondrial activity (203.76 ± 82.77 vs. -69.55 ± 21.00; p = 0.047), underlying scarce metabolic plasticity. These findings do not demonstrate higher prevalence of AD in sIBM patients, but evidences of prediabetogenic conditions were found. Glucose deregulation in myositis suggests the contribution of lifestyle conditions, such as restricted mobility. Additionally, molecular evidences from sIBM fibroblasts confirm that mitochondrial dysfunction may play a role. Monitoring T2DM development and mitochondrial contribution to disease in myositis patients could set a path for novel therapeutic options.

RevDate: 2020-05-15

Nasseri B, Zareian P, H Alizade (2020)

Apelin attenuates streptozotocin-induced learning and memory impairment by modulating necroptosis signaling pathway.

International immunopharmacology, 84:106546 pii:S1567-5769(19)32806-1 [Epub ahead of print].

Apelin is a neuropeptide that plays an important role in neuronal protection. In this study, we investigated the effects of apelin intracerebroventricular administration on spatial learning and memory-related behaviors, and necroptosis signaling pathways in the hippocampus of streptozotocin (STZ) -injected rats. Apelin treatment was implemented following STZ-induced dementia for 15 days. After conducting a behavioral test (Morris Water Maze), the cellular and molecular aspects were examined to detect the apelin effect on the necroptosis signaling pathway. We demonstrated that STZ administration significantly slowed down the learning capability. However apelin treatment notably reversed this neuroinflammation induced behavioral impairment. Furthermore, molecular investigations showed that apelin treatment reduced the hippocampal RIP1, RIP3, and TNF-α level. Our results suggest that apelin treatment attenuates STZ-induced dementia. This effect may be mediated by inhibition of the necroptosis signaling pathway which seems to be associated with the ability of apelin to reduce central TNF-α level. This data provides evidence of the neuroprotective effect of apelin on STZ-induced learning and memory impairment and characterize some of the underlying mechanisms.

RevDate: 2020-05-15

Leiteritz A, Baumanns S, U Wenzel (2020)

Amyloid-beta (Aβ1-42)-induced paralysis in Caenorhabditis elegans is reduced through NHR-49/PPARalpha.

Neuroscience letters pii:S0304-3940(20)30312-8 [Epub ahead of print].

Alzheimer´s disease is a neurodegenerative disorder characterized by the misfolding and aggregation of amyloid β (Aβ). Agonists of peroxisomal proliferator-activated receptors (PPARs) are discussed as anti-amyloidogenic compounds, e.g. due to their cholesterol-lowering activities. In a previous study we have shown in Caenorhabditis elegans expressing human Aβ in muscle cells, that inhibition of steroid-signaling, by RNAi of respective members of the signaling pathway or by reducing cellular cholesterol uptake, both increases the nuclear translocation of the foxo transcription factor DAF-16 and concomitantly reduces Aβ-induced paralysis. Using RNAi in the present study we show that NHR-49/PPARalpha inhibits steroidal-signaling upstream of DAF-9, a cytochrome P450-dependent enzyme which generates dafachronic acids as ligands for the nuclear hormone receptor DAF-12, and upstream of DAF-12 itself. The NHR-49/PPARalpha agonist fenofibrate reduces Aβ-induced paralysis in dependence on nhr-49 and nuclear translocation of DAF-16. In conclusion, activation of NHR-49/PPARalpha inhibits the steroidal-signaling pathway which increases the nuclear translocation of DAF-16 and inhibits the Aβ-induced phenotype in an Alzheimer model of C. elegans.

RevDate: 2020-05-14

Suryadevara V, Kluppel M, Monte FD, et al (2020)

The Unraveling: Cardiac and Musculoskeletal Defects and their Role in Common Alzheimer disease Morbidity and Mortality.

The American journal of pathology pii:S0002-9440(20)30235-2 [Epub ahead of print].

Alzheimer disease (AD), characterized by deterioration of cognitive capabilities, is prevalent among 44 million people worldwide. Beyond memory deficits, the most common AD co-morbidities include swallowing defects (muscle), fractures (bone, muscle), and heart failure. The underlying causes of these co-morbidities and their role in AD pathophysiology are currently unknown. This review is the first to summarize the emerging picture of the cardiac and musculoskeletal deficits in human AD. We present the involvement of the heart, characterized by diastolic heart failure, the presence of amyloid deposits, and electrophysiological changes compared to age-matched controls. The characteristic musculoskeletal defects in AD come from recent clinical studies and include potential underlying mechanisms (bone) in animal models. These studies detail a primary muscle weakness (without a loss of muscle mass) in patients with mild cognitive impairment, with progression of cognitive impairment to AD associating with ongoing muscle weakness AND the onset of muscle atrophy. We conclude by reviewing the loss of bone density in AD patients, paralleling their increase in fracture and fall risk is specific populations. These studies paint broad AD as a systemic disease in broad strokes, which may help elucidate AD pathophysiology and to allow new ways to think about therapeutic intervention, diagnostic biomarkers, and the pathogenesis of this multi-disciplinary disease.

RevDate: 2020-05-13

Formica C, Bonanno L, Todaro A, et al (2020)

The role of mind theory in patients affected by neurodegenerative disorders and impact on caregiver burden.

Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia pii:S0967-5868(20)30864-X [Epub ahead of print].

BACKGROUND: Theory of Mind (ToM) is defined as the ability to understand mental and emotional state. This ability is assessed also in neurodegenerative disease. Few studies have investigated the impact that social cognition of patients could have on caregiver burden. The aim of this study was to investigate a possible correlation in level of social cognition impairment between patients with different neurodegenerative disorders and their caregivers with possible impact on caregivers burden.

METHODS: we enrolled 48 patients with dementia divided in different groups: Fronto-Temporal Dementia (FTD), Alzheimer Disease (AD), and Mild Cognitive Impairment (MCI) and also the three groups of their respective caregivers. All subjects were submitted to ToM tests, and the caregiver groups also to Caregiver Burden Inventory (CBI) to evaluate level of burden.

RESULTS: Our results showed that ToM was more impaired in FTD patients and in their caregivers In addition, FTD group showed more impaired performances in tasks related to emotional skills.

CONCLUSIONS: We suggested that ToM impairment of patients are related to ToM impairment of caregivers with differences of scores in caregiver groups. The caregiver difficulties to understand, attribute and describe emotional and mental states of their relatives develop distress and inability in burden management and disorders relative to neurodegenerative disease.

RevDate: 2020-05-13

Kim JT, Jedrychowski MP, Wei W, et al (2020)

A Plasma Protein Network Regulates PM20D1 and N-Acyl Amino Acid Bioactivity.

Cell chemical biology pii:S2451-9456(20)30146-X [Epub ahead of print].

N-acyl amino acids are a family of cold-inducible circulating lipids that stimulate thermogenesis. Their biosynthesis is mediated by a secreted enzyme called PM20D1. The extracellular mechanisms that regulate PM20D1 or N-acyl amino acid activity in the complex environment of blood plasma remains unknown. Using quantitative proteomics, here we show that PM20D1 circulates in tight association with both low- and high-density lipoproteins. Lipoprotein particles are powerful co-activators of PM20D1 activity in vitro and N-acyl amino acid biosynthesis in vivo. We also identify serum albumin as a physiologic N-acyl amino acid carrier, which spatially segregates N-acyl amino acids away from their sites of production, confers resistance to hydrolytic degradation, and establishes an equilibrium between thermogenic "free" versus inactive "bound" fractions. These data establish lipoprotein particles as principal extracellular sites of N-acyl amino acid biosynthesis and identify a lipoprotein-albumin network that regulates the activity of a circulating thermogenic lipid family.

RevDate: 2020-05-13

Bersini S, Arrojo E Drigo R, Huang L, et al (2020)

Transcriptional and Functional Changes of the Human Microvasculature during Physiological Aging and Alzheimer Disease.

Advanced biosystems, 4(5):e2000044.

Aging of the circulatory system correlates with the pathogenesis of a large spectrum of diseases. However, it is largely unknown which factors drive the age-dependent or pathological decline of the vasculature and how vascular defects relate to tissue aging. The goal of the study is to design a multianalytical approach to identify how the cellular microenvironment (i.e., fibroblasts) and serum from healthy donors of different ages or Alzheimer disease (AD) patients can modulate the functionality of organ-specific vascular endothelial cells (VECs). Long-living human microvascular networks embedding VECs and fibroblasts from skin biopsies are generated. RNA-seq, secretome analyses, and microfluidic assays demonstrate that fibroblasts from young donors restore the functionality of aged endothelial cells, an effect also achieved by serum from young donors. New biomarkers of vascular aging are validated in human biopsies and it is shown that young serum induces angiopoietin-like-4, which can restore compromised vascular barriers. This strategy is then employed to characterize transcriptional/functional changes induced on the blood-brain barrier by AD serum, demonstrating the importance of PTP4A3 in the regulation of permeability. Features of vascular degeneration during aging and AD are recapitulated, and a tool to identify novel biomarkers that can be exploited to develop future therapeutics modulating vascular function is established.

RevDate: 2020-05-13

Oguz M, Kalay E, Akocak S, et al (2020)

Synthesis of calix[4]azacrown substituted sulphonamides with antioxidant, acetylcholinesterase, butyrylcholinesterase, tyrosinase and carbonic anhydrase inhibitory action.

Journal of enzyme inhibition and medicinal chemistry, 35(1):1215-1223.

A series of novel calix[4]azacrown substituted sulphonamide Schiff bases was synthesised by the reaction of calix[4]azacrown aldehydes with different substituted primary and secondary sulphonamides. The obtained novel compounds were investigated as inhibitors of six human (h) isoforms of carbonic anhydrases (CA, EC Their antioxidant profile was assayed by various bioanalytical methods. The calix[4]azacrown substituted sulphonamide Schiff bases were also investigated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase enzymes, associated with several diseases such as Alzheimer, Parkinson, and pigmentation disorders. The new sulphonamides showed low to moderate inhibition against hCAs, AChE, BChE, and tyrosinase enzymes. However, some of them possessed relevant antioxidant activity, comparable with standard antioxidants used in the study.

RevDate: 2020-05-13

Alexander CM, Martyr A, Savage SA, et al (2020)

Measuring Awareness in People With Dementia: Results of a Systematic Scoping Review.

Journal of geriatric psychiatry and neurology [Epub ahead of print].

BACKGROUND: Awareness of the diagnosis or related changes in functioning varies in people with dementia (PwD), with implications for the well-being of PwD and their carers. Measuring awareness in a clinical setting could facilitate tailored support and optimize involvement in personal health and care decisions. This scoping review aimed to identify validated methods of assessing awareness in dementia and appraise their clinical utility.

METHOD: A systematic search was conducted of English-language publications that measured awareness in PwD, in 6 electronic databases. Search terms included dement*, Alzheimer*, Pick disease, and awareness, unawareness, anosognosia, insight, denial, metacognit*, or discrepanc*.

RESULTS: We screened 30,634 articles, finding 345 articles that met our inclusion criteria. We identified 76 measures, most commonly using a discrepancy questionnaire comparing evaluations of function by PwD and an informant. There were 30 awareness measures developed and validated for use in dementia populations but few designed for general clinical use.

CONCLUSIONS: Although we found a range of clinical indications for measuring awareness, there were few studies investigating clinical applications and few tools designed for clinical purposes. Further investigation and development of a person-centered tool could facilitate health and care choices in mild-to-moderate dementia.

RevDate: 2020-05-13

Lanthier C, Dallemagne P, Lecoutey C, et al (2020)

Therapeutic modulators of the serotonin 5-HT4 receptor: a patent review (2014-present).

Expert opinion on therapeutic patents [Epub ahead of print].

Introduction: Numerous chemotypes have been described over time in order to generate potent and selective 5-HT4R ligands. Both agonists and antagonists have demonstrated their interest in several disease models. This culminates with the FDA approval of tegaserod and prucalopride in the recent years.Areas covered: This review summarizes the patent applications from 2014 to present, dedicated to the use or the description of novel 5-HT4R modulators. Several novel ligands and scaffolds have been industrially protected mainly in the field of central nervous system (CNS) pathologies as well as gastrointestinal disorders, including the combination with other drugs or for veterinary uses.Expert opinion: The therapeutic potential of 5-HT4R modulators has been explored for several years in animal models, but also linked to potential safety issues with initial ligands. The current use of prucalopride in humans demonstrates that its toxicity is not linked to the target and that 5-HT4R modulators are safe in humans. Therefore, an important number of studies and patents has continued in the recent years to expand the use of 5-HT4R modulators, not only to treat gastrointestinal disorders, but also for CNS pathologies. This article details current efforts in this development.

RevDate: 2020-05-13

Mattsson-Carlgren N, Leuzy A, Janelidze S, et al (2020)

The implications of different approaches to define AT(N) in Alzheimer disease.

Neurology pii:WNL.0000000000009485 [Epub ahead of print].

OBJECTIVE: To compare different β-amyloid (Aβ), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies.

METHODS: A total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disease [AD] dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU and 144 CI [138 MCI and 6 AD dementia]). Biomarkers for A were CSF Aβ42 and amyloid-PET ([18F]flutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET ([18F]flortaucipir); and for (N), hippocampal volume, temporal cortical thickness, and CSF neurofilament light (NfL). Binarization of biomarkers was achieved using cutoffs defined in other cohorts. The relationship between different AT(N) combinations and cognitive trajectories (longitudinal Mini-Mental State Examination scores) was examined using linear mixed modeling and coefficient of variation.

RESULTS: Among CU participants, A-T-(N)- or A+T-(N)- variants were most common. However, more T+ cases were seen using p-tau than tau PET. Among CI participants, A+T+(N)+ was more common; however, more (N)+ cases were seen for MRI measures relative to CSF NfL. Tau PET best predicted longitudinal cognitive decline in CI and p-tau in CU participants. Among CI participants, continuous T (especially tau PET) and (N) measures improved the prediction of cognitive decline compared to binary measures.

CONCLUSIONS: Our findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.

RevDate: 2020-05-13

Turkez H, Cacciatore I, Arslan ME, et al (2020)

Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates.

Biomolecules, 10(5): pii:biom10050737.

Cyclic dipeptides administered by both parenteral and oral routes are suggested as promising candidates for the treatment of neurodegeneration-related pathologies. In this study, we tested Cyclo (His-Pro) isomers (cHP1-4) for their anti-Alzheimer potential using a differentiated human neuroblastoma cell line (SH-SY5Y) as an Alzheimer's disease (AD) experimental model. The SH-SY5Y cell line was differentiated by the application of all-trans retinoic acid (RA) to obtain mature neuron-like cells. Amyloid-beta 1-42 (Aβ1-42) peptides, the main effector in AD, were administered to the differentiated cell cultures to constitute the in vitro disease model. Next, we performed cell viability analyses 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays) to investigate the neuroprotective concentrations of cyclodipeptides using the in vitro AD model. We evaluated acetylcholinesterase (AChE), α- and β-secretase activities (TACE and BACE1), antioxidant potency, and apoptotic/necrotic properties and performed global gene expression analysis to understand the main mechanism behind the neuroprotective features of cHP1-4. Moreover, we conducted sister chromatid exchange (SCE), micronucleus (MN), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) analyses to evaluate the genotoxic damage potential after applications with cHP1-4 on cultured human lymphocytes. Our results revealed that cHP1-4 isomers provide a different degree of neuroprotection against Aβ1-42-induced cell death on the in vitro AD model. The applications with cHP1-4 isomers altered the activity of AChE but not the activity of TACE and BACE1. Our analysis indicated that the cHP1-4 increased the total antioxidant capacity without altering total oxidative status levels in the cellular AD model and that cHP1-4 modulated the alterations of gene expressions by Aβ1-42 exposure. We also observed that cHP1-4 exhibited noncytotoxic and non-genotoxic features in cultured human whole blood cells. In conclusion, cHP1-4 isomers, especially cHP4, have been explored as novel promising therapeutics against AD.

RevDate: 2020-05-12

Beeri MS, Uribarri J, Cai W, et al (2020)

Human Brain and Serum Advanced Glycation End Products are Highly Correlated: Preliminary Results of Their Role in Alzheimer Disease and Type 2 Diabetes.

Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 26(5):576-577.

RevDate: 2020-05-12

Namdar Khatibani M, Mehri A, Jalaie S, et al (2020)

Developing Verb Picture Naming Test for Persian adults and determining its psychometric properties.

Applied neuropsychology. Adult [Epub ahead of print].

There are a few standardized assessment tools in Persian language. The present study was carried out to develop a Verb Picture Naming Test and assessing its psychometric properties. In this cross-sectional study, a total of 230 verbs were selected based on their frequency, familiarity, age of acquisition, visual complexity, name agreement, image agreement, syllable length, transitivity, and compound or simple verbs. To determine content and face validity, 230 pictures of verbs were given to 15 experts, and then 180 final pictures were divided into original and parallel versions. Both versions of the test were performed on 50 healthy adults and 20 patients with Alzheimer's diseases. Results showed that face and content validity of these versions was more than .85 and .98. Intraclass Correlation Coefficient (ICC) for total scores was equal to .98 (p < .001, 95%CI: .97-.99) and .96 (p < .001, 95%CI: .93-.98). Standard Error of Measurement (SEM) and Smallest Detectable Change (SDC) of total scores were equal to .93 and 2.66 in version1 and 1.27 and 3.12 in version 2, respectively. The two versions of Persian Verb Picture Naming Test were found to be valid and reliable, so the clinicians can use it in clinical settings.


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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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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