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Bibliography on: Alzheimer Disease — Treatment

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 30 Jun 2022 at 01:33 Created: 

Alzheimer Disease — Treatment

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. Because of this lack of understanding of the root cause for Alzheimer's Disease, no direct treatment for the condition is yet available. However, this bibliography specifically searches for the idea of treatment in conjunction with Alzheimer's to make it easier to track literature that explores the possibility of treatment.

Created with PubMed® Query: alzheimer[TIAB] AND treatment[TIAB] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2022-06-29

Tariq S, Mutahir S, Khan MA, et al (2022)

Synthesis, in vitro cholinesterase inhibition, molecular docking, DFT and ADME studies of novel 1,3,4-oxadiazole 2-thiol derivatives.

Chemistry & biodiversity [Epub ahead of print].

A sequence of 1,3,4-oxadiazole 2-thiol derivatives bearing various alkyl or aryl moieties was designed, synthesized, and characterized by modern spectroscopic methods to yield 17 compounds (6a - 6q) which were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes in search of 'lead' compounds for the treatment of Alzheimer disease (AD). The compounds 6q, 6p, 6k, 6o, and 6l showed inhibitory capability against AChE and BChE, with IC 50 values ranging from 11.730.49 to 27.360.29 µM for AChE and 21.830.39 to 39.430.44 µM for BChE, inhibiting both enzymes within a limited range. The SAR ascertained that the substitution of the aromatic moiety had a profound effect on the AChE and BChE inhibitory potential as compared to the aliphatic substitutions which were supported by the molecular docking studies. In silico ADME studies reinforced the drug-likeness of most of the synthesized molecules. These results were additionally supplemented by the molecular orbital analysis (HOMO-LUMO) and electrostatic potential maps got from DFT calculations. ESP maps expose that on all structures, there are two potential binding sites conquered by the most positive and most negative districts.

RevDate: 2022-06-27

Galvin-McLaughlin D, Klee D, Memmott T, et al (2022)

Methodology and preliminary data on feasibility of a neurofeedback protocol to improve visual attention to letters in mild Alzheimer's disease.

Contemporary clinical trials communications, 28:100950 pii:S2451-8654(22)00067-9.

Background: Brain-computer interface (BCI) systems are controlled by users through neurophysiological input for a variety of applications, including communication, environmental control, and motor rehabilitation. Although individuals with severe speech and physical impairment are the primary users of this technology, BCIs have emerged as a potential tool for broader populations, including delivering cognitive training/interventions with neurofeedback (NFB).

Methods: This paper describes the development and preliminary testing of a protocol for use of a BCI system with NFB as an intervention for people with mild Alzheimer's disease (AD). The intervention focused on training visual attention and language skills, as AD is often associated with functional impairments in both. This funded pilot study called for enrolling five participants with mild AD in a six-week BCI EEG-based NFB intervention that followed a four-to-seven-week baseline phase. While two participants completed the study, the remaining three participants could not complete the intervention phase because of COVID-19 restrictions.

Results: Preliminary pilot results suggested: (1) participants with mild AD were able to participate in a study with multiple assessments per week and complete all outcome measures, (2) most outcome measures were reliable during the baseline phase, and (3) all participants with mild AD learned to operate a BCI spelling system with training.

Conclusions: Although preliminary results demonstrate practical feasibility to deliver NFB intervention using a BCI to adults with AD, completion of the protocol in its entirety with more participants is needed to further assess whether implementing NFB-based cognitive intervention is justified by functional treatment outcomes.

Trial registration: This study was registered with ClinicalTrials.gov (NCT03790774).

RevDate: 2022-06-25

Kim HH, NH Jung (2022)

Effects of Assistive Technology Application in Dementia Intervention for People with Mild Cognitive Impairment & Mild Alzheimer Type Dementia and Caregiver.

Alternative therapies in health and medicine pii:AT7524 [Epub ahead of print].

Background: Dementia, a degenerative disease, requires alternative treatment to maintain function, but previous studies suggest only the therapeutic effect of a temporary program.

Primary Study Objective: The current study aimed to examine the effects of assistive technologies on cognitive function, daily living ability, and psychosocial symptoms in elderlies with mild cognitive impairment, elderlies with mild dementia and their caregivers.

Design: The research team designed an experimental study that used application as the intervention.

Setting: To recruit participants living in the local community, research participation was supported through local public health centers, welfare centers, and social welfare organizations. Evaluation and intervention were conducted by visiting the participant's home.

Participant: The study participants were 29 Mild Cognitive Impairment (MCI) and 16 mild Alzheimer type dementia (AD) patients over the age of 75 with a total of 45 patients, 10 MCI caregivers and 11 AD caregivers with a total of 21 caregivers.

Intervention: The assistive technologies used for intervention are 3 area (8 daily living assistive devices, 7 safety assistive technologies, and 7 cognitive assistive technologies). Up to 5 assistive technologies were provided to one subject, and they were instructed to use them every day for 8 weeks.

Outcome measure: Participants were evaluated at baseline and postintervention using specific scales appropriate to an area: cognitive function, activities of daily living, depression, anxiety, quality of life, satisfaction.

Results: Cognitive function showed statistically significant changes in the MCI group. Basic activities of daily living, depression, anxiety, quality of life, satisfaction showed statistically significant positive effects in both MCI and AD groups. Instrumental activities of daily living did not show any statistically significant differences.

Conclusion: As an alternative to dementia care in the future, the application and management of assistive technologies for each area should be provided at the government level.

RevDate: 2022-06-25

Kullenberg H, Rossen J, Johansson UB, et al (2022)

Increased levels of insulin-degrading enzyme in patients with type 2 diabetes mellitus.

Endocrine [Epub ahead of print].

PURPOSE: Decreasing levels of serum insulin-degrading enzyme (IDE) have been associated with an increased risk for Alzheimer´s disease (AD) in patients with type 2 diabetes mellitus (T2DM). Research on serum IDE levels in patients with T2DM is sparse and the aim of this study was to explore serum levels of IDE in patients with T2DM.

METHOD: Blood serum samples were obtained from a biobank. Samples from subjects with T2DM and without metabolic disease were divided into subgroups; lifestyle treatment (n = 10), oral antidiabetic treatment (n = 17), insulin treatment (n = 20) and metabolically healthy controls (n = 18). Serum levels of IDE were analysed using specific ELISA assays.

RESULTS: Serum levels of IDE were elevated in subjects with T2DM compared to metabolically healthy individuals (p = 0.033). No significant differences were detected between treatment subgroups.

CONCLUSION: The present study indicates that patients with T2DM have increased serum IDE levels, compared to metabolically healthy individuals. However, for IDE to be clinically useful as a biomarker, its full function and possible use needs to be further elucidated in larger studies showing reproducible outcomes.

RevDate: 2022-06-24

Budryn G, Majak I, Grzelczyk J, et al (2022)

Hydroxybenzoic Acids as Acetylcholinesterase Inhibitors: Calorimetric and Docking Simulation Studies.

Nutrients, 14(12): pii:nu14122476.

One of the symptoms of Alzheimer's disease (AD) is low acetylcholine level due to high acetylcholinesterase (AChE) activity. For this reason, AChE inhibitors are used in the treatment of AD, the prolonged use of which may cause a cholinergic crisis. There is a need to search for safe natural AChE inhibitors. The study analyzed 16 hydroxybenzoic acids using calorimetry and docking simulation as AChE inhibitors. All tested compounds were shown to inhibit the hydrolysis of ACh. The best properties were shown by methyl syringinate, which acted as competitive inhibitor at a catalytic site. The tested compounds also interacted with the anionic or peripheral binding site known to block β-amyloid plaques formation. The activity of the tested hydroxybenzoic acids IC50 ranged from 5.50 to 34.19 µmol/µmol of AChE, and the binding constant Ka from 20.53 to 253.16 L/mol, which proves their reversible, non-toxic effect, and activity at physiological concentrations.

RevDate: 2022-06-24

Azman KF, R Zakaria (2022)

Recent Advances on the Role of Brain-Derived Neurotrophic Factor (BDNF) in Neurodegenerative Diseases.

International journal of molecular sciences, 23(12): pii:ijms23126827.

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are essential for neuronal survival and growth. The signaling cascades initiated by BDNF and its receptor are the key regulators of synaptic plasticity, which plays important role in learning and memory formation. Changes in BDNF levels and signaling pathways have been identified in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, and have been linked with the symptoms and course of these diseases. This review summarizes the current understanding of the role of BDNF in several neurodegenerative diseases, as well as the underlying molecular mechanism. The therapeutic potential of BDNF treatment is also discussed, in the hope of discovering new avenues for the treatment of neurodegenerative diseases.

RevDate: 2022-06-23

Coerver K, Yu MM, D'Abreu A, et al (2022)

Practical Considerations in the Administration of Aducanumab for the Neurologist.

Neurology. Clinical practice, 12(2):169-175.

Aducanumab (Aduhelm), developed by the biotechnology firm Biogen in Cambridge, MA, was approved using the less common accelerated approval pathway by the Federal Drug Administration (FDA) reserved for treatments that fill a significant unmet need.1 Its approval on June 7, 2021, has been met with an outpouring of opinions from prescribers, insurers, advocacy groups, and hospital systems regarding its risk-benefit profile.2-4 Originally approved for all forms of Alzheimer disease (AD), the FDA updated aducanumab's labeling on July 8, 2021, for "treatment in patients with mild cognitive impairment (MCI) or mild dementia stage of disease, the population in which treatment was initiated in clinical trials."5 With 6 million people nationally in the United States who suffer from AD and an anticipated one-third of those who may now fulfill the criteria under the revised labeling, the implications of aducanumab's approval continue to generate national interest.6.

RevDate: 2022-06-22

Lirong W, Mingliang Z, Mengci L, et al (2022)

The clinical and mechanistic roles of bile acids in depression, Alzheimer's disease, and stroke.

Proteomics [Epub ahead of print].

The burden of neurological and neuropsychiatric disorders continues to grow with significant impacts on human health and social economy worldwide. Increasing clinical and preclinical evidences have implicated that bile acids (BAs) are involved in the onset and progression of neurological and neuropsychiatric diseases. Here, we summarized recent studies of BAs in three types of highly prevalent brain disorders, depression, Alzheimer's disease, and stroke. The shared and specific BA profiles were explored and potential markers associated with disease development and progression were summarized. The mechanistic roles of BAs were reviewed with focuses on inflammation, gut-brain-microbiota axis, cellular apoptosis. We also discussed future perspectives for the prevention and treatment of neurological and neuropsychiatric disorders by targeting BAs and related molecules and gut microbiota. Our understanding of BAs and their roles in brain disorders is still evolving. A large number of questions still need to be addressed on the emerging crosstalk among central, peripheral, intestine and their contribution to brain and mental health. This article is protected by copyright. All rights reserved.

RevDate: 2022-06-22

Schinle M, Erler C, Kaliciak M, et al (2022)

Digital Health Apps in the Context of Dementia: Questionnaire Study to Assess the Likelihood of Use Among Physicians.

JMIR formative research, 6(6):e35961 pii:v6i6e35961.

BACKGROUND: Age-related diseases such as dementia are playing an increasingly important role in global population development. Thus, prevention, diagnostics, and interventions require more accessibility, which can be realized through digital health apps. With the app on prescription, Germany made history by being the first country worldwide to offer physicians the possibility to prescribe and reimburse digital health apps as of the end of the year 2020.

OBJECTIVE: Considering the lack of knowledge about correlations with the likelihood of use among physicians, this study aimed to address the question of what makes the use of a digital health app by physicians more likely.

METHODS: We developed and validated a novel measurement tool-the Digital Health Compliance Questionnaire (DHCQ)-in an interdisciplinary collaboration of experts to assess the role of proposed factors in the likelihood of using a health app. Therefore, a web-based survey was conducted to evaluate the likelihood of using a digital app called DemPredict to screen for Alzheimer dementia. Within this survey, 5 latent dimensions (acceptance, attitude toward technology, technology experience, payment for time of use, and effort of collection), the dependent variable likelihood of use, and answers to exploratory questions were recorded and tested within directed correlations. Following a non-probability-sampling strategy, the study was completed by 331 physicians from Germany in the German language, of whom 301 (90.9%) fulfilled the study criteria (eg, being in regular contact with patients with dementia). These data were analyzed using a range of statistical methods to validate the dimensions of the DHCQ.

RESULTS: The DHCQ revealed good test theoretical measures-it showed excellent fit indexes (Tucker-Lewis index=0.98; comparative fit index=0.982; standardized root mean square residual=0.073; root mean square error of approximation=0.037), good internal consistency (Cronbach α=.83), and signs of moderate to large correlations between the DHCQ dimensions and the dependent variable. The correlations between the variables acceptance, attitude toward technology, technology experience, and payment for the time of use and the dependent variable likelihood of use ranged from 0.29 to 0.79, and the correlation between effort of the collection and likelihood of use was -0.80. In addition, we found high levels of skepticism regarding data protection, and the age of the participants was found to be negatively related to their technical experience and attitude toward technology.

CONCLUSIONS: In the context of the results, increased communication between the medical and technology sectors and significantly more awareness raising are recommended to make the use of digital health apps more attractive to physicians as they can be adjusted to their everyday needs. Further research could explore the connection between areas such as adherence on the patient side and its impact on the likelihood of use by physicians.

RevDate: 2022-06-21

Maria de Souza M, Ribeiro Cenci A, Faoro Teixeira K, et al (2022)

DYRK1A inhibitors and perspectives for the treatment of Alzheimer's disease.

Current medicinal chemistry pii:CMC-EPUB-124652 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common form of dementia, especially in the elderly. Due to the increase in life expectancy, in recent years there has been an exorbitant growth in the number of people affected by this disease, causing serious problems for health systems. In recent years, research has been intensified to find new therapeutic approaches that prevent the progression of the disease. In this sense, recent studies indicate that the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) gene, which is located on chromosome 21q22.2 and overexpressed in Down syndrome (DS), may play a significant role in developmental brain disorders and early onset neurodegeneration, neuronal loss and dementia in DS and AD. Inhibiting DYRK1A may serve to stop the phenotypic effects of its overexpression and, therefore, is a potential treatment strategy for the prevention of age-associated neurodegeneration, including Alzheimer-type pathology.

OBJECTIVE: in this review, we investigate the contribution of DYRK1A inhibitors as potential anti-AD agents.

METHODS: A search in the literature to compile an in vitro dataset including IC50 values involving DYRK1A was performed from 2014 to the present day. In addition, we carried out structure-activity relationship studies based on in vitro and in silico data.

RESULTS: molecular modeling and enzyme kinetics studies indicate that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity.

CONCLUSION: further evaluation of DYRK1A inhibitors may contribute to new therapeutic approaches for AD.

RevDate: 2022-06-21

Jellinger KA (2022)

Morphological basis of Parkinson disease-associated cognitive impairment: an update.

Journal of neural transmission (Vienna, Austria : 1996) [Epub ahead of print].

Cognitive impairment is one of the most salient non-motor symptoms of Parkinson disease (PD) that poses a significant burden on the patients and carers as well as being a risk factor for early mortality. People with PD show a wide spectrum of cognitive dysfunctions ranging from subjective cognitive decline and mild cognitive impairment (MCI) to frank dementia. The mean frequency of PD with MCI (PD-MCI) is 25.8% and the pooled dementia frequency is 26.3% increasing up to 83% 20 years after diagnosis. A better understanding of the underlying pathological processes will aid in directing disease-specific treatment. Modern neuroimaging studies revealed considerable changes in gray and white matter in PD patients with cognitive impairment, cortical atrophy, hypometabolism, dopamine/cholinergic or other neurotransmitter dysfunction and increased amyloid burden, but multiple mechanism are likely involved. Combined analysis of imaging and fluid markers is the most promising method for identifying PD-MCI and Parkinson disease dementia (PDD). Morphological substrates are a combination of Lewy- and Alzheimer-associated and other concomitant pathologies with aggregation of α-synuclein, amyloid, tau and other pathological proteins in cortical and subcortical regions causing destruction of essential neuronal networks. Significant pathological heterogeneity within PD-MCI reflects deficits in various cognitive domains. This review highlights the essential neuroimaging data and neuropathological changes in PD with cognitive impairment, the amount and topographical distribution of pathological protein aggregates and their pathophysiological relevance. Large-scale clinicopathological correlative studies are warranted to further elucidate the exact neuropathological correlates of cognitive impairment in PD and related synucleinopathies as a basis for early diagnosis and future disease-modifying therapies.

RevDate: 2022-06-21
CmpDate: 2022-06-21

Valenzuela M, Duncan T, Abey A, et al (2022)

Autologous skin-derived neural precursor cell therapy reverses canine Alzheimer dementia-like syndrome in a proof of concept veterinary trial.

Stem cell research & therapy, 13(1):261.

BACKGROUND: Older companion dogs naturally develop a dementia-like syndrome with biological, clinical and therapeutic similarities to Alzheimer disease (AD). Given there has been no new safe, clinically effective and widely accessible treatment for AD for almost 20 years, an all-new cell therapeutic approach was trialled in canine veterinary patients, and further modelled in aged rats for more detailed neurobiological analysis.

METHODS: A Phase 1/2A veterinary trial was conducted in N = 6 older companion dogs with definitive diagnosis of Canine Cognitive Dysfunction (CCD). Treatment comprised direct microinjection of 250,000 autologous skin-derived neuroprecursors (SKNs) into the bilateral hippocampus using MRI-guided stereotaxis. Safety was assessed clinically and efficacy using the validated Canine Cognitive Dysfunction Rating Scale (CCDR) at baseline and 3-month post treatment. Intention to treat analysis imputed a single patient that had a surgical adverse event requiring euthanasia. Three dog brains were donated following natural death and histology carried out to quantify Alzheimer pathology as well as immature neurons and synapses; these were compared to a brain bank (N = 12) of untreated aged dogs with and without CCD. Further, an age-related memory dysfunction rat model (N = 16) was used to more closely evaluate intrahippocampal engraftment of canine SKN cells, focusing on mnemonic and synaptic effects as well as donor cell survival, neurodifferentation and electrophysiologic circuit integration in a live hippocampal slice preparation.

RESULTS: Four out-of-five dogs improved on the primary clinical CCDR endpoint, three fell below diagnostic threshold, and remarkably, two underwent full syndromal reversal lasting up to 2 years. At post mortem, synaptic density in the hippocampus specifically was nine standard deviations above non-treated dogs, and intensity of new neurons also several fold higher. There was no impact on AD pathology or long-term safety signals. Modelling in aged rats replicated the main canine trial findings: hippocampally-dependent place memory deficits were reversed and synaptic depletion rescued. In addition, this model confirmed donor cell survival and migration throughout the hippocampus, neuronal differentiation in situ, and physiologically-correct integration into pyramidal layer circuits.

CONCLUSIONS: With further development, SKN cell therapy may have potential for treating carefully chosen AD patients based on neurosynaptic restoration in the hippocampus.

RevDate: 2022-06-20

Mecê AM, Abreu VC, Lamas GM, et al (2022)

Lithium Intoxication as a cause of reversible dementia mimicking FDG PET features of Alzheimer's disease.

Dementia & neuropsychologia, 16(2):249-252.

Rapidly progressive dementia (RPD) is a rare neurological disorder. Drug toxicity is among the differential diagnoses, including the use of lithium, in which an overdosage might cause cognitive dysfunction. Clinical suspicion, laboratory confirmation, and drug interruption are key points in the management of lithium intoxication. We described a 66-year-old female patient under treatment with lithium who developed an RPD associated with parkinsonian symptoms. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) showed an "Alzheimer-like" pattern, while cerebrospinal fluid biomarkers for the disease were negative. There was a significant clinical and radiological improvement after lithium interruption. Lithium intoxication is a potentially reversible cause of RPD, as demonstrated in this case report. Drug discontinuation should be considered even in patients with normal levels of this metal, if cognitive impairment is detected. 18F-FDG PET/CT images may show an "Alzheimer-like" image pattern in acute intoxication and are useful for monitoring these patients.

RevDate: 2022-06-20

Abiyev A, Yakaryılmaz FD, ZA Öztürk (2022)

A new diagnostic approach in Alzheimer's disease: The critical flicker fusion threshold.

Dementia & neuropsychologia, 16(1):89-96.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Although AD treatment is still insufficient despite all the recent developments, detection and treatment in the early stage of disease have provided more clinical benefits.

Objective: In this study, we aimed to use the critical flicker fusion (CFF) threshold test to diagnose AD in the early stage.

Methods: In this study, 120 patients (above 65 years of age) and 50 control groups who were admitted to geriatrics outpatient clinic and diagnosed in early- and middle-stage AD were included. The remaining 58 patients and 25 healthy volunteers underwent comprehensive geriatric assessment and CFF testing.

Results: The mean CFF value of AD group was significantly lower than the control group (36.44±7.00 vs. 44.24±3.82, p<0.001, respectively). There was a significant difference in standardized mini-mental state examination (MMSE) score in both groups (18.05±5.25 vs. 25.96±2.85, p<0.001, respectively). There was also a positive correlation between CFF value and MMSE score (p<0.001, r=0.459). Thirty-four patients were in the early-stage AD group and 24 patients were in the middle-stage AD group. There was a significant difference in CFF values between the three groups when we compared the patients in early- and middle-stage AD and control groups (p<0.001). The mean CFF values in patients with early- and middle-stage AD were 37.93±7.33 and 34.97±7.43, respectively. The mean age, gender, education level, and the number of drugs used did not show a statistically significant difference in both groups (p>0.05). The cutoff value for the CFF variable was determined as 39 Hz [p<0.001; area under the curve (AUC)=0.852; sensitivity=70.69% (95% confidence interval [95%CI] 57.3-81.9); specificity=92.00% (95%CI 74.00-99.00)].

Conclusions: There is a significant difference in mean CFF values between AD and healthy groups. CFF testing may play an important role in diagnosing AD in the early stage.

RevDate: 2022-06-21
CmpDate: 2022-06-21

Maltais M, de Souto Barreto P, Bowman GL, et al (2022)

Omega-3 Supplementation for the Prevention of Cognitive Decline in Older Adults: Does It Depend on Homocysteine Levels?.

The journal of nutrition, health & aging, 26(6):615-620.

BACKGROUND: Recent evidence point towards an interaction between omega-3 (n-3) polyunsaturated fatty acids (PUFA) and plasma homocysteine (Hcy).

OBJECTIVES: This study tested the hypothesis that effects of red blood cell n-3 PUFA are modified according to baseline plasma Hcy in the large Mulit-domain Alzheimer Prevention Trial (MAPT) throughout the 3-years of treatment with an additional 2 years of observational follow-up.

DESIGN: Experimental study.

PARTICIPANTS: From the 1680 participants that were randomized in the four groups of the MAPT study (two of which received n-3 PUFA, the other two without n-3 PUFA), 782 were selected because they had baseline data on both Hcy and n-3 PUFA.

MEASUREMENTS: Cognitive performance was measured with a broad set of cognitive tests including free and total recall of the cued selective reminding test, digit symbol substitution test, category naming test and Trail-making tests (TMT-A and B) and Clinical dementia rating scale.

RESULTS: We found a significant association between TMT-A and red blood cell n-3 PUFA levels in participants with Hcy values ≤16.8 µMol/L after adjustments at baseline (Estimate: -1.3, 95% CI: -2.3; -0.3, p=0.01). Additionally, participants with high Hcy values had a significant worsening after adjustments in TMT-B after a 5-year n-3 PUFA supplementation, compared to low levels of Hcy (Mean difference: 34.8, 95% CI: 7.8;61.7).

CONCLUSION: This study shows that Hcy levels could modify the association between red blood cell n-3 PUFA and executive function. People with high Hcy may benefit less from a n-3 PUFA supplementation to prevent cognitive decline.

RevDate: 2022-06-21
CmpDate: 2022-06-21

Newberg AB, Coble R, Khosravi M, et al (2022)

Positron Emission Tomography-Based Assessment of Cognitive Impairment and Dementias, Critical Role of Fluorodeoxyglucose in such Settings.

PET clinics, 17(3):479-494.

Positron emission tomography (PET) has been a key component in the diagnostic armamentarium for assessing neurodegenerative diseases such as Alzheimer or Parkinson disease. PET imaging has been useful for diagnosing these disorders, identifying their pathophysiology, and following their treatment. Further, PET imaging has been extensively used for both clinical and research purposes, particularly for helping with potential therapeutic approaches for managing neurodegenerative diseases. This article will review the current literature regarding PET imaging in patients with neurodegenerative disorders. This includes an evaluation of the most commonly used tracer fluorodeoxyglucose that measures cerebral glucose metabolism, tracers that assess neurotransmitter systems, and tracers designed to reveal disease-specific pathophysiological processes. With the continuing development of an expanding variety of radiopharmaceuticals, PET imaging will likely play a prominent role in future research and clinical applications for neurodegenerative diseases.

RevDate: 2022-06-21

Majerova P, Olesova D, Golisova G, et al (2022)

Analog of kynurenic acid decreases tau pathology by modulating astrogliosis in rat model for tauopathy.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 152:113257.

Kynurenines have immunomodulatory and neuroactive properties and can influence the central nervous system. Previous studies showed the involvement of the kynurenines in the pathogenesis and progression of neurodegenerative disease. In neurodegenerative disorders, including tauopathies, the tryptophan metabolism is shifted toward neurotoxic agents and the reduction of neuroprotectant products. Astrocyte-derived kynurenic acid serves as a neuroprotectant. However, systemic administration of kynurenic acid is not effective because of low permeability across the blood-brain barrier (BBB). We used a kynurenic acid analog with similar biological activity but higher brain permeability to overcome BBB limitations. In the present study, we used amide derivate of kynurenic acid N-(2-N, N-dimethylaminoethyl)- 4-oxo-1 H-quinoline-2-carboxamid (KYNA-1). We administered KYNA-1 for three months to tau transgenic rats SHR-24 and analyzed the effect on tau pathology and activation of glial cells. Primary glial cell cultures were applied to identify the mechanism of the KYNA-1 effect. KYNA-1 was not toxic to rats after chronic three-month administration. When chronically administered, KYNA-1 reduced hyperphosphorylation of insoluble tau in the brain of transgenic rats. Noteworthily, the plasma total tau was also reduced. We determined that the effect of KYNA-1 on tau pathology was induced through the modulation of glial activation. KYNA-1 inhibited LPS induced activation of astrocytes and induced transformation of microglia to M2 phenotype. We identified that the administration of KYNA-1 reduced tau hyperphosphorylation and neuroinflammation. KYNA-1 may serve as a promising treatment for tauopathies.

RevDate: 2022-06-20

George N, Jawaid Akhtar M, Al Balushi KA, et al (2022)

Rational drug design strategies for the development of promising multi-target directed indole hybrids as Anti-Alzheimer agents.

Bioorganic chemistry, 127:105941 pii:S0045-2068(22)00346-7 [Epub ahead of print].

Alzheimer's disease (AD) is a neurological disorder that leads to dementia i.e., progressive memory loss accompanied with worsening of thinking ability of an individual. The cause of AD is not fully understood but it progresses with age where brain cells gradually die over time. According to the World Health Organization (WHO), currently 50 million people worldwide are affected by dementia and 60-70% of the cases belong to AD. Cumulative research over the past few decades have shown that molecules that act at a single target possess limited efficacy since these investigational drugs are not able to act against complex pathologies and thus do not provide permanent cure. Designing of multi-target directed ligands (MTDLs) appears to be more beneficial and a rational approach to treat chronic complex diseases including neurodegenerative diseases. Recently, MTDLs are being extensively researched by the medicinal chemists for the development of drugs for the treatment of various multifactorial diseases. Indole is one of the privileged scaffolds which is considered as an essential mediator between the gut-brain axis because of its neuroprotective, anti-inflammatory, β-amyloid anti-aggregation and antioxidant activities. Herein, we have reviewed the potential of some indole-hybrids acting at multiple targets in the pathogenesis of AD. We have reviewed research articles from the year 2014-2021 from various scientific databases and highlighted the synthetic strategies, mechanisms of neuroprotection, toxicity, structure activity relationships and molecular docking studies of various indole-hybrid derivatives. This literature review of published data on indole derivatives indicated that developing indole hybrids have improved the pharmacokinetic profile with lower toxicity, provided synergistic effect, helped to develop more potent compounds and prevented drug-drug interactions. It is evident that this class of compounds have potential to inhibit multiple enzymes targets involved in the pathogenesis of AD and therefore indole hybrids as MTDLs may play an important role in the development of anti-AD molecules.

RevDate: 2022-06-21

Fu X, Liu J, Xie J, et al (2022)

Identification of potential therapeutic and diagnostic characteristics of Alzheimer disease by targeting the miR-132-3p/FOXO3a-PPM1F axis in APP/PS1 mice.

Brain research, 1790:147983 pii:S0006-8993(22)00207-4 [Epub ahead of print].

Alzheimer disease (AD) is a neurodegenerative disorder, which is characterized by progressive impairment of memory and cognition. Early diagnosis and treatment of AD has become a leading topic of research. In this study, we explored the effects of the miR-132-3p/FOXO3a-PPM1F axis on the onset of AD for possible early diagnosis and therapy. We found that miR-132-3p levels in the hippocampus and blood were drastically decreased in APP/PS1 mice from 9 months of age, and bi-directional manipulation of miR-132-3p levels induced magnified effects on learning memory behaviors, and manifestation of AD-related pathological characteristics and inflammatory cytokines in APP/PS1 mice of relevant ages. The hippocampal PPM1F expression levels were significantly elevated in APP/PS1 mice from 3 months of age, which was correlated with miR-132-3p levels at different ages. Overexpression of PPM1F remarkably accelerated the progression of learning memory deficits and associated pathological factors in APP/PS1 mice. Further, we showed that miR-132-3p modulated the expression of PPM1F via FOXO3a in HT22 cells. Finally, using peripheral blood samples of human study participants, we found that the miR-132-3p and PPM1F expression levels in patients with AD were also altered with prominent correlations. In conclusion, miR-132-3p indirectly regulates PPM1F expression by targeting FOXO3a, which could play an extensive role in contributing to the establishment of early diagnosis, treatment, and pathogenesis of AD.

RevDate: 2022-06-16

Paes-Colli Y, Aguiar AFL, Isaac AR, et al (2022)

Phytocannabinoids and Cannabis-Based Products as Alternative Pharmacotherapy in Neurodegenerative Diseases: From Hypothesis to Clinical Practice.

Frontiers in cellular neuroscience, 16:917164.

Historically, Cannabis is one of the first plants to be domesticated and used in medicine, though only in the last years the amount of Cannabis-based products or medicines has increased worldwide. Previous preclinical studies and few published clinical trials have demonstrated the efficacy and safety of Cannabis-based medicines in humans. Indeed, Cannabis-related medicines are used to treat multiple pathological conditions, including neurodegenerative disorders. In clinical practice, Cannabis products have already been introduced to treatment regimens of Alzheimer's disease, Parkinson's disease and Multiple Sclerosis's patients, and the mechanisms of action behind the reported improvement in the clinical outcome and disease progression are associated with their anti-inflammatory, immunosuppressive, antioxidant, and neuroprotective properties, due to the modulation of the endocannabinoid system. In this review, we describe the role played by the endocannabinoid system in the physiopathology of Alzheimer, Parkinson, and Multiple Sclerosis, mainly at the neuroimmunological level. We also discuss the evidence for the correlation between phytocannabinoids and their therapeutic effects in these disorders, thus describing the main clinical studies carried out so far on the therapeutic performance of Cannabis-based medicines.

RevDate: 2022-06-12

Kajikawa T, Mastellos DC, Hasturk H, et al (2022)

C3-targeted host-modulation approaches to oral inflammatory conditions.

Seminars in immunology pii:S1044-5323(22)00025-2 [Epub ahead of print].

Periodontitis is an inflammatory disease caused by biofilm accumulation and dysbiosis in subgingival areas surrounding the teeth. If not properly treated, this oral disease may result in tooth loss and consequently poor esthetics, deteriorated masticatory function and compromised quality of life. Epidemiological and clinical intervention studies indicate that periodontitis can potentially aggravate systemic diseases, such as, cardiovascular disease, type 2 diabetes mellitus, rheumatoid arthritis, and Alzheimer disease. Therefore, improvements in the treatment of periodontal disease may benefit not only oral health but also systemic health. The complement system is an ancient host defense system that plays pivotal roles in immunosurveillance and tissue homeostasis. However, complement has unwanted consequences if not controlled appropriately or excessively activated. Complement overactivation has been observed in patients with periodontitis and in animal models of periodontitis and drives periodontal inflammation and tissue destruction. This review places emphasis on a promising periodontal host-modulation therapy targeting the complement system, namely the complement C3-targeting drug, AMY-101. AMY-101 has shown safety and efficacy in reducing gingival inflammation in a recent Phase 2a clinical study. We also discuss the potential of AMY-101 to treat peri-implant inflammatory conditions, where complement also seems to be involved and there is an urgent unmet need for effective treatment.

RevDate: 2022-06-14

Yao Q, Tang F, Wang Y, et al (2022)

Effect of cerebellum stimulation on cognitive recovery in patients with Alzheimer disease: A randomized clinical trial.

Brain stimulation pii:S1935-861X(22)00104-8 [Epub ahead of print].

INTRODUCTION: Evidence indicates that the cerebellum is involved in cognitive processing. However, the specific mechanisms through which the cerebellum repetitive transcranial magnetic stimulation (rTMS) contributes to the cognitive state are unclear.

METHODS: In the current randomized, double-blind, sham-controlled trial, 27 patients with Alzheimer's disease (AD) were randomly allotted to one of the two groups: rTMS-real or rTMS-sham. We investigated the efficacy of a four-week treatment of bilateral cerebellum rTMS to promote cognitive recovery and alter specific cerebello-cerebral functional connectivity.

RESULTS: The cerebellum rTMS significantly improves multi-domain cognitive functions, directly associated with the observed intrinsic functional connectivity between the cerebellum nodes and the dorsolateral prefrontal cortex (DLPFC), medial frontal cortex, and the cingulate cortex in the real rTMS group. In contrast, the sham stimulation showed no significant impact on the clinical improvements and the cerebello-cerebral connectivity.

CONCLUSION: Our results depict that 5 Hz rTMS of the bilateral cerebellum is a promising, non-invasive treatment of cognitive dysfunction in AD patients. This cognitive improvement is accompanied by brain connectivity modulation and is consistent with the pathophysiological brain disconnection model in AD patients.

RevDate: 2022-06-13

Lin J, Niu Z, Xue Y, et al (2022)

Chronic Vitamin D3 Supplementation Alleviates Cognition Impairment via Inhibition of Oxidative Stress Regulated by PI3K/AKT/Nrf2 in APP/PS1 Transgenic Mice.

Neuroscience letters pii:S0304-3940(22)00286-5 [Epub ahead of print].

Oxidative stress plays essential role in the pathogenesis of Alzheimer's disease, and vitamin D3 (VD3) is a nutrient with neuroprotective and antioxidant activities. The present study aimed to confirm the neuroprotective effect and the ameliorative effect of cortical oxidative stress of VD3 in APP/PS1 transgenic mice. APP/PS1 mice were treated with VD3 for 20 weeks. After treatment, Morris Water Maze test was used to evaluate cognitive level. Western blotting was used to determine APP, p-tau, tau and PI3K/AKT/Nrf2 pathway-related protein expression levels. Immunohistochemical staining was performed to determine the levels of β amyloid peptide (Aβ) deposition. Enzyme linked immunosorbent assay was used to determine the 25(OH)D3 levels and oxidative stress status. Our results showed that treatment with VD3 ameliorated behavioral deficits of APP/PS1 mice. In addition, the administration of VD3 significantly increased the cortical 25(OH)D3 levels, while reducing the levels of cortical Aβ deposition and decreasing the expression levels of cortical APP, tau and p-tau in APP/PS1 mice. Moreover, VD3 protected the cortex against oxidative stress by enhancing the levels of superoxide dismutase, glutathione and total antioxidant capacity, and downregulating the malondialdehyde levels. Furthermore, VD3 clearly activated the PI3K/AKT/Nrf2 pathway, thereby elevating the expression levels of HO1 and NQO1. We concluded that VD3 improved cognitive function and cortical Alzheimer-like pathology of APP/PS1 mice, which may be related to the inhibition of oxidative stress via activation the PI3K/AKT/Nrf2 pathway.

RevDate: 2022-06-13

Wang J, Battioui C, McCarthy A, et al (2022)

Evaluating the Use of Digital Biomarkers to Test Treatment Effects on Cognition and Movement in Patients with Lewy Body Dementia.

Journal of Parkinson's disease pii:JPD213126 [Epub ahead of print].

BACKGROUND: PRESENCE was a Phase 2 trial assessing mevidalen for symptomatic treatment of Lewy body dementia (LBD). Participants received daily doses (10, 30, or 75 mg) of mevidalen (LY3154207) or placebo for 12 weeks.

OBJECTIVE: To evaluate if frequent cognitive and motor tests using an iPad app and wrist-worn actigraphy to track activity and sleep could detect mevidalen treatment effects in LBD.

METHODS: Of 340 participants enrolled in PRESENCE, 238 wore actigraphy for three 2-week periods: pre-, during, and post-intervention. A subset of participants (n = 160) enrolled in a sub-study using an iPad trial app with 3 tests: digital symbol substitution (DSST), spatial working memory (SWM), and finger-tapping. Compliance was defined as daily test completion or watch-wearing ≥23 h/day. Change from baseline to week 12 (app) or week 8 (actigraphy) was used to assess treatment effects using Mixed Model Repeated Measures analysis. Pearson correlations between sensor-derived features and clinical endpoints were assessed.

RESULTS: Actigraphy and trial app compliance was > 90% and > 60%, respectively. At baseline, daytime sleep positively correlated with Epworth Sleepiness Scale score (p < 0.01). Physical activity correlated with improvement on Movement Disorder Society -Unified Parkinson Disease Rating Scale (MDS-UPDRS) part II (p < 0.001). Better scores of DSST and SWM correlated with lower Alzheimer Disease Assessment Scale -Cognitive 13-Item Scale (ADAS-Cog13) (p < 0.001). Mevidalen treatment (30 mg) improved SWM (p < 0.01), while dose-dependent decreases in daytime sleep (10 mg: p < 0.01, 30 mg: p < 0.05, 75 mg: p < 0.001), and an increase in walking minutes (75 mg dose: p < 0.001) were observed, returning to baseline post-intervention.

CONCLUSION: Devices used in the LBD population achieved adequate compliance and digital metrics detected statistically significant treatment effects.

RevDate: 2022-06-10

Han BH, Cofell B, Everhart E, et al (2022)

Amentoflavone Promotes Cellular Uptake and Degradation of Amyloid-Beta in Neuronal Cells.

International journal of molecular sciences, 23(11): pii:ijms23115885.

Deposition of fibrillar forms of amyloid β-protein (Aβ) is commonly found in patients with Alzheimer's disease (AD) associated with cognitive decline. Impaired clearance of Aβ species is thought to be a major cause of late-onset sporadic AD. Aβ secreted into the extracellular milieu can be cleared from the brain through multiple pathways, including cellular uptake in neuronal and non-neuronal cells. Recent studies have showed that the naturally-occurring polyphenol amentoflavone (AMF) exerts anti-amyloidogenic effects. However, its effects on metabolism and cellular clearance of Aβ remain to be tested. In the present study, we demonstrated that AMF significantly increased the cellular uptake of both Aβ1-40 and Aβ1-42, but not inverted Aβ42-1 in mouse neuronal N2a cells. Though AMF promoted internalization of cytotoxic Aβ1-42, it significantly reduced cell death in our assay condition. Our data further revealed that the internalized Aβ is translocated to lysosomes and undergoes enzymatic degradation. The saturable kinetic of Aβ uptake and our pharmacologic experiments showed the involvement of receptor-mediated endocytosis, in part, through the class A scavenger receptors as a possible mechanism of action of AMF. Taken together, our findings indicate that AMF can lower the levels of extracellular Aβ by increasing their cellular uptake and clearance, suggesting the therapeutic potential of AMF for the treatment of AD.

RevDate: 2022-06-10

Licastro F (2022)

Special Issue Editorial: "Infections, Inflammation and Neurodegeneration in Alzheimer Disease" Infections, Neuronal Senescence, and Dementia.

International journal of molecular sciences, 23(11): pii:ijms23115865.

Alzheimer's disease (AD) is a complex chronic disease of the brain characterized by several neurodegenerative mechanisms and is responsible for most dementia cases in the elderly. Declining immunity during ageing is often associated with peripheral chronic inflammation, and chronic neuroinflammation is a constant component of AD brain pathology. In the Special Issue published in 2021 eight papers were collected regarding different aspects of neurodegeneration associated with AD. Five papers presented and discussed infectious agents involved in brain AD pathology and three discussed data regarding receptors regulation and possible treatment of the disease. Below I will discuss and further elaborate on topics related to infections, inflammation, and neurodegenerative pathways in AD and brain senescence. The topic presented here may contribute to early intervention protocols for preventing or slowing the progression of cognitive deterioration in the elderly.

RevDate: 2022-06-09

Rose RV, JS Kass (2022)

The Medicolegal and Ethical Dimensions of Physician Prescription Reluctance.

Continuum (Minneapolis, Minn.), 28(3):937-941.

ABSTRACT: This article addresses the potential legal ramifications for neurologists caring for patients with Alzheimer disease (AD) who elect neither to prescribe aducanumab nor to refer patients with AD for treatment with aducanumab. To prevail against a neurologist for failing to prescribe aducanumab or refer for aducanumab treatment, the plaintiff would have to establish that the neurologist's failure to prescribe the medication or refer for treatment was a breach of the standard of care. The standard of care is conceptualized as the generally accepted approach to diagnosing or treating a condition. However, the controversy surrounding the US Food and Drug Administration's (FDA's) approval process for aducanumab (which was based on the drug's efficacy at reducing brain amyloidosis rather than on clinically meaningful efficacy) as well as the American Academy of Neurology (AAN) position statement on aducanumab and the recent decision by the Centers for Medicare & Medicaid Services (CMS) to limit Medicare coverage of the drug and its associated costs to patients enrolled in qualifying clinical trials indicate that aducanumab cannot yet be considered the standard of care for the treatment of AD. Although deciding not to prescribe aducanumab does not violate the standard of care, neurologists treating patients with AD and not recommending this treatment should explain to their patients and their patients' surrogate decision makers why they are not recommending the treatment.

RevDate: 2022-06-09

Carlsson CM (2022)

Management of Dementia.

Continuum (Minneapolis, Minn.), 28(3):885-900.

PURPOSE OF REVIEW: This article describes an approach to managing patients following a diagnosis of dementia, including medical management, nonpharmacologic strategies, safety interventions, caregiver support, mobilization of community resources, and advanced care planning.

RECENT FINDINGS: Dementia clinical syndromes are frequently caused by mixed pathologies, leading to varied clinical presentations that include memory loss, behavioral changes, communication challenges, safety concerns, and loss of independent function. Medications for treating dementia currently target cognitive and behavioral symptoms, although disease-modifying therapies for Alzheimer disease may be making their way into widespread clinical practice soon. Identification and treatment of co-occurring medical problems, such as obstructive sleep apnea, adverse medication effects, mood disorders, hearing loss, pain, alcohol misuse, and vascular risk factors, may mitigate the impact of these conditions on cognitive decline. Mobilization of clinical and community-based interprofessional teams will ensure that people with dementia and their care partners have the expertise, support, and access to resources they need. Addressing goals of care early in the disease course will allow people with dementia to contribute to their care plan by expressing their wishes.

SUMMARY: Developing a structured approach to treating common causes of dementia and related comorbid medical conditions, identifying a local network of interprofessional clinical and community-based referrals, and providing readily available educational resources will help clinicians provide quality dementia care management that extends beyond the clinic visit. Encouraging patients and families to engage in clinical research will advance the identification of effective therapies, preventive strategies, and quality care models for the future.

RevDate: 2022-06-08

Rejc L, Gómez-Vallejo V, Joya A, et al (2022)

Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography.

Alzheimer's research & therapy, 14(1):80.

BACKGROUND: Validation of new biomarkers of Alzheimer disease (AD) is crucial for the successful development and implementation of treatment strategies. Additional to traditional AT(N) biomarkers, neuroinflammation biomarkers, such as translocator protein (TSPO) and cystine/glutamine antiporter system (xc-), could be considered when assessing AD progression. Herein, we report the longitudinal investigation of [18F]DPA-714 and [18F]FSPG for their ability to detect TSPO and xc- biomarkers, respectively, in the 5xFAD mouse model for AD.

METHODS: Expression of TSPO and xc- system was assessed longitudinally (2-12 months of age) on 5xFAD mice and their respective controls by positron emission tomography (PET) imaging using radioligands [18F]DPA-714 and [18F]FSPG. In parallel, in the same mice, amyloid-β plaque deposition was assessed with the amyloid PET radiotracer [18F]florbetaben. In vivo findings were correlated to ex vivo immunofluorescence staining of TSPO and xc- in microglia/macrophages and astrocytes on brain slices. Physiological changes of the brain tissue were assessed by magnetic resonance imaging (MRI) in 12-month-old mice.

RESULTS: PET studies showed a significant increase in the uptake of [18F]DPA-714 and [18F]FSPG in the cortex, hippocampus, and thalamus in 5xFAD but not in WT mice over time. The results correlate with Aβ plaque deposition. Ex vivo staining confirmed higher TSPO overexpression in both, microglia/macrophages and astrocytes, and overexpression of xc- in non-glial cells of 5xFAD mice. Additionally, the results show that Aβ plaques were surrounded by microglia/macrophages overexpressing TSPO. MRI studies showed significant tissue shrinkage and microstructural alterations in 5xFAD mice compared to controls.

CONCLUSIONS: TSPO and xc- overexpression can be assessed by [18F]DPA-714 and [18F]FSPG, respectively, and correlate with the level of Aβ plaque deposition obtained with a PET amyloid tracer. These results position the two tracers as promising imaging tools for the evaluation of disease progression. Longitudinal in vivo study in the 5xFAD mouse model shows that TSPO and oxidative stress assessment through [18F]DPA-714 and [18F]FSPG-PET imaging, respectively, could serve as a potential tool for the evaluation of Alzheimer disease progression.

RevDate: 2022-06-07

Somaa FA, de Graaf TA, AT Sack (2022)

Transcranial Magnetic Stimulation in the Treatment of Neurological Diseases.

Frontiers in neurology, 13:793253.

Transcranial Magnetic Stimulation (TMS) has widespread use in research and clinical application. For psychiatric applications, such as depression or OCD, repetitive TMS protocols (rTMS) are an established and globally applied treatment option. While promising, rTMS is not yet as common in treating neurological diseases, except for neurorehabilitation after (motor) stroke and neuropathic pain treatment. This may soon change. New clinical studies testing the potential of rTMS in various other neurological conditions appear at a rapid pace. This can prove challenging for both practitioners and clinical researchers. Although most of these neurological applications have not yet received the same level of scientific/empirical scrutiny as motor stroke and neuropathic pain, the results are encouraging, opening new doors for TMS in neurology. We here review the latest clinical evidence for rTMS in pioneering neurological applications including movement disorders, Alzheimer's disease/mild cognitive impairment, epilepsy, multiple sclerosis, and disorders of consciousness.

RevDate: 2022-06-06

Qin Q, Wang M, Yin Y, et al (2022)

The Specific Mechanism of TREM2 Regulation of Synaptic Clearance in Alzheimer's Disease.

Frontiers in immunology, 13:845897.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Synaptic dysfunction is an integral feature of AD pathophysiology and a significant factor in early cognitive impairment in AD. Microglia, which are intrinsic immune cells in the central nervous system, play important regulatory roles in the process of synapse formation. Microglia can refine synaptic connections through synaptic clearance to ensure accurate synaptic transmission. Synaptic clearance is not only existed during central nervous system development but also aberrantly activated during AD pathology. However, the mechanisms of synaptic clearance in AD remain to be investigated. TREM2 is involved in the synaptic clearance of microglia, acting alone or with other molecules, such as apolipoprotein E (APOE). In addition, C1q is essential for microglia-mediated synaptic clearance. In this review, we systematically summarized the potential mechanisms of microglia involved in synaptic clearance, comprehensively reviewed the role of TREM2 in microglia regulating synaptic clearance and proposed our hypothesis that TREM2 interacts with APOE and C1q to promote synaptic clearance. This review provides new insights into the role of TREM2 regulation in microglia synaptic clearance and provides potential prospects for the treatment of AD.

RevDate: 2022-06-06

Liu XL, Ouyang FB, Hu LT, et al (2022)

Mesenchymal Stem Cells Improve Cognitive Impairment and Reduce Aβ Deposition via Promoting AQP4 Polarity and Relieving Neuroinflammation in Rats With Chronic Hypertension-Induced Cerebral Small-Vessel Disease.

Frontiers in aging neuroscience, 14:883503.

Cerebral small-vessel disease (CSVD) is the main cause of vascular cognitive impairment (VCI), and the accumulation of amyloid β-protein (Aβ) may be significantly involved in CSVD-induced VCI. The imbalance between Aβ production and clearance is believed to be an important pathological mechanism of Aβ deposition in Alzheimer disease. In this study, we aimed to disclose the roles of aquaporin 4 (AQP4) and neuroinflammation in CSVD, which were the key factors for Aβ clearance and production, respectively, and the effect of mesenchymal stem cells (MSCs) on Aβ deposition and these two factors. The stroke-prone renovascular hypertensive (RHRSP) rats were grouped and received MSC and MSC + AS1517499 (an inhibitor of pSTAT6). The latter was used to explore the underlying mechanism. The cognitive function, white matter lesions, Aβ expression, expression, and polarity of AQP4, neuroinflammation and the STAT6 pathway were investigated. Compared with sham-operated rats, RHRSP rats showed spatial cognitive impairment, white matter lesions and Aβ deposition. Moreover, AQP4 polarity disorder and neuroinflammatory activation were found, which were linked to Aβ deposition. Treatment with MSCs markedly improved cognitive tasks and reduced Aβ deposition but failed to reduce white-matter lesions. Furthermore, MSCs not only promoted AQP4 polarity but also alleviated neuroinflammation probably through the STAT6 pathway. The present study demonstrated that Aβ deposition, AQP4 polarity disorder and neuroinflammation might be involved in CSVD and the regulatory effects of MSCs on them suggested potential therapeutic value for CSVD.

RevDate: 2022-06-07

García Marín ID, Camarillo López RH, Martínez OA, et al (2022)

New compounds from heterocyclic amines scaffold with multitarget inhibitory activity on Aβ aggregation, AChE, and BACE1 in the Alzheimer disease.

PloS one, 17(6):e0269129 pii:PONE-D-21-37357.

The preset neurodegenerations in Alzheimer disease (AD) are due to several mechanisms such as amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, neurofibrillary tangles, cholinergic dysfunction, among others. The aim of this work was to develop multitarget molecules for the treatment of AD. Therefore, a family of 64 molecules was designed based on ligand structure pharmacophores able to inhibit the activity of beta secretase (BACE1) and acetylcholinesterase (AChE) as well as to avoid amyloid beta (Aβ1-42) oligomerization. The backbone of designed molecules consisted of a trisubstituted aromatic ring, one of the substituents was a heterocyclic amine (piperidine, morpholine, pyrrolidine or N-methyl pyrrolidine) separated from the aromatic system by three carbon atoms. The set of compounds was screened in silico employing molecular docking calculations and chemoinformatic analyses. Based on Gibbs free energy of binding, binding mode and in silico predicted toxicity results, three of the best candidates were selected, synthesized, and evaluated in vitro; F3S4-m, F2S4-m, and F2S4-p. All three compounds prevented Aβ1-42 aggregation (F3S4-m in 30.5%, F2S4-p in 42.1%, and F2S4-m in 60.9%). Additionally, inhibitory activity against AChE (ki 0.40 μM and 0.19 μM) and BACE1 (IC50 15.97 μM and 8.38 μM) was also observed for compounds F2S4-m and F3S4-m, respectively. Despite the BACE IC50 results demonstrated that all compounds are very less potent respect to peptidomimetic inhibitor (PI-IV IC50 3.20 nM), we can still say that F3S4-m is capable to inhibit AChE and BACE1.

RevDate: 2022-06-03

Malaiya A, Singhai M, Singh M, et al (2022)

Recent Update on the Alzheimer's Disease Progression, Diagnosis and Treatment Approaches.

Current drug targets pii:CDT-EPUB-123997 [Epub ahead of print].

Alzheimer's disease (AD) is a multifactorial, progressive, neurodegenerative disorder, manifested by the loss of memory and cognitive abilities, behavioral disturbance and progressive impairment of activities of daily life. The sharp rise in the number of AD patients has brought it with-in the top eight health issues in the world. It is associated with the distribution of misfolded aggre-gates of protein within the brain. However, Alois Alzheimer initially mentioned that the reduction in brain volume in AD might be associated with the "deposition of a special substance in the cortex". The resulting plaque found in extracellular space in the AD brain and hippocampus region, known as senile plaques, is the characteristic feature underlying Alzheimer's pathology, where the role of amy-loid-β (Aβ) peptide formation from proteolytic cleavage of amyloid precursor protein (APP) by secre-tase enzyme is eminent. Therefore, this review has highlighted the molecular pathophysiology of AD with a variety of available diagnostic and treatment strategies for the management of the disease, with a focus on the advancement toward clinical research to provide new effective and safe tool in the diagnosis, treatment or management of AD.

RevDate: 2022-06-01

Chapleau M, Iaccarino L, Soleimani-Meigooni D, et al (2022)

The Role of Amyloid PET in Imaging Neurodegenerative Disorders: A Review.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 63(Suppl 1):13S-19S.

Imaging of amyloid deposition using PET has been available in research studies for 2 decades and has been approved for clinical use by the U.S. Food and Drug Administration, the European Medicines Agency, and other regulatory agencies around the world. Amyloid PET is a crucial tool for the diagnosis of Alzheimer disease, as it allows the noninvasive detection of amyloid plaques, a core neuropathologic feature that defines the disease. The clinical use of amyloid PET is expected to increase with recent accelerated approval in the United States of aducanumab, an antiamyloid monoclonal antibody, for the treatment of mild cognitive impairment and mild dementia due to Alzheimer disease. However, amyloid pathology can also be found in cognitively unimpaired older adults and in patients with other neurodegenerative disorders. The aim of this review is to provide an up-to-date overview of the application of amyloid PET in neurodegenerative diseases. We provide an in-depth analysis of the clinical, pathologic, and imaging correlates; a comparison with other available biomarkers; and a review of the application of amyloid PET in clinical trials and clinical utility studies.

RevDate: 2022-06-01

Groot C, Villeneuve S, Smith R, et al (2022)

Tau PET Imaging in Neurodegenerative Disorders.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 63(Suppl 1):20S-26S.

The advent of PET ligands that bind tau pathology has enabled the quantification and visualization of tau pathology in aging and in Alzheimer disease (AD). There is strong evidence from neuropathologic studies that the most widely used tau PET tracers (i.e., 18F-flortaucipir, 18F-MK6240, 18F-RO948, and 18F-PI2620) bind tau aggregates formed in AD in the more advanced (i.e., ≥IV) Braak stages. However, tracer binding in most non-AD tauopathies is weaker and overlaps to a large extent with known off-target binding regions, limiting the quantification and visualization of non-AD tau pathology in vivo. Off-target binding is generally present in the substantia nigra, basal ganglia, pituitary, choroid plexus, longitudinal sinuses, meninges, or skull in a tracer-specific manner. Most cross-sectional studies use the inferior aspect of the cerebellar gray matter as a reference region, whereas for longitudinal analyses, an eroded white matter reference region is sometimes selected. No consensus has yet been reached on whether to use partial-volume correction of tau PET data. Although an increased neocortical tau PET signal is rare in cognitively unimpaired individuals, even in amyloid-β-positive cases, such a signal holds important prognostic information because preliminary data suggest that an elevated tau PET signal predicts cognitive decline over time. Also, in symptomatic stages of AD (i.e., mild cognitive impairment or AD dementia), tau PET shows great potential as a prognostic marker because an elevated baseline tau PET retention forecasts future cognitive decline and brain atrophy. For differential diagnostic use, the primary utility of tau PET is to differentiate AD dementia from other neurodegenerative diseases, as is in line with the conditions for the approval of 18F-flortaucipir by the U.S. Food and Drug Administration for clinical use. The differential diagnostic performance drops substantially at the mild-cognitive-impairment stage of AD, and there is no sufficient evidence for detection of sporadic non-AD primary tauopathies at the individual level for any of the currently available tau PET tracers. In conclusion, while the field is currently addressing outstanding methodologic issues, tau PET is gradually moving toward clinical application as a diagnostic and possibly prognostic marker in dementia expert centers and as a tool for selecting participants, assessing target engagement, and monitoring treatment effects in clinical trials.

RevDate: 2022-06-01

Spurrier J, Nicholson L, Fang XT, et al (2022)

Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q.

Science translational medicine, 14(647):eabi8593.

Microglia-mediated synaptic loss contributes to the development of cognitive impairments in Alzheimer's disease (AD). However, the basis for this immune-mediated attack on synapses remains to be elucidated. Treatment with the metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), BMS-984923, prevents β-amyloid oligomer-induced aberrant synaptic signaling while preserving physiological glutamate response. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [18F]FPEB positron emission tomography (PET) at doses shown to be safe in rodents and nonhuman primates. In aged mouse models of AD (APPswe/PS1ΔE9 overexpressing transgenic and AppNL-G-F/hMapt double knock-in), SAM treatment fully restored synaptic density as measured by [18F]SynVesT-1 PET for SV2A and by histology, and the therapeutic benefit persisted after drug washout. Phospho-TAU accumulation in double knock-in mice was also reduced by SAM treatment. Single-nuclei transcriptomics demonstrated that SAM treatment in both models normalized expression patterns to a far greater extent in neurons than glia. Last, treatment prevented synaptic localization of the complement component C1Q and synaptic engulfment in AD mice. Thus, selective modulation of mGluR5 reversed neuronal gene expression changes to protect synapses from damage by microglial mediators in rodents.

RevDate: 2022-06-01

Pereira GRC, Gonçalves LM, Abrahim-Vieira BA, et al (2022)

In silico analyses of acetylcholinesterase (AChE) and its genetic variants in interaction with the anti-Alzheimer drug Rivastigmine.

Journal of cellular biochemistry [Epub ahead of print].

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Despite causing great social and economic impact, there is currently no cure for AD. The most effective therapy to manage AD symptoms is based on acetylcholinesterase inhibitors (AChEi), from which rivastigmine presented numerous benefits. However, mutations in AChE, which affect approximately 5% of the population, can modify protein structure and function, changing the individual response to Alzheimer's treatment. In this study, we performed computer simulations of AChE wild type and variants R34Q, P135A, V333E, and H353N, identified by one or more genome-wide association studies, to evaluate their effects on protein structure and interaction with rivastigmine. The functional effects of AChE variants were predicted using eight machine learning algorithms, while the evolutionary conservation of AChE residues was analyzed using the ConSurf server. Autodock4.2.6 was used to predict the binding modes for the hAChE-rivastigmine complex, which is still unknown. Molecular dynamics (MD) simulations were performed in triplicates for the AChE wild type and mutants using the GROMACS packages. Among the analyzed variants, P135A was classified as deleterious by all the functional prediction algorithms, in addition to occurring at highly conserved positions, which may have harmful consequences on protein function. The molecular docking results suggested that rivastigmine interacts with hAChE at the upper active-site gorge, which was further confirmed by MD simulations. Our MD findings also suggested that the complex hAChE-rivastigmine remains stable over time. The essential dynamics revealed flexibility alterations at the active-site gorge upon mutations P135A, V333E, and H353N, which may lead to strong and nonintuitive consequences to hAChE binding. Nonetheless, similar binding affinities were registered in the MMPBSA analysis for the hAChE wild type and variants when complexed to rivastigmine. Finally, our findings indicated that the rivastigmine binding to hAChE is an energetically favorable process mainly driven by negatively charged amino acids.

RevDate: 2022-06-01

Djemil S, Sames AM, DTS Pak (2022)

ACh Transfers: Homeostatic Plasticity of Cholinergic Synapses.

Cellular and molecular neurobiology [Epub ahead of print].

The field of homeostatic plasticity continues to advance rapidly, highlighting the importance of stabilizing neuronal activity within functional limits in the context of numerous fundamental processes such as development, learning, and memory. Most homeostatic plasticity studies have been focused on glutamatergic synapses, while the rules that govern homeostatic regulation of other synapse types are less understood. While cholinergic synapses have emerged as a critical component in the etiology of mammalian neurodegenerative disease mechanisms, relatively few studies have been conducted on the homeostatic plasticity of such synapses, particularly in the mammalian nervous system. An exploration of homeostatic mechanisms at the cholinergic synapse may illuminate potential therapeutic targets for disease management and treatment. We will review cholinergic homeostatic plasticity in the mammalian neuromuscular junction, the autonomic nervous system, central synapses, and in relation to pathological conditions including Alzheimer disease and DYT1 dystonia. This work provides a historical context for the field of cholinergic homeostatic regulation by examining common themes, unique features, and outstanding questions associated with these distinct cholinergic synapse types and aims to inform future research in the field.

RevDate: 2022-05-17

Plowey ED, Bussiere T, Rajagovindan R, et al (2022)

Alzheimer disease neuropathology in a patient previously treated with aducanumab.

Acta neuropathologica [Epub ahead of print].

Amyloid beta (Aβ) plaque is a defining pathologic feature of Alzheimer disease (AD). Aducanumab, a monoclonal IgG1 that selectively binds aggregated species of Aβ, has been shown by amyloid positron emission tomography (Amyloid PET) to reduce Aβ plaques in patients with prodromal and mild AD. This is the first autopsy report of the AD neuropathology in a patient previously treated with aducanumab. The patient was an 84-year-old woman who was randomized to the placebo arm of the PRIME Phase 1b study (221AD103). The patient progressed to moderate dementia (MMSE = 14/30), beyond the targeted early AD treatment stage, before receiving aducanumab in the long-term extension (LTE). The patient then received 32 monthly doses of aducanumab, titrated up to 6 mg/kg, for a cumulative dose of 186 mg/kg. In the LTE, Amyloid PET scans demonstrated robust Aβ plaque reduction, from a composite standard uptake value ratio (SUVR) of 1.5 at screening to < 1.1 at 56 weeks post-aducanumab dosing. MRI examinations were negative for amyloid-related imaging abnormalities (ARIA). She passed away in hospice care 4 months after her last dose of aducanumab. The postmortem neuropathologic examination confirmed AD neuropathologic changes. Aβ and IBA1 immunohistochemistry assays demonstrated sparse residual Aβ plaque engaged by amoeboid reactive microglia. Phospho-Tau (pTau) immunohistochemistry demonstrated neocortical neurofibrillary degeneration (Braak stage V, NIA/AA Stage B3). However, the density of pTau neuropathology, including neuritic plaque pTau (NP-Tau), appeared lower in the PRIME LTE Patient compared to a reference cohort of untreated Braak stage V-VI, NIA/AA Stage B3 AD cases. Taken together, this case report is the first to provide Amyloid PET and neuropathologic evidence substantiating the impact of aducanumab to reduce Aβ plaque neuropathology in a patient with AD. Furthermore, this report underscores the critical importance of autopsy neuropathology studies to augment our understanding of aducanumab's mechanism of action and impact on AD biomarkers.

RevDate: 2022-05-31

Ansari B, Behl T, Pirzada AS, et al (2022)

Caralluma edulis (Apocynaceae): A comprehensive review on its Traditional uses, Phytochemical profile and pharmacological effects.

Current topics in medicinal chemistry pii:CTMC-EPUB-124008 [Epub ahead of print].

Caralluma edulis is a well-known species of the genus Caralluma from Apocynaceae, commonly known as chunga. Caralluma species are mostly succulent perennial herbs, several of which are edible species. The plant has an outstanding therapeutic background in the traditional system of treatment. It has been recommended for the treatment of a number medical disorder such as hypertension, Alzheimer disease, rheumatism, gastric problems and leprosy. Traditionally the stem was boiled in water and this extract was then used to cure diabetes. The pharmacological effects of C.edulis have also been explored in various in vitro and in vivo experiments. In this regard, the extract of the plant exhibited strong antioxidant activity, analgesic, against inflammation as well as xylene mediated ear edema for topical effects. The significant anti-hyperlipidemic effect of the plant extract is also reported. However, the extract was found insignificant in the reversal of alloxan-induced diabetes in rabbit model at test doses. These pharmacological effects are strongly supported by the presence of different bioactive phytochemicals in the plant. These groups of compounds include sterols, terpenoids, flavonoids, and pregnane glycosides. C.edulis is a very potential member of the genus Caralluma with strong traditional history, phytochemistry and phytopharmacology, needed further exploration for clinically used lead compounds. In this review, we have focused to combined different reported data on the traditional uses of the plant, phytochemical profile and pharmacological effects in different experimental assay and subsequent future prospects.

RevDate: 2022-05-31

Turhan G, Küçük H, EO Isik (2022)

Spatio-temporal convolution for classification of alzheimer disease and mild cognitive impairment.

Computer methods and programs in biomedicine, 221:106825 pii:S0169-2607(22)00207-3 [Epub ahead of print].

BACKGROUND AND OBJECTIVE: Dementia refers to the loss of memory and other cognitive abilities. Alzheimer's disease (AD), which patients eventually die from, is the most common cause of dementia. In USA, %60 to %80 of dementia cases, are caused by AD. An estimate of 5.2 million people from all age groups have been diagnosed with AD in 2014. Mild cognitive impairment (MCI) is a preliminary stage of dementia with noticeable changes in patient's cognitive abilities. Individuals, who bear MCI symptoms, are prone to developing AD. Therefore, identification of MCI patients is very critical for a plausible treatment before it reaches to AD, the irreversible stage of this neurodegenerative disease.

METHODS: Development of machine learning algorithms have recently gained a significant pace in early diagnosis of Alzheimer's disease (AD). In this study, a (2+1)D convolutional neural network (CNN) architecture has been proposed to distinguish mild cognitive impairment (MCI) from AD, based on structural magnetic resonance imaging (MRI). MRI scans of AD and MCI subjects were procured from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. 507 scans of 223 AD patients and 507 scans of 204 MCI patients were obtained for the computational experiments.

RESULTS: The outcome and robustness of 2D convolutions, 3D convolutions and (2+1)D convolutions were compared. The CNN algorithms incorporated 2 to 6 convolutional layers, depending on the architecture, followed by 4 pooling layers and 3 fully connected layers. (2+1)D convolutional neural network model resulted in the best classification performance with 85% auc score, in addition to an almost two times faster convergence compared to classical 3D CNN methods.

CONCLUSIONS: Application of (2+1)D CNN algorithm to large datasets and deeper neural network models can provide a significant advantage in speed, due to its architecture handling images in spatial and temporal dimensions separately.

RevDate: 2022-05-31

Batawi AH (2022)

Ginkgo biloba extract mitigates the neurotoxicity of AlCl3 in Alzheimer rat's model: Role of Apolipoprotein E4 and clusterin genes in stimulating ROS generation and apoptosis.

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

Purpose: Alzheimer's disease (AD) appears as a result of an increase in the accumulation of amyloid beta peptide (Aβ) and a decrease in neurotransmitters (Acetylcholine) within the brain cells which may be due to increase in acetylcholinesterase (AchE) activity and change in expression of Apolipoprotein E4 (ApoE4) and Clusterin (Clu) genes. The aim of the present study was using natural products such as Ginkgo biloba (G. biloba) extract that has the potential to reduce Aβ formation and increase AchE inhibition with its ability to save neuronal DNA from damage. Methods: Sixty male aged rats were divided into six experimental groups exposed to AlCl3 to induce AD model and were treated with G. biloba extract. Collected brain tissues were used to assess the apoptosis rate, reactive oxygen species (ROS) generation, AchE inhibitory activity, expression alteration in ApoE4 and Clu genes, DNA fragmentations and gutathione peroxidase (GPx) activity. Results: The results exhibited that rats exposed to AlCl3 increased significantly rate of apoptosis, ROS formation, DNA fragmentation, up-regulation of ApoE4 and Clu genes as well as decrease of AchE inhibitory activity and GPx activity compared with those in control rats. However, treatment of AlCl3-rats with G. biloba extract improved the above neurotoxicity results induced by AlCl3 exposure. Conclusion: It is therefore likely that G. biloba extract's protective properties against AD are due to its ability to activate the response against oxidative stress.

RevDate: 2022-05-28

Buchke S, Sharma M, Bora A, et al (2022)

Mitochondria-Targeted, Nanoparticle-Based Drug-Delivery Systems: Therapeutics for Mitochondrial Disorders.

Life (Basel, Switzerland), 12(5): pii:life12050657.

Apart from ATP generation, mitochondria are involved in a wide range of functions, making them one of the most prominent organelles of the human cell. Mitochondrial dysfunction is involved in the pathophysiology of several diseases, such as cancer, neurodegenerative diseases, cardiovascular diseases, and metabolic disorders. This makes it a target for a variety of therapeutics for the diagnosis and treatment of these diseases. The use of nanoparticles to target mitochondria has significant importance in modern times because they provide promising ways to deliver drug payloads to the mitochondria by overcoming challenges, such as low solubility and poor bioavailability, and also resolve the issues of the poor biodistribution of drugs and pharmacokinetics with increased specificity. This review assesses nanoparticle-based drug-delivery systems, such as liposomes, DQAsome, MITO-Porters, micelles, polymeric and metal nanocarriers, as well as quantum dots, as mitochondria-targeted strategies and discusses them as a treatment for mitochondrial disorders.

RevDate: 2022-05-28

Russ H, Mazzanti M, Parsons C, et al (2022)

The Small Molecule GAL-201 Efficiently Detoxifies Soluble Amyloid β Oligomers: New Approach towards Oral Disease-Modifying Treatment of Alzheimer's Disease.

International journal of molecular sciences, 23(10): pii:ijms23105794.

Soluble amyloid β (Aβ) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer's disease (AD). That makes soluble Aβ oligomers a promising drug target. In addition to eliminating these toxic species from the patients' brain with antibody-based drugs, a new class of drugs is emerging, namely Aβ aggregation inhibitors or modulators, which aim to stop the formation of toxic Aβ oligomers at the source. Here, pharmacological data of the novel Aβ aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aβ1-42 monomers (KD = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aβ oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aβ1-42 oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aβ oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aβ1-42 monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile.

RevDate: 2022-05-27

Tung BT, Hang TTT, Kim NB, et al (2022)

Molecular docking and molecular dynamics approach to identify potential compounds in Huperzia squarrosa for treating Alzheimer's disease.

Journal of complementary & integrative medicine pii:jcim-2021-0462 [Epub ahead of print].

OBJECTIVES: Alzheimer's disease (AD) is a lingering progressive neurodegenerative disorder that causes patients to lose cognitive function. The enzyme Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Monoamine oxidase A (MAO A), Beta-secretase cleavage enzyme (BACE 1) and N-methyl-D-aspartate (NMDA) receptors play an important role in the pathogenesis of Alzheimer's disease. Therefore, inhibiting enzymes is an effective method to treat Alzheimer disease. In this study, we evaluated in silico inhibitory effects of AChE, BuChE, MAO A, BACE 1 and NMDA enzyme of Huperzia squarrosa's compounds.

METHODS: The three-dimensional (3D) of N-methyl-D-aspartate receptor (PDB ID: 1PBQ), enzyme β-secretase 1 (PDB ID: 4X7I), enzyme monoamine oxidase A (PDB ID: 2Z5X), enzyme butyrylcholinesterase (PDB ID: 4BDS) and enzyme acetylcholinesterase (PDB ID: 1EVE) were retrieved from the Protein Data Bank RCSB. Molecular docking was done by Autodock vina software and molecular dynamics (MD) simulation of the ligand-protein complex with the least binding energy pose was perfomed by MOE. Lipinski Rule of Five is used to compare compounds with drug-like and non-drug-like properties. Pharmacokinetic parameters of potential compounds were evaluated using the pkCSM tool.

RESULTS: Based on previous publication of Huperzia squarrosa, we have collected 15 compounds. In these compounds, huperzine B, huperzinine, lycoposerramine U N-oxide, 12-epilycodine N-oxide showed strongly inhibit the five AChE, BuChE, MAO A, BACE 1 and NMDA targets for Alzheimer's treatment. Lipinski rule of five and ADMET predict have shown that four above compounds have drug-likeness properties, good absorption ability and cross the blood-brain barrier, which have the most potential to become drugs for the treatment of Alzheimer's in the future. Furthermore, MD study showed that huperzine B and huperzinine have stability of the docking pose with NMDA target.

CONCLUSIONS: In this study, we found two natural compounds in Huperzia squarrosa including Huperzine B and Huperzinine have drug-likeness properties, good absorption ability and cross the blood-brain barrier, which have potential to become drugs for the treatment of Alzheimer's in the future.

RevDate: 2022-05-24

Zhang JY, Ma S, Liu X, et al (2022)

Activating transcription factor 6 regulates cystathionine to increase autophagy and restore memory in Alzheimer' s disease model mice.

Biochemical and biophysical research communications, 615:109-115 pii:S0006-291X(22)00751-3 [Epub ahead of print].

Endoplasmic reticulum stress (ER stress) plays a crucial role in the process of Alzheimer's disease (AD). Activating transcription factor 6 (ATF6) is a crucial sensor of ER stress. In AD patients, the homeostasis of the endogenous signal H2S produced by cystathionine γ-lyase (CTH) is in disbalance. However, the role of ATF6 and CTH in AD is rarely reported. Herein, we found that ATF6 and CTH were reduced in AD patients and APP/PS1 mice by immunohistochemistry and western blots. In LN229 and U87 MG cells, knockdown of ATF6 attenuated CTH expression, whereas overexpression of ATF6 resulted in upregulation of CTH. Brain-specific ATF6 knockout mice expressed significantly down-regulated CTH in the hippocampus and cortex compared to wild-type mice. Mechanistically, ATF6 and CTH increased H2S generation and autophagy-related proteins. Further we observed that CTH promoted the sulfhydration of αSNAP. This is probably to be the specific mechanism by which AFT6 promotes autophagy. Through in vivo studies, we found that αSNAP sulfhydration expression was significantly lower in ATF6 knockout mice than in wild-type mice. Decreased ATF6 impaired spatial memory retention, while addition of CTH rescued memory loss. Together, we demonstrate that ATF6 positively regulates the expression of CTH, which is closely related to the rescue of AD. Targeting the ATF6/CTH signal pathway may provide a new strategy for the treatment of AD.

RevDate: 2022-05-21

Neri S, Mastroianni G, Gardella E, et al (2022)

Epilepsy in neurodegenerative diseases.

Epileptic disorders : international epilepsy journal with videotape, 24(2):249-273.

Although epilepsy as a comorbidity in neurodegenerative disorders is increasingly recognized, its incidence is still underestimated and the features of epilepsy in the different neurodegenerative conditions are still poorly defined. Improved health care, resulting in increased longevity, will unavoidably lead to an increment of epilepsy cases in the elderly. Thus, it is conceivable to expect that neurologists will have to deal with these comorbid conditions to a growing extent in the future. In this seminar, we provide an updated overview of the clinical features, pathophysiological mechanisms and diagnostic and treatment approaches of epilepsy in the most common neurodegenerative disorders (such as Alzheimer disease and other types of dementia, Parkinson disease, Down syndrome, prion diseases, and progressive myoclonus epilepsies), aiming to provide a tool that can help epileptologists and neurologists in the diagnosis and management of this increasingly reported comorbidity.

RevDate: 2022-05-20

El-Ganainy SO, Soliman OA, Ghazy AA, et al (2022)

Intranasal Oxytocin Attenuates Cognitive Impairment, β-Amyloid Burden and Tau Deposition in Female Rats with Alzheimer's Disease: Interplay of ERK1/2/GSK3β/Caspase-3.

Neurochemical research [Epub ahead of print].

Oxytocin is a neuropeptide hormone that plays an important role in social bonding and behavior. Recent studies indicate that oxytocin could be involved in the regulation of neurological disorders. However, its role in modulating cognition in Alzheimer's disease (AD) has never been explored. Hence, the present study aims to investigate the potential of chronic intranasal oxytocin in halting memory impairment & AD pathology in aluminum chloride-induced AD in female rats. Morris water maze was used to assess cognitive dysfunction in two-time points throughout the treatment period. In addition, neuroprotective effects of oxytocin were examined by assessing hippocampal acetylcholinesterase activity, β-amyloid 1-42 protein, and Tau levels. In addition, ERK1/2, GSK3β, and caspase-3 levels were assessed as chief neurobiochemical mediators in AD. Hippocampi histopathological changes were also evaluated. These findings were compared to the standard drug galantamine alone and combined with oxytocin. Results showed that oxytocin restored cognitive functions and improved animals' behavior in the Morris test. This was accompanied by a significant decline in acetylcholinesterase activity, 1-42 β-amyloid and Tau proteins levels. Hippocampal ERK1/2 and GSK3β were also reduced, exceeding galantamine effects, thus attenuating AD pathological hallmarks formation. Determination of caspase-3 revealed low cytoplasmic positivity, indicating the ceasing of neuronal death. Histopathological examination confirmed these findings, showing restored hippocampal cells structure. Combined galantamine and oxytocin treatment showed even better biochemical and histopathological profiles. It can be thus concluded that oxytocin possesses promising neuroprotective potential in AD mediated via restoring cognition and suppressing β-amyloid, Tau accumulation, and neuronal death.

RevDate: 2022-05-20

Beach TG (2022)

A History of Senile Plaques: From Alzheimer to Amyloid Imaging.

Journal of neuropathology and experimental neurology, 81(6):387-413.

Senile plaques have been studied in postmortem brains for more than 120 years and the resultant knowledge has not only helped us understand the etiology and pathogenesis of Alzheimer disease (AD), but has also pointed to possible modes of prevention and treatment. Within the last 15 years, it has become possible to image plaques in living subjects. This is arguably the single greatest advance in AD research since the identification of the Aβ peptide as the major plaque constituent. The limitations and potentialities of amyloid imaging are still not completely clear but are perhaps best glimpsed through the perspective gained from the accumulated postmortem histological studies. The basic morphological classification of plaques into neuritic, cored and diffuse has been supplemented by sophisticated immunohistochemical and biochemical analyses and increasingly detailed mapping of plaque brain distribution. Changes in plaque classification and staging have in turn contributed to changes in the definition and diagnostic criteria for AD. All of this information continues to be tested by clinicopathological correlations and it is through the insights thereby gained that we will best be able to employ the powerful tool of amyloid imaging.

RevDate: 2022-05-20

Zúñiga Santamaría T, Yescas Gómez P, Fricke Galindo I, et al (2022)

Pharmacogenetic studies in Alzheimer disease.

Neurologia (Barcelona, Spain), 37(4):287-303.

INTRODUCTION: Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.

DEVELOPMENT: We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.

CONCLUSIONS: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as ageing.

RevDate: 2022-05-19

Yener G, Hünerli-Gündüz D, Yıldırım E, et al (2022)

Treatment effects on event-related EEG potentials and oscillations in Alzheimer's disease.

International journal of psychophysiology : official journal of the International Organization of Psychophysiology pii:S0167-8760(22)00128-3 [Epub ahead of print].

Alzheimer's disease dementia (ADD) is the most diffuse neurodegenerative disorder belonging to mild cognitive impairment (MCI) and dementia in old persons. This disease is provoked by an abnormal accumulation of amyloid-beta and tauopathy proteins in the brain. Very recently, the first disease-modifying drug has been licensed with reserve (i.e., Aducanumab). Therefore, there is a need to identify and use biomarkers probing the neurophysiological underpinnings of human cognitive functions to test the clinical efficacy of that drug. In this regard, event-related electroencephalographic potentials (ERPs) and oscillations (EROs) are promising candidates. Here, an Expert Panel from the Electrophysiology Professional Interest Area of the Alzheimer's Association and Global Brain Consortium reviewed the field literature on the effects of the most used symptomatic drug against ADD (i.e., Acetylcholinesterase inhibitors) on ERPs and EROs in ADD patients with MCI and dementia at the group level. The most convincing results were found in ADD patients. In those patients, Acetylcholinesterase inhibitors partially normalized ERP P300 peak latency and amplitude in oddball paradigms using visual stimuli. In these same paradigms, those drugs partially normalize ERO phase-locking at the theta band (4-7 Hz) and spectral coherence between electrode pairs at the gamma (around 40 Hz) band. These results are of great interest and may motivate multicentric, double-blind, randomized, and placebo-controlled clinical trials in MCI and ADD patients for final cross-validation.

RevDate: 2022-05-19

Park KH, Jang JW, Suh J, et al (2022)

Executive Summary of the 2021 International Conference of Korean Dementia Association: A Report From the Academic Committee of the Korean Dementia Association.

Dementia and neurocognitive disorders, 21(2):45-58.

Recently, aducanumab, a beta amyloid targeted immunotherapy, has been approved by the US Food and Drug Administration for the treatment of Alzheimer's dementia (AD). Although many questions need to be answered, this approval provides a promising hope for the development of AD drugs that could be supported by new biomarkers such as blood-based ones and composite neuropsychological tests that can confirm pathologic changes in early stages of AD. It is important to elucidate the complexity of AD which is known to be associated with other factors such as vascular etiologies and neuro-inflammation. Through the second international conference of the Korean Dementia Association (KDA), researchers from all over the world have participated in the exchange of opinions with KDA members on the most up-to-date topics. The Academic Committee of the KDA summarizes lectures to provide the depth of the conference as well as discussions. This will be an important milestone to widen the latest knowledge in the research of AD's diagnosis, therapeutics, pathogenesis that can lead to the establishment of future directions.

RevDate: 2022-05-19

R M, M S, C V (2022)

The Involvement of Melatonin and Tasimelteon against Alzheimer's Disease.

Current drug safety pii:CDS-EPUB-123681 [Epub ahead of print].

BACKGROUND: Alzheimer's disease is an age-dependent neurodegenerative disease with a progressive cognition and memory loss, insomnia and other abnormal behavioral changes. Amongst various hypothesis for the AD pathophysiology, the occupational stress-induced Alzheimer's has recently caught up an escalation in AD cases.

OBJECTIVE: Studies pertaining to the same suggests that stress leads to insomnia or sleep disruption, which further leads to neuroinflammation cum oxidative stress, both of which are major harbingers towards AD. Additionally, overall sleep deficit is associated with a progressive cognitive and memory decline, which adds more inconvenience to Alzheimer's disease. Based on this, any triumphant AD management needs a pharmacological intervention that can not only antagonize the amyloid beta induced neurotoxicity but also correct the sleep-wake cycle disruption. Chronobiotic therapeutics like melatonin offer vital neuroprotective effects by eliciting its action through more than one of the pathologies of AD. This is also bolstered by the finding that endogenous melatonin levels are lower in AD patients. This melatonin replacement therapy can be especially useful in AD treatment, but only in the early phases of the disease and in cases where the melatonin receptors are intact and functioning.

CONCLUSION: To negate such limitations, and to extend the action and therapeutic efficacy of melatonin-mediated actions towards AD treatment, melatonin analogue like Tasimelteon can pose a high therapeutic value in AD treatment superior to that provided by melatonin. This review encapsulates all details about how AD is believed to occur, how current situations influence it along with how melatonin and Tasimelteon act towards treating Alzheimer's.

RevDate: 2022-05-17

Nagai Y, Yamazaki T, Sugita T, et al (2022)

Brexpiprazole-Associated Pisa Syndrome (Pleurothotonus) in a Patient With Dementia.

Clinical neuropharmacology, 45(3):72-73.

OBJECTIVES: The aims of the study were to report brexpiprazole-induced Pisa syndrome (PS) in a patient with Alzheimer disease and to discuss the pathophysiology and the treatment of PS.

METHODS: We report a 71-year-old female patient with Alzheimer disease. After 2 months medication of brexpiprazole, she presented PS. By switching to quetiapine, the symptom was ameliorated; however, transient acute dystonia was occurred.

CONCLUSIONS: Drug-induced PS may be associated with dopamine-acetylcholine imbalance. This imbalance causes the dysfunction of the cortex and basal ganglia and the dysfunction of sensory and somatosensory system. Stopping the offending drugs is a choice for the treatment of PS. This is the first report of PS-induced brexpiprazole.

RevDate: 2022-05-16

Andrade JM, Pachar P, Trujillo L, et al (2022)

Suillin: A mixed-type acetylcholinesterase inhibitor from Suillus luteus which is used by Saraguros indigenous, southern Ecuador.

PloS one, 17(5):e0268292 pii:PONE-D-21-28384.

Suillus luteus (L.) Roussel is an edible mushroom commonly known as slippery jack or "Kallampa" by indigenous people from Loja province. It is used in traditional medicine to manage gastrointestinal disorders and headaches. In addition, edible mushrooms have been used for neurodegenerative diseases; however, there is no report about the anticholinesterase effect produced by this species. The aim of this work was to isolate the main secondary metabolite of Suillus luteus and characterize its inhibitory potential against acetylcholinesterase. Fruiting bodies were extracted with ethanol (EtOH) and ethyl acetate (EtOAc). From the EtOAc, suillin, is reported as the major compound. The cholinesterase inhibitory potential of extracts and the major isolated compound was assessed by Ellman´s method and progression curves were recorded at 405 nm for 60 min. Donepezil hydroclhoride was used as a positive control. The samples were dissolved in methanol at 10 mg/mL and two more 10× dilutions were included to obtain final concentrations of 1, 0.1 and 0.01 mg/mL at the mix of reaction. IC50, Km, Vmax, and Ki were calculated for suillin. Suillin (200 mg) along with linoleic acid, ergosterol peroxide and ergosterol were isolated. The EtOH and EtOAc extracts exerted a moderate inhibitory effect (IC50 > 200 μg/mL. In adittion, suillin exerted a non-competitive mixed mechanism. against AChE with an IC50 value of 31.50 μM and Ki of 17.25 μM. To the best of our knowledge, this is the first report of the anticholinesterase effect of Suillus luteus and suillin. The kinetic parameters and the moderate potency of the compound determined in this study, encourage us to propose suillin as a promising chemopreventing agent for the treatment of neurodegenerative diseases such as Alzheimer.

RevDate: 2022-05-16

Shang Q, Zhang Q, Liu X, et al (2022)

Prediction of Early Alzheimer Disease by Hippocampal Volume Changes under Machine Learning Algorithm.

Computational and mathematical methods in medicine, 2022:3144035.

This research was aimed at discussing the application value of different machine learning algorithms in the prediction of early Alzheimer's disease (AD), which was based on hippocampal volume changes in magnetic resonance imaging (MRI). In the research, the 84 cases in American Alzheimer's disease neuroimaging initiative (ADNI) database were selected as the research data. Based on the scoring results of cognitive function, all cases were divided into three groups, including cognitive function normal (normal group), early mild cognitive impairment (e-MCI group), and later mild cognitive impairment (l-MCI group) groups. Each group included 28 cases. The features of hippocampal volume changes in MRI images of the patients in different groups were extracted. The samples of training set and test set were established. Besides, the established support vector machine (SVM), decision tree (DT), and random forest (RF) prediction models were used to predict e-MCI. Metalinear regression was utilized to analyze MRI feature data, and the predictive accuracy, sensitivity, and specificity of different models were calculated. The result showed that the volumes of hippocampal left CA1, left CA2-3, left CA4-DG, left presubiculum, left tail, right CA2-3, right CA4-DG, right presubiculum, and right tail in e-MCI group were all smaller than those in normal group (P < 0.01). The corresponding volume of hippocampal subregions in l-MCI group was remarkably reduced compared with that in normal group (P < 0.001). The volumes of regions left CA1, left CA2-3, left CA4-DG, right CA2-3, right CA4-DG, and right presubiculum were all positively correlated with logical memory test-delay recall (LMT-DR) score (R 2 = 0.1702, 0.3779, 0.1607, 0.1620, 0.0426, and 0.1309; P < 0.001). The predictive accuracy of training set sample by DT, SVM, and RF was 86.67%, 93.33%, and 98.33%, respectively. Based on the changes in the volumes of left CA4-DG, right CA2-3, and right CA4-DG, the predictive accuracy of e-MCI and l-MCI by RF model was both higher than those by DT model (P < 0.01). Besides, the predictive accuracy, sensitivity, and specificity of e-MCI by RF model was all notably higher than those by DT model (P < 0.01). The above results demonstrated that the effective early AD prediction models were established by the volume changes in hippocampal subregions, which was based on RF in the research. The establishment of early AD prediction models offered certain reference basis to the diagnosis and treatment of AD patients.

RevDate: 2022-05-16

Lacroix C, Alleman-Brimault I, Zalta A, et al (2022)

What Do We Know About Medical Cannabis in Neurological Disorders and What Are the Next Steps?.

Frontiers in pharmacology, 13:883987 pii:883987.

Medical use of cannabis has been receiving growing attention over the last few decades in modern medicine. As we know that the endocannabinoid system is largely involved in neurological disorders, we focused on the scientific rationale of medical cannabis in three neurological disorders: amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease through pharmacological plausibility, clinical studies, and patients' view. Clinical studies (randomized controlled trials, open-label studies, cohorts, and case reports) exploring medical cannabis in these disorders show different results depending on the methods and outcomes. Some show benefits on motor symptoms and others on non-motor symptoms and quality of life. Concerning patients' view, several web surveys were collected, highlighting the real use of cannabis to relieve symptoms of neurological disorders, mostly outside a medical pathway. This anarchic use keeps questioning particularly in terms of risks: consumption of street cannabis, drug-drug interactions with usual medical treatment, consideration of medical history, and adverse reactions (psychiatric, respiratory, cardiovascular disorders, etc.), underlining the importance of a medical supervision. To date, most scientific data support the therapeutic potential of cannabis in neurological disorders. As far as patients and patients' associations are calling for it, there is an urgent need to manage clinical studies to provide stronger evidence and secure medical cannabis use.

RevDate: 2022-05-14

Esselun C, Dieter F, Sus N, et al (2022)

Walnut Oil Reduces Aβ Levels and Increases Neurite Length in a Cellular Model of Early Alzheimer Disease.

Nutrients, 14(9): pii:nu14091694.

(1) Background: Mitochondria are the cells' main source of energy. Mitochondrial dysfunction represents a key hallmark of aging and is linked to the development of Alzheimer's disease (AD). Maintaining mitochondrial function might contribute to healthy aging and the prevention of AD. The Mediterranean diet, including walnuts, seems to prevent age-related neurodegeneration. Walnuts are a rich source of α-linolenic acid (ALA), an essential n3-fatty acid and the precursor for n3-long-chain polyunsaturated fatty acids (n3-PUFA), which might potentially improve mitochondrial function. (2) Methods: We tested whether a lipophilic walnut extract (WE) affects mitochondrial function and other parameters in human SH-SY5Y cells transfected with the neuronal amyloid precursor protein (APP695). Walnut lipids were extracted using a Soxhlet Extraction System and analyzed using GC/MS and HPLC/FD. Adenosine triphosphate (ATP) concentrations were quantified under basal conditions in cell culture, as well as after rotenone-induced stress. Neurite outgrowth was investigated, as well as membrane integrity, cellular reactive oxygen species, cellular peroxidase activity, and citrate synthase activity. Beta-amyloid (Aβ) was quantified using homogenous time-resolved fluorescence. (3) Results: The main constituents of WE are linoleic acid, oleic acid, α-linolenic acid, and γ- and δ-tocopherol. Basal ATP levels following rotenone treatment, as well as citrate synthase activity, were increased after WE treatment. WE significantly increased cellular reactive oxygen species but lowered peroxidase activity. Membrane integrity was not affected. Furthermore, WE treatment reduced Aβ1-40 and stimulated neurite growth. (4) Conclusions: WE might increase ATP production after induction of mitochondrial biogenesis. Decreased Aβ1-40 formation and enhanced ATP levels might enhance neurite growth, making WE a potential agent to enhance neuronal function and to prevent the development of AD. In this sense, WE could be a promising agent for the prevention of AD.

RevDate: 2022-05-14

Michailidis M, Tata DA, Moraitou D, et al (2022)

Antidiabetic Drugs in the Treatment of Alzheimer's Disease.

International journal of molecular sciences, 23(9): pii:ijms23094641.

The public health burden of type 2 diabetes mellitus and Alzheimer's disease is steadily increasing worldwide, especially in the population of older adults. Epidemiological and clinical studies suggest a possible shared pathophysiology between the two diseases and an increased risk of AD in patients with type 2 diabetes mellitus. Therefore, in recent years, there has been a substantial interest in identifying the mechanisms of action of antidiabetic drugs and their potential use in Alzheimer's disease. Human studies in patients with mild cognitive impairment and Alzheimer's disease have shown that administration of some antidiabetic medications, such as intranasal insulin, metformin, incretins, and thiazolidinediones, can improve cognition and memory. This review aims to examine the latest evidence on antidiabetic medications as a potential candidate for the treatment of Alzheimer's disease.

RevDate: 2022-05-13

Pradhan LK, Sahoo PK, Chauhan S, et al (2022)

Recent Advances Towards Diagnosis and Therapeutic Fingerprinting for Alzheimer's Disease.

Journal of molecular neuroscience : MN [Epub ahead of print].

Since the report of "a peculiar severe disease process of the cerebral cortex" by Alois Alzheimer in 1906, it was considered to be a rare condition characterized by loss of cognition, memory impairment, and pathological markers such as senile plaques or neurofibrillary tangles (NFTs). Later on, the report was published in the textbook "Psychiatrie" and the disease was named as Alzheimer's disease (AD) and was known to be the consequences of aging; however, owing to its complex etiology, there is no cure for the progressive neurodegenerative disorder. Our current understanding of the mechanisms involved in the pathogenesis of AD is still at the mechanistic level. The treatment strategies applied currently only alleviate the symptoms and co-morbidities. For instance, the available treatments such as the usage of acetylcholinesterase inhibitors and N-methyl D-aspartate antagonists have minimal impact on the disease progression and target the later aspects of the disease. The recent advancements in the last two decades have made us more clearly understand the pathophysiology of the disease which has led to the development of novel therapeutic strategies. This review gives a brief idea about the various facets of AD pathophysiology and its management through modern investigational therapies to give a new direction for development of targeted therapeutic measures.

RevDate: 2022-05-13

Yang SY, He XY, Dobkin C, et al (2022)

Infantile Neurodegeneration results from Mutants of 17β-Hydroxysteroid Dehydrogenase Type 10 rather than Aβ-Binding Alcohol Dehydrogenase.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 36 Suppl 1:.

Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10), a mitochondrial homo-tetrameric multifunctional protein encoded by the HSD17B10 gene is necessary for brain cognitive function. Missense mutations on this gene resulted in HSD10 mitochondrial disease, an inborn error in isoleucine metabolism. A 5-methylcytosine hotspot in this gene underlying a 388C ̵T transition leads to the HSD10(p.R130C) mutant responsible for about half cases of infantile neurodegeneration. Less females suffers with this disease and usually has milder clinical manifestation due to the X-inactivation. The binding capability of this dehydrogenase to Aβ-peptide may play a role in senile neurodegeneration, namely Alzheimer disease, but it appears unrelated to infantile neurodegeneration. Unfortunately, this research field has been interfered by reports of the Aβ-peptide binding alcohol dehydrogenase (ABAD) or endoplasmic reticulum-associated Aβ binding protein (ERAB). Both reflect some dubious features of 17β-HSD10. It is clarified here that ERAB is merely a subunit of 17β-HSD10, having a fictitious association with the endoplasmic reticulum. 17β-HSD10 exhibits L-3-hydroxyacyl-CoA dehydrogenase activity so also known as short chain 3-hydorxyacyl-CoA dehydrogenase (SCHAD), but it is not involved in the ketone body metabolism as reported for ABAD's function in the cellular response to nutritional stress. Furthermore, the reported generalized alcohol dehydrogenase data underlying the ABAD activity could not be based upon valid reproducible experiments, and the rediscovery of its mitochondrial localization was preceded by unreferenced 17β-HSD10 research. Clarification of unreliable ABAD/ERAB data may invigorate this research field, and open new approaches to the understanding and treatment of the HSD17B10gene related disorders including infantile neurodegeneration and Alzheimer's disease.

RevDate: 2022-05-11

Burkett BJ, Babcock JC, Lowe VJ, et al (2022)

PET Imaging of Dementia: Update 2022.

Clinical nuclear medicine pii:00003072-990000000-00127 [Epub ahead of print].

ABSTRACT: PET imaging plays an essential role in achieving earlier and more specific diagnoses of dementia syndromes, important for clinical prognostication and optimal medical management. This has become especially vital with the recent development of pathology-specific disease-modifying therapy for Alzheimer disease, which will continue to evolve and require methods to select appropriate treatment candidates. Techniques that began as research tools such as amyloid and tau PET have now entered clinical use, making nuclear medicine physicians and radiologists essential members of the care team. This review discusses recent changes in the understanding of dementia and examines the roles of nuclear medicine imaging in clinical practice. Within this framework, multiple cases will be shown to illustrate a systematic approach of FDG PET interpretation and integration of PET imaging of specific molecular pathology including dopamine transporters, amyloid, and tau. The approach presented here incorporates contemporary understanding of both common and uncommon dementia syndromes, intended as an updated practical guide to assist with the sophisticated interpretation of nuclear medicine examinations in the context of this rapidly and continually developing area of imaging.

RevDate: 2022-05-11

Wassef HR, PM Colletti (2022)

Commentary: Aducanumab-Related ARIA: Paean or Lament?.

Clinical nuclear medicine [Epub ahead of print].

ABSTRACT: Høilund-Carlsen and colleagues raise important issues related to amyloid PET, diagnosis of Alzheimer disease, and recently approved antiamyloid treatment aducanumab. We discuss new developments that may direct us to methods of presymptomatic detection of Alzheimer disease and development of effective prevention and therapy.

RevDate: 2022-05-11

Ritchie CW, Waymont JMJ, Pennington C, et al (2022)

The Scottish Brain Health Service Model: Rationale and Scientific Basis for a National Care Pathway of Brain Health Services in Scotland.

The journal of prevention of Alzheimer's disease, 9(2):348-358.

In order to address the oft-cited societal, economic, and health and social care impacts of neurodegenerative diseases, such as Alzheimer's disease, we must move decisively from reactive to proactive clinical practice and to embed evidence-based brain health education throughout society. Most disease processes can be at least partially prevented, slowed, or reversed. We have long neglected to intervene in neurodegenerative disease processes, largely due to a misconception that their predominant symptom - cognitive decline - is a normal, age-related process, but also due to a lack of multi-disciplinary collaboration. We now understand that there are modifiable risk factors for neurodegenerative diseases, that successful management of common comorbidities (such as diabetes and hypertension) can reduce the incidence of neurodegenerative disease, and that disease processes begin (and, crucially, can be detected, reduced, and delayed, prevented, or treated) decades earlier in life than had previously been appreciated. Brain Health Scotland, established by Scottish Government and working in partnership with Alzheimer Scotland, propose far-reaching public health and clinical practice approaches to reduce neurodegenerative disease incidence. Focusing here on Brain Health Scotland's clinical offerings, we present the Scottish Model for Brain Health Services. To our knowledge, the Scottish Model for Brain Health, built on foundations of personalised risk profiling, targeted risk reduction and prevention, early disease detection, equity of access, and harnessing comprehensive data to assist in clinical decision-making, marks the first example of a nationwide approach to overhauling clinical, societal, and political approaches to the prevention, assessment, and treatment of neurodegenerative disease.

RevDate: 2022-05-11

Lewis CK, Bernstein OM, Grill JD, et al (2022)

Anxiety and Depressive Symptoms and Cortical Amyloid-β Burden in Cognitively Unimpaired Older Adults.

The journal of prevention of Alzheimer's disease, 9(2):286-296.

BACKGROUND: There is evidence of relationships between behavioral symptoms and increased risk for Alzheimer's Disease and/or Alzheimer's Disease biomarkers. However, the nature of this relationship is currently unknown.

OBJECTIVES: To evaluate the relationship between anxiety and depressive symptoms and amyloid-β deposition in cognitively unimpaired older adults, and to assess mediating effects of either objective or subjective cognitive skills.

DESIGN: Cross-sectional analysis of screening data from participants enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study (ClinicalTrials.gov Identifier: NCT02008357).

SETTING: Data analysis.

PARTICIPANTS: 4492 cognitively unimpaired adults, age 65-85, enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study.

MEASUREMENTS: We used linear regression to estimate the associations between amyloid-β standard uptake value ratio (SUVR) and Geriatric Depression Scale (GDS) and State Trait Anxiety Inventory (STAI) scores while adjusting for potential confounding factors as well as for Cognitive Function Index (CFI) or Preclinical Alzheimer's Cognitive Composite (PACC) scores as possible mediational variables.

RESULTS: 4399 subjects with complete covariates were included (mean age: 71.3, 59% female), GDS ranged 0-13 (mean: 1.0), and STAI ranged 6-24 (mean: 9.9). Amyloid-β SUVR was modestly associated with STAI; mean STAI score was estimated to be 0.275 points higher (95% CI: 0.038, 0.526; p-value = 0.023) for each 0.5-point increase in cortical amyloid-β SUVR. Subjective cognitive decline (CFI) attenuated the relationship between SUVR and STAI, while objective cognitive function (PACC) did not. No statistically significant relationship between SUVR and GDS was observed (p = 0.326).

CONCLUSIONS: In cognitively unimpaired adults with low levels of depression and anxiety, cortical amyloid-β deposition is associated with anxiety but not depressive symptoms. Attenuation of this relationship by subjective cognitive difficulties suggests that anxiety may be partly due to such a perception resulting from cortical amyloid-β deposition.

RevDate: 2022-05-09

Yuan A, CS Lee (2022)

Retinal Biomarkers for Alzheimer Disease: The Facts and the Future.

Asia-Pacific journal of ophthalmology (Philadelphia, Pa.), 11(2):140-148.

ABSTRACT: Alzheimer disease (AD) is a significant cause of morbidity and mortality worldwide, with limited treatment options and considerable diagnostic challenges. Identification and validation of retinal changes that correlate with clinicopathologic features of AD could provide a noninvasive method of screening and monitoring progression of disease, with notable implications for developing new therapies, particularly in its preclinical stages. Retinal biomarkers that have been studied to date include structural changes in neurosensory retinal layers, alterations in vascular architecture and function, and pathologic deposition of proteins within the retina, which have all demonstrated variable correlation with the presence of preclinical or clinical AD. Evolution of specialized retinal imaging modalities and advances in artificial intelligence hold great promise for future study in this burgeoning field. The current status of research in retinal biomarkers, and some of the challenges that will need to be addressed in future work, are reviewed herein.

RevDate: 2022-05-09

Rafii MS, Sol O, Mobley WC, et al (2022)

Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome: A Phase 1b Randomized Clinical Trial.

JAMA neurology pii:2792226 [Epub ahead of print].

Importance: Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-β (Aβ). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aβ pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined.

Objective: To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aβ immunoglobulin G titers.

This multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up.

Interventions: Participants were randomized to receive 7 subcutaneous injections of ACI-24, 300 μg or 1000 μg, or placebo.

Main Outcomes and Measures: Primary outcomes were measures of safety and tolerability as well as antibody titers.

Results: Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aβ immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 μg and 2 receiving 1000 μg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aβ1-40 and Aβ1-42 levels among individuals receiving ACI-24.

Conclusions and Relevance: In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aβ antibody titers were not associated with any adverse findings. These results support progression to clinical trials using an optimized formulation of the ACI-24 vaccine among individuals with DS.

Trial Registration: ClinicalTrials.gov Identifier: NCT02738450.

RevDate: 2022-05-09

Revuelta M, Urrutia J, Villarroel A, et al (2022)

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer's Disease: Possible Therapeutic Role of KV1.3 Channel Blockade.

Frontiers in cellular neuroscience, 16:868842.

Increase of deposits of amyloid β peptides in the extracellular matrix is landmark during Alzheimer's Disease (AD) due to the imbalance in the production vs. clearance. This accumulation of amyloid β deposits triggers microglial activation. Microglia plays a dual role in AD, a protective role by clearing the deposits of amyloid β peptides increasing the phagocytic response (CD163, IGF-1 or BDNF) and a cytotoxic role, releasing free radicals (ROS or NO) and proinflammatory cytokines (TNF-α, IL-1β) in response to reactive gliosis activated by the amyloid β aggregates. Microglia activation correlated with an increase KV1.3 channels expression, protein levels and current density. Several studies highlight the importance of KV1.3 in the activation of inflammatory response and inhibition of neural progenitor cell proliferation and neuronal differentiation. However, little is known about the pathways of this activation in neural stem cells differentiation and proliferation and the role in amyloid β accumulation. In recent studies using in vitro cells derived from mice models, it has been demonstrated that KV1.3 blockers inhibit microglia-mediated neurotoxicity in culture reducing the expression and production of the pro-inflammatory cytokines IL-1β and TNF-α through the NF-kB and p38MAPK pathway. Overall, we conclude that KV1.3 blockers change the course of AD development, reducing microglial cytotoxic activation and increasing neural stem cell differentiation. However, further investigations are needed to establish the specific pathway and to validate the use of this blocker as therapeutic treatment in Alzheimer patients.

RevDate: 2022-05-07

Shabbir A, Rehman K, Akash MSH, et al (2022)

Differential neuroprotective effect of curcuminoid formulations in aluminum chloride-induced Alzheimer's disease.

Environmental science and pollution research international [Epub ahead of print].

Alzheimer's disease (AD) is a slowly progressive brain degenerative disorder which gradually impairs memory, thinking, and ability to perform easy routine tasks. This degenerative disorder mainly targets the elderly people and has imposed an endemic burden on society. Hence, there is a crucial need to investigate the efficacious herbal pharmacotherapies that can effectively mitigate and prevent the pathological hallmarks of AD. The current study aims to explore the potential efficacy of curcuminoid-rich extract (CRE) and its ternary complex (TC). Experimental rodents were administered with AlCl3 (300 mg/kg) to induce AD and treated with rivastigmine, curcuminoid crude extract, CRE, and TC orally for three consecutive weeks. Neurobehavioral, biochemical, and histopathological studies were performed from the last week of the study period. The mRNA expression of different pathological biomarkers was estimated by RT-qPCR analysis. The results of the study suggested that CRE and TC significantly improved the behavioral, biochemical parameters and acetylcholinesterase inhibitory activity in treatment groups. Histological analysis was also carried out indicating that the neurodegenerative changes and neuronal loss were stabilized by CRE and TC supplementation. CRE and TC supplementation remarkably downregulated the interleukin-1α, tumor necrosis factor-α, interleukin-1β, acetylcholinesterase, and β-secretase pathological gene expression. Hence, it was concluded that CRE and TC may act as promising candidates in the prevention of AD via numerous underlying signaling pathways.

RevDate: 2022-05-06

Wang Z, S Cheng (2022)

Effects of Pramipexole Combined with Nerve Growth Factor on Cognitive Impairment and Urinary AD7c-NTP Expression in Patients with Parkinson's Disease.

Computational and mathematical methods in medicine, 2022:3398732.

Objective: To explore the effects of pramipexole combined with nerve growth factor (NGF) on cognitive impairment and urinary Alzheimer-associated neural thread protein (AD7c-NTP) expression in patients with Parkinson's disease (PD).

Methods: Fifty patients with PD treated in our hospital from February 2020 to April 2021 were enrolled. The patients were arbitrarily assigned into control group and study group. The former was treated with pramipexole, and the latter was treated with pramipexole combined with NGF. The efficacy, cognitive function, serum inflammatory factors, cortisol levels, serum macrophage migration inhibitory factor (MIF), brain-derived neurotrophic factor (BDNF), urine AD7c-NTP levels, and the incidence of adverse reactions were compared.

Results: First of all, the effective rate in the study group was higher compared to the control group (P < 0.05). After treatment, the cognitive function was enhanced, and the scores of Montreal cognitive assessment (MoCA) in the study group were higher compared to the control group (P < 0.05). The levels of serum IL-6, CRP, and TNF-α decreased after treatment, and the levels of serum IL-6, CRP, and TNF-α in the study group were remarkably lower compared to the control group (P < 0.05). In addition, the levels of serum DA, NE, and 5-HT increased after treatment, and the levels of serum DA, NE, and 5-HT in the study group were remarkably higher compared to the control group (P < 0.05). Then, the levels of serum MIF and urine AD7c-NTP decreased and BDNF increased after treatment, and the level of BDNF in the study group was higher compared to the control group, while the levels of serum MIF and urine AD7c-NTP in the study group were lower compared to the control group (P < 0.05). Finally, the adverse reactions were compared. The incidence of adverse reactions in the study group was lower compared to the control group, and the difference exhibited not statistically significant (16.00% vs. 24.00%, P > 0.05).

Conclusion: Pramipexole combined with NGF therapy not only can effectively strengthen the cognitive impairment of patients with PD and promote clinical efficacy and high safety but also can inhibit inflammatory state, regulate brain neurotransmitters, and reduce urinary AD7c-NTP levels.

RevDate: 2022-05-05

Tang Y, Zhang D, Zhang Y, et al (2022)

Cross-seeding between Aβ and SEVI indicates a pathogenic link and gender difference between alzheimer diseases and AIDS.

Communications biology, 5(1):417.

Amyloid-β (Aβ) and semen-derived enhancer of viral infection (SEVI) are considered as the two causative proteins for central pathogenic cause of Alzheimer's disease (AD) and HIV/AIDS, respectively. Separately, Aβ-AD and SEVI-HIV/AIDS systems have been studied extensively both in fundamental research and in clinical trials. Despite significant differences between Aβ-AD and SEVI-HIV/AIDS systems, they share some commonalities on amyloid and antimicrobial characteristics between Aβ and SEVI, there are apparent overlaps in dysfunctional neurological symptoms between AD and HIV/AIDS. Few studies have reported a potential pathological link between Aβ-AD and SEVI-HIV/AIDS at a protein level. Here, we demonstrate the cross-seeding interactions between Aβ and SEVI proteins using in vitro and in vivo approaches. Cross-seeding of SEVI with Aβ enabled to completely prevent Aβ aggregation at sub-stoichiometric concentrations, disaggregate preformed Aβ fibrils, reduce Aβ-induced cell toxicity, and attenuate Aβ-accumulated paralysis in transgenic AD C. elegans. This work describes a potential crosstalk between AD and HIV/AIDS via the cross-seeding between Aβ and SEVI, identifies SEVI as Aβ inhibitor for possible treatment or prevention of AD, and explains the role of SEVI in the gender difference in AD.

RevDate: 2022-05-02

Whitehouse PJ, V Saini (2022)

Making the Case for the Accelerated Withdrawal of Aducanumab.

Journal of Alzheimer's disease : JAD pii:JAD220264 [Epub ahead of print].

U.S. Food and Drug Administration-s (FDA) approval of aducanumab (Aduhelm® in the US) as a treatment for mild cognitive impairment of the Alzheimer type and Alzheimer-s disease has raised such major concerns about efficacy, safety, FDA processes, and regulatory capture that Biogen-s license to market this biologic should be immediately withdrawn. Aducanumab has not demonstrated benefit to patients, failed to meet regulatory guidelines, and is likely to cause both individual and societal harm.

RevDate: 2022-04-29

Ahmed K, Mitchell DGV, Blair M, et al (2022)

Disentangling Reversal-learning Impairments in Frontotemporal Dementia and Alzheimer Disease.

Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology [Epub ahead of print].

BACKGROUND: Individuals with frontotemporal dementia (FTD) often present with poor decision-making, which can affect both their financial and social situations. Delineation of the specific cognitive impairments giving rise to impaired decision-making in individuals with FTD may inform treatment strategies, as different neurotransmitter systems have been associated with distinct patterns of altered decision-making.

OBJECTIVE: To use a reversal-learning paradigm to identify the specific cognitive components of reversal learning that are most impaired in individuals with FTD and those with Alzheimer disease (AD) in order to inform future approaches to treatment for symptoms related to poor decision-making and behavioral inflexibility.

METHOD: We gave 30 individuals with either the behavioral variant of FTD or AD and 18 healthy controls a stimulus-discrimination reversal-learning task to complete. We then compared performance in each phase between the groups.

RESULTS: The FTD group demonstrated impairments in initial stimulus-association learning, though to a lesser degree than the AD group. The FTD group also performed poorly in classic reversal learning, with the greatest impairments being observed in individuals with frontal-predominant atrophy during trials requiring inhibition of a previously advantageous response.

CONCLUSION: Taken together, these results and the reversal-learning paradigm used in this study may inform the development and screening of behavioral, neurostimulatory, or pharmacologic interventions aiming to address behavioral symptoms related to stimulus-reinforcement learning and response inhibition impairments in individuals with FTD.

RevDate: 2022-04-28

Li S, AM Stern (2022)

Bioactive human Alzheimer brain soluble Aβ: pathophysiology and therapeutic opportunities.

Molecular psychiatry [Epub ahead of print].

The accumulation of amyloid-β protein (Aβ) plays an early role in the pathogenesis of Alzheimer's disease (AD). The precise mechanism of how Aβ accumulation leads to synaptic dysfunction and cognitive impairment remains unclear but is likely due to small soluble oligomers of Aβ (oAβ). Most studies have used chemical synthetic or cell-secreted Aβ oligomers to study their pathogenic mechanisms, but the Aβ derived from human AD brain tissue is less well characterized. Here we review updated knowledge on the extraction and characterization of bioactive human AD brain oAβ and the mechanisms by which they cause hippocampal synaptic dysfunction. Human AD brain-derived oAβ can impair hippocampal long-term potentiation (LTP) and enhance long-term depression (LTD). Many studies suggest that oAβ may directly disrupt neuronal NMDA receptors, AMPA receptors and metabotropic glutamate receptors (mGluRs). oAβ also impairs astrocytic synaptic functions, including glutamate uptake, D-serine release, and NMDA receptor function. We also discuss oAβ-induced neuronal hyperexcitation. These results may suggest a multi-target approach for the treatment of AD, including both oAβ neutralization and reversal of glutamate-mediated excitotoxicity.

RevDate: 2022-04-28

Vecchio F (2022)

Cognitive training and neuromodulation for Alzheimer treatment.

Aging, undefined(undefined): pii:204044 [Epub ahead of print].

RevDate: 2022-04-28

Yamaguchi S, M Narukawa (2022)

Combinations of Drug Candidate Properties Affecting Development Success and Discontinuation for 5 Diseases: Lymphoma, Non-Small Cell Lung Cancer, Arthritis, Depression, and Alzheimer Disease.

Journal of clinical pharmacology [Epub ahead of print].

The effects of the properties of drug candidates on their successful approval for the treatment of diseases are substantial. However, the success rate of candidates when their properties are combined has not been sufficiently evaluated. We aimed to identify combinations of properties (target, action, and modality) that increased the approval success rate of drug candidates for 5 diseases as well as to understand the characteristics of discontinued candidates. We calculated the approval success rates by combining the properties of drug candidates developed for 5 diseases (non-small cell lung cancer, lymphoma, arthritis, depression, and Alzheimer disease [AD]), using candidates for which clinical development was initiated between 2000 and 2010. We also analyzed the phases and the reasons for the discontinuation of candidates of the 5 diseases for which development was discontinued. Probable combinations of properties with relatively high success rates for the diseases except for Alzheimer disease were found. These combinations of properties were considered appropriate in light of the pathology of each disease. The percentage of candidates discontinued in phase III for Alzheimer disease was higher than that for the other diseases. The reasons for discontinuation showed different trends between combinations of properties that had high and low approval success rates. As the effects of the properties of candidates on the success rate vary depending on the intended disease, pharmaceutical companies need to consider the probability of success of candidates for individual diseases for more efficient candidate selection.

RevDate: 2022-04-27

Jacobson N, Lithgow B, Jafari Jozani M, et al (2022)

The Effect of Transcranial Alternating Current Stimulation With Cognitive Training on Executive Brain Function in Individuals With Dementia: Protocol for a Crossover Randomized Controlled Trial.

JMIR research protocols, 11(4):e37282 pii:v11i4e37282.

BACKGROUND: Although memory and cognitive declines are associated with normal brain aging, they may also be precursors to dementia.

OBJECTIVE: We aim to offer a novel approach to prevent or slow the progress of neurodegenerative dementia, or plausibly, improve the cognitive functions of individuals with dementia.

METHODS: We will recruit and enroll 75 participants (older than 50 years old with either mild cognitive impairment or probable early or moderate dementia) for this double-blind randomized controlled study to estimate the efficacy of active transcranial alternating current stimulation with cognitive treatment (in comparison with sham transcranial alternating current stimulation). This will be a crossover study; a cycle consists of sham or active treatment for a period of 4 weeks (5 days per week, in two 30-minute sessions with a half-hour break in between), and participants are randomized into 2 groups, with stratification by age, sex, and cognitive level (measured with the Montreal Cognitive Assessment). Outcomes will be assessed before and after each treatment cycle. The primary outcomes are changes in Wechsler Memory Scale Older Adult Battery and Alzheimer Disease Assessment Scale scores. Secondary outcomes are changes in performance on tests of frontal lobe functioning (verbal fluency), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), mood changes (Montgomery-Åsberg Depression Rating Scale), and short-term recall (visual 1-back task). Exploratory outcome measures will also be assessed: static and dynamic vestibular response using electrovestibulography, neuronal changes using functional near-infrared spectroscopy, and change in spatial orientation using virtual reality navigation.

RESULTS: As of February 10, 2022, the study is ongoing: 7 patients have been screened, and all were deemed eligible for and enrolled in the study; 4 participants have completed baseline assessments.

CONCLUSIONS: We anticipate that transcranial alternating current stimulation will be a well-tolerated treatment, with no serious side effects and with considerable short- and long-term cognitive improvements.

TRIAL REGISTRATION: Clinicaltrials.gov NCT05203523; https://clinicaltrials.gov/show/NCT05203523.

DERR1-10.2196/37282.

RevDate: 2022-04-25

Danish SM, Gupta A, Khan UA, et al (2022)

Intranasal Cerium Oxide Nanoparticles Ameliorate Cognitive Function in Rats with Alzheimer's via Anti-Oxidative Pathway.

Pharmaceutics, 14(4):.

Cerium oxide nanoparticles (CNPs), owing to their antioxidant property, have recently emerged as therapeutic candidate for Alzheimer's disease (AD). However, intravenous CNPs are limited due to their poor physicochemical properties, rapid blood clearance and poor blood-brain penetration. Thus, we developed intranasal CNPs and evaluated its potential in experimental AD. CNPs were synthesized using homogenous precipitation method and optimized through Box-Behnken Design. The formation of CNPs was confirmed by UV spectroscopy and FTIR. The optimized CNP were spherical, small (134.0 ± 3.35 nm), uniform (PDI, 0.158 ± 0.0019) and stable (ZP, -21.8 ± 4.94 mV). The presence of Ce in CNPs was confirmed by energy-dispersive X-ray analysis. Further, the X-ray diffraction spectra revealed that the CNPs were nano-crystalline. The DPPH assay showed that at concentration of 50 µg/mL, the percentage radical scavenging was 95.40 ± 0.006%. Results of the in vivo behavioral studies in the scopolamine-induced Alzheimer rat model showed that intranasal CNPs dose dependently reversed cognitive ability. At dose of 6 mg/kg the morris water maze results (escape latency, path length and dwell time) and passive avoidance results (retention latency) were significantly different from untreated group but not significantly different from positive control group (rivastigmine patch, 13.3 mg/24 h). Further, biochemical estimation showed that intranasal CNP upregulated the levels of SOD and GSH in brain. In conclusion, intranasal CNPs, through its antioxidant effect, could be a prospective therapeutics for the treatment of cognitive impairment in AD.

RevDate: 2022-04-25

Aguilar-Pineda JA, Paco-Coralla SG, Febres-Molina C, et al (2022)

In Silico Analysis of the Antagonist Effect of Enoxaparin on the ApoE4-Amyloid-Beta (Aβ) Complex at Different pH Conditions.

Biomolecules, 12(4): pii:biom12040499.

Apolipoprotein E4 (ApoE4) is thought to increase the risk of developing Alzheimer's disease. Several studies have shown that ApoE4-Amyloid β (Aβ) interactions can increment amyloid depositions in the brain and that this can be augmented at low pH values. On the other hand, experimental studies in transgenic mouse models have shown that treatment with enoxaparin significantly reduces cortical Aβ levels, as well as decreases the number of activated astrocytes around Aβ plaques. However, the interactions between enoxaparin and the ApoE4-Aβ proteins have been poorly explored. In this work, we combine molecular dynamics simulations, molecular docking, and binding free energy calculations to elucidate the molecular properties of the ApoE4-Aβ interactions and the competitive binding affinity of the enoxaparin on the ApoE4 binding sites. In addition, we investigated the effect of the environmental pH levels on those interactions. Our results showed that under different pH conditions, the closed form of the ApoE4 protein, in which the C-terminal domain folds into the protein, remains stabilized by a network of hydrogen bonds. This closed conformation allowed the generation of six different ApoE4-Aβ interaction sites, which were energetically favorable. Systems at pH5 and 6 showed the highest energetic affinity. The enoxaparin molecule was found to have a strong energetic affinity for ApoE4-interacting sites and thus can neutralize or disrupt ApoE4-Aβ complex formation.

RevDate: 2022-04-25

Romero-Márquez JM, Navarro-Hortal MD, Jiménez-Trigo V, et al (2022)

An Olive-Derived Extract 20% Rich in Hydroxytyrosol Prevents β-Amyloid Aggregation and Oxidative Stress, Two Features of Alzheimer Disease, via SKN-1/NRF2 and HSP-16.2 in Caenorhabditis elegans.

Antioxidants (Basel, Switzerland), 11(4):.

Olive milling produces olive oil and different by-products, all of them very rich in different bioactive compounds like the phenolic alcohol hydroxytyrosol. The aim of the present study was to investigate the effects of an olive fruit extract 20% rich in hydroxytyrosol on the molecular mechanisms associated with Alzheimer disease features like Aβ- and tau- induced toxicity, as well as on oxidative stress in Caenorhabditis elegans. Moreover, characterization of the extracts, regarding the profile and content of phenolics, as well as total antioxidant ability, was investigated. The study of lethality, growth, pharyngeal pumping, and longevity in vivo demonstrated the lack of toxicity of the extract. One hundred μg/mL of extract treatment revealed prevention of oxidative stress and a delay in Aβ-induced paralysis related with a lower presence of Aβ aggregates. Indeed, the extract showed the ability to avoid a certain degree of proteotoxicity associated with aggregation of the tau protein. According to RNAi tests, SKN-1/NRF2 transcription factor and the overexpression of HSP-16.2 were mechanistically associated in the observed effects.

RevDate: 2022-04-22

Høilund-Carlsen PF, Werner TJ, Alavi A, et al (2022)

Aducanumab-Related Amyloid-Related Imaging Abnormalities: Paean or Lament?.

Clinical nuclear medicine pii:00003072-990000000-00111 [Epub ahead of print].

ABSTRACT: When the FDA granted accelerated approval of Biogen's Alzheimer disease drug, aducanumab (marketed as Aduhelm), it deviated from its mission of guaranteeing drug safety and efficacy because the approval was based exclusively on a perceived dose-dependent reduction in brain amyloid deposits and not upon a proven clinical effect. We believe that the amyloid-PET scans, perceived as showing decreasing amyloid deposits, are an expression of increased cerebral cell death due to aducanumab treatment, so that with time one should instead expect a worsening and not an improvement in the treated patients' condition.

RevDate: 2022-04-21

Pomilio C, Pérez NG, Calandri I, et al (2022)

Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study.

GeroScience [Epub ahead of print].

We evaluated the effect of the antidiabetic drug metformin on patients enrolled in the ADNI study considering patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Employing data from this observational study, we performed a principal component analysis focusing on the cognitive sphere by evaluating data from neuropsychological tests included in a modified version of the Alzheimer's Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite (ADCS-PACC). Second, we included the levels of amyloid-β, tau, and phosphorylated tau in CSF. We found that MCI metformin-treated patients were globally characterized as subjects with a better cognitive performance and CSF biomarkers profile than the mean population of MCI patients. On the other hand, control subjects and type 2 diabetes patients (T2D) were paired by age, gender, ApoE allele, and years of education, defining three groups: MCI, MCI + T2D, and MCI + T2D + metformin. We evaluated the effect of T2D and metformin treatment employing the PACC score and composites defined from standardized ADNI variables to evaluate the memory and learning function. We found that MCI + T2D patients had a worse cognitive performance than MCI patients, but this deleterious effect was not observed in MCI + T2D + metformin patients. These cognitive variations were associated with changes in cortical thickness and hippocampal volume. Finally, no differences were found in metabolic plasmatic parameters (glycemia, cholesterol, triglycerides). Our study-employing different strategies for data analysis from the global study ADNI-shows a beneficial effect of metformin treatment on cognitive performance, CSF biomarkers profile, and neuroanatomical measures in MCI due to AD patients.

RevDate: 2022-04-21
CmpDate: 2022-04-21

Mundal LJ, Igland J, Svendsen K, et al (2022)

Association of Familial Hypercholesterolemia and Statin Use With Risk of Dementia in Norway.

JAMA network open, 5(4):e227715 pii:2791295.

Importance: Hypercholesterolemia, which is a cardiovascular risk factor, may also be associated with dementia risk. The benefit of statin treatment on dementia risk is controversial.

Objective: To determine whether individuals with familial hypercholesterolemia (FH), who have been exposed to lifelong hypercholesterolemia, have an excess risk of dementia and whether statin use is associated with dementia risk.

This was a prospective cohort study performed from 2008 to 2018 in Norway. Statistical analysis was performed from January 2021 to February 2022. This study included individuals with genetically verified FH and age-matched and sex-matched controls obtained from the general Norwegian population.

Exposures: Dementia was defined according to International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes F00-03 and G30.

Main Outcomes and Measures: Incident cases of total dementia, vascular dementia, Alzheimer disease-dementia in Alzheimer disease, and data on lipid-lowering medication were obtained from the Norwegian Patient Registry, Cause of Death Registry, and the Norwegian Prescription Database. Hazard ratios (HRs) for risk of dementia for individuals with FH vs matched controls were calculated using Cox regression. The cumulative sum of defined daily doses (DDDs) of statins prescribed during study follow-up was calculated for individuals with FH and was analyzed as a time-varying covariate with 3 levels: 1 to 4999 DDDs, 5000 to 10 000 DDDs, and more than 10 000 DDDs.

Results: Among the 3520 individuals with FH (1863 women [52.9%]; mean [SD] age at the start of follow-up, 51.8 [11.5] years) and the 69 713 controls (36 958 women [53.0%]; mean [SD] age at the start of follow-up, 51.7 [11.5] years), 62 patients with FH (39 women [62.9%]) and 1294 controls (801 women [61.9%]) had developed dementia over the course of 10 years of follow-up. Most dementia cases occurred among individuals aged 70 years and older (39 patients with FH [62.9%] and 870 patients [67.2%] in the control group). We found no excess risk of dementia in patients with FH vs matched controls (HR for total dementia, 0.9; 95% CI, 0.7-1.2). There was no association between cumulative DDDs of statins and total dementia in patients with FH with HRs of 1.2 (95% CI, 0.4-3.8) for cumulative DDDs of 5000 to 10 000 and 1.9 (95% CI, 0.7-5.0) for cumulative DDDs greater than 10 000.

Conclusions and Relevance: These findings suggest that individuals with FH have no excess risk of dementia compared with age-matched and sex-matched controls and that there is no association between use of statins and risk of dementia in patients with FH.

RevDate: 2022-04-18

Young CB, Winer JR, Younes K, et al (2022)

Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease.

JAMA neurology pii:2790807 [Epub ahead of print].

Importance: Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease.

Objective: To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated β-amyloid (A+).

This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n = 447; ADNI, n = 433; HABS, n = 190; and Wisconsin, n = 328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022.

Main Outcomes and Measures: Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined.

Results: The 447 A4 participants (A+ group, 392; and normal β-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867 = -2.597; P = .03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin.

Conclusions and Relevance: This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

RevDate: 2022-04-19

Han G, Zhen W, Dai Y, et al (2022)

Dihuang-Yinzi Alleviates Cognition Deficits via Targeting Energy-Related Metabolism in an Alzheimer Mouse Model as Demonstrated by Integration of Metabolomics and Network Pharmacology.

Frontiers in aging neuroscience, 14:873929.

Energy metabolism disturbance and the consequent reactive oxygen species (ROS) overproduction play a key and pathogenic role in the onset and progression of Alzheimer's disease (AD). Dihuang-Yinzi (DHYZ) is a traditional Chinese herbal prescription clinically applied to treat AD and other neurodegenerative diseases for a long time. However, the systematical metabolic mechanism of DHYZ against AD remains largely unclear. Here we aimed to explore the mechanism of DHYZ in the treatment of AD comprehensively in an in vivo metabolic context by performing metabolomics analysis coupled with network pharmacology study and experimental validation. The network pharmacology was applied to dig out the potential target of DHYZ against AD. The metabolomics analysis based on UPLC-HRMS was carried out to profile the urine of 2× Tg-AD mice treated with DHYZ. By integrating network pharmacology and metabolomics, we found DHYZ could ameliorate 4 key energy-related metabolic pathways, including glycerophospholipid metabolism, nicotinate/nicotinamide metabolism, glycolysis, and tricarboxylic acid cycle. Besides, we identified 5 potential anti-AD targets of DHYZ, including DAO, HIF1A, PARP1, ALDH3B2, and ACHE, and 14 key differential metabolites involved in the 4 key energy-related metabolic pathways. Furthermore, DHYZ depressed the mitochondrial dysfunction and the resultant ROS overproduction through ameliorating glycerophospholipid metabolism disturbance. Thereby DHYZ increased nicotinamide adenine dinucleotide (NAD+) content and promoted glycolysis and tricarboxylic acid (TCA) cycle, and consequently improved oxidative phosphorylation and energy metabolism. In the present study, we provided a novel, comprehensive and systematic insight into investigating the therapeutic efficacy of DHYZ against AD via ameliorating energy-related metabolism.

RevDate: 2022-04-19

Coker-Ayo OO, Nathaniel SI, Poupore N, et al (2022)

Sex Differences in Demographic and Pharmacological Factors in Alzheimer Patients With Dementia and Cognitive Impairments.

Frontiers in behavioral neuroscience, 16:828782.

Objective: The current study investigates sex differences associated with pharmacological and demographic characteristics in Alzheimer patients (AD) with dementia (ADD) or mild cognitive impairment (MCI).

Method: A retrospective analytical approach was used to analyze data from 45,696 AD patients with MCI or ADD. The univariate analysis was used to determine differences in demographic, and pharmacological characteristics for male and female ADD and MCI-AD patients. Multivariate analysis was used to predict specific pharmacological and demographic factors that are associated with male and female MCI and ADD patients.

Result: In the adjusted analysis for male patients, Hispanics [0.166,0.020 - 1.355, P = 0.094] or African Americans [OR = 2.380, 95% CI,2.120 - 2.674, P < 0.001], were more likely to have MCI-AD and be treated with galantamine [OR = 0.559, 95% CI, 0.382 - 0.818, P = 0.003], donepezil [OR = 1.639, 95% CI,1.503 - 1.787, P < 0.001], rivastigmine [OR = 1.394, 95% CI,1.184 - 1.642, P < 0.001], olanzapine [OR = 2.727, 95% CI,2.315 - 3.212, P < 0.001], risperidone [OR = 2.973, 95% CI,2.506 - 3.526, P < 0.001], present with increasing age [1.075,1.071 - 1.079, P < 0.001], and are on tobacco use [OR = 1.150, 95% CI,1.054 - 1.254, P = 0.002]. For female patients, buspirone [OR = 0.767, 95% CI, 0.683 - 0.861, P < 0.001] and a history of alcohol (ETOH) use [OR = 0.484, 95% CI, 0.442 - 0.529, P < 0.001] were associated with MCI-AD. Increasing age [OR = 1.096, 95% CI, 1.093 - 1.100, P < 0.001], donepezil [OR = 2.185, 95% CI, 2.035 - 2.346, P < 0.001], memantine [OR = 2.283, 95% CI, 2.104 - 2.477, P < 0.001] aripiprazole [OR = 1.807, 95% CI, 1.544 - 2.113, P < 0.001] olanzapine [OR = 2.289, 95% CI, 1.986 - 2.640, P < 0.001] risperidone [OR = 2.548, 95% CI, 2.246 - 2.889, P < 0.001] buspirone [OR = 0.767, 95% CI, 0.683 - 0.861, P < 0.001] escitalopram [OR = 1.213, 95% CI,1.119 - 1.315, P < 0.001] African Americans [OR = 1.395, 95% CI, 1.268 - 1.535, P < 0.001] and tobacco use [OR = 1.150, 95% CI, 1.073 - 1.233, P < 0.001] were associated with ADD.

Conclusion: Our findings reveal that MCI-AD patients were more likely to be Hispanics or African American males treated with rivastigmine, olanzapine and citalopram. African American females were associated with ADD and more likely to be treated with buspirone and presented with a history of ETOH. This finding suggests the need for a pharmacological treatment approach encompassing sex-sensitive strategies for MCI-AD and ADD patients.

RevDate: 2022-04-15

Ankul Singh S , Chitra V (2022)

The role of plant-based products in the prevention of neurological complications.

Drug metabolism letters pii:DML-EPUB-122520 [Epub ahead of print].

BACKGROUND: Neurological complications are most likely to be fatal and cause loss of ability to function or care for self. These include Alzheimer's disease and cognitive impairment. The main aim of the review is to determine the effects of various drugs and their cognitive risk with the need to opt for herbal therapy as an adjuvant in treating neurological conditions like Alzheimer's disease with lesser-known side effects. The Methodology: Involved a detailed literature survey which was performed through an online database, such as Science Direct, Google Scholar, Scopus, Cochrane, and PubMed. The study included randomized trials and original research conducted by herbal supplements on animal models to assess expression of upregulation of signalling pathways. Various studies involved in treating dementia, neurological disorders, Alzheimer disease, cognitive dysfunction were included.

RESULTS: Found that various studies involved plant-based products were showing improvement in prevention of disease and signalling pathways with lesser-known side effects.

CONCLUSION: It was observed that plant-based products play a major role in the prevention of neurological complications. Herbal medicines could most suitably prevent Alzheimer's risk with less known side effects in contrast with the existing treatment patterns. However, to improve the utility of herbal medicines, more evidences from in vitro, in vivo, and clinical trials need to be addressed.

RevDate: 2022-04-15

Pomilio AB, Vitale AA, AJ Lazarowski (2022)

Uncommon Noninvasive Biomarkers for the Evaluation and Monitoring of the Etiopathogenesis of Alzheimer's Disease.

Current pharmaceutical design pii:CPD-EPUB-122523 [Epub ahead of print].

BACKGROUND: Alzheimer´s disease (AD) is the most widespread dementia in the world, followed by vascular dementia. Since AD is a heterogeneous disease that shows several varied phenotypes, it is not easy to make an accurate diagnosis, so it arises when the symptoms are clear and the disease is already very advanced. Therefore, it is important to find out biomarkers for AD early diagnosis that facilitate treatment or slow down the disease. Classic biomarkers are obtained from cerebrospinal fluid and plasma, along with brain imaging by positron emission tomography. Attempts have been made to discover uncommon biomarkers from other body fluids, which are addressed in this update.

OBJECTIVE: This update aims to describe recent biomarkers from minimally invasive body fluids for the patients, such as saliva, urine, eye fluid or tears.

METHODS: Biomarkers were determined in patients versus controls by single tandem mass spectrometry, and immunoassays. Metabolites were identified by nuclear magnetic resonance, and microRNAs with genome-wide high-throughput real-time polymerase chain reaction-based platforms.

RESULTS: Biomarkers from urine, saliva, and eye fluid were described, including peptides/proteins, metabolites, and some microRNAs. The association with AD neuroinflammation and neurodegeneration was analyzed, highlighting the contribution of matrix metalloproteinases, the immune system and microglia, as well as the vascular system.

CONCLUSION: Unusual biomarkers have been developed, which distinguish each stage and progression of the disease, and are suitable for the early AD diagnosis. An outstanding relationship of biomarkers with neuroinflammation and neurodegeneration was assessed, clearing up concerns of the etiopathogenesis of AD.

RevDate: 2022-04-12

Samim KS, Khatik GL, AK Datusalia (2022)

Strategies for treatment of disease-associated dementia beyond Alzheimer disease: An update.

Current neuropharmacology pii:CN-EPUB-122440 [Epub ahead of print].

Memory, cognition, dementia, and neurodegeneration are complexly interlinked processes through various mechanistic pathways leading to a range of clinical outcomes. These are strongly associated with pathological conditions like Alzheimer's disease, Parkinson's disease, schizophrenia, stroke and are a growing concern for their timely diagnosis and management. Several cognition-enhancing interventions for management include non-pharmacological interventions like diet, exercise, and physical activity, while pharmacological interventions include medicinal agents, herbal agents, and nutritional supplements. This review critically analyzed and discussed the currently available agents under different drug development phase designed to target either of the molecular targets including cholinergic receptor, glutamatergic system, GABAergic targets, glycine site, serotonergic targets, histamine receptors, etc. Understanding memory formation and pathways involved therein aids in opening the new gateways to treating cognitive disorders. However, clinical studies suggest that there is still a dearth of knowledge about the pathological mechanism involved in neurological conditions, making the dropouts of agents from initial phases of clinical trial conducive. Hence, better understandings of the molecular basis of the disease biology, mode of drug action, and interlinked mechanistic pathways are required.

RevDate: 2022-04-11

Gabel M, Bollinger RM, Coble DW, et al (2022)

Retaining Participants in Longitudinal Studies of Alzheimer's Disease.

Journal of Alzheimer's disease : JAD pii:JAD215710 [Epub ahead of print].

BACKGROUND: Retention of study participants is essential to advancing Alzheimer's disease (AD) research and developing therapeutic interventions. However, recent multi-year AD studies have lost 25% to 39% of participants.

OBJECTIVE: We surveyed a random sample of 443 participants (Clinical Dementia Rating [CDR]≤1) at four Alzheimer Disease Research Centers to elucidate perceived facilitators and barriers to continued participation in longitudinal AD research.

METHODS: Reasons for participation were characterized with factor analysis. Effects of perceived fulfillment of one's own goals and complaints on attendance and likelihood of dropout were estimated with logistic regression models. Open-ended responses suggesting study improvements were analyzed with a Latent Dirichlet Allocation topic model.

RESULTS: Factor analyses revealed two categories, personal benefit and altruism, as drivers of continued participation. Participants with cognitive impairment (CDR > 0) emphasized personal benefits more than societal benefits. Participants with higher trust in medical researchers were more likely to emphasize broader social benefits. A minority endorsed any complaints. Higher perceived fulfillment of one's own goals and fewer complaints were related to higher attendance and lower likelihood of dropout. Facilitators included access to medical center support and/or future treatment, learning about AD and memory concerns, and enjoying time with staff. Participants' suggestions emphasized more feedback about individual test results and AD research.

CONCLUSION: The results confirmed previously identified facilitators and barriers. Two new areas, improved communication about individual test results and greater feedback about AD research, emerged as the primary factors to improve participation.

RevDate: 2022-04-13
CmpDate: 2022-04-12

Chen S, Gan D, Lin S, et al (2022)

Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms.

Theranostics, 12(6):2722-2740.

Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis, Alzheimer disease, cardiovascular diseases, cancers, obesity and other metabolic abnormalities. Metformin, the most widely used antidiabetic drug, has been reported to delay aging and display protective effect on attenuating progression of various aging-related diseases by impacting key hallmark events of aging, including dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, altered intercellular communication, telomere attrition, genomic instability, epigenetic alterations, stem cell exhaustion and cellular senescence. In this review, we provide updated information and knowledge on applications of metformin in prevention and treatment of aging and aging-related diseases. We focus our discussions on the roles and underlying mechanisms of metformin in modulating aging and treating aging-related diseases.

RevDate: 2022-04-12
CmpDate: 2022-04-12

Tong XK, Royea J, E Hamel (2022)

Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer's disease.

Cell death & disease, 13(4):325.

We previously showed that simvastatin (SV) restored memory in a mouse model of Alzheimer disease (AD) concomitantly with normalization in protein levels of memory-related immediate early genes in hippocampal CA1 neurons. Here, we investigated age-related changes in the hippocampal memory pathway, and whether the beneficial effects of SV could be related to enhanced neurogenesis and signaling in the Wnt/β-catenin pathway. APP mice and wild-type (WT) littermate controls showed comparable number of proliferating (Ki67-positive nuclei) and immature (doublecortin (DCX)-positive) granule cells in the dentate gyrus until 3 months of age. At 4 months, Ki67 or DCX positive cells decreased sharply and remained less numerous until the endpoint (6 months) in both SV-treated and untreated APP mice. In 6 month-old APP mice, dendritic extensions of DCX immature neurons in the molecular layer were shorter, a deficit fully normalized by SV. Similarly, whereas mature granule cells (calbindin-immunopositive) were decreased in APP mice and not restored by SV, their dendritic arborizations were normalized to control levels by SV treatment. SV increased Prox1 protein levels (↑67.7%, p < 0.01), a Wnt/β-catenin signaling target, while significantly decreasing (↓61.2%, p < 0.05) the upregulated levels of the β-catenin-dependent Wnt pathway inhibitor DKK1 seen in APP mice. In APP mice, SV benefits were recapitulated by treatment with the Wnt/β-catenin specific agonist WAY-262611, whereas they were fully abolished in mice that received the Wnt/β-catenin pathway inhibitor XAV939 during the last month of SV treatment. Our results indicate that activation of the Wnt-β-catenin pathway through downregulation of DKK1 underlies SV neuronal and cognitive benefits.

RevDate: 2022-04-23
CmpDate: 2022-04-12

Desai RJ, Varma VR, Gerhard T, et al (2022)

Comparative Risk of Alzheimer Disease and Related Dementia Among Medicare Beneficiaries With Rheumatoid Arthritis Treated With Targeted Disease-Modifying Antirheumatic Agents.

JAMA network open, 5(4):e226567.

Importance: Cytokine signaling, including tumor necrosis factor (TNF) and interleukin (IL)-6, through the Janus-kinase (JAK)-signal transducer and activator of transcription pathway, was hypothesized to attenuate the risk of Alzheimer disease and related dementia (ADRD) in the Drug Repurposing for Effective Alzheimer Medicines (DREAM) initiative based on multiomics phenotyping.

Objective: To evaluate the association between treatment with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept and risk of incident ADRD.

This cohort study was conducted among US Medicare fee-for-service patients with rheumatoid arthritis aged 65 years and older from 2007 to 2017. Patients were categorized into 3 cohorts based on initiation of tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors compared with a common comparator abatacept (a T-cell activation inhibitor). Analyses were conducted from August 2020 to August 2021.

Main Outcomes and Measures: The main outcome was onset of ADRD based on diagnosis codes evaluated in 4 alternative analysis schemes: (1) an as-treated follow-up approach, (2) an as-started follow-up approach incorporating a 6-month induction period, (3) incorporating a 6-month symptom to diagnosis period to account for misclassification of ADRD onset, and (4) identifying ADRD through symptomatic prescriptions and diagnosis codes. Hazard ratios (HRs) with 95% CIs were calculated from Cox proportional hazard regression after adjustment for 79 preexposure characteristics through propensity score matching.

Results: After 1:1 propensity score matching to patients using abatacept, a total of 22 569 propensity score-matched patient pairs, including 4224 tofacitinib pairs (mean [SD] age 72.19 [5.65] years; 6945 [82.2%] women), 6369 tocilizumab pairs (mean [SD] age 72.01 [5.46] years; 10 105 [79.4%] women), and 11 976 TNF inhibitor pairs (mean [SD] age 72.67 [5.91] years; 19 710 [82.3%] women), were assessed. Incidence rates of ADRD varied from 2 to 18 per 1000 person-years across analyses schemes. There were no statistically significant associations of ADRD with tofacitinib (analysis 1: HR, 0.90 [95% CI, 0.55-1.51]; analysis 2: HR, 0.78 [95% CI, 0.53-1.13]; analysis 3: HR, 1.29 [95% CI, 0.72-2.33]; analysis 4: HR, 0.50 [95% CI, 0.21-1.20]), tocilizumab (analysis 1: HR, 0.82 [95% CI, 0.55-1.21]; analysis 2: HR, 1.05 [95% CI, 0.81-1.35]; analysis 3: HR, 1.21 [95% CI, 0.75-1.96]; analysis 4: HR, 0.78 [95% CI, 0.44-1.39]), or TNF inhibitors (analysis 1: HR, 0.93 [95% CI, 0.72-1.20]; analysis 2: HR, 1.02 [95% CI, 0.86-1.20]; analysis 3: HR, 1.13 [95% CI, 0.86-1.48]; analysis 4: 0.90 [95% CI, 0.60-1.37]) compared with abatacept. Results from prespecified subgroup analysis by age, sex, and baseline cardiovascular disease were consistent except in patients with cardiovascular disease, for whom there was a potentially lower risk of ADRD with TNF inhibitors vs abatacept, but only in analyses 2 and 4 (analysis 1: HR, 0.76 [95% CI, 0.50-1.16]; analysis 2: HR, 0.74 [95% CI, 0.56-0.99]; analysis 3: HR, 1.03 [95% CI, 0.65-1.61]; analysis 4: HR, 0.45 [95% CI, 0.21-0.98]).

Conclusions and Relevance: This cohort study did not find any association of risk of ADRD in patients treated with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept.

RevDate: 2022-04-18

Singh A, Ujjwal RR, Naqvi S, et al (2022)

Formulation development of tocopherol polyethylene glycol nanoengineered polyamidoamine dendrimer for neuroprotection and treatment of Alzheimer disease.

Journal of drug targeting [Epub ahead of print].

Amyloid-beta (Aβ) aggregates deposition at extra neuronal sites induces neurotoxicity and major hallmarks of Alzheimer's disease (AD). To reduce the Aβ fibril toxicity, multi-functional polyamidoamine (PAMAM) dendrimer was conjugated with tocopheryl polyethylene glycol succinate-1000 (TPGS) which acts as a carrier matrix for the delivery of neuroprotective molecule piperine (PIP). This PIP-TPGS-PAMAM dendrimer was fabricated to mitigate the Aβ1-42 fibril toxicity on SHSY5Y cells. TPGS-PAMAM was fabricated through carbodiimide coupling reaction, and PIP was encapsulated in dendrimer through solvent injection method to prepare PIP-TPGS-PAMAM. Antioxidant assay of PIP-TPGS-PAMAM showed 90.18% inhibition of 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radicals compared to free PIP, which was 28.27%. The SHSY5Y cells showed 37.25% for negative control group and 82.55% cell viability for PIP-TPGS-PAMAM treated group against Aβ1-42 toxicity. PIP-TPGS-PAMAM reduced the ROS activity to 15.21% and 48.5% for free PIP treated in cell group. Similarly, extent of Aβ1-42-induced apoptosis also reduced significantly from 38.2% to 12.36% in PIP-TPGS-PAMAM treated group. In addition, PIP-TPGS-PAMAM also disaggregated the Aβ1-42 fibril in SHSY5Y cells. Our findings suggested that PIP-TPGS-PAMAM showed mitigation of Aβ1-42-induced toxicity in neuronal cells, which can offer excellent prospect of neuroprotection and AD therapy.

RevDate: 2022-04-08

Aisen PS, Jimenez-Maggiora GA, Rafii MS, et al (2022)

Early-stage Alzheimer disease: getting trial-ready.

Nature reviews. Neurology [Epub ahead of print].

Slowing the progression of Alzheimer disease (AD) might be the greatest unmet medical need of our time. Although one AD therapeutic has received a controversial accelerated approval from the FDA, more effective and accessible therapies are urgently needed. Consensus is growing that for meaningful disease modification in AD, therapeutic intervention must be initiated at very early (preclinical or prodromal) stages of the disease. Although the methods for such early-stage clinical trials have been developed, identification and recruitment of the required asymptomatic or minimally symptomatic study participants takes many years and requires substantial funds. As an example, in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Trial (the first phase III trial to be performed in preclinical AD), 3.5 years and more than 5,900 screens were required to recruit and randomize 1,169 participants. A new clinical trials infrastructure is required to increase the efficiency of recruitment and accelerate therapeutic progress. Collaborations in North America, Europe and Asia are now addressing this need by establishing trial-ready cohorts of individuals with preclinical and prodromal AD. These collaborations are employing innovative methods to engage the target population, assess risk of brain amyloid accumulation, select participants for biomarker studies and determine eligibility for trials. In the future, these programmes could provide effective tools for pursuing the primary prevention of AD. Here, we review the lessons learned from the AD trial-ready cohorts that have been established to date, with the aim of informing ongoing and future efforts towards efficient, cost-effective trial recruitment.

RevDate: 2022-04-05

Ren R, Qi J, Lin S, et al (2022)

The China Alzheimer Report 2022.

General psychiatry, 35(1):e100751.

China's population has rapidly aged over the recent decades of social and economic development as neurodegenerative disorders have proliferated, especially Alzheimer's disease (AD) and related dementias (ADRD). AD's incidence rate, morbidity, and mortality have steadily increased to make it presently the fifth leading cause of death among urban and rural residents in China and magnify the resulting financial burdens on individuals, families and society. The 'Healthy China Action' plan of 2019-2030 promotes the transition from disease treatment to health maintenance for this expanding population with ADRD. This report describes related epidemiological trends, evaluates the economic burden of the disease, outlines current clinical diagnosis and treatment status and delineates existing available public health resources. More specifically, it examines the public health impact of ADRD, including prevalence, mortality, costs, usage of care, and the overall effect on caregivers and society. In addition, this special report presents technical guidance and supports for the prevention and treatment of AD, provides expertise to guide relevant governmental healthcare policy development and suggests an information platform for international exchange and cooperation.

RevDate: 2022-04-05

Vidal-Palencia L, Ramon-Duaso C, González-Parra JA, et al (2022)

Gene Expression Analysis of the Endocannabinoid System in Presymptomatic APP/PS1 Mice.

Frontiers in pharmacology, 13:864591.

Alzheimer's disease (AD) is the most common type of dementia and neurodegeneration. The actual cause of AD progression is still unknown and no curative treatment is available. Recently, findings in human samples and animal models pointed to the endocannabinoid system (ECS) as a promising therapeutic approach against AD. However, the specific mechanisms by which cannabinoid drugs induce potential beneficial effects are still undefined. For this reason, it is required a full characterization of the ECS at different time points of AD progression considering important factors such as sex or the analysis of different brain regions to improve future cannabinoid-dependent therapies in AD. Thus, the main aim of the present study is to expand our knowledge of the status of the ECS in a presymptomatic period (3 months of age) using the AD mouse model APP/PS1 mice. First, we evaluated different behavioral domains including anxiety, cognitive functions, and social interactions in male and female APP/PS1 mice at 4 months of age. Although a mild working memory impairment was observed in male APP/PS1 mice, in most of the behaviors assessed we found no differences between genotypes. At 3 months of age, we performed a characterization of the ECS in different brain regions of the APP/PS1 mice considering the sex variable. We assessed the expression of the ECS components by quantitative Real-Time Polymerase Chain Reaction in the hippocampus, prefrontal cortex, hypothalamus, olfactory bulb, and cerebellum. Interestingly, gene expression levels of the type-1 and type-2 cannabinoid receptors and the anabolic and catabolic enzymes, differed depending on the brain region and the sex analyzed. For example, CB1R expression levels decreased in both hippocampus and prefrontal cortex of male APP/PS1 mice but increased in female mice. In contrast, CB2R expression was decreased in females, whereas males tended to have higher levels. Overall, our data indicated that the ECS is already altered in APP/PS1 mice at the presymptomatic stage, suggesting that it could be an early event contributing to the pathophysiology of AD or being a potential predictive biomarker.

RevDate: 2022-04-03

Mathew A, Balaji E V, Pai SRK, et al (2022)

Current Drug Targets in Alzheimer's Associated Memory Impairment: A Comprehensive Review.

CNS & neurological disorders drug targets pii:CNSNDDT-EPUB-122156 [Epub ahead of print].

Alzheimer's disease (AD) is the most prevalent form of dementia among geriatrics. It is a progressive, degenerative neurologic disorder that causes memory and cognition loss. The accumulation of amyloid fibrils and neurofibrillary tangles in the brain of AD patients is a distinguishing feature of the disease. Therefore, most of the current therapeutic goals are targeting inhibition of beta-amyloid synthesis and aggregation as well as tau phosphorylation and aggregation. There is also a loss of the cholinergic neurons in the basal forebrain and first-generation therapeutic agents were primarily focused on compensating for this loss of neurons. However, cholinesterase inhibitors can only alleviate cognitive symptoms of AD and cannot reduce the progression of the disease. Understanding the molecular and cellular changes associated with AD pathology has advanced significantly in recent decades. The etiology of AD is complex with a substantial portion of sporadic AD emerging from unknown reasons and a lesser proportion of early-onset familial AD (FAD) caused by mutation in several genes, such as the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) genes. Hence, efforts are being made to discover novel strategies for these targets for the AD therapy. A new generation of AChE and BChE inhibitors is currently being explored and evaluated in human clinical trials for AD symptomatic treatment. Other approaches for slowing the progression of AD include serotonergic modulation, H3 receptor antagonism, phosphodiesterase, COX-2, and MAO-B inhibition. The present review provides an insight into the possible therapeutic strategies and their molecular mechanisms enlightening perception on classical and future treatment approaches.

RevDate: 2022-04-25

Tarafdar A, Wolska N, Krisp C, et al (2022)

The amyloid peptide β disrupts intercellular junctions and increases endothelial permeability in a NADPH oxidase 1-dependent manner.

Redox biology, 52:102287 pii:S2213-2317(22)00059-3 [Epub ahead of print].

Alzheimer's disease is the most common form of dementia and is associated with the accumulation of amyloid peptide β in the brain parenchyma. Vascular damage and microvascular thrombosis contribute to the neuronal degeneration and the loss of brain function typical of this disease. In this study, we utilised a murine model of Alzheimer's disease to evaluate the neurovascular effects of this disease. Upon detection of an increase in the phosphorylation of the endothelial surface receptor VE-cadherin, we focused our attention on endothelial cells and utilised two types of human endothelial cells cultured in vitro: 1) human umbilical vein endothelial cells (HUVECs) and 2) human brain microvascular endothelial cells (hBMECs). Using an electrical current impedance system (ECIS) and FITC-albumin permeability assays, we discovered that the treatment of human endothelial cells with amyloid peptide β causes a loss in their barrier function, which is oxidative stress-dependent and similarly to our observation in mouse brain associates with VE-cadherin phosphorylation. The activation of the superoxide anion-generating enzyme NADPH oxidase 1 is responsible for the oxidative stress that leads to the disruption of barrier function in human endothelial cells in vitro. In summary, we have identified a novel molecular mechanism explaining how the accumulation of amyloid peptide β in the brain parenchyma may induce the loss of neurovascular barrier function, which has been observed in patients. Neurovascular leakiness plays an important role in brain inflammation and neuronal degeneration driving the progression of the Alzheimer's disease. Therefore, this study provides a novel and promising target for the development of a pharmacological treatment to protect neurovascular function and reduce the progression of the neurodegeneration in Alzheimer's patients.

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RJR Experience and Expertise

Researcher

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.

Educator

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.

Administrator

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.

Technologist

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.

Publisher

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.

Speaker

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.

Facilitator

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.

Designer

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

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Curriculum Vitae for R J Robbins

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