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14 Nov 2022 at 01:58
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Bibliography on: Alzheimer Disease — Treatment


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 14 Nov 2022 at 01:58 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®)


RevDate: 2022-11-09

Chen J, Spencer MRT, Buchongo P, et al (2022)

Hospital-based Health Information Technology Infrastructure: Evidence of Reduced Medicare Payments and Racial Disparities Among Patients With ADRD.

Medical care [Epub ahead of print].

BACKGROUND: Alzheimer disease and related dementia (ADRD) is one of the most expensive health conditions in the United States. Understanding the potential cost-savings or cost-enhancements of Health Information Technology (HIT) can help policymakers understand the capacity of HIT investment to promote population health and health equity for patients with ADRD.

OBJECTIVES: This study examined access to hospital-based HIT infrastructure and its association with racial and ethnic disparities in Medicare payments for patients with ADRD.

RESEARCH DESIGN: We used the 2017 Medicare Beneficiary Summary File, inpatient claims, and the American Hospital Annual survey. Our study focused on community-dwelling Medicare fee-for-service beneficiaries who were diagnosed with ADRD. Our study focused on hospital-based telehealth-postdischarge (e.g., remote patient monitoring) and telehealth-treatment (e.g., psychiatric and addiction treatment) services.

RESULTS: Results showed that hospital-based telehealth postdischarge services were associated with significantly higher total Medicare payment and acute inpatient Medicare payment per person per year among patients with ADRD on average. The associations between hospital-based telehealth-treatment services and payments were not significant. However, the association varied by patient's race and ethnicity. The reductions of the payments associated with telehealth postdischarge and treatment services were more pronounced among Black patients with ADRD. Telehealth-treatment services were associated with significant payment reductions among Hispanic patients with ADRD.

CONCLUSION: Results showed that having hospital-based telehealth services might be cost-enhancing at the population level but cost-saving for Black and Hispanic patients with ADRD. Results suggested that personalized HIT services might be necessary to reduce the cost associated with ADRD treatment for racial and ethnic minority groups.

RevDate: 2022-11-09

Wang G, Li Y, Xiong C, et al (2022)

Evaluation of dose-dependent treatment effects after mid-trial dose escalation in biomarker, clinical, and cognitive outcomes for gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Alzheimer's & dementia (Amsterdam, Netherlands), 14(1):e12367 pii:DAD212367.

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect.

Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes.

Results: Both gantenerumab and solanezumab demonstrated dose-dependent treatment effects (significant for gantenerumab, non-significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose-dependent treatment effects were observed in clinical or cognitive outcomes.

Conclusions: Mid-trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases.

Highlights: We evaluated the dose-dependent treatment effect of two different amyloid-specific immunotherapies.Dose-dependent treatment effects were observed in some biomarkers.No dose-dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations.

RevDate: 2022-10-22

Kawakami I, Iga JI, Takahashi S, et al (2022)

Towards an understanding of the pathological basis of senile depression and incident dementia: Implications for treatment.

Psychiatry and clinical neurosciences [Epub ahead of print].

Senile depression (SD) is a heterogeneous syndrome. Several clinical profiles are more likely to appear in SD than in early-life depression, but it remains unclear whether the pathophysiology is different. The prevalence of dementia increases with aging, and the underlying pathophysiological processes in the preclinical phase begin even before cognitive deficits or neurological signs appear. SD may be either a risk factor for developing dementia or a prodromal stage of dementia. The inconsistent findings regarding the association between SD and incident dementia may be attributable to the neuropathological heterogeneity underlying SD. Most studies have focused on patients with the clinical diagnosis of Alzheimer disease (AD) as an outcome, but several clinicopathological studies suggest that primary age-related tauopathy and argyrophilic grain disease may account for a proportion of cases clinically misdiagnosed as AD in the elderly population. Furthermore, most AD cases have additional neuropathologic changes such as cerebrovascular disease and Lewy body disease. Here, we review the neuropathological findings linking SD to incident dementia, focusing on common age-related neuropathologies. In particular, the roles of disturbance of neural circuity, imbalance of monoaminergic systems, dysregulation of the hypothalamic-pituitary-adrenal axis, and elevated neuroinflammatory status are discussed. Finally, we review the current treatment of SD in the context of age-related neuropathological changes.

RevDate: 2022-11-07

Decourt B, Noorda K, Noorda K, et al (2022)

Review of Advanced Drug Trials Focusing on the Reduction of Brain Beta-Amyloid to Prevent and Treat Dementia.

Journal of experimental pharmacology, 14:331-352 pii:265626.

Alzheimer disease (AD) is the most common neurodegenerative disease and typically affects patients older than age 65. Around this age, the number of neurons begins to gradually decrease in healthy brains, but brains of patients with AD show a marked increase in neuron death, often resulting in a significant loss of cognitive abilities. Cognitive skills affected include information retention, recognition capabilities, and language skills. At present, AD can be definitively diagnosed only through postmortem brain biopsies via the detection of extracellular amyloid beta (Aβ) plaques and intracellular hyperphosphorylated tau neurofibrillary tangles. Because the levels of both Aβ plaques and tau tangles are increased, these 2 proteins are thought to be related to disease progression. Although relatively little is known about the cause of AD and its exact pathobiological development, many forms of treatment have been investigated to determine an effective method for managing AD symptoms by targeting Aβ. These treatments include but are not limited to using small molecules to alter the interactions of Aβ monomers, reducing hyperactivation of neuronal circuits altering Aβ's molecular pathway of synthesis, improving degradation of Aβ, employing passive immunity approaches, and stimulating patients' active immunity to target Aβ. This review summarizes the current therapeutic interventions in Phase II/III of clinical development or higher that are capable of reducing abnormal brain Aβ levels to determine which treatments show the greatest likelihood of clinical efficacy. We conclude that, in the near future, the most promising therapeutic interventions for brain Aβ pathology will likely be passive immunotherapies, with aducanumab and donanemab leading the way, and that these drugs may be combined with antidepressants and acetylcholine esterase inhibitors, which can modulate Aβ synthesis.

RevDate: 2022-11-04

Liu M, Li Z, Ouyang Y, et al (2022)

Material basis and integrative pharmacology of danshen decoction in the treatment of cardiovascular diseases.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 108:154503 pii:S0944-7113(22)00591-8 [Epub ahead of print].

BACKGROUND: Cardiovascular diseases (CVDs) are among the primary and predominant threats to human health with increasing incidence. Danshen Decoction (DSD) as an adjuvant therapy can benefit CVDs patients by improving clinical efficacy.

PURPOSE: The purpose of this study was to identify the active components and potential pharmacological mechanisms of DSD by combining mass spectrometry with a network pharmacology strategy and to review the use of DSD in the treatment of CVDs.

METHOD: First, the composition of DSD was analyzed by ultrahigh-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS). Second, the network pharmacology method was used to elucidate the underlying material basis and possible pharmacological mechanism of DSD for the treatment of CVDs. Finally, clinical and experimental studies on DSD in the past ten years were retrieved from the PubMed and CNKI database, and the content of these studies was used to summarize the latest progress in DSD treatment of CVDs.

OUTCOME: A total of 35 compounds were found in DSD by manual identification from the analysis of MS, which may be the material basis for the therapeutic effect of DSD. After taking the intersection of 2086 targets related to CVDs, these 35 compounds are considered to play a role in the treatment of CVDs through 210 targets including signal transducer and activator of transcription 3 (STAT3), sarcoma (SRC) and phosphoinositide-3-kinase regulatory subunit (PIK3R), and a total of 168 signaling pathways were involved in the regulation of CVDs by DSD, including PI3K-AKT signaling pathway, Alzheimer disease, and Rap1 signaling pathway. A total of 29 clinical studies using DSD in the treatment of CVDs were included in the literature review, and these studies showed the positive significance of DSD as adjuvant therapy, while 14 experimental studies included in the literature review also demonstrated the effectiveness of DSD in the treatment of CVDs.

CONCLUSION: DSD plays a role in the treatment of CVDs through a variety of active ingredients. Large-scale clinical research and more in-depth experimental research will help to further reveal the mechanism of DSD in the treatment of CVDs.

RevDate: 2022-11-03

Leijenaar JF, Ingala S, Sudre CH, et al (2022)

Decreased integrity of the monoaminergic tract is associated with a positive response to MPH in patients with vascular cognitive impairment - proof of principle study STREAM-VCI.

Cerebral circulation - cognition and behavior, 3:100128 pii:S2666-2450(22)00093-9.

Background: Patients with vascular cognitive impairment (VCI) are very heterogeneous in both symptoms and type of cerebrovascular pathology. This might be an important reason why there is no symptomatic treatment available for VCI patients. In this study, we investigated in patients with VCI, whether there was an association between a positive response to methylphenidate and galantamine and the type of cerebrovascular disease, structural damage to specific neurotransmitter systems, cerebral perfusion, and presence of co-morbid Alzheimer (AD) pathology.

Methods: We included 27 VCI patients (mean age 67 years ± 8,30% female) from the STREAM-VCI trial who received placebo, methylphenidate(10 mg), and galantamine(16 mg) in a single challenge, cross-over design. In this study, we classified patients improving on a task for executive functioning after methylphenidate compared to placebo as methylphenidate responders (MPH+; resp. non-responders, MPH-) and patients improving on a task for memory after galantamine compared to placebo as galantamine responders (GAL+; resp. non-responders, GAL-). On baseline MRI, we visually assessed measures of cerebrovascular disease, automatically segmented white matter hyperintensities, used diffusion tensor imaging to visualize the integrity of monoaminergic and cholinergic neurotransmitter systems with mean diffusivity (MD) and fractional anisotropy (FA). Comorbid AD pathology was assessed using CSF or amyloid-PET. We tested differences between responders and non-responders using ANOVA, adjusting for age and sex.

Results: Nine patients were MPH+ vs 18 MPH-. MPH+ had higher MD (1.22 ± 0.07 vs 0.94 ± 0.05); p = .001) and lower FA (0.38 ± .01 vs 0.43 ± .01); p = .04) in the monoaminergic tract compared to MPH-. Eight patients were GAL+ and 18 GAL-. We found no differences between GAL+ and GAL- in any of the MRI measures. Information on co-morbid AD pathology was present in 17 patients. AD pathology tended to be more frequent in GAL+ vs GAL- (5(71%) vs 2(20%); p = .06).

Conclusions: In patients with VCI, we found that decreased integrity of the monoaminergic tract is associated with a positive response to MPH. Responsiveness to galantamine may be related to co-morbid AD pathology.

RevDate: 2022-11-02

Samara AA, Liampas I, Dadouli K, et al (2022)

Preeclampsia, gestational hypertension and incident dementia: A systematic review and meta-analysis of published evidence.

Pregnancy hypertension, 30:192-197 pii:S2210-7789(22)00109-X [Epub ahead of print].

OBJECTIVE: Novel data support a possible correlation between preeclampsia and congenital dysfunction.

STUDY DESIGN: A systematic review of the literature and a meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and meta-Analyses (PRISMA) guidelines and the Cochrane Handbook for Systematic Reviews of Interventions.

MAIN OUTCOME MEASURE: To investigate the association between the risk of future of dementia (vascular dementia, AD and dementia of any type) in women with a history of preeclampsia, based on current literature.

RESULTS: Overall, three studies and 2.309.946 women were included in the present meta-analysis. There was no statistically significant association between history of preeclampsia or pregnancy hypertension disease and any type of dementia (p = 0.14 and p = 0.29, respectively). In contrast, there was a statistically significant difference between history of preeclampsia and vascular dementia (HR: 2.60; 95 %CI: 2.03-3.33; p < 0.001). Furthermore, history of preeclampsia does not increase the risk for Alzheimer disease (Fixed Effects pooled-HR: 1.17; 95 %CI: 0.98-1.40; p = 0.08). Similarly, women with hypertensive disorder of pregnancy (HDP) had no statistically significant increased risk for later onset of any dementia (Fixed Effects pooled-HR: 1.08; 95 %CI: 0.93-1.25; p = 0.29).

CONCLUSIONS: History of preeclampsia increases the risk of vascular dementia. These patients are expected to benefit from screening for early symptoms of dementia, allowing early diagnosis and treatment. However, due to several limitations, further studies with large cohorts are required to elucidate the association between preeclampsia and dementia.

RevDate: 2022-11-02

Roytman M, Mashriqi F, Al-Tawil K, et al (2022)

Amyloid-Related Imaging Abnormalities: An Update.

AJR. American journal of roentgenology [Epub ahead of print].

Amyloid-related imaging abnormalities (ARIA) is a term introduced in 2010 to encompass a spectrum of MRI findings observed in patients receiving investigational anti-amyloid beta (Aβ) immunotherapies for Alzheimer disease (AD). The entity can be broadly categorized into ARIA-E, characterized by edema and effusion, and ARIA-H, characterized by microhemorrhages and superficial siderosis. ARIA typically occurs early in the treatment course and has a higher incidence in patients who are apolipoprotein E ε4 allele carriers. ARIA-E has an additional dose dependence, with higher incidence in patients receiving higher doses of anti-Aβ immunotherapies. ARIA is often asymptomatic and self-resolving. The recognition of ARIA has implications for patient selection and monitoring for Aβ immunotherapies, and its development can potentially lead to a pause or discontinuation of therapy. The FDA's first approval of an Aβ-targeted mAb for AD treatment in 2021 will lead to such therapy's expanded use beyond the clinical trial setting and to radiologists more commonly encountering ARIA in clinical practice. This review explores the theorized pathophysiologic mechanisms for ARIA, describes the MRI findings and grading schemes for ARIA-E and AREA-H, and summarizes relevant Aβ immunotherapies. Through such knowledge, radiologists can optimally impact the management of patients receiving targeted AD therapies.

RevDate: 2022-10-28

Boada M, Kiprov D, Anaya F, et al (2022)

Feasibility, safety, and tolerability of two modalities of plasma exchange with albumin replacement to treat elderly patients with Alzheimer's disease in the AMBAR study.

Journal of clinical apheresis [Epub ahead of print].

BACKGROUND: In the Alzheimer Management by Albumin Replacement (AMBAR) study, mild-to-moderate Alzheimer's disease (AD) patients were treated with a plasma exchange (PE) program. Feasibility and safety of PE in this specific population are poorly understood and were analyzed in detail in this study.

METHODS: Qualified patients were treated with 6 weeks of weekly conventional therapeutic plasma exchange (TPE) with albumin replacement followed by monthly low-volume plasma exchange (LVPE) for 12 months. The patients were divided into four groups: placebo (sham PE treatment), low-albumin (20 g), low-albumin + intravenous immunoglobulin (IVIG) (10 g), and high-albumin (40 g) + IVIG (20 g). Adverse events (AEs) were recorded and analyzed for all PE treatment groups and PE modalities.

RESULTS: PE procedure-related AEs were more common in the active treatment groups (16.9% out of 1283 TPE and 12.5% out of 2203 LVPE were associated with at least one AE, a similar rate than in other PE indications) than in the placebo group (0.7% out of 1223 sham PE). Percentage of procedures with at least one AEs was higher with central venous access compared to peripheral venous access in all three active treatment groups (20.1% vs 13.1%, respectively).

CONCLUSION: The TPE and LVPE procedures used in the AMBAR study on mild-to-moderate AD population were as safe and feasible as in other therapeutic applications of PE or routine plasmapheresis.

RevDate: 2022-10-28

Assaran AH, Akbarian M, Amirahmadi S, et al (2022)

Ellagic acid prevents oxidative stress and memory deficits in a rat model of scopolamine-induced Alzheimer's disease.

Central nervous system agents in medicinal chemistry pii:CNSAMC-EPUB-127228 [Epub ahead of print].

Background Ellagic acid (EA) has various pharmacological effects such as anti-inflammatory and anti-oxidant effects. Objective This study aimed to investigate the effects EA on learning and memory dysfunction as well as oxidative stress in scopolamine-induced amnesic rats. Methods The studied rats were treated according to the following protocol: Control (group 1) and scopolamine (group 2) groups received saline (intraperitoneal injection (i.p.)) while the treatment groups (group 3-5) were given EA (25, 50, and 100 mg/kg, i.p.) for 3 weeks. Thereafter, their behavioral performance was evaluated using Morris water maze (MWM) and passive avoidance (PA) tasks. Notably, scopolamine was injected (into groups II-V at a dose of 2 mg/kg, i.p.) before conducting the tasks. Finally, the oxidative stress indicators in the brain were measured. Results EA reduced the escape latencies and distances during learning phase of MWM. The results of probe trials also indicated that EA improved memory retrieval and helped the animals recall the platform. Moreover, EA increased delay and light time, while decreasing the frequency of entries to the dark area of PA. In the EA-treated groups, the level of malondialdehyde was decreased, while the levels of total thiol groups, superoxide dismutase, and catalase were increased. Conclusion EA prevented the negative effects of scopolamine on learning and memory which is probably mediated via modulating oxidative stress. Hence, EA could be considered as a potential alternative therapy in dementia.

RevDate: 2022-10-27

Honorio P, Hannongbua S, P Saparpakorn (2022)

Roles of hybrid donepezil scaffolds as potent human acetylcholinesterase inhibitors using in silico interaction analysis, drug-likeness, and pharmacokinetics prediction.

Chemico-biological interactions pii:S0009-2797(22)00432-X [Epub ahead of print].

Acetylcholinesterase (AChE) is currently one of the potent targets for the treatment of Alzheimer's disease (AD). The discovery of promising new AChE inhibitors using a hybridisation method is considered as one of the effective strategies to overcome AD. In this study, potent hybrid donepezils previously reported as AChE inhibitors were investigated to gain an insight into the key binding interaction of their scaffolds, using molecular docking, molecular dynamics simulations and quantum chemical calculations. The results indicated that the key interactions found in both donepezil and the selected hybrid donepezils were the π-π interaction to Trp86 in the catalytic anionic site (CAS) and Trp286 and Tyr341 in the peripheral anionic site (PAS) in the AChE binding pocket. Moreover, the modification of the scaffolds revealed the adaptation of the orientation in the binding pocket and additional important interactions from the modified scaffold, such as H-bond and H-π interactions to Asp74, Tyr124 and Tyr337. In addition, the HOMO-LUMO prediction indicated the binding interaction by considering the electron transfer between the hybrid donepezils and key residues, such as Trp86 and Trp286. The bioavailability, drug-likeness and pharmacokinetics predictions confirmed the suitability of the hybrid donepezils for AD drug development. Most of the selected hybrid donepezils revealed good bioavailability, drug-likeness properties and pharmacokinetics; however, some need improved pharmacokinetic properties. The obtained information highlights the significance of the scaffold from the hybridisation method, which will be helpful for AD drug design and development in the future.

RevDate: 2022-10-27

de Torre MP, Cavero RY, MI Calvo (2022)

Anticholinesterase Activity of Selected Medicinal Plants from Navarra Region of Spain and a Detailed Phytochemical Investigation of Origanum vulgare L. ssp. vulgare.

Molecules (Basel, Switzerland), 27(20): pii:molecules27207100.

Alzheimer's disease is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment due to a severe loss of cholinergic neurons in specific brain areas. It is the most common type of dementia in the aging population. Although many anti-acetylcholinesterase (AChE) drugs are already available on the market, their performance sometimes yields unexpected results. For this reason, research works are ongoing to find potential anti-AChE agents both from natural and synthetic sources. In this study, 90 extracts from 30 native and naturalized medicinal plants are tested by TLC and Ellman's colorimetric assay at 250, 125 and 62.5 μg/mL in order to determine the inhibitory effect on AChE. In total, 21 out of 90 extracts show high anti-AChE activity (75-100% inhibition) in a dose-dependent manner. Among them, ethanolic extract from aerial parts of O. vulgare ssp. vulgare shows an IC50 value 7.7 times lower than galantamine. This research also establishes the chemical profile of oregano extract by TLC, HPLC-DAD and LC-MS, and twenty-three compounds are identified and quantified. Dihydroxycinnamic acids and flavonoids are the most abundant ones (56.90 and 25.94%, respectively). Finally, total phenolic compounds and antioxidant properties are quantified by colorimetric methods. The total phenolic content is 207.64 ± 0.69 µg/mg of extract. The antioxidant activity is measured against two radicals, DPPH and ABTS. In both assays, the oregano extract shows high activity. The Pearson correlation matrix shows the relationship between syringic acids, a type of dihydroxybenzoic acid, and anti-AChE (r2 = -0.9864) and antioxidant activity (r2 = 0.9409 and 0.9976). In conclusion, the results of this study demonstrate promising potential new uses of these medicinal herbs for the treatment of Alzheimer's. Origanum vulgare ssp. vulgare and syringic acids, which have anti-AChE activity and beneficial antioxidant capacity, can be highlighted as potential candidates for the development of drugs for the treatment of Alzheimer's disease and other diseases characterized by a cholinergic deficit.

RevDate: 2022-10-27

Predes D, Maia LA, Matias I, et al (2022)

The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway.

International journal of molecular sciences, 23(20): pii:ijms232012078.

The Wnt/β-catenin signaling pathway dictates cell proliferation and differentiation during embryonic development and tissue homeostasis. Its deregulation is associated with many pathological conditions, including neurodegenerative disease, frequently downregulated. The lack of efficient treatment for these diseases, including Alzheimer's disease (AD), makes Wnt signaling an attractive target for therapies. Interestingly, novel Wnt signaling activating compounds are less frequently described than inhibitors, turning the quest for novel positive modulators even more appealing. In that sense, natural compounds are an outstanding source of potential drug leads. Here, we combine different experimental models, cell-based approaches, neuronal culture assays, and rodent behavior tests with Xenopus laevis phenotypic analysis to characterize quercitrin, a natural compound, as a novel Wnt signaling potentiator. We find that quercitrin potentiates the signaling in a concentration-dependent manner and increases the occurrence of the Xenopus secondary axis phenotype mediated by Xwnt8 injection. Using a GSK3 biosensor, we describe that quercitrin impairs GSK3 activity and increases phosphorylated GSK3β S9 levels. Treatment with XAV939, an inhibitor downstream of GSK3, impairs the quercitrin-mediated effect. Next, we show that quercitrin potentiates the Wnt3a-synaptogenic effect in hippocampal neurons in culture, which is blocked by XAV939. Quercitrin treatment also rescues the hippocampal synapse loss induced by intracerebroventricular injection of amyloid-β oligomers (AβO) in mice. Finally, quercitrin rescues AβO-mediated memory impairment, which is prevented by XAV939. Thus, our study uncovers a novel function for quercitrin as a Wnt/β-catenin signaling potentiator, describes its mechanism of action, and opens new avenues for AD treatments.

RevDate: 2022-10-27

Jin W, Kam MK, Lee SW, et al (2022)

Peroxiredoxin 2 Ameliorates AβO-Mediated Autophagy by Inhibiting ROS via the ROS-NRF2-p62 Pathway in N2a-APP Swedish Cells.

Antioxidants (Basel, Switzerland), 11(10): pii:antiox11101889.

In Alzheimer's disease, reactive oxygen species (ROS) are generated by the deposition of amyloid-beta oligomers (AβOs), which represent one of the important causes of neuronal cell death. Additionally, AβOs are known to induce autophagy via ROS induction. Previous studies have shown that autophagy upregulation aggravates neuronal cell death. In this study, the effects of peroxiredoxin 2 (Prx2), a member of the peroxidase family of antioxidant enzymes, on regulating AβO-mediated autophagy were investigated. Prx2 decreased AβO-mediated oxidative stress and autophagy in N2a-APPswe cells. Further, we examined the relationship between the neuronal protective effect of Prx2 and a decrease in autophagy. Similar to the effects of N-acetyl cysteine, Prx2 decreased AβO-induced ROS and inhibited p62 protein expression levels by downregulating the activation of NRF2 and its translocation to the nucleus. In addition, treatment with 3-methyladenine, an autophagy inhibitor, ameliorates neuronal cell death. Overall, these results demonstrate that the Prx2-induced decrease in autophagy was associated with the inhibition of ROS via the ROS-NRF2-p62 pathway in N2a-APPswe cells. Therefore, our results revealed that Prx2 is a potential therapeutic target in anti-Alzheimer therapy.

RevDate: 2022-10-27

Rudnicka-Drożak E, Drożak P, Mizerski G, et al (2022)

Endothelial Progenitor Cells in Neurovascular Disorders-A Comprehensive Overview of the Current State of Knowledge.

Biomedicines, 10(10): pii:biomedicines10102616.

Endothelial progenitor cells (EPCs) are a population of cells that circulate in the blood looking for areas of endothelial or vascular injury in order to repair them. Endothelial dysfunction is an important component of disorders with neurovascular involvement. Thus, the subject of involvement of EPCs in such conditions has been gaining increasing scientific interest in recent years. Overall, decreased levels of EPCs are associated with worse disease outcome. Moreover, their functionalities appear to decline with severity of disease. These findings inspired the application of EPCs as therapeutic targets and agents. So far, EPCs appear safe and promising based on the results of pre-clinical studies conducted on their use in the treatment of Alzheimer's disease and ischemic stroke. In the case of the latter, human clinical trials have recently started to be performed in this subject and provided optimistic results thus far. Whereas in the case of migraine, existing findings pave the way for testing EPCs in in vitro studies. This review aims to thoroughly summarize current knowledge on the role EPCs in four disorders with neurovascular involvement, which are Alzheimer's disease, cerebral small vessel disease, ischemic stroke and migraine, with a particular focus on the potential practical use of these cells as a treatment remedy.

RevDate: 2022-10-26

Hsu JL, Wei YC, Toh CH, et al (2022)

Magnetic Resonance Images Implicate That Glymphatic Alterations Mediate Cognitive Dysfunction in Alzheimer Disease.

Annals of neurology [Epub ahead of print].

OBJECTIVE: The glymphatic system cleans amyloid and tau proteins from the brain in animal studies of Alzheimer disease (AD). However, there is no direct evidence showing this in humans.

METHODS: Participants (n = 50, 62.6 ± 5.4 years old, 36 women) with AD and normal controls underwent amyloid positron emission tomography (PET), tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS).

RESULTS: ALPS-indexes showed negative correlations with deposition of amyloid and tau on PET images and positive correlations with cognitive scores even after adjusting for age, sex, years of education, and APOE4 genotype covariates in multiple AD-related brain regions (all p < 0.05). Mediation analysis showed that ALPS-index acted as a significant mediator between regional standardized uptake value ratios of amyloid and tau images and cognitive dysfunction even after correcting for multiple covariates in AD-related brain regions. These regions are responsible for attention, memory, and executive function, which are vulnerable to sleep deprivation.

INTERPRETATION: Glymphatic system activity may act as a significant mediator in AD-related cognitive dysfunction even after adjusting for multiple covariates and gray matter volumes. ALPS-index may provide useful disease progression or treatment biomarkers for patients with AD as an indicator of modulation of glymphatic activity. ANN NEUROL 2022.

RevDate: 2022-10-24

Pontrello CG, McWhirt JM, Glabe CG, et al (2022)

Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer's Disease Mouse Model.

Journal of Alzheimer's disease : JAD pii:JAD220824 [Epub ahead of print].

BACKGROUND: Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer's disease (AD).

OBJECTIVE: To profile the progression of pathology in AD.

METHODS: We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan.

RESULTS: Intracellular accumulation of aggregated Aβ in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but the decline was accelerated in 3xTg-AD brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAβ. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAβ and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAβ accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine.

CONCLUSION: The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by an pAkt/tAkt metabolic shift in CA1, iAβ accumulation in CA1, and extracellular Aβ deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes.

RevDate: 2022-10-24

Wang J, Wang B, T Zhou (2022)

The Advance on Frontotemporal Dementia (FTD)'s Neuropathology and Molecular Genetics.

Mediators of inflammation, 2022:5003902.

The morbidity of frontotemporal dementia (FTD), one of the most prevalent dementias praccox, is second to Alzheimer disease (AD). It is different with AD that FTD has a rapider course and a higher mortality. FTD has not yet been fully understood in terms of etiology or pathogenesis, but genetic factors are believed to be involved. In this paper, we were committed to providing a comprehensive overview to FTD in aspects of the neuropathology features and the relevant molecular genetics advances, so that there would be insights to those researchers in search of novel approaches in FTD diagnosis and treatment.

RevDate: 2022-10-17

Pontecorvo MJ, Lu M, Burnham SC, et al (2022)

Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial.

JAMA neurology pii:2797022 [Epub ahead of print].

Importance: Plasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures of treatment outcomes.

Objective: To analyze the association of donanemab treatment with plasma biomarkers associated with Alzheimer disease.

TRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to December 4, 2020, across 56 sites in the US and Canada. Exploratory biomarkers were prespecified with the post hoc addition of plasma glial fibrillary acidic protein and amyloid-β. Men and women aged 60 to 85 years with gradual and progressive change in memory function for at least 6 months were included. A total of 1955 participants were assessed for eligibility. Key eligibility criteria include Mini-Mental State Examination scores of 20 to 28 and elevated amyloid and intermediate tau levels.

Interventions: Randomized participants received donanemab or placebo every 4 weeks for up to 72 weeks. The first 3 doses of donanemab were given at 700 mg and then increased to 1400 mg with blinded dose reductions as specified based on amyloid reduction.

Main Outcomes and Measures: Change in plasma biomarker levels after donanemab treatment.

Results: In TRAILBLAZER-ALZ, 272 participants (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) were randomized. Plasma levels of phosphorylated tau217 (pTau217) and glial fibrillary acidic protein were significantly lower with donanemab treatment compared with placebo as early as 12 weeks after the start of treatment (least square mean change difference vs placebo, -0.04 [95% CI, -0.07 to -0.02]; P = .002 and -0.04 [95% CI, -0.07 to -0.01]; P = .01, respectively). No significant differences in plasma levels of amyloid-β 42/40 and neurofilament light chain were observed between treatment arms at the end of treatment. Changes in plasma pTau217 and glial fibrillary acidic protein were significantly correlated with the Centiloid percent change in amyloid (Spearman rank correlation coefficient [R] = 0.484 [95% CI, 0.359-0.592]; P < .001 and R = 0.453 [95% CI, 0.306-0.579]; P < .001, respectively) following treatment. Additionally, plasma levels of pTau217 and glial fibrillary acidic protein were significantly correlated at baseline and following treatment (R = 0.399 [95% CI, 0.278-0.508], P < .001 and R = 0.393 [95% CI, 0.254-0.517]; P < .001, respectively).

Conclusions and Relevance: Significant reductions in plasma biomarkers pTau217 and glial fibrillary acidic protein compared with placebo were observed following donanemab treatment in patients with early symptomatic Alzheimer disease. These easily accessible plasma biomarkers might provide additional evidence of Alzheimer disease pathology change through anti-amyloid therapy. Usefulness in assessing treatment response will require further evaluation.

Trial Registration: ClinicalTrials.gov Identifier: NCT03367403.

RevDate: 2022-10-21

Kater MSJ, Huffels CFM, Oshima T, et al (2022)

Prevention of microgliosis halts early memory loss in a mouse model of Alzheimer's disease.

Brain, behavior, and immunity pii:S0889-1591(22)00414-7 [Epub ahead of print].

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline, the neuropathological formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. The best cellular correlates of the early cognitive deficits in AD patients are synapse loss and gliosis. In particular, it is unclear whether the activation of microglia (microgliosis) has a neuroprotective or pathological role early in AD. Here we report that microgliosis is an early mediator of synaptic dysfunction and cognitive impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We found that the appearance of microgliosis, synaptic dysfunction and behavioral impairment coincided with increased soluble Aβ42 levels, and occurred well before the presence of Aβ plaques. Inhibition of microglial activity by treatment with minocycline (MC) reduced gliosis, synaptic deficits and cognitive impairments at early pathological stages and was most effective when provided preventive, i.e., before the onset of microgliosis. Interestingly, soluble Aβ levels or Aβ plaques deposition were not affected by preventive MC treatment at an early pathological stage (4 months) whereas these were reduced upon treatment at a later stage (6 months). In conclusion, this study demonstrates the importance of early-stage prevention of microgliosis on the development of cognitive impairment in APP/PS1 mice, which might be clinically relevant in preventing memory loss and delaying AD pathogenesis.

RevDate: 2022-10-18

Gómez-Virgilio L, Reyes-Gutiérrez GS, Silva-Lucero MD, et al (2022)

Etiology, risk factors, treatments and current status of Alzheimer's disease in Mexico.

Gaceta medica de Mexico, 158(4):235-241.

Alzheimer's disease is a neurodegenerative disorder whose etiology continues to be discussed, to the point that there are different hypotheses that seek to clarify it, in addition to the fact that, given its multifactorial nature, there are different risk factors associated with its development. As regards diagnosis, advances in molecule detection techniques at femtomolar scales have allowed to distinguish between healthy and diseased subjects at relatively early stages, although there is still much to be done. Aducanumab is a monoclonal antibody targeted against Aβ, whose marketing approval by the Food and Drug Administration has been questioned by the international medical community, given the controversial results in clinical trials. Approval of this antibody as a disease-modifying treatment for Alzheimer's disease opens the door to continue using this type of treatments, but with different therapeutic targets, such as, for example, tau protein. Finally, given the population tendency towards longevity, conditions such as Alzheimer's disease are gaining epidemiological importance, which is why it is imperative to analyze and link what is being done in the social, familiar, clinical and research fields and, most importantly, to find those areas of opportunity for the benefit of the patient.

RevDate: 2022-10-17

Infantino R, Boccella S, Scuteri D, et al (2022)

2-pentadecyl-2-oxazoline prevents cognitive and social behaviour impairments in the Amyloid β-induced Alzheimer-like mice model: Bring the α2 adrenergic receptor back into play.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 156:113844 pii:S0753-3322(22)01233-1 [Epub ahead of print].

The 2-pentadecyl-2-oxazoline (PEA-OXA) is a natural compound with protective action in neuro-inflammation. We have previously shown that PEA-OXA behaves as an α2 adrenergic receptor (α2AR) antagonist and a putative protean agonist on histamine H3 receptors. Recently, neuroinflammation and monoaminergic neurotransmission dysfunction has drawn particular attention in Alzheimer Disease (AD) pathophysiology. In this context, the objective of this study was to investigate the effects of the dual-acting PEA-OXA in an AD-like model in mice. A combined computational and experimental approach was used to evaluate the ability of PEA-OXA to bind α2A-AR subtype, and to investigate the effects of PEA-OXA treatment on neuropathological (behavioural and functional) effects induced by soluble Amyloid β 1-42 (sAβ1-42) intracerebroventricular injection. Computational analysis revealed the PEA-OXA ability to bind the α2A-AR, a pharmacological target for AD, in two alternative poses, one overlapping the Na+ binding site. In vivo studies indicated that chronic treatment with PEA-OXA (10 mg/kg, os) restored the cognitive (discriminative and spatial memory) deficits and social impairments induced by sAβ injection. Consistently, electrophysiological analysis showed a recovery of the long-term potentiation in the hippocampus (Lateral Entorhinal Cortex-Dentate Gyrus pathway), while neuroinflammation, i.e., increased pro-inflammatory cytokines levels and microglia cells density were reduced. These data provide the basis for further investigation of the pro-cognitive aptitude of PEA-OXA by proposing it as an adjuvant in the treatment in AD, for which the available pharmacological approaches remain unsatisfactory. Moreover, this study offers new future direction in research investigating the role of α2AR in neuropsychiatric illness and therapies.

RevDate: 2022-10-14

Mohtashami Z, Singh MK, Salimiaghdam N, et al (2022)

MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases.

International journal of molecular sciences, 23(19): pii:ijms231911991.

MOTS-c, a 16 amino acid mitochondrial derived peptide, is encoded from the 12S rRNA region of the mitochondrial genome. Under stress conditions, MOTS-c translocates to the nucleus where it regulates a wide range of genes in response to metabolic dysfunction. It is colocalized to mitochondria in various tissues and is found in plasma, but the levels decline with age. Since MOTS-c has important cellular functions as well as a possible hormonal role, it has been shown to have beneficial effects on age-related diseases including Diabetes, Cardiovascular diseases, Osteoporosis, postmenopausal obesity and Alzheimer. Aging is characterized by gradual loss of (mitochondrial) metabolic balance, decreased muscle homeostasis and eventual diminished physical capability, which potentially can be reversed with MOTS-c treatment. This review examines the latest findings on biological effects of MOTS-c as a nuclear regulatory peptide and focuses on the role of MOTS-c in aging and age-related disorders, including mechanisms of action and therapeutic potential.

RevDate: 2022-10-13
CmpDate: 2022-10-13

Dorman G, O'Neill S, Appiani F, et al (2022)

Do we treat dementia of the Alzheimer type or Alzheimer's disease? Anti-dementia drugs in the era of biomarkers.

Vertex (Buenos Aires, Argentina), 33(157):62-65.

Approved drug treatments for Alzheimer´s disease (AD) are symptomatic and don´t modify the disease course. These include acetylcholinesterase inhibitors (AchI) and N-methyl-D-aspartate receptor antagonist, memantine. Around 20 years ago, these drugs were approved for Alzheimer type Dementia. This wasbased on clinical trials which inclusion criteria were focused on a clinical amnestic AD presentation. At that time, subjects with an atypical AD clinical presentation or biomarkers were not included in the pharmacological trials. New biomarkers that detect amyloid and neurodegeneration have allowed us to evaluate pathological changes compatible with AD. These new advances from aclinical and biomarkers perspective allowed a diagnostic criteria update; going from an exclusively clinical criteria to one that is hybrid: clinical presentation and biomarkers based criteria.New biomarkers facilitate the early diagnosis of AD and other dementias.However, they also generate new challenges and questions regarding the adequate pharmacological treatment.There is a need for clinical trials that evaluate anti-dementia drug’s efficacy based on current diagnostic criteria (clinical profile and biomarkers) and new practice guidelines. In addition, regulatory authorities should update ACHI and memantine indications.This will help doctors to prescribe the best possible treatment for this specific population without increasing risks.

RevDate: 2022-10-12

Popp J, Georgescu D, Bürge M, et al (2022)

[Biomarkers for the diagnosis of cognitive impairment - Recommendations from the Swiss Memory Clinics].

Praxis, 111(13):738-744.

Biomarkers for the diagnosis of cognitive impairment - Recommendations from the Swiss Memory Clinics Abstract. Molecular cerebrospinal fluid (CSF) biomarkers of neurodegenerative diseases are now part of the established diagnostic tools for the clinical investigation of cognitive disorders in the elderly. Biomarkers allow for earlier and more accurate differential diagnosis, and are recommended by the Swiss Memory Clinics as an additional investigation based upon individual indication. Information and counselling are needed both before and after biomarker-supported diagnosis. The procedures for diagnostic lumbar punctures and pre-analytical sample handling should follow published recommendations. The results must be interpreted in the context of the other available history and assessment outcome. Thanks to recent research progress, blood-based biomarkers and other non-invasive markers are expected to become available for clinical practice in the near future. This trend will likely lead to a much broader utilisation of biomarkers and may accelerate the development of effective and individually tailored prevention and treatment approaches. This review article provides an overview over the current state of biomarkers and provides the recommendations of the Swiss Memory Clinics for their use in clinical practice.

RevDate: 2022-10-11

Piazza F, Caminiti SP, Zedde M, et al (2022)

Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies.

Neurology, 99(12):e1265-e1277.

BACKGROUND AND OBJECTIVES: Amyloid-related imaging abnormalities suggestive of vasogenic edema or sulcal effusion (ARIA-E) are the most common adverse events complicating Alzheimer disease (AD) immunotherapy with anti-β-amyloid (Aβ) monoclonal antibodies. ARIA-E can also occur spontaneously in cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with increased CSF levels of anti-Aβ autoantibodies. Although the pathophysiologic mechanisms of ARIA-E remain to be fully elucidated, experimental evidence from ex vivo studies suggests that gantenerumab and aducanumab enable microglial activation. However, the in vivo evidence for a direct association between neuroinflammation and ARIA-E in patients with high CSF anti-Aβ (auto)antibody levels has never been demonstrated.

METHODS: The spatial distribution and temporal variations of microglial activation associated with levels of anti-Aβ autoantibodies at (sub)acute presentation of ARIA-E and after corticosteroid therapy were evaluated in a longitudinal case series of patients with CAA-ri, the spontaneous variant of the iatrogenic ARIA-E reported in Aβ-lowering immunotherapy with monoclonal antibodies. Multimodal and multiparametric MRI was used for CAA and ARIA-E severity quantification, according to validated scoring system; CSF testing for anti-Aβ autoantibodies and AD biomarkers; 11C-PK11195 PET for activated microglia.

RESULTS: At (sub)acute presentation, we found focal peaks of microglial activation having a greater spatial colocalization with ARIA-E compared with chronic age-related white matter change imaging abnormalities. The severity of ARIA-E and the magnitude of the associated microglial activation were greater in patients having AD and severe CAA concomitant disease compared with patients having CAA only. CSF anti-Aβ autoantibodies at presentation were high in all patients and markedly decreased at posttreatment follow-up, in parallel with clinical resolution of acute symptoms, reduced ARIA-E severity, and reduced microglial activation.

DISCUSSION: Our findings extend the current notion of ARIA-E by providing the first in vivo 11C-PK11195 PET evidence for an association between microglial activation and the magnitude and severity of ARIA-E in patients with increased CSF concentration of anti-Aβ autoantibodies and comorbid AD and CAA disease. Our results highlight CSF testing for anti-Aβ autoantibodies as a promising diagnostic, prognostic, and therapy response biomarker to help guide future treatment and management decisions in real clinical practice and clinical trials.

RevDate: 2022-10-11

Dubbelman MA, Verrijp M, Terwee CB, et al (2022)

Determining the Minimal Important Change of Everyday Functioning in Dementia: Pursuing Clinical Meaningfulness.

Neurology, 99(9):e954-e964.

BACKGROUND AND OBJECTIVES: Decline in everyday functioning is a key clinical change in Alzheimer disease and related disorders (ADRD). An important challenge remains the determination of what constitutes a clinically meaningful change in everyday functioning. We aimed to investigate this by establishing the minimal important change (MIC): the smallest amount of change that has a meaningful effect on patients' lives. We retrospectively investigated meaningful change in a memory clinic cohort.

METHODS: In the first, qualitative part of the study, community-recruited informal caregivers of patients with ADRD and memory clinic clinicians completed a survey in which they judged various situations representing changes in everyday functioning. Their judgments of meaningful change were used to determine thresholds for MIC, both for decline and improvement, on the Amsterdam Instrumental Activities of Daily Living (IADL) Questionnaire. In the second, quantitative part, we applied these values in an independent longitudinal cohort study of unselected memory clinic patients.

RESULTS: MIC thresholds were established at the average threshold of caregivers (N = 1,629; 62.4 ± 9.5 years; 77% female) and clinicians (N = 13): -2.2 points for clinically meaningful decline and +5.0 points for clinically meaningful improvement. Memory clinic patients (N = 230; 64.3 ± 7.7 years; 39% female; 60% dementia diagnosis) were followed for 1 year, 102 (45%) of whom showed a decline larger than the MIC, after a mean of 6.7 ± 3.5 months. Patients with a dementia diagnosis and more atrophy of the medial temporal lobe had larger odds (odds ratio [OR] = 3.4, 95% CI [1.5-7.8] and OR = 5.0, 95% CI [1.2-20.0], respectively) for passing the MIC threshold for decline than those with subjective cognitive complaints and no atrophy.

DISCUSSION: We were able to operationalize clinically meaningful decline in IADL by determining the MIC. The usefulness of the MIC was supported by our findings from the clinical sample that nearly half of a sample of unselected memory clinic patients showed a meaningful decline in less than a year. Disease stage and medial temporal atrophy were predictors of functional decline greater than the MIC. Our findings provide guidance in interpreting changes in IADL and may help evaluate treatment effects and monitor disease progression.

RevDate: 2022-10-10

Greenberg BD, Pettigrew C, Soldan A, et al (2022)

CSF Alzheimer Disease Biomarkers: Time-Varying Relationships With MCI Symptom Onset and Associations With Age, Sex, and ApoE4.

Neurology, 99(15):e1640-e1650.

BACKGROUND AND OBJECTIVES: This study aimed to examine whether baseline CSF measures of Alzheimer disease (AD)-related pathology are associated with the time to onset of mild cognitive impairment (MCI) and whether these associations differ by age, sex, Apolipoprotein E (ApoE4) status, and proximal (≤7 years) vs distal (>7 years) time to symptom onset.

METHODS: Measures of amyloid (Aβ1-42 and Aβ1-40), phospho-tau (ptau181), and total tau (t-tau) were determined from CSF samples obtained at baseline from participants in an ongoing longitudinal project, known as the Biomarkers for Older Controls at Risk for Alzheimer Disease study (BIOCARD) study. The fully automated, Lumipulse G immunoassay was used to analyze the specimens. Cox regression models were used to examine the relationship of baseline biomarker levels with time to symptom onset of MCI and interactions with age, sex, and ApoE allelic status in subjects who progressed from normal cognition to MCI.

RESULTS: Analyses included 273 participants from the BIOCARD cohort, who were cognitively normal and predominantly middle-aged at baseline, and have been followed for an average of 16 years (max = 23.6). During follow-up, 94 progressed to MCI (median time to symptom onset = 6.9 years). In Cox regression models, elevated ptau181 and t-tau levels were associated with time to MCI symptom onset if it occurred within 7 years of baseline (HR 1.386 and 1.329; p = 0.009 and 0.017, respectively), while a lower Aβ42/Aβ40 ratio was associated with symptom onset if it occurred >7 years from baseline (HR 0.596, p = 0.003). There were also significant 3-way CSF × age × sex interactions for ptau181 and Aβ42/Aβ40, with follow-up analyses indicating that associations between these biomarkers and progression to MCI were stronger among men than among women, but this difference between sexes diminished with increasing age.

DISCUSSION: The lengthy follow-up of BIOCARD participants permitted an examination of time-varying associations between CSF AD biomarkers with MCI symptom onset and the influence of sex, baseline age, and ApoE4 genotype on these associations. These factors may inform clinical trial enrollment strategies, or trial duration and outcomes, which may use these measures as surrogate markers of treatment response.

RevDate: 2022-10-10

Yin L, Zhou Y, Liu H, et al (2022)

LYECs: lysosome-enhancing compounds as potential therapeutic approaches for Alzheimer disease.

Autophagy [Epub ahead of print].

More than 55 million people are suffering from Alzheimer's disease (AD), but there is still no effective treatment for it. Therefore, novel therapeutic approaches and regulatory mechanisms of protein quality control need to be further evaluated and dissected. The lysosome is one of the major degradative organelles that maintain cellular homeostasis and protein quality control. In our recent study, we have identified a group of LYsosome-Enhancing Compounds (LYECs), which significantly promote the activation of TFEB (transcription factor EB) and lysosome biogenesis via inhibiting dopamine transporters (DAT). Injection of LH2-051, a member of the LYECs identified in this study, significantly improves learning, memory, and cognitive function of APP-PSEN1 mice, in which the enhanced capability of lysosomal degradation promotes the clearance of amyloid protein aggregates. In summary, this study reports novel mechanisms of neurotransporter-mediated lysosome biogenesis and shows that DAT inhibition can alleviate the pathogenesis of Alzheimer's disease.

RevDate: 2022-10-10

Deng C, Chen H, Meng Z, et al (2022)

Roles of traditional chinese medicine regulating neuroendocrinology on AD treatment.

Frontiers in endocrinology, 13:955618.

The incidence of sporadic Alzheimer's disease (AD) is increasing in recent years. Studies have shown that in addition to some genetic abnormalities, the majority of AD patients has a history of long-term exposure to risk factors. Neuroendocrine related risk factors have been proved to be strongly associated with AD. Long-term hormone disorder can have a direct detrimental effect on the brain by producing an AD-like pathology and result in cognitive decline by impairing neuronal metabolism, plasticity and survival. Traditional Chinese Medicine(TCM) may regulate the complex process of endocrine disorders, and improve metabolic abnormalities, as well as the resulting neuroinflammation and oxidative damage through a variety of pathways. TCM has unique therapeutic advantages in treating early intervention of AD-related neuroendocrine disorders and preventing cognitive decline. This paper reviewed the relationship between neuroendocrine and AD as well as the related TCM treatment and its mechanism. The advantages of TCM intervention on endocrine disorders and some pending problems was also discussed, and new insights for TCM treatment of dementia in the future was provided.

RevDate: 2022-10-09

Boustani M, Doty EG, Garrison LP, et al (2022)

Assessing the Cost-effectiveness of a Hypothetical Disease-Modifying Therapy With Limited Duration for the Treatment of Early Symptomatic Alzheimer Disease.

Clinical therapeutics pii:S0149-2918(22)00322-8 [Epub ahead of print].

PURPOSE: Clinical trials have produced promising results for disease-modifying therapies (DMTs) for Alzheimer's disease (AD); however, the evidence on their potential cost-effectiveness is limited. This study assesses the cost-effectiveness of a hypothetical DMT with a limited treatment duration in AD.

METHODS: We developed a Markov state-transition model to estimate the cost-effectiveness of a hypothetical DMT plus best supportive care (BSC) versus BSC alone among Americans living with mild cognitive impairment (MCI) due to AD or mild AD. AD states included MCI due to AD, mild AD, moderate AD, severe AD, and death. A hypothetical DMT was assumed to confer a 30% reduction in progression from MCI and mild AD. The base case annual drug acquisition cost was assumed to be $56,000. Other medical and indirect costs were obtained from published literature or list prices. Utilities for patients and caregivers were obtained from the published literature and varied by AD state and care setting (community care or long-term care). We considered 3 DMT treatment strategies: (1) treatment administered until patients reached severe AD (continuous strategy), (2) treatment administered for a maximum duration of 18 months or when patients reached severe AD (fixed-duration strategy), and (3) 40% of patients discontinuing treatment at 6 months because of amyloid plaque clearance and the remaining patients continuing treatment until 18 months or until they reached severe AD (test-and-discontinue strategy). Incremental cost-effectiveness ratios (ICERs) were calculated as the incremental cost per quality-adjusted life-year (QALY) gained.

FINDINGS: From the health care sector perspective, continuous treatment with a hypothetical DMT versus BSC resulted in an ICER of $612,354 per QALY gained. The ICER decreased to $157,288 per QALY gained in the fixed-duration strategy, driven by large reductions in treatment costs. With 40% of patients discontinuing treatment at 6 months (test-and-discontinue strategy), the ICER was $125,631 per QALY gained. In sensitivity and scenario analyses, the ICER was the most sensitive to changes in treatment efficacy, treatment cost, and the initial population AD state distribution. From the modified societal perspective, ICERs were 6.3%, 20.4%, and 25.1% lower than those from the health care sector perspective for the continuous, fixed-duration, and test-and-discontinue strategies, respectively.

IMPLICATIONS: Under a set of assumptions for annual treatment costs and the magnitude and duration of treatment efficacy, DMTs used for a limited duration may deliver value consistent with accepted US cost-effectiveness thresholds.

RevDate: 2022-10-06

Hook A, Randall JL, Grubb CM, et al (2022)

Anti-cholinergic drug burden in patients with dementia increases after hospital admission: a multicentre cross-sectional study.

BMC geriatrics, 22(1):783.

BACKGROUND: Anticholinergic medications are drugs that block cholinergic transmission, either as their primary therapeutic action or as a secondary effect. Patients with dementia may be particularly sensitive to the central effects of anticholinergic drugs. Anticholinergics also antagonise the effects of the main dementia treatment, cholinesterase inhibitors. Our study aimed to investigate anticholinergic prescribing for dementia patients in UK acute hospitals before and after admission.

METHODS: We included 352 patients with dementia from 17 UK hospital sites in 2019. They were all inpatients on surgical, medical or Care of the Elderly wards. Information about each patient's medications were collected using a standardised form, and the anticholinergic drug burden of each patient was calculated with an evidence-based online calculator. Wilcoxon's rank test was used to look at the correlation between two subgroups upon admission and discharge.

RESULTS: On admission to hospital, 37.8% of patients had an anticholinergic burden score ≥ 1 and 5.68% ≥3. On discharge, 43.2% of patients with an anticholinergic burden score ≥ 1 and 9.1% ≥3. The increase in scores was statistically significant (p = 0.001). Psychotropics were the most common group of anticholinergic medications prescribed at discharge. Of those patients taking cholinesterase inhibitors, 44.9% were also prescribed anticholinergic medications.

CONCLUSIONS: Our cross-sectional, multicentre study found that people with dementia are commonly prescribed anticholinergic medications, even if concurrently taking cholinesterase inhibitors, and are significantly more likely to be discharged from hospital with a higher anticholinergic burden than on admission.

RevDate: 2022-10-05

Skaria AP (2022)

The economic and societal burden of Alzheimer disease: managed care considerations.

The American journal of managed care, 28(10 Suppl):S188-S196.

Alzheimer disease (AD) is the most common cause of dementia and the sixth leading cause of death in the United States. Today, more than 6 million Americans are living with AD and that number is expected to increase to 13.8 million by 2060. The progressive debilitating nature of this illness and the absence of disease-modifying treatments contributes to a substantial economic and societal burden on the healthcare system. In 2022, the estimated healthcare costs associated with AD treatment were $321 billion, with costs projected to exceed $1 trillion by 2050. These cost-of-care projections are based on direct healthcare costs and are likely underestimated because indirect costs associated with AD treatment are usually not included. Indirect costs such as loss in productivity, diminished quality of life, and an increasing dependence on informal unpaid care provided by family caregivers augments the economic and societal burden of this disease. As drug development continues to evolve, the emergence of disease-modifying therapy may help to offset the burden associated with AD-related dementia. Managed care organizations are uniquely positioned to mitigate costs and positively impact outcomes through the promotion of disease awareness, early diagnosis, and treatment and disease management programs focused on multidisciplinary care coordination and caregiver support.

RevDate: 2022-10-05

Hill AM (2022)

Alzheimer disease and the evolving treatment landscape.

The American journal of managed care, 28(10 Suppl):S179-S187.

Alzheimer disease (AD) is an irreversible, progressive neurodegenerative disorder that destroys memory and the ability to think, slowly over time. AD is the leading type of dementia, accounting for 60% to 80% of cases, and the sixth leading cause of death in the United States. AD, which can range from mild to severe, is thought to occur secondary to the aggregation and accumulation of β-amyloid peptides, abnormal phosphorylation of tau protein, and neuroinflammation. Current treatment options vary depending on the severity of AD, and emerging treatment options continue to arise. Managed care organizations are in an excellent position to implement viable patient care ecosystems to support patients and caregivers in decreasing AD progression and its consequences. Vigilance in identifying AD and providing early treatment is crucial to improving patient outcomes and burden of disease on patients, caregivers, and health systems.

RevDate: 2022-10-03

Hong S, Han K, Kim KS, et al (2022)

The Risk of Neurodegenerative Diseases in Patients With Acromegaly: A Cohort Study.

Neurology pii:WNL.0000000000201010 [Epub ahead of print].

BACKGROUND AND OBJECTIVES: A few recent studies have reported an association between insulin-like growth factor-1 (IGF-1) and neurodegenerative disease, but there was no report on any association between acromegaly and neurodegenerative disease. We investigated whether the risk of Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases were increased among patients with acromegaly using nationwide data of Korea.

METHODS: We studied the association between acromegaly and Parkinson's disease and dementia in 1,611 patients with acromegaly and controls (age- and sex-matched 8055 participants with no diagnosis of acromegaly) from the National Health Insurance System database between 2006 and 2016 with a mean follow-up period of 7.34 years. Cox proportional hazards regression analysis was used to assess the risk of all outcomes in patients with acromegaly compared with controls with adjusting for age, sex, household income, place, type 2 diabetes, hypertension, and dyslipidaemia.

RESULTS: The average age of the acromegaly patients and the controls was 54.16 years old (40.4% men). The incidence rate of Parkinson's disease in patients with acromegaly (1.54 per 1,000 person-years) was significantly higher than that in the control group (0.55 per 1,000 person-years) (log-rank test p=0.001). Acromegaly was associated with a higher risk of Parkinson's disease (hazard ratio [HR]= 2.609, 95% confidence interval [CI]: 1.410 to 2.609) than the control. In addition, acromegaly was associated with a higher risk of all-cause dementia (HR=2.299, 95% CI: 1.362-3.881), Alzheimer`s disease (HR=2.228, 95% CI: 1.191-4.168) and Non-AD dementia (HR=6.553, 95% CI: 1.754-24.482) than the control during the first three years after diagnosis and treatment. In subgroup analysis, diabetes was associated with higher risk of all-cause dementia (P for interaction=0.028) in patients with acromegaly compared with controls.

DISCUSSION: Our study results suggest that acromegaly is associated with neurodegenerative disease. Further study is needed on the association between IGF-1/growth hormone level and neurodegenerative disease.

RevDate: 2022-10-03

Paramanick D, Singh VD, VK Singh (2022)

Neuroprotective effect of phytoconstituents via nanotechnology for treatment of Alzheimer diseases.

Journal of controlled release : official journal of the Controlled Release Society pii:S0168-3659(22)00661-7 [Epub ahead of print].

Alzheimer's disease (AD) is a neurological condition characterised by cognitive and behavioural dysfunction. The presence of the blood brain barrier (BBB), which prevents medications from entering the brain, makes treating AD difficult. Currently, existing therapeutic modalities provide symptomatic alleviation while also being unsafe. Phytoconstituents are gaining popularity due to their neuroprotective properties and ability to target many pathogenic pathways involved with AD. However, because to their lower BBB permeability, poor solubility, and low bioavailability, they have failed to reduce disease progression and treat Alzheimer's disease. Nanotechnology is an emerging tool for overcoming these obstacles in brain drug delivery. Thus, the development of phytochemical-loaded nanocarrier systems can reduce these barriers while improving neuroprotective benefits. In this review, we summarised prospective targets, methodologies for brain drug delivery, phytoconstituents, and their nanocarrier system developed for the management and treatment of AD. Researchers looking for an alternate method to treat AD were given new insight by emphasising obstacles and future prospects.

RevDate: 2022-10-03

Wilkins CH, Windon CC, Dilworth-Anderson P, et al (2022)

Racial and Ethnic Differences in Amyloid PET Positivity in Individuals With Mild Cognitive Impairment or Dementia: A Secondary Analysis of the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) Cohort Study.

JAMA neurology pii:2796653 [Epub ahead of print].

Importance: Racial and ethnic groups with higher rates of clinical Alzheimer disease (AD) are underrepresented in studies of AD biomarkers, including amyloid positron emission tomography (PET).

Objective: To compare amyloid PET positivity among a diverse cohort of individuals with mild cognitive impairment (MCI) or dementia.

Secondary analysis of the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS), a single-arm multisite cohort study of Medicare beneficiaries who met appropriate-use criteria for amyloid PET imaging between February 2016 and September 2017 with follow-up through January 2018. Data were analyzed between April 2020 and January 2022. This study used 2 approaches: the McNemar test to compare amyloid PET positivity proportions between matched racial and ethnic groups and multivariable logistic regression to assess the odds of having a positive amyloid PET scan. IDEAS enrolled participants at 595 US dementia specialist practices. A total of 21 949 were enrolled and 4842 (22%) were excluded from the present analysis due to protocol violations, not receiving an amyloid PET scan, not having a positive or negative scan, or because of small numbers in some subgroups.

Exposures: In the IDEAS study, participants underwent a single amyloid PET scan.

Main Outcomes and Measures: The main outcomes were amyloid PET positivity proportions and odds.

Results: Data from 17 107 individuals (321 Asian, 635 Black, 829 Hispanic, and 15 322 White) with MCI or dementia and amyloid PET were analyzed between April 2020 and January 2022. The median (range) age of participants was 75 (65-105) years; 8769 participants (51.3%) were female and 8338 (48.7%) were male. In the optimal 1:1 matching analysis (n = 3154), White participants had a greater proportion of positive amyloid PET scans compared with Asian participants (181 of 313; 57.8%; 95% CI, 52.3-63.2 vs 142 of 313; 45.4%; 95% CI, 39.9-50.9, respectively; P = .001) and Hispanic participants (482 of 780; 61.8%; 95% CI, 58.3-65.1 vs 425 of 780; 54.5%; 95% CI, 51.0-58.0, respectively; P = .003) but not Black participants (359 of 615; 58.4%; 95% CI, 54.4-62.2 vs 333 of 615; 54.1%; 95% CI, 50.2-58.0, respectively; P = .13). In the adjusted model, the odds of having a positive amyloid PET scan were lower for Asian participants (odds ratio [OR], 0.47; 95% CI, 0.37-0.59; P < .001), Black participants (OR, 0.71; 95% CI, 0.60-0.84; P < .001), and Hispanic participants (OR, 0.68; 95% CI, 0.59-0.79; P < .001) compared with White participants.

Conclusions and Relevance: Racial and ethnic differences found in amyloid PET positivity among individuals with MCI and dementia in this study may indicate differences in underlying etiology of cognitive impairment and guide future treatment and prevention approaches.

RevDate: 2022-10-03

Valverde A, J Mitrofanis (2022)

Photobiomodulation for Hypertension and Alzheimer's Disease.

Journal of Alzheimer's disease : JAD pii:JAD220632 [Epub ahead of print].

Although the cause(s) of Alzheimer's disease in the majority of cases remains elusive, it has long been associated with hypertension. In animal models of the disease, hypertension has been shown to exacerbate Alzheimer-like pathology and behavior, while in humans, hypertension during mid-life increases the risk of developing the disease later in life. Unfortunately, once individuals are diagnosed with the disease, there are few therapeutic options available. There is neither an effective symptomatic treatment, one that treats the debilitating cognitive and memory deficits, nor, more importantly, a neuroprotective treatment, one that stops the relentless progression of the pathology. Further, there is no specific preventative treatment that offsets the onset of the disease. A key factor or clue in this quest for an effective preventative and therapeutic treatment may lie in the contribution of hypertension to the disease. In this review, we explore the idea that photobiomodulation, the application of specific wavelengths of light onto body tissues, can reduce the neuropathology and behavioral deficits in Alzheimer's disease by controlling hypertension. We suggest that treatment with photobiomodulation can be an effective preventative and therapeutic option for this neurodegenerative disease.

RevDate: 2022-10-03

Yang YH, Hsieh SW, Chang HW, et al (2022)

Gamma Frequency Inhibits the Secretion and Aggregation of Amyloid-β and Decreases the Phosphorylation of mTOR and Tau Proteins in vitro.

Journal of Alzheimer's disease : JAD pii:JAD220307 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) was the main cause of dementia in an aging society; unfortunately, there is no effective treatment for AD now. Meditation has been reported to thicken the cerebral cortex, and gamma wave at a frequency of 40 hertz (Hz) was recorded during the meditation process from the brain. Previous study showed that non-invasive scintillation gamma frequency oscillation increased the space in recognition and memory of auditory cortex hippocampal gyrus in AD mice model. However, the AD-related molecular change by exposure of 40 Hz gamma frequency in brain cells was still unclear.

OBJECTIVE: We investigated the AD-related molecular change by exposure of 40 Hz gamma frequency in SH-SY5Y cells.

METHODS: We designed the light and sound generators at 40 Hz gamma frequency for this study. SH-SY5Y cells were exposed to sound or light of 40 Hz gamma frequency, respectively. The concentrations of amyloid-β40 (Aβ40) and amyloid-β42 (Aβ42) were quantified by enzyme-linked immunosorbent assay. The protein levels were examined by western blotting. The aggregation of Aβ42 was examined by thioflavin T assay.

RESULTS: Our results showed that the secretion of Aβ, phosphorylation of AKT, mTOR, and tau, and aggregation of Aβ42 were significantly inhibited by 40 Hz gamma frequency in SH-SY5Y cells. The phosphorylation of 4E-BP1, downstream of mTOR, was induced by 40 Hz gamma frequency in SH-SY5Y cells.

CONCLUSION: Our study showed 40 Hz gamma frequency involved in the inhibition of secretion and aggregation of Aβ and inhibition of p-Tau protein expression through the mTOR/4E-BP1/Tau signaling pathway.

RevDate: 2022-10-03

Lakra N, Matore BW, Banjare P, et al (2022)

Pharmacophore based virtual screening of cholinesterase inhibitors: search of new potential drug candidates as antialzheimer agents.

In silico pharmacology, 10(1):18 pii:133.

Alzheimer's disease (AD) is a distinctive medical condition characterized by loss of memory, orientation, and cognitive impairments, which is an exceptionally universal form of neurodegenerative disease. The statistical data suggested that it is the 3rd major cause of death in older persons. Butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors play a vital role in the treatment of AD. Coumarins, natural derivatives, are reported as cholinesterase inhibitors and emerges as a promising scaffold for design of ligands targeting enzymes and pathological alterations related to AD. In this regard, the 3D QSAR pharmacophore models were developed for coumarin scaffold containing BChE and AChE inhibitors. Several 3D QSAR pharmacophore models were developed with FAST, BEST, and CEASER methods, and finally, statistically robust models (based on correlation coefficient, cost value, and RMSE value) were selected for further analysis for both targets. The important features ((HBA 1, HBA 2, HY, RA (BChE) HBA 1, HBA 2, HY, PI, (AChE)) were identified for good inhibitory activity of coumarin derivatives. Finally, the selected models were applied to various database compounds to find potential BChE and AChE inhibitors, and we found 13 for BChE and 1 potent compound for AChE with an estimated activity of IC50 < 10 µM. Further, the Lipinski filters, and ADMET analysis supports the selected compounds to become a drug candidate. These selected BChE and AChE inhibitors can be used in the treatment of AD.

Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-022-00133-1.

RevDate: 2022-10-03

Rad ES, Eidi A, Minai-Tehrani D, et al (2022)

Neuroprotective Effect of Root Extracts of Berberis Vulgaris (Barberry) on Oxidative Stress on SH-SY5Y Cells.

Journal of pharmacopuncture, 25(3):216-223.

Objectives: Oxidative stress plays a key role in chronic and acute brain disorders and neuronal damage associated with Alzheimer disease (AD) and other neurodegeneration symptoms. The neuroprotective effects of berberine and Berberis vulgaris (barberry) root extract against apoptosis induced by hydrogen peroxide (H2O2) in the human SH-SY5Y cell line were studied.

Methods: The methanolic extraction of barberry root was performed using a maceration procedure. Oxidative stress was induced in SH-SY5Y cells by H2O2, and an MTT assay was applied to evaluate the neuroprotective effects of berberine and barberry root extract. The cells were pretreated with the half maximal inhibitory concentration (IC50) of each compound (including berberine, barberry root extract, and H2O2), and the anti-apoptotic effects of all components were investigated using RT-PCR.

Results: The SH-SY5Y cell viability increased in both groups exposed to 75 and 150 ppm barberry extract compared with that in the H2O2-treated group. The data showed that exposing SH-SY5Y cells to 30 ppm berberine significantly increased the cell viability compared with the H2O2-treated group; treatment with 150 and 300 ppm berberine and H2O2 significantly decreased the SH-SY5Y cell viability and was associated with berberine cytotoxicity. The mRNA levels of Bax decreased significantly under treatment with berberine at 30 ppm compared with the control group. A significant increase in Bcl-2 expression was observed only after treatment with the IC50 of berberine. The expression level of Bcl-2 in cells exposed to both berberine and barberry extracts was also significantly higher than that in cells exposed to H2O2.

Conclusion: The outcomes of this study suggest that treatment of SH-SY5Y cells with barberry extract and berberine could suppress apoptosis by regulating the actions of Bcl-2 family members.

RevDate: 2022-10-03

Selbaek G, Stuebs J, Engedal K, et al (2022)

Blood pressure trajectories over 35 years and dementia risk: A retrospective study: The HUNT study.

Frontiers in aging neuroscience, 14:931715.

High blood pressure is a well-established risk factor of dementia. However, the timing of the risk remains controversial. The aim of the present study was to compare trajectories of systolic blood pressure (SBP) over a 35-year follow-up period in the Health Survey in Trøndelag (HUNT) from study wave 1 to 4 in people with and without a dementia diagnosis at wave 4 (HUNT4). This is a retrospective cohort study of participants aged ≥ 70 years in HUNT4, where 9,720 participants were assessed for dementia. In the HUNT study all residents aged ≥ 20 years have been invited to four surveys: HUNT1 1984-86, HUNT2 1995-97, HUNT3 2006-08 and HUNT4 2017-19. The study sample was aged 70-102 years (mean 77.6, SD 6.0) at HUNT4, 54% were women and 15.5% had dementia, 8.8% had Alzheimer's disease (AD), 1.6% had vascular dementia (VaD) and 5.1% had other types of dementia. Compared to those without dementia at HUNT4, those with dementia at HUNT4 had higher SBP at HUNT1 and HUNT2, but lower SBP at HUNT4. These differences at HUNT1 and 2 were especially pronounced among women. Results did not differ across birth cohorts. For dementia subtypes at HUNT4, the VaD group had a higher SBP than the AD group at HUNT2 and 3. Age trajectories in SBP showed that the dementia group experienced a steady increase in SBP until 65 years of age and a decrease from 70 to 90 years. SBP in the no- dementia group increased until 80 years before it leveled off from 80 to 90 years. The present study confirms findings of higher midlife SBP and lower late-life SBP in people with dementia. This pattern may have several explanations and it highlights the need for close monitoring of BP treatment in older adults, with frequent reappraisal of treatment needs.

RevDate: 2022-10-02

Makrakis D, Holt SK, Bernick C, et al (2022)

Intravesical BCG and Incidence of Alzheimer Disease in Patients With Bladder Cancer: Results From an Administrative Dataset.

Alzheimer disease and associated disorders pii:00002093-990000000-00029 [Epub ahead of print].

INTRODUCTION: Alzheimer disease (AD) is a common neurodegenerative disease, and immunomodulation offers treatment opportunities. Preclinical data suggest that intravesical Bacillus Calmette-Guerin (BCG) treatment could delay AD development. We investigated this relationship in a population-based cancer database.

SAMPLE AND METHODS: We queried the Surveillance, Epidemiology, and End Results-Medicare database for patients with high-risk nonmuscle-invasive bladder cancer (hrNMIBC). BCG dosage and subsequent Alzheimer diagnosis were collected through ICD-9/10 codes. Multivariable Cox regression was performed to assess the association between BCG therapy and subsequent Alzheimer diagnosis.

RESULTS: We identified 26,584 hrNMIBC patients; 51% received BCG and 8.3% were diagnosed with Alzheimer. BCG exposure was significantly associated with lower Alzheimer occurrence (hazard ratio: 0.73, P<0.05), which was dose-dependent. Increasing age, female sex, Black race, and increasing comorbidity index were significantly associated with a greater risk of subsequent Alzheimer diagnosis.

DISCUSSION: Treatment with intravesical BCG among patients with hrNMIBC was associated with a significantly lower risk for subsequent Alzheimer diagnosis, which seemed dose-dependent.

RevDate: 2022-10-01

Zhou K, He J, Quan L, et al (2022)

Clinical efficacy of acupuncture combined with Western medicine in the treatment of mild to moderate Alzheimer disease: A protocol of a randomized controlled trial.

Medicine, 101(39):e30705.

BACKGROUND: Alzheimer disease (AD) is a common cause of dementia, and there are still a lack of treatment options to reverse or prevent disease progression. Existing evidence shows that acupuncture has advantages in the treatment of AD, but whether the efficacy of acupuncture belongs to the placebo effect remains controversial, and there is no strict placebo-controlled clinical study to evaluate the efficacy and safety of acupuncture combined with Western medicine in the treatment of AD.

METHODS: This is a prospective randomized, a single-blind, sham-acupuncture controlled trial to study the clinical efficacy of acupuncture combined with Western medicine in the treatment of mild to moderate AD. Participants will be randomly divided into treatment and control groups. The treatment group using acupuncture combined with donepezil hydrochloride orally, and the control group using sham acupuncture combined with donepezil hydrochloride orally, followed up for 24 weeks after 24 weeks of continuous treatment. Outcome measures included: AD assessment scale-cognitive subscale, mini-mental state examination, activities of daily living, neuropsychiatric inventory questionnaire, serum superoxide dismutase, and homocysteine levels. Finally, SPASS 21.0 software was used for statistical analysis of the data.

DISCUSSION: This study will evaluate the efficacy of acupuncture combined with Western medicine in improving cognitive function and activities of daily living in AD patients. The results of this study will verify whether the efficacy of acupuncture in the treatment of AD belongs to the placebo effect, which will also provide a reference for the clinical use of acupuncture combined with Western medicine in the treatment of AD.

TRIAL REGISTRATION: The TCTR identification number is TCTR20220817004.

RevDate: 2022-09-30

Skirrow C, Meszaros M, Meepegama U, et al (2022)

Validation of a Remote and Fully Automated Story Recall Task to Assess for Early Cognitive Impairment in Older Adults: Longitudinal Case-Control Observational Study.

JMIR aging, 5(3):e37090 pii:v5i3e37090.

BACKGROUND: Story recall is a simple and sensitive cognitive test that is commonly used to measure changes in episodic memory function in early Alzheimer disease (AD). Recent advances in digital technology and natural language processing methods make this test a candidate for automated administration and scoring. Multiple parallel test stimuli are required for higher-frequency disease monitoring.

OBJECTIVE: This study aims to develop and validate a remote and fully automated story recall task, suitable for longitudinal assessment, in a population of older adults with and without mild cognitive impairment (MCI) or mild AD.

METHODS: The "Amyloid Prediction in Early Stage Alzheimer's disease" (AMYPRED) studies recruited participants in the United Kingdom (AMYPRED-UK: NCT04828122) and the United States (AMYPRED-US: NCT04928976). Participants were asked to complete optional daily self-administered assessments remotely on their smart devices over 7 to 8 days. Assessments included immediate and delayed recall of 3 stories from the Automatic Story Recall Task (ASRT), a test with multiple parallel stimuli (18 short stories and 18 long stories) balanced for key linguistic and discourse metrics. Verbal responses were recorded and securely transferred from participants' personal devices and automatically transcribed and scored using text similarity metrics between the source text and retelling to derive a generalized match score. Group differences in adherence and task performance were examined using logistic and linear mixed models, respectively. Correlational analysis examined parallel-forms reliability of ASRTs and convergent validity with cognitive tests (Logical Memory Test and Preclinical Alzheimer's Cognitive Composite with semantic processing). Acceptability and usability data were obtained using a remotely administered questionnaire.

RESULTS: Of the 200 participants recruited in the AMYPRED studies, 151 (75.5%)-78 cognitively unimpaired (CU) and 73 MCI or mild AD-engaged in optional remote assessments. Adherence to daily assessment was moderate and did not decline over time but was higher in CU participants (ASRTs were completed each day by 73/106, 68.9% participants with MCI or mild AD and 78/94, 83% CU participants). Participants reported favorable task usability: infrequent technical problems, easy use of the app, and a broad interest in the tasks. Task performance improved modestly across the week and was better for immediate recall. The generalized match scores were lower in participants with MCI or mild AD (Cohen d=1.54). Parallel-forms reliability of ASRT stories was moderate to strong for immediate recall (mean rho 0.73, range 0.56-0.88) and delayed recall (mean rho=0.73, range=0.54-0.86). The ASRTs showed moderate convergent validity with established cognitive tests.

CONCLUSIONS: The unsupervised, self-administered ASRT task is sensitive to cognitive impairments in MCI and mild AD. The task showed good usability, high parallel-forms reliability, and high convergent validity with established cognitive tests. Remote, low-cost, low-burden, and automatically scored speech assessments could support diagnostic screening, health care, and treatment monitoring.

RevDate: 2022-09-27

Jeong HT, Sung HH, Lee JH, et al (2022)

Relationship Between Calcium Channel Blockers Therapy and Cognitive Function Improvement in Cognitive Decline Patients with Cerebrovascular Disease.

High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension [Epub ahead of print].

INTRODUCTION: Amlodipine belongs to a class of calcium channel blockers that relax blood vessels to allow easier flow of blood. Higher blood pressure (BP) is associated with cerebrovascular disease and is an important contributor to cognitive decline and dementia.

AIM: This study aimed to evaluate the effect of 24 weeks of S-amlodipine besylate therapy on cognitive function in patients with hypertension and cerebrovascular disease.

METHODS: The data were obtained from a study of post-market surveillance of S-amlodipine besylate.

RESULTS: A total of 545 subjects (mean age 67 ± 9.68 years) with hypertension and ischemic cerebrovascular disease were enrolled. Patients with a baseline Mini-Mental State Examination (MMSE) score above 26 were assigned to the cognitive normal (CN) (n = 294) group, and those with MMSE score less than 26 were in the cognitive decline (CD) (n = 251) group. After 24 weeks of treatment with S-amlodipine besylate 5 mg, MMSE and Global Deterioration Scale (GDS) were evaluated again. Changes in MMSE were compared in the target BP reached (TBPR) and non-reached (NTBPR) groups and for CN and CD groups. Treatment with 5 mg of S-amlodipine besylate for 24 weeks improved MMSE and GDS scores (p < 0.001). The CD group showed improvement in MMSE score regardless of whether target BP was obtained (TBPR: p < 0.001, NTBPR: p < 0.01). However, the CN classification was not significant for either TBPR or NTBPR groups.

CONCLUSIONS: S-amlodipine besylate improved cognition of the CD group with hypertension and cerebrovascular disease regardless of obtaining target BP.

RevDate: 2022-09-28
CmpDate: 2022-09-28

Shah A, Hussain-Shamsy N, Strudwick G, et al (2022)

Digital Health Interventions for Depression and Anxiety Among People With Chronic Conditions: Scoping Review.

Journal of medical Internet research, 24(9):e38030 pii:v24i9e38030.

BACKGROUND: Chronic conditions are characterized by their long duration (≥1 year), need for ongoing medical attention, and limitations in activities of daily living. These can often co-occur with depression and anxiety as common and detrimental comorbidities among the growing population living with chronic conditions. Digital health interventions (DHIs) hold promise in overcoming barriers to accessing mental health support for these individuals; however, the design and implementation of DHIs for depression and anxiety in people with chronic conditions are yet to be explored.

OBJECTIVE: This study aimed to explore what is known in the literature regarding DHIs for the prevention, detection, or treatment of depression and anxiety among people with chronic conditions.

METHODS: A scoping review of the literature was conducted using the Arksey and O'Malley framework. Searches of the literature published in 5 databases between 1990 and 2019 were conducted in April 2019 and updated in March 2021. To be included, studies must have described a DHI tested with, or designed for, the prevention, detection, or treatment of depression or anxiety in people with common chronic conditions (arthritis, asthma, diabetes mellitus, heart disease, chronic obstructive pulmonary disease, cancer, stroke, and Alzheimer disease or dementia). Studies were independently screened by 2 reviewers against the inclusion and exclusion criteria. Both quantitative and qualitative data were extracted, charted, and synthesized to provide a descriptive summary of the trends and considerations for future research.

RESULTS: Database searches yielded 11,422 articles across the initial and updated searches, 53 (0.46%) of which were included in this review. DHIs predominantly sought to provide treatment (44/53, 83%), followed by detection (5/53, 9%) and prevention (4/53, 8%). Most DHIs were focused on depression (36/53, 68%), guided (32/53, 60%), tailored to chronic physical conditions (19/53, 36%), and delivered through web-based platforms (20/53, 38%). Only 2 studies described the implementation of a DHI.

CONCLUSIONS: As a growing research area, DHIs offer the potential to address the gap in care for depression and anxiety among people with chronic conditions; however, their implementation in standard care is scarce. Although stepped care has been identified as a promising model to implement efficacious DHIs, few studies have investigated the use of DHIs for depression and anxiety among chronic conditions using such models. In developing stepped care, we outlined DHI tailoring, guidance, and intensity as key considerations that require further research.

RevDate: 2022-09-23

Ribeiro TC, Sábio RM, Luiz MT, et al (2022)

Curcumin-Loaded Mesoporous Silica Nanoparticles Dispersed in Thermo-Responsive Hydrogel as Potential Alzheimer Disease Therapy.

Pharmaceutics, 14(9): pii:pharmaceutics14091976.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. Curcumin-loaded mesoporous silica nanoparticles (MSN-CCM) can overcome the drawbacks related to the free curcumin (CCM) clinical application, such as water insolubility and low bioavailability, besides acting over the main causes associated to AD. A thermo-responsive hydrogel is an interesting approach for facilitating the administration of the nanosystem via a nasal route, as well as for overcoming mucociliary clearance mechanisms. In light of this, MSN-CCM were dispersed in the hydrogel and evaluated through in vitro and in vivo assays. The MSNs and MSN-CCM were successfully characterized by physicochemical analysis and a high value of the CCM encapsulation efficiency (EE%, 87.70 ± 0.05) was achieved. The designed thermo-responsive hydrogel (HG) was characterized by rheology, texture profile analysis, and ex vivo mucoadhesion, showing excellent mechanical and mucoadhesive properties. Ex vivo permeation studies of MSN-CCM and HG@MSN-CCM showed high permeation values (12.46 ± 1.08 and 28.40 ± 1.88 μg cm-2 of CCM, respectively) in porcine nasal mucosa. In vivo studies performed in a streptozotocin-induced AD model confirmed that HG@MSN-CCM reverted the cognitive deficit in mice, acting as a potential formulation in the treatment of AD.

RevDate: 2022-09-23

Chayrov R, Volkova T, Perlovich G, et al (2022)

Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug.

Pharmaceuticals (Basel, Switzerland), 15(9): pii:ph15091108.

Glutamate is an excitatory neurotransmitter in the nervous system. Excessive glutamate transmission can lead to increased calcium ion expression, related to increased neurotoxicity. Memantine is used for treating patients with Alzheimer's disease (AD) due to its protective action on the neurons against toxicity caused by over activation of N-methyl-D-aspartate receptors. Nootropics, also called "smart drugs", are used for the treatment of cognitive deficits. In this work, we evaluate the neuroprotective action of four memantine analogues of glycine derivatives, including glycyl-glycine, glycyl-glycyl-glycine, sarcosine, dimethylglycine and three conjugates with nootropics, modafinil, piracetam and picamilon. The new structural memantine derivatives improved cell viability against copper-induced neurotoxicity in APPswe cells and glutamate-induced neurotoxicity in SH-SY5Y cells. Among these novel compounds, modafinil-memantine, piracetam-memantine, sarcosine-memantine, dimethylglycine-memantine, and glycyl-glycine-memantine were demonstrated with good EC50 values of the protective effects on APPswe cells, accompanied with moderate amelioration from glutamate-induced neurotoxicity. In conclusion, our study demonstrated that novel structural derivatives of memantine might have the potential to develop promising lead compounds for the treatment of AD. The solubility of memantine analogues with nootropics and memantine analogues with glycine derivatives in buffer solutions at pH 2.0 and pH 7.4 simulating the biological media at 298.15 K was determined and the mutual influence of the structural fragments in the molecules on the solubility behavior was analyzed. The significative correlation equations relating the solubility and biological properties with the structural HYBOT (Hydrogen Bond Thermodynamics) descriptors were derived. These equations would greatly simplify the task of the directed design of the memantine analogues with improved solubility and enhanced bioavailability.

RevDate: 2022-09-21

Santisteban MM, Iadecola C, D Carnevale (2022)

Hypertension, Neurovascular Dysfunction, and Cognitive Impairment.

Hypertension (Dallas, Tex. : 1979) [Epub ahead of print].

Hypertension affects a significant proportion of the adult and aging population and represents an important risk factor for vascular cognitive impairment and late-life dementia. Chronic high blood pressure continuously challenges the structural and functional integrity of the cerebral vasculature, leading to microvascular rarefaction and dysfunction, and neurovascular uncoupling that typically impairs cerebral blood supply. Hypertension disrupts blood-brain barrier integrity, promotes neuroinflammation, and may contribute to amyloid deposition and Alzheimer pathology. The mechanisms underlying these harmful effects are still a focus of investigation, but studies in animal models have provided significant molecular and cellular mechanistic insights. Remaining questions relate to whether adequate treatment of hypertension may prevent deterioration of cognitive function, the threshold for blood pressure treatment, and the most effective antihypertensive drugs. Recent advances in neurovascular biology, advanced brain imaging, and detection of subtle behavioral phenotypes have begun to provide insights into these critical issues. Importantly, a parallel analysis of these parameters in animal models and humans is feasible, making it possible to foster translational advancements. In this review, we provide a critical evaluation of the evidence available in experimental models and humans to examine the progress made and identify remaining gaps in knowledge.

RevDate: 2022-09-19

Huang X, Wang YJ, Y Xiang (2022)

Bidirectional communication between brain and visceral white adipose tissue: Its potential impact on Alzheimer's disease.

EBioMedicine, 84:104263 pii:S2352-3964(22)00445-5 [Epub ahead of print].

A variety of axes between brain and abdominal organs have been reported, but the interaction between brain and visceral white adipose tissue (vWAT) remains unclear. In this review, we summarized human studies on the association between brain and vWAT, and generalized their interaction and the underlying mechanisms according to animal and cell experiments. On that basis, we come up with the concept of the brain-vWAT axis (BVA). Furthermore, we analyzed the potential mechanisms of involvement of BVA in the pathogenesis of Alzheimer's disease (AD), including vWAT-derived fatty acids, immunological properties of vWAT, vWAT-derived retinoic acid and vWAT-regulated insulin resistance. The proposal of BVA may expand our understanding to some extent of how the vWAT impacts on brain health and diseases, and provide a novel approach to study the pathogenesis and treatment strategies of neurodegenerative disorders.

RevDate: 2022-09-19

Tariot PN, Braeckman R, C Oh (2022)

Comparison of Steady-State Pharmacokinetics of Donepezil Transdermal Delivery System with Oral Donepezil.

Journal of Alzheimer's disease : JAD pii:JAD220530 [Epub ahead of print].

BACKGROUND: Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States.

OBJECTIVE: To compare steady-state pharmacokinetics of once-weekly 10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil.

METHODS: Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18-55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state on Week 5.

RESULTS: All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% [90% CI]) for maximum plasma concentration and area under the plasma concentration versus time curve (0-168 h) were 88.7 (81.7-96.2) and 108.6 (100.5-117.4) for 10-mg/d and 86.1 (79.8-92.9) and 105.3 (97.6-113.6) for dose-normalized 5-mg/d TDS and were generally within the 80% -125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively).

CONCLUSION: Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type.

RevDate: 2022-09-19
CmpDate: 2022-09-19

Newby D, Linden AB, Fernandes M, et al (2022)

Comparative effect of metformin versus sulfonylureas with dementia and Parkinson's disease risk in US patients over 50 with type 2 diabetes mellitus.

BMJ open diabetes research & care, 10(5):.

INTRODUCTION: Type 2 diabetes is a risk factor for dementia and Parkinson's disease (PD). Drug treatments for diabetes, such as metformin, could be used as novel treatments for these neurological conditions. Using electronic health records from the USA (OPTUM EHR) we aimed to assess the association of metformin with all-cause dementia, dementia subtypes and PD compared with sulfonylureas.

RESEARCH DESIGN AND METHODS: A new user comparator study design was conducted in patients ≥50 years old with diabetes who were new users of metformin or sulfonylureas between 2006 and 2018. Primary outcomes were all-cause dementia and PD. Secondary outcomes were Alzheimer's disease (AD), vascular dementia (VD) and mild cognitive impairment (MCI). Cox proportional hazards models with inverse probability of treatment weighting (IPTW) were used to estimate the HRs. Subanalyses included stratification by age, race, renal function, and glycemic control.

RESULTS: We identified 96 140 and 16 451 new users of metformin and sulfonylureas, respectively. Mean age was 66.4±8.2 years (48% male, 83% Caucasian). Over the 5-year follow-up, 3207 patients developed all-cause dementia (2256 (2.3%) metformin, 951 (5.8%) sulfonylurea users) and 760 patients developed PD (625 (0.7%) metformin, 135 (0.8%) sulfonylurea users). After IPTW, HRs for all-cause dementia and PD were 0.80 (95% CI 0.73 to 0.88) and 1.00 (95% CI 0.79 to 1.28). HRs for AD, VD and MCI were 0.81 (0.70-0.94), 0.79 (0.63-1.00) and 0.91 (0.79-1.04). Stronger associations were observed in patients who were younger (<75 years old), Caucasian, and with moderate renal function.

CONCLUSIONS: Metformin users compared with sulfonylurea users were associated with a lower risk of all-cause dementia, AD and VD but not with PD or MCI. Age and renal function modified risk reduction. Our findings support the hypothesis that metformin provides more neuroprotection for dementia than sulfonylureas but not for PD, but further work is required to assess causality.

RevDate: 2022-09-13

Singh S, Hema , Sharma N, et al (2022)

Focusing the pivotal role of nanotechnology in Huntington's disease: an insight into the recent advancements.

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

Neurodegeneration is the loss of neuronal capacity and structure over time which causes neurodegenerative disorders like Alzheimer, amyotrophic lateral sclerosis, Parkinson, and Huntington's disease (HD). This review is primarily concerned with HD, which was fully described by George Huntington in 1872. In developed countries, HD has become another common single-gene neurological disorder. Because of its autosomal dominant inheritance, the sickness affects both individuals and their families. Huntington disease has been recognized as a disorder that affects the complete body and brain in which the mutant huntingtin polyglutamine (polyQ) sequence is extensively increased and gets correlated to CAG trinucleotide which codes for glutamine (Q). These proteins have characteristics that produce apoptosis and dysfunction. HD is a lethal condition which needs an immediate diagnosis and treatment, and therefore, nanoparticle has come into sight out as opportunistic strategies for treatment of HD. Nanostructures have great potential to cross the blood brain barrier and also prevent breakdown of active molecule and reduces the drug toxicity. This review explains the distinguishing symptoms, genetics, and stages during the development of Huntington's disease, and also provides an overview of HD with an emphasis on its epidemiology, pathogenesis, and management. This review focuses on the latest studies on nanotechnology-related technologies, i.e., magnetic nanoparticle, solid lipid nanoparticle, and polymeric nanoparticle for Huntington's disease treatment. The pioneering patents and in-progress clinical trials related to Huntington's disease has also been summarized in this review.

RevDate: 2022-09-12

Shcherbinin S, Evans CD, Lu M, et al (2022)

Association of Amyloid Reduction After Donanemab Treatment With Tau Pathology and Clinical Outcomes: The TRAILBLAZER-ALZ Randomized Clinical Trial.

JAMA neurology pii:2795844 [Epub ahead of print].

Importance: β-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease.

Objective: To perform post hoc analyses of amyloid reduction after donanemab treatment and assess its association with tau pathology and clinical measures.

The Study of LY3002813 in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ) was a phase 2, placebo-controlled, randomized clinical trial conducted from December 18, 2017, to December 4, 2020, with a double-blind period of up to 76 weeks and a 48-week follow-up period. The study was conducted at 56 centers in the US and Canada. Enrolled were participants from 60 to 85 years of age with gradual and progressive change in memory function for 6 months or more, early symptomatic Alzheimer disease, elevated amyloid, and intermediate tau levels.

Interventions: Donanemab (an antibody specific for the N-terminal pyroglutamate β-amyloid epitope) dosing was every 4 weeks: 700 mg for the first 3 doses, then 1400 mg for up to 72 weeks. Blinded dose-reduction evaluations occurred at 24 and 52 weeks based on amyloid clearance.

Main Outcomes and Measures: Change in amyloid, tau, and clinical decline after donanemab treatment.

Results: The primary study randomized 272 participants (mean [SD] age, 75.2 [5.5] years; 145 female participants [53.3%]). The trial excluded 1683 of 1955 individuals screened. The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (Spearman correlation coefficient r, -0.54; 95% CI, -0.66 to -0.39; P < .001). Modeling provides a hypothesis that amyloid would not reaccumulate to the 24.1-centiloid threshold for 3.9 years (95% prediction interval, 1.9-8.3 years) after discontinuing donanemab treatment. Donanemab slowed tau accumulation in a region-dependent manner as measured using neocortical and regional standardized uptake value ratios with cerebellar gray reference region. A disease-progression model found a significant association between percentage amyloid reduction and change on the integrated Alzheimer Disease Rating Scale only in apolipoprotein E (APOE) ε4 carriers (95% CI, 24%-59%; P < .001).

Conclusions and Relevance: Results of post hoc analyses for donanemab-treated participants suggest that baseline amyloid levels were directly associated with the magnitude of amyloid reduction and inversely associated with the probability of achieving complete amyloid clearance. The donanemab-induced slowing of tau was more pronounced in those with complete amyloid clearance and in brain regions identified later in the pathologic sequence. Data from other trials will be important to confirm aforementioned observations, particularly treatment response by APOE ε4 status.

Trial Registration: ClinicalTrials.gov Identifier: NCT03367403.

RevDate: 2022-09-13

Zhang P, Maimaiti Z, Aili G, et al (2022)

Vitis vinifera L. Flavones Regulate Hippocampal Neurons via Autophagy in APP/PS1 Alzheimer Model Mice.

Evidence-based complementary and alternative medicine : eCAM, 2022:8554184.

Background: Alzheimer's disease (AD) is a neurodegenerative disease and our current treatment approach can only delay its course rather than cure it completely. Flavones from Vitis vinifera L. have been reported to promote synaptic plasticity and indirectly affect the expression of cholinergic neurotransmitters in a rat model of Alzheimer's disease.

Objective: The aim of the study is to explore the effect of Vitis vinifera L. in APP/PS1 Alzheimer model mice.

Methods: APP/PS1 AD mice were used as the research subjects, and the mice were divided into a model group, donepezil group, VTF low-dose group, VTF medium-dose group, and VTF high-dose group. C57BL/6 mice served as a control group. The autophagosomes were observed by a transmission electron microscope, and the expressions of LC3I, LC3IIand Beclin-1 were determined by Western blotting. The results of qRT-PCR are consistent with Western blotting.

Results: VTF can exert a positive regulatory effect on AD mice by inhibiting autophagy.

Conclusion: Our study supports that intragastrically administration of VTF is effective and operable in Alzheimer's disease mice, and that inhibition of excessive autophagy may be one of the potential reasons why VTF exerts a therapeutic effect on AD.

RevDate: 2022-09-13

Karaca Ş, Osmaniye D, Sağlık BN, et al (2022)

Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer's disease.

RSC advances, 12(36):23626-23636.

The use of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors is a new approach in the treatment of Alzheimer disease (AD). In this work, 14 new benzothiazoles (4a-4n) were designed and synthesized. In biological activity studies, the AChE, butyrylcholinesterase (BChE), MAO-A and MAO-B inhibitory potentials of all compounds were evaluated using the in vitro fluorometric method. Additionally, amyloid beta (Aβ)-aggregation inhibitory effects of active compounds were evaluated by means of an in vitro kit-based method. The biological evaluation showed that compounds 4a, 4d, 4f, 4h, 4k and 4m displayed significant activity against AChE and MAO-B enzymes. Compound 4f displayed inhibitory activity against AChE and MAO-B enzyme with IC50 values of 23.4 ± 1.1 nM and 40.3 ± 1.7 nM, respectively. It has been revealed that compound 4f may have the potential to inhibit AChE and MAO-B enzymes, as well as the ability to prevent the formation of beta amyloid plaques accumulated in the brains of patients suffering from AD. In silico studies also support the obtained biological activity findings. Compound 4f provided strong interactions with the active site of both enzymes. In particular, the interaction of compound 4f with flavin adenine dinucleotide (FAD) in the MAO-B enzyme active site is a promising and exciting finding.

RevDate: 2022-09-13
CmpDate: 2022-09-13

Matsuda N, Nakari I, K Takadama (2022)

Unstable Circadian Rhythm of Heart Rate of Alzheimer Dementia Based on Biological Data of Mattress Sensor.

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference, 2022:1129-1132.

It is important to detect daily Alzheimer dementia (AD) possibility using unconstrained mattress sensors because dementia takes time before subjective symptoms appear and the main treatment is to slow the rate of progression. Forcusing on circadian rhythm disorder which tend to occur with AD, this paper analyzes the features of unstable circadian rhythms of heart rate associated with its weakening and misalignment in AD. It is found that the external feature of heart rate of AD that of up and down changes seen frequently compared to that of healthy subjects makes the multiple types of effects on the estimation process of the AD detection method based on the circadian instability represented by the trigonometric regression equation estimated from the heart rate. So, we designed two feature values from the effects and analyzed them in an analysis experiment. An analysis experiment was conducted on the heart rate of total 72 days data of one AD patient and total 30 days data of 21 healthy people, and the result confirmed significant differences between the AD and the healthy people at from 0.01% to 0.1 % level for the first feature and at from 0.1% to 5% level for the second feature. And the result shows the possibility that differences in the heart rate features is found between AD and healthy people.

RevDate: 2022-09-09

Shirbhate E, Patel VK, Tiwari P, et al (2022)

Combination therapy for the treatment of alzheimer's disease: recent progress and future prospects.

Current topics in medicinal chemistry pii:CTMC-EPUB-126188 [Epub ahead of print].

BACKGROUND: The management of Alzheimer's disease is challenging due to its complexity. However, the currently approved and marketed treatments for this neurodegenerative disorder revolves around cholinesterase inhibitors and glutamate regulators or the combination of these agents. Despite the prompt assurance of many new drugs, several agents were unsuccessful, especially in phase II or III trials, not meeting efficacy endpoints.

OBJECTIVE: The execution of effective treatment approaches through further trials investigating a rational combination of agents is necessitude for Alzheimer's disease.

METHOD: For this review, more than 248 relevant scientific papers were considered from a variety of databases (Scopus, Web of Science, Google Scholar, Sciencedirect, and Pubmed) using the keywords Alzheimer's disease, amyloid-β, combination therapies, cholinesterase inhibitors, dementia, glutamate regulators, AD hypothesis.

RESULT AND DISCUSSION: The researcher's intent for either developing a disease-modifying therapeutic means for aiming in the early phases of dementia and/or optimizing the available symptomatic treatments principally committed to the more advanced stages of Alzheimer's. Since Alzheimer possesses multifactorial pathogenesis, designing a multimodal therapeutic intervention for targeting different pathological processes of dementia may appear to be the most practical method to alter the course of disease progression.

CONCLUSION: The combination approach may even allow for providing individual agents in lower doses, with reducible cost and side effects. Numerous studies on combination therapy predicted better clinical efficacy than monotherapy. The below literature review highlights the major clinical studies (both symptomatic and disease-modifying) conducted in the past decade on combination therapy to combat the cognitive disorder.

RevDate: 2022-09-06

Dang TK, Hong SM, Dao VT, et al (2022)

Neuroprotective effects of total alkaloids fraction of Huperzia serrata on scopolamine-induced neurodegenerative animals.

Phytotherapy research : PTR [Epub ahead of print].

Huperzia serrata contains Huperzine A (HupA)-an alkaloid used to treat cognitive dysfunction. In this study, we used the total alkaloids (HsAE) to investigate their potential in managing cognitive impairment in comparison with HupA. The antioxidant activity was measured by DPPH assay. In the cellular study, the cell viability and level of ACh of SH-SY5Y cells were evaluated after pretreated with HsAE and scopolamine. For in vivo assay, mice were pre-treated with HsAE, and HupA and undergone scopolamine injection for cognitive impairment. The behavioral tests including the Y-maze and Morris water maze test and the AChE activity, the SOD, CAT, MDA level in the hippocampus and cortex were evaluated. HsAE showed significant scavenging properties on DPPH radicals. HsAE was not toxic to SH-SY5Y cells, and can rescue these cells upon scopolamine treatment. Intriguingly, HsAE showed the neuroprotection against scopolamine-induced amnesia in mice. Moreover, HsAE decreased AChE activity, MDA level, increased antioxidative enzyme activity in the hippocampus as well as cortex of mice, which was relatively better than that of HupA. These findings suggested that HsAE may significantly protect the neurons of mice with scopolamine-induced memory impairment connected to AChE depletion and oxidative stress.

RevDate: 2022-09-03

Nuzzo D, Frinchi M, Giardina C, et al (2022)

Neuroprotective and Antioxidant Role of Oxotremorine-M, a Non-selective Muscarinic Acetylcholine Receptors Agonist, in a Cellular Model of Alzheimer Disease.

Cellular and molecular neurobiology [Epub ahead of print].

Alzheimer disease (AD) is a multifactorial and age-dependent neurodegenerative disorder, whose pathogenesis, classically associated with the formation of senile plaques and neurofibrillary tangles, is also dependent on oxidative stress and neuroinflammation chronicization. Currently, the standard symptomatic therapy, based on acetylcholinesterase inhibitors, showed a limited therapeutic potential, whereas disease-modifying treatment strategies are still under extensive research. Previous studies have demonstrated that Oxotremorine-M (Oxo), a non-selective muscarinic acetylcholine receptors agonist, exerts neurotrophic functions in primary neurons, and modulates oxidative stress and neuroinflammation phenomena in rat brain. In the light of these findings, in this study, we aimed to investigate the neuroprotective effects of Oxo treatment in an in vitro model of AD, represented by differentiated SH-SY5Y neuroblastoma cells exposed to Aβ1-42 peptide. The results demonstrated that Oxo treatment enhances cell survival, increases neurite length, and counteracts DNA fragmentation induced by Aβ1-42 peptide. The same treatment was also able to block oxidative stress and mitochondria morphological/functional impairment associated with Aβ1-42 cell exposure. Overall, these results suggest that Oxo, by modulating cholinergic neurotransmission, survival, oxidative stress response, and mitochondria functionality, may represent a novel multi-target drug able to achieve a therapeutic synergy in AD. Illustration of the main pathological hallmarks and mechanisms underlying AD pathogenesis, including neurodegeneration and oxidative stress, efficiently counteracted by treatment with Oxo, which may represent a promising therapeutic molecule. Created with BioRender.com under academic license.

RevDate: 2022-09-06

Merone M, D'Addario SL, Mirino P, et al (2022)

A multi-expert ensemble system for predicting Alzheimer transition using clinical features.

Brain informatics, 9(1):20.

Alzheimer's disease (AD) diagnosis often requires invasive examinations (e.g., liquor analyses), expensive tools (e.g., brain imaging) and highly specialized personnel. The diagnosis commonly is established when the disorder has already caused severe brain damage, and the clinical signs begin to be apparent. Instead, accessible and low-cost approaches for early identification of subjects at high risk for developing AD years before they show overt symptoms are fundamental to provide a critical time window for more effective clinical management, treatment, and care planning. This article proposes an ensemble-based machine learning algorithm for predicting AD development within 9 years from first overt signs and using just five clinical features that are easily detectable with neuropsychological tests. The validation of the system involved both healthy individuals and mild cognitive impairment (MCI) patients drawn from the ADNI open dataset, at variance with previous studies that considered only MCI. The system shows higher levels of balanced accuracy, negative predictive value, and specificity than other similar solutions. These results represent a further important step to build a preventive fast-screening machine-learning-based tool to be used as a part of routine healthcare screenings.

RevDate: 2022-09-03

Uytun A, Osmaniye D, Sağlık BN, et al (2022)

Synthesis of Novel Thiosemicarbazone Derivatives and Investigation of Their Dual AChE and MAO-B Inhibitor Effects.

Journal of molecular recognition : JMR [Epub ahead of print].

In this study, 15 thiosemicarbazone derivatives were synthesized. Analysis of the obtained compounds were performed by means of 1 H-NMR, 13 C-NMR and HRMS spectroscopic methods. The inhibition effect of the obtained compounds on cholinesterase (ChE) and monoaminoxidase (MAO) enzymes was investigated with in vitro methods. None of the compounds showed significant activity on butyrylcholinesterase (BChE) enzyme. On the other hand, compounds 3b, 3c, 3e, 3k, 3l, 3m, 3n and 3o displayed significant activity on AChE while compounds 3f, 3i, 3k, 3l, 3m, 3n, 3o also showed remarkable effects on MAO-B enzymes. For the selected compounds, docking studies were performed and the enzyme active site and binding modes were determined. It was revealed that the strongest interaction with AChE and MAO-B enzyme active sites was observed with the compound 3k. Another important factor in the treatment of diseases affecting the central nervous system such as Alzheimer's is the ability of the compounds to cross the blood-brain barrier. Additionally, the agents planned for the treatment of these diseases must also pass the blood-brain barrier. Therefore, in silico BBB penetration properties of active compound were investigated. This article is protected by copyright. All rights reserved.

RevDate: 2022-09-20
CmpDate: 2022-09-16

Fernandez MA, Bah F, Ma L, et al (2022)

Loss of endosomal exchanger NHE6 leads to pathological changes in tau in human neurons.

Stem cell reports, 17(9):2111-2126.

Disruption of endolysosomal and autophagy-lysosomal systems is increasingly implicated in neurodegeneration. Sodium-proton exchanger 6 (NHE6) contributes to the maintenance of proper endosomal pH, and loss-of function mutations in the X-linked NHE6 lead to Christianson syndrome (CS) in males. Neurodegenerative features of CS are increasingly recognized, with postmortem and clinical data implicating a role for tau. We generated cortical neurons from NHE6 knockout (KO) and isogenic wild-type control human induced pluripotent stem cells. We report elevated phosphorylated and sarkosyl-insoluble tau in NHE6 KO neurons. We demonstrate that NHE6 KO leads to lysosomal and autophagy dysfunction involving reduced lysosomal number and protease activity, diminished autophagic flux, and p62 accumulation. Finally, we show that treatment with trehalose or rapamycin, two enhancers of autophagy-lysosomal function, each partially rescue this tau phenotype. We provide insight into the neurodegenerative processes underlying NHE6 loss of function and into the broader role of the endosome-lysosome-autophagy network in neurodegeneration.

RevDate: 2022-09-02

Faloye KO, Mahmud S, Fakola EG, et al (2022)

Revealing the Acetylcholinesterase Inhibitory Potential of Phyllanthus amarus and Its Phytoconstituents: In Vitro and in Silico Approach.

Bioinformatics and biology insights, 16:11779322221118330.

The inhibition of acetylcholinesterase plays a vital role in the treatment of Alzheimer disease. This study aimed to explore the acetylcholinesterase inhibition potential of Phyllanthus amarus and its phytoconstituents through an in vitro and in silico approach. The in vitro acetylcholinesterase inhibitory activity of P amarus was carried out, followed by the molecular docking studies of its phytoconstituents. The top-ranked molecules identified through molecular docking were subjected to molecular dynamics simulation (MDS) and density functional theory (DFT) studies. The results obtained revealed the methanolic extract of P amarus as a potent acetylcholinesterase inhibitor, while amarosterol A, hinokinin, β-sitosterol, stigmasterol and ellagic acid were identified as potential acetylcholinesterase inhibitors. The MDS and DFT results are in agreement with those obtained from the docking studies. Our findings suggest further studies on the hit molecules.

RevDate: 2022-08-31

Sati B, Alka T, A Chaudhary (2022)

Structural Scaffolds as Anti- Alzheimer Agents.

Medicinal chemistry (Shariqah (United Arab Emirates)) pii:MC-EPUB-125456 [Epub ahead of print].

BACKGROUND: Understanding the cognitive and behavioral aspects of Alzheimer's disease-related dementia is surely a sturdy task to deal with. In recent years, a broad search for novel anti-Alzheimer agents has been continuously conducted. The malfunctioning of various neurotransmitter systems and the accumulation of abnormal proteins in the brain are the two key characteristics of this disorder. This is supported by a growing amount of evidence. Some Pharmacophoric groups/combinations exhibit potential neuroprotective activity.

METHODS: This study aims to compile the most recent and interesting target/target combinations/ pharmacophoric combinations to cure Alzheimer's disease. We concentrated our efforts to find the ability of certain pharmacophoric elements to interfere with various enzymatic and/or receptor systems, or to work as neuroprotective agents. These pharmacophoric elements may be proved to be promising leads for future multi target anti-Alzheimer drug discovery programs.

RESULT: Anticholinesterase drugs were mentioned as the best treatment thus far. Additionally, impairments in the serotonergic, GABAergic, noradrenergic, dopaminergic, and glutaminergic and few other pathways have all been linked to memory, speech, behavioral and other alterations in Alzheimer's disease.

CONCLUSION: This includes the study of workable pharmacophoric groups/combinations, receptors/enzymatic systems and related hypothesis to find the promising therapeutic lead compounds which could work as future anti-Alzheimer drugs. We discuss future work that would improve our understanding about this Disease.

RevDate: 2022-08-30

Arora D, Bhatt S, Kumar M, et al (2022)

QbD-based rivastigmine tartrate-loaded solid lipid nanoparticles for enhanced intranasal delivery to the brain for Alzheimer's therapeutics.

Frontiers in aging neuroscience, 14:960246.

Alzheimer's disease (AD) is a neurodegenerative disease that affects a wide range of populations and is the primary cause of death in various countries. The treatment of AD is still restricted to oral conventional medicines that act only superficially. Fabrication of intranasal solid lipid nanoparticulate system for the uptake of therapeutic agents will act as a convincing approach with limited off-site toxicity and increased pharmacological activity. The objective of this study was to formulate, optimize, and evaluate the efficiency of rivastigmine tartrate (RT)-loaded intranasal solid lipid nanoparticles (SLNs) employing the solvent-evaporation diffusion method. To optimize the formulation parameters, the central composite design (CCD) was used. Lipid concentration (X1) and surfactant concentration (X2) were considered to be independent variables, while particle size (Y1), percentage entrapment efficiency (Y2), and percentage drug release (Y3) were considered as responses. The solid lipid was glyceryl monostearate, while the surfactant was polysorbate 80. The optimized formulation has a particle size of 110.2 nm, % entrapment efficiency of 82.56%, and % drug release of 94.86%. The incompatibility of drug excipients was established by differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). Nasal histopathology tests on sheep mucosa revealed that the developed SLNs were safe to utilize for intranasal delivery with no toxicity. Ex vivo permeation investigations revealed that the flux and diffusion coefficients for RT solid lipid nanoparticles and RT solution were 3.378 g/cm2 /h and 0.310-3 cm2 /h, respectively. Stability studies demonstrated that the developed SLNs were stable when stored under various storage conditions. The viability and vitality of adopting a lipid particle delivery system for improved bioavailability via the intranasal route were also established in the in vivo pharmacokinetic investigations. According to the histopathological and pharmacokinetic investigations, the developed formulations were safe, non-lethal, efficient, and robust. These results suggest the potentiality provided by rivastigmine tartrate-loaded solid lipid nanoparticles for nasal delivery.

RevDate: 2022-08-31

Perez FP, Arvidson DM, Taylor TP, et al (2022)

Numerical Analysis and Design of an EMF Birdcage Wearable Device for the Treatment of Alzheimer's Disease: A Feasibility Study.

Journal of biomedical science and engineering, 15(8):219-227.

In this study, we performed a numerical analysis of a novel EMF Birdcage wearable device for the treatment of Alzheimer's disease (AD). We designed the new device to generate and radiate a frequency of 64 MHz and a specific absorption rate (SAR) of 0.6 W/kg to a simulated human brain tissue. We determined these parameters from our experimental studies on primary human brain cultures at the Indiana University School of Medicine (IUSM). We found that this frequency and SAR decreased the toxic Aβ levels in the cell cultures. The frequency of 64 MHZ has good skin depth penetration, which will easily pass through the various head layers, including hair, skin, fat, dura, the cerebrospinal (CSF), and grey matter, and reach deeply into the brain tissues. The SAR of 0.6 W/kg was achieved with lower power input and energy, decreasing the probability of thermal injury. Therefore, these parameters enhance the safety of these potential treatments. This Birdcage device emulates a small-scale MRI machine, producing the same 64 MHz frequency at much lower operating input power. In this work, we utilized a high-frequency simulation system (HFSS/EMPro) software to produce the birdcage structure for the required EMF parameters. The 64 MHz radiating frequency produced the scattering S11 parameter of -15 dbs. We obtained a SAR of 0.6 W/kg when an input power of 100 W was applied. The coil dimensions were found to be near 15 cm in height and 22 cm in diameter, which fits in wearable systems. We found that the distribution of the electric field and SAR radiate homogeneously over the simulated human head with good penetration into the brain, which proves to be an appropriate potential therapeutic strategy for Alzheimer's disease.

RevDate: 2022-08-26

Schurad B, Koch C, Schug B, et al (2022)

Comparative Bioavailability study of a Novel Multi-day Patch Formulation of Rivastigmine (twice weekly) with Exelon® Transdermal Patch (daily). A randomized clinical trial.

BACKGROUND: Rivastigmine, a reversible AChEI for symptomatic treatment of mild to moderately severe Alzheimer's dementia is administered in once daily transdermal patches enabling an easier and continuous drug delivery. A novel multi-day (twice week) patch formulation with greater convenience for patients' therapeutic management, was developed.

OBJECTIVE: To assess the bioequivalence under SS conditions of the multiple-day rivastigmine transdermal patch (Test Product, RID-TDS) in comparison to the once daily Exelon® transdermal patch (Reference Product), both at a release rate of 9.5 mg/24 h.

DESIGN: Single center, open-label, randomized, multiple dose study in healthy male adults in a 2-period, 2-sequence-crossover design with multiple applications.

METHODS: Patches were applied on 11 consecutive days for Exelon® and 4-3-4-day regimen for the multiday test patch (RID-TDS), separated by a 14-day wash-out period. The safety, local tolerability and inhibitory effect of rivastigmine on plasma BuChE activity were also evaluated.

RESULTS: 57 subjects completed the study according to the protocol. Calculated point estimates and 90% CI for all primary parameters (AUC96-264, Cmax96-264 and Cmin96-264) were within the predefined acceptance interval of 80.00 - 125.00%. They were 113.64% (107.33 - 120.33), 105.14% (98.38 - 112.38) and 107.82% (97.78 - 118.89) respectively. Satisfactory adhesion (CI of mean adhesion above 90%) was demonstrated for RID-TDS but not for Exelon®.

CONCLUSION: Bioequivalence was demonstrated between RID-TDS mg twice a week and Exelon® once a day in SS. Patch adhesion favored RID-TDS despite the longer dosing interval. Both products were well tolerated.

TRIAL REGISTRATION NUMBER: Protocols are registered in ClinicalTrials.gov: NCT03659435 and EudraCT: 2018-001570-18.

RevDate: 2022-08-30
CmpDate: 2022-08-29

Dhamodharan J, Sekhar G, A Muthuraman (2022)

Epidermal Growth Factor Receptor Kinase Inhibitor Ameliorates β-Amyloid Oligomer-Induced Alzheimer Disease in Swiss Albino Mice.

Molecules (Basel, Switzerland), 27(16):.

Alzheimer's disease (AD) is one of the major neurodegenerative disorders, and its incidence increases globally every year. Currently, available AD drugs symptomatically treat AD with multiple adverse effects. Gefitinib (GE) is an epidermal growth factor receptor (EGFR) kinase inhibitor. EGFR is the preferred target for the treatment of AD, whereas the effect of GE in AD conditions is limited. The present study was designed to explore the ameliorative potential of GE in Aβ1-42 oligomer-induced neurotoxicity in AD mice. AD was induced by intracerebroventricular (i.c.v.) injection of Aβ1-42 oligomer (4 μg/4 μL) into the lateral ventricles of the mouse brain. The test compound, i.e., GE (2 and 4 mg/kg of body weight), was administered orally on days 10, 13, 16, 19, 22, 25, and 28, and the reference drug, i.e., donepezil (DP, 2 mg/kg), was administered orally from the 10th to 28th days. The behavioral changes were screened by the Morris water maze (MWM) test. Furthermore, biomarkers i.e., brain acetylcholinesterase (AChE), thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH) levels were estimated from brain samples. The AD-associated histopathological changes were analyzed by hematoxylin and eosin staining. The administration of GE significantly ameliorated the AD-associated behavioral, biochemical, and histopathological changes. The ameliorative effect of GE against the Aβ1-42 oligomer-associated neurotoxicity was due to its potent inhibition of EGFR kinase activation, as well as its antioxidant and antilipid peroxidative effect.

RevDate: 2022-08-30

Kang M, Lee DB, Kwon S, et al (2022)

Effectiveness of Nootropics in Combination with Cholinesterase Inhibitors on Cognitive Function in Mild-to-Moderate Dementia: A Study Using Real-World Data.

Journal of clinical medicine, 11(16):.

The clinical benefits of nootropics in the treatment of cognitive decline has been either limited or controversial. This study aimed to observe the effectiveness of cholinesterase inhibitor (ChEI) and nootropics combination in the treatment of cognitive impairment in dementia. Data were based on electronic medical records in a university health system. Patients with mild-to-moderate dementia and no history of prior cognitive enhancer use were included (n = 583). The subjects were categorized into the ChEI only group and the ChEI and nootropics combination group. The primary outcome measure was the change in cognitive function, as assessed by the mini-mental state examination (MMSE) from baseline to 300-400 days after the first ChEI prescription. Subsequent analyses were conducted in consideration of the dementia type, medical adherence, and type of nootropics. The changes in MMSE scores from baseline to endpoint were not significantly different between the two groups. In Alzheimer's dementia, the combination group showed significantly less deterioration in MMSE language subscale scores compared to the ChEI only group (F = 6.86, p = 0.009), and the difference was consistent in the highly adherent subjects (F = 10.16, p = 0.002). The choline alfoscerate and the ginkgo biloba extract subgroups in Alzheimer's dementia showed more significant improvements in the MMSE language subscale scores compared to the other nootropics subgroup (F = 7.04, p = 0.001). The present study showed that the effectiveness of ChEI and nootropics combination on cognition may appear differently according to the dementia type. This emphasizes the need for well-controlled studies to generalize the effectiveness of nootropics across various clinical settings.

RevDate: 2022-08-30
CmpDate: 2022-08-29

Dieter F, Esselun C, GP Eckert (2022)

Redox Active α-Lipoic Acid Differentially Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer and Its Control Cells.

International journal of molecular sciences, 23(16):.

INTRODUCTION: Alpha lipoic acid (ALA) is a sulphur-containing organic compound, derived from octanoic acid, and an important cofactor for mitochondrial respiratory enzymes. It has strong antioxidant properties that improve mitochondrial function. We investigated if ALA improves mitochondrial dysfunction in a cellular model of Alzheimer's disease (AD).

METHODS: SH-SY5Y-APP695 cells were used as a model for an early stage of AD. Vector-transfected SH-SY5Y-MOCK cells served as controls. Using these cells, we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, and citrate synthase activity (CS) in cells treated with ALA. Cells were treated for 24 h with different concentrations of ALA and with or without the complex I inhibitor rotenone.

RESULTS: Incubation with ALA showed a significant increase in ATP levels in both SH-SY5Y-APP695 and SH-SY5Y-MOCK cells. MMP levels were elevated in SH-SY5Y-MOCK cells, treatment with rotenone showed a reduction in MMP, which could be partly alleviated after incubation with ALA in SH-SY5Y-MOCK cells. ALA treatment showed significant differences in respiration chain complex activities in SH-SY5Y-MOCK cells. Citrate synthase activity was unaffected. ROS levels were significantly lower in both cell lines treated with ALA.

CONCLUSIONS: ALA increased the activity of the different complexes of the respiratory chain, and consequently enhanced the MMP, leading to increased ATP levels indicating improved mitochondrial function. ALA only marginally protects from additional rotenone-induced mitochondrial stress.

RevDate: 2022-08-30
CmpDate: 2022-08-29

Theiss EL, Griebsch LV, Lauer AA, et al (2022)

Vitamin B12 Attenuates Changes in Phospholipid Levels Related to Oxidative Stress in SH-SY5Y Cells.

Cells, 11(16):.

Oxidative stress is closely linked to Alzheimer's disease (AD), and is detected peripherally as well as in AD-vulnerable brain regions. Oxidative stress results from an imbalance between the generation and degradation of reactive oxidative species (ROS), leading to the oxidation of proteins, nucleic acids, and lipids. Extensive lipid changes have been found in post mortem AD brain tissue; these changes include the levels of total phospholipids, sphingomyelin, and ceramide, as well as plasmalogens, which are highly susceptible to oxidation because of their vinyl ether bond at the sn-1 position of the glycerol-backbone. Several lines of evidence indicate that a deficiency in the neurotropic vitamin B12 is linked with AD. In the present study, treatment of the neuroblastoma cell line SH-SY5Y with vitamin B12 resulted in elevated levels of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and plasmalogens. Vitamin B12 also protected plasmalogens from hydrogen peroxide (H2O2)-induced oxidative stress due to an elevated expression of the ROS-degrading enzymes superoxide-dismutase (SOD) and catalase (CAT). Furthermore, vitamin B12 elevates plasmalogen synthesis by increasing the expression of alkylglycerone phosphate synthase (AGPS) and choline phosphotransferase 1 (CHPT1) in SH-SY5Y cells exposed to H2O2-induced oxidative stress.

RevDate: 2022-08-30

Grossmann K (2022)

Direct Oral Anticoagulants (DOACs) for Therapeutic Targeting of Thrombin, a Key Mediator of Cerebrovascular and Neuronal Dysfunction in Alzheimer's Disease.

Biomedicines, 10(8):.

Although preclinical research and observer studies on patients with atrial fibrillation concluded that direct oral anticoagulants (DOACs) can protect against dementia like Alzheimer's disease (AD), clinical investigation towards therapeutical approval is still pending. DOACs target pathological thrombin, which is, like toxic tau and amyloid-ß proteins (Aß), an early hallmark of AD. Especially in hippocampal and neocortical areas, the release of parenchymal Aß into the blood induces thrombin and proinflammatory bradykinin synthesis by activating factor XII of the contact system. Thrombin promotes platelet aggregation and catalyzes conversion of fibrinogen to fibrin, leading to degradation-resistant, Aß-containing fibrin clots. Together with oligomeric Aß, these clots trigger vessel constriction and cerebral amyloid angiopathy (CAA) with vessel occlusion and hemorrhages, leading to vascular and blood-brain barrier (BBB) dysfunction. As consequences, brain blood flow, perfusion, and supply with oxygen (hypoxia) and nutrients decrease. In parenchymal tissue, hypoxia stimulates Aß synthesis, leading to Aß accumulation, which is further enhanced by BBB-impaired perivascular Aß clearance. Aß trigger neuronal damage and promote tau pathologies. BBB dysfunction enables thrombin and fibrin(ogen) to migrate into parenchymal tissue and to activate glial cells. Inflammation and continued Aß production are the results. Synapses and neurons die, and cognitive abilities are lost. DOACs block thrombin by inhibiting its activity (dabigatran) or production (FXa-inhibitors, e.g., apixaban, rivaroxaban). Therefore, DOAC use could preserve vascular integrity and brain perfusion and, thereby, could counteract vascular-driven neuronal and cognitive decline in AD. A conception for clinical investigation is presented, focused on DOAC treatment of patients with diagnosed AD in early-stage and low risk of major bleeding.

RevDate: 2022-09-02

Sabbagh MN, B Decourt (2022)

COR388 (atuzaginstat): an investigational gingipain inhibitor for the treatment of Alzheimer disease.

Expert opinion on investigational drugs [Epub ahead of print].

INTRODUCTION: Evidence from in vitro and in vivo studies demonstrates that amyloid beta (Aβ) oligomers have potent, broad-spectrum antimicrobial properties created by fibrils that entrap pathogens and disrupt their membranes. Data suggest that Aβ may play a protective role in the innate immune response to microbial infections and that Aβ in the brain plays a damaging role when the inflammatory response is not well controlled.

AREAS COVERED: This paper describes the relationship between periodontal disease and Alzheimer disease (AD), the role of Porphyromonas gingivalis and its secreted gingipains in AD, and the potential of the gingipain inhibitor atuzaginstat (COR388) to modulate AD neuropathologies.

EXPERT OPINION: P. gingivalis is opsonized by Aβ42, is capable of entering the brain, and is an accelerant of neuropathologies in rodent models of AD. Thus, in our opinion, this bacteria is highly likely to be a pathogen capable of initiating or precipitating the progression of AD, which agrees with the pathogen hypothesis of clinical AD development.

RevDate: 2022-08-24

Huggins B, M Farris (2022)

Vitamin D3 promotes longevity in Caenorhabditis elegans.

GeroScience [Epub ahead of print].

Vitamin D deficiency is associated with a variety of age-related diseases and is becoming increasingly more prevalent in the population over time. Some diseases associated with deficiency are cardiovascular disease, cancer, and neurodegeneration. This association, as well as the fact that vitamin D has been demonstrated to play an important role in a variety of extraskeletal processes, has led some to claim that vitamin D is an essential longevity vitamin. However, the role of vitamin D in healthy aging has been difficult to determine. In order to study vitamin D in the context of aging, the model organism, Caenorhabditis elegans (C. elegans), was employed. To study vitamin D's impact on aging and age-related disease, lifespan and health span were measured across three different genetic strains of C. elegans. Strains investigated were wildtype (N2), worms with a mutant vitamin D receptor ortholog (nhr-8), and worms engineered to represent Alzheimer disease (gnals2). Bioinformatic analysis of available public data was also performed in order to identify the transcriptional response produced in N2 worms treated with vitamin D3. Treatment with vitamin D3 significantly extended the lifespan of N2 worms and rescued nhr-8 worms, which typically have decreased lifespans compared to N2. Treatment with vitamin D3 minimally extended the lifespan of gnals2 worms. Similar results were obtained for measures of health span, quantified as motility through time. Differentially expressed genes upon treatment with vitamin D3 were largely associated with biological processes such as the innate immune response and metabolism of xenobiotic compounds in the worms, which may explain the observed increase in lifespan and health span.

RevDate: 2022-09-19

Liu H, Zhong L, Dai Q, et al (2022)

Astragalin alleviates cognitive deficits and neuronal damage in SAMP8 mice through upregulating estrogen receptor expression.

Metabolic brain disease [Epub ahead of print].

Senile plaques composed of β-amyloid protein (Aβ) and neurofibrillary tangles (NFTs) composed of intracellular hyper-phosphorylated tau are major causes of cognitive impairment and neuronal damage in Alzheimer disease (AD). Astragalin (AST), a naturally-occurring flavonoid compound, was reported to have neuroprotective effects in the brain, but its effects in AD remain unknown. Herein, the learning and memory deficits were alleviated and neuronal damage in the hippocampus were inhibited after the senescence-accelerated mouse prone 8 (SAMP8) mouse were given AST (5 mg/kg or 10 mg/kg) daily by gavage for 2 months. Furthermore, AST reduced Aβ1-40 and Aβ1-42 deposition, decreased β-carboxyl-terminal fragment (β-CTF) protein level and tau hyper-phosphorylation, but increased α-CTF protein level and glycogen synthase kinase-3beta (GSK-3β) phosphorylation in hippocampus of SAMP8 mice. Meanwhile, the effects of AST on AD were also explored in vitro by treating primary neurons with amyloid-β1-42 oligomers (Aβ1-42O). Consistently, AST also alleviated amyloid-β1-42 oligomers (Aβ1-42O)-induced neuronal damage, amyloid plaques, and tau phosphorylation in vitro model. Of note, estrogen receptor (ER)α and ERβ expression in the hippocampus of SAMP8 mice and Aβ1-42O-treated neurons was significantly decreased but their levels were increased by AST. Moreover, in vivo and in vitro experiments revealed that ER antagonist, Fulvestrant, reversed the effects caused by AST. Altogether, our investigation indicates that AST may ameliorate cognitive deficits and AD-type pathologies in SAMP8 mice and Aβ1-42O-treated neurons through upregulating ERα and ERβ expression. Our findings indicate the value of AST as a potential reagent for AD treatment.

RevDate: 2022-08-23
CmpDate: 2022-08-22

Li XL, Gao RX, Zhang Q, et al (2022)

A bibliometric analysis of neuroimaging biomarkers in Parkinson disease based on Web of Science.

Medicine, 101(33):e30079.

BACKGROUND: This study aimed to analyze and summarize the research hotspots and trends in neuroimaging biomarkers (NMBM) in Parkinson disease (PD) based on the Web of Science core collection database and provide new references for future studies.

METHODS: Literature regarding NMBM in PD from 1998 to 2022 was analyzed using the Web of Science core collection database. We utilized CiteSpace software (6.1R2) for bibliometric analyses of countries/institutions/authors, keywords, keyword bursts, references, and their clusters.

RESULTS: A total of 339 studies were identified with a continually increasing annual trend. The most productive country and collaboration was the United States. The top research hotspot is PD cognitive disorder. NMBM and artificial intelligence medical imaging have been applied in the clinical diagnosis, differential diagnosis, treatment, and prognosis of PD. The trends in this field include research on T1 weighted structure magnetic resonance imaging in accordance with voxel-based morphometry, PD cognitive disorder, and neuroimaging features of Lewy body dementia and Alzheimer disease.

CONCLUSION: The development of NMBM in PD will be effectively promoted by drawing on international research hotspots and cutting-edge technologies, emphasizing international collaboration and institutional cooperation at the national level, and strengthening interdisciplinary research.

RevDate: 2022-08-16
CmpDate: 2022-08-16

Sharif Nia H, Sivarajan Froelicher E, Hosseini L, et al (2022)

Development and validation of the care challenge scale in family caregivers of people with Alzheimer's disease.

Frontiers in public health, 10:921858.

Background: Alzheimer's disease (AD) is a progressive and debilitating disorder that strongly affects people with AD and their families. The changes in signs of the disease and its treatment lead to many challenges in people with AD that affect the performance and the ability of caregivers, their social life, and physical, emotional, and psychological aspects of caregivers' health. Therefore, this study was designed to develop and validate the Care Challenge Scale (CCS) for family caregivers of people with AD in the care context of Iran.

Method: This is a cross-sectional study, and the primary scale was based on 14 semi-structured interviews with family caregivers of Iranian people with AD. In the next phase, the psychometric features were assessed, including the face validity (qualitative and quantitative), content validity (qualitative and quantitative), item analysis, structural validity (exploratory and confirmatory factors), and construct validity (convergent and discriminant validity). Finally, the reliability was assessed using internal consistency (Cronbach's alpha, McDonald's omega coefficient, and the average inter-item correlation), stability (intraclass correlation coefficient), and absolute reliability.

Results: Totally, 435 Iranian family caregivers filled out online questionnaires, with a mean age of 50.26(±13.24) years. Based on the results of the qualitative phase, an item pool was generated with 389 items, and after deleting overlapping and unrelated items, the CCS with 14 items was created. The results of the quantitative phase showed that the CCS consists of two factors with 10 items each, which are named effective role-play challenge and lack of social-financial support, and they explained 42.23% of the total variance. Furthermore, the results of confirmatory factor analysis showed a good fitness of the scale structure model, and it had convergent and discriminant validity. The reliability indexes showed this scale has internal consistency and stability.

Conclusion: The most care challenge among Iranian family caregivers of people with AD is effective role-play challenges and lack of social-financial support. The scale as designed has good validity, internal consistency, and stability that can be used by therapists, nurses, and researchers for the assessment of the challenges of this population.

RevDate: 2022-08-16
CmpDate: 2022-08-16

Small GW (2022)

Updates in the Management of Mild Cognitive Impairment and Alzheimer Disease.

The Journal of family practice, 71(6 Suppl):S82-S87.

LEARNING OBJECTIVES: At the end of the activity, participants will be able to:Implement evidence-based methods for cognitive impairment screening in primary care. Identify correct diagnostic criteria for mild cognitive impairment (MCI) and Alzheimer disease (AD) based on current guideline recommendations. Design appropriate and effective treatment plans for patients with MCI and AD and refer to a specialist when necessary. Describe advances in testing and treatment for AD that may impact dementia care.

RevDate: 2022-08-13

Yang B, Bao W, S Hong (2022)

Alzheimer-Compound Identification Based on Data Fusion and forgeNet_SVM.

Frontiers in aging neuroscience, 14:931729.

Rapid screening and identification of potential candidate compounds are very important to understand the mechanism of drugs for the treatment of Alzheimer's disease (AD) and greatly promote the development of new drugs. In order to greatly improve the success rate of screening and reduce the cost and workload of research and development, this study proposes a novel Alzheimer-related compound identification algorithm namely forgeNet_SVM. First, Alzheimer related and unrelated compounds are collected using the data mining method from the literature databases. Three molecular descriptors (ECFP6, MACCS, and RDKit) are utilized to obtain the feature sets of compounds, which are fused into the all_feature set. The all_feature set is input to forgeNet_SVM, in which forgeNet is utilized to provide the importance of each feature and select the important features for feature extraction. The selected features are input to support vector machines (SVM) algorithm to identify the new compounds in Traditional Chinese Medicine (TCM) prescription. The experiment results show that the selected feature set performs better than the all_feature set and three single feature sets (ECFP6, MACCS, and RDKit). The performances of TPR, FPR, Precision, Specificity, F1, and AUC reveal that forgeNet_SVM could identify more accurately Alzheimer-related compounds than other classical classifiers.

RevDate: 2022-09-10

Cogswell PM, Barakos JA, Barkhof F, et al (2022)

Amyloid-Related Imaging Abnormalities with Emerging Alzheimer Disease Therapeutics: Detection and Reporting Recommendations for Clinical Practice.

AJNR. American journal of neuroradiology [Epub ahead of print].

Monoclonal antibodies are emerging disease-modifying therapies for Alzheimer disease that require brain MR imaging for eligibility assessment as well as for monitoring for amyloid-related imaging abnormalities. Amyloid-related imaging abnormalities result from treatment-related loss of vascular integrity and may occur in 2 forms. Amyloid-related imaging abnormalities with edema or effusion are transient, treatment-induced edema or sulcal effusion, identified on T2-FLAIR. Amyloid-related imaging abnormalities with hemorrhage are treatment-induced microhemorrhages or superficial siderosis identified on T2* gradient recalled-echo. As monoclonal antibodies become more widely available, treatment screening and monitoring brain MR imaging examinations may greatly increase neuroradiology practice volumes. Radiologists must become familiar with the imaging appearance of amyloid-related imaging abnormalities, how to select an appropriate imaging protocol, and report findings in clinical practice. On the basis of clinical trial literature and expert experience from clinical trial imaging, we summarize imaging findings of amyloid-related imaging abnormalities, describe potential interpretation pitfalls, and provide recommendations for a standardized imaging protocol and an amyloid-related imaging abnormalities reporting template. Standardized imaging and reporting of these findings are important because an amyloid-related imaging abnormalities severity score, derived from the imaging findings, is used along with clinical status to determine patient management and eligibility for continued monoclonal antibody dosing.

RevDate: 2022-08-11

Zeng H, Fang X, Zhao Y, et al (2022)

EMCI: A Novel EEG-Based Mental Workload Assessment Index of Mild Cognitive Impairment.

IEEE transactions on biomedical circuits and systems, PP: [Epub ahead of print].

As aging deepens, early detection of mild cognitive impairment (MCI) is increasingly important to prevent Alzheimer Dementia (AD) and improve the quality of life of older adults. In recent years, a large number of studies focus on the abnormal brain cognitive function of MCI, while ignoring the quantitative evaluation of MCI's mental workload. In this study, we propose a workload index for MCI screening, named EMCI, which is a linear discriminant cumulative estimate of subjects' electroencephalography (EEG) power spectra in [Formula: see text] and [Formula: see text] rhythms. Then, we design a matched prototype system to verify the effectiveness of EMCI. The results show that the EMCI is sensitive to changes of subjects' mental workload, and is significantly lower in MCI than in HC (Health control), which may be precisely caused by cognitive dysfunction. The proposed EMCI index can be used for online assessment of mental workload in older adults, which can help achieve quick screening of MCI and provide a critical window for clinical treatment interventions.

RevDate: 2022-08-11

Maglione AV, do Nascimento BPP, Ribeiro MO, et al (2022)

Triiodothyronine Treatment reverses Depression-Like Behavior in a triple-transgenic animal model of Alzheimer's Disease.

Metabolic brain disease [Epub ahead of print].

Alzheimer disease's (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. The central nervous system is an important target of thyroid hormones (TH). An inverse association between serum triiodothyronine (T3) levels and the risk of AD symptoms and progression has been reported. We investigated the effects of T3 treatment on the depression-like behavior in male transgenic 3xTg-AD mice. Animals were divided into 2 groups treated with daily intraperitoneal injections of 20 ng/g of body weight (b.w.) L-T3 (T3 group) or saline (vehicle, control group). The experimental protocol lasted 21 days, and behavioral tests were conducted on days 18-20. At the end of the experiment, the TH profile and hippocampal gene expression were evaluated. The T3-treated group significantly increased serum T3 and decreased thyroxine (T4) levels. When compared to control hippocampal samples, the T3 group exhibited attenuated glycogen synthase kinase-3 (GSK3), metalloproteinase 10 (ADAM10), amyloid-beta precursor-protein (APP), serotonin transporter (SERT), 5HT1A receptor, monocarboxylate transporter 8 (MCT8) and bone morphogenetic protein 7 (BMP-7) gene expression, whereas augmented superoxide dismutase 2 (SOD2) and Hairless gene expression. T3-treated animals also displayed reduced immobility time in both the tail suspension and forced swim tests, and in the latter presented a higher latency time compared to the control group. Therefore, our findings suggest that in an AD mouse model, T3 supplementation promotes improvements in depression-like behavior, through the modulation of the serotonergic related genes involved in the transmission mediated by 5HT1A receptors and serotonin reuptake, and attenuated disease progression.

RevDate: 2022-08-27

Curcic J, Vallejo V, Sorinas J, et al (2022)

Description of the Method for Evaluating Digital Endpoints in Alzheimer Disease Study: Protocol for an Exploratory, Cross-sectional Study.

JMIR research protocols, 11(8):e35442.

BACKGROUND: More sensitive and less burdensome efficacy end points are urgently needed to improve the effectiveness of clinical drug development for Alzheimer disease (AD). Although conventional end points lack sensitivity, digital technologies hold promise for amplifying the detection of treatment signals and capturing cognitive anomalies at earlier disease stages. Using digital technologies and combining several test modalities allow for the collection of richer information about cognitive and functional status, which is not ascertainable via conventional paper-and-pencil tests.

OBJECTIVE: This study aimed to assess the psychometric properties, operational feasibility, and patient acceptance of 10 promising technologies that are to be used as efficacy end points to measure cognition in future clinical drug trials.

METHODS: The Method for Evaluating Digital Endpoints in Alzheimer Disease study is an exploratory, cross-sectional, noninterventional study that will evaluate 10 digital technologies' ability to accurately classify participants into 4 cohorts according to the severity of cognitive impairment and dementia. Moreover, this study will assess the psychometric properties of each of the tested digital technologies, including the acceptable range to assess ceiling and floor effects, concurrent validity to correlate digital outcome measures to traditional paper-and-pencil tests in AD, reliability to compare test and retest, and responsiveness to evaluate the sensitivity to change in a mild cognitive challenge model. This study included 50 eligible male and female participants (aged between 60 and 80 years), of whom 13 (26%) were amyloid-negative, cognitively healthy participants (controls); 12 (24%) were amyloid-positive, cognitively healthy participants (presymptomatic); 13 (26%) had mild cognitive impairment (predementia); and 12 (24%) had mild AD (mild dementia). This study involved 4 in-clinic visits. During the initial visit, all participants completed all conventional paper-and-pencil assessments. During the following 3 visits, the participants underwent a series of novel digital assessments.

RESULTS: Participant recruitment and data collection began in June 2020 and continued until June 2021. Hence, the data collection occurred during the COVID-19 pandemic (SARS-CoV-2 virus pandemic). Data were successfully collected from all digital technologies to evaluate statistical and operational performance and patient acceptance. This paper reports the baseline demographics and characteristics of the population studied as well as the study's progress during the pandemic.

CONCLUSIONS: This study was designed to generate feasibility insights and validation data to help advance novel digital technologies in clinical drug development. The learnings from this study will help guide future methods for assessing novel digital technologies and inform clinical drug trials in early AD, aiming to enhance clinical end point strategies with digital technologies.


RevDate: 2022-08-31
CmpDate: 2022-08-11

Zhang C, Sun L, H Sun (2022)

Effects of magnesium valproate adjuvant therapy on patients with dementia: A systematic review and meta-analysis.

Medicine, 101(31):e29642.

BACKGROUND: Current research has found contradictory results on the treatment of magnesium valproate (VPM) in patients with dementia (PwD).

OBJECTIVES: Here, we conducted a meta-analysis to evaluate the efficacy and safety of VPM in the adjuvant treatment of PwD.

PURPOSE: Current research has found contradictory results on the treatment of VPM in PwD. Here, we conducted a meta-analysis to evaluate the efficacy and safety of VPM in the adjuvant treatment of PwD.

METHODS: MEDLINE via PubMed, Cochrane Library, EBSCO, Embase, China National Knowledge (CNKI), and Wan Fang databases were researched to gather relevant data on magnesium valproate assistant therapy for patients with dementia (PwD) by using medical subject headings and term words.

RESULTS: After the final screening, 22 RCT studies (a total of 1899 participants) were included in this meta-analysis, which compared VPM adjuvant treatment with antidementia or psychotropic drug monotherapy. Significant differences were found in the scores on mini-mental state examination (P = .028), Alzheimer disease assessment scale cognitive subscale (P < .05), Bech-Rafaelsen Mania Rating Scale (P < .05), behavioral pathology in Alzheimer disease rating scale (P = .001), activities of daily living (P < .05), and Pittsburgh Sleep Quality Index (P < .05). Besides, the levels of inflammatory factors including IL-1β, IL-6, and TNF-α were significantly lower than those in the monotherapy group (P < .05). While there was no increase in the incidence of adverse events (P = .383), VPM as an assistant therapy is generally well tolerated in PwD.

CONCLUSION: By meta-analysis, evidence was found to support VPM additional used for the treatment of cognitive function, psychiatric symptoms, or disease improvement in PwD. VPM may be a potential drug to aid in the treatment of dementia patients. However, there was lack of enough evidence to classification of dementia severity in our inclusion study. More research is still needed, including clinical trials evaluating VPM as a complementary therapy.

RevDate: 2022-08-31
CmpDate: 2022-08-11

Yang Q, Liu J, Huang KL, et al (2022)

A systematic review of the efficacy of donepezil hydrochloride combined with nimodipine on treating vascular dementia.

Medicine, 101(31):e29307.

BACKGROUND: Vascular dementia (VaD) is a comprehensive syndrome related to the damage of cognitive function and various cerebral vascular illnesses. VaD is also generally recognized as the second most common type of dementia after Alzheimer disease, contributing to 30% of the dementia population in Asia and developing countries. The ability of donepezil hydrochloride and nimodipine had been respectively proven in improving cognitive function in vascular dementia. However, whether the combined application of both drugs contribute to better efficacy remains as a research hotspot. Studies had shown definite satisfactory result with such combination, however evidence-based evaluation of the efficacy is still lacking. Therefore, meta-analysis is employed in this study to evaluate the efficacy and safety of using donepezil hydrochloride combined with nimodipine in treating VaD to provide references for clinical treatments. The efficacy of donepezil hydrochloride combined with nimodipine on treating vascular dementia is systematically reviewed to provide evidence-based references for clinical applications.

METHODS: Both Chinese and English databases were searched from the start till August, 2020 for any RCT regarding the combined use of the 2 drugs in treating vascular dementia. Two investigators would later evaluate and screened out research and data based on an improved Jaded scale. Software Rev Man 5.3.0 was employed to carry out meta-analysis on clinical effificacy, mini-mental state examination (MMSE) ratings, activity of daily living (ADL) ratings, and clinical dementia scale (CDR) ratings.

RESULTS: Donepezil hydrochloride combined with nimodipine had demonstrated satisfactory efficacy on the treatment of vascular dementia. Improvements were namely spotted on MMSE scale, ADL scale, and CDR scale, with the utmost efficacy by 12 weeks after intervention.

CONCLUSIONS: Donepezil hydrochloride combined with nimodipine had good efficacy in the treatment of patients with vascular dementia, mainly in terms of improving the Simple MMSE scores, the ability to use daily living scale (ADL) scores and the CDR, and the best results were obtained after 12 weeks of intervention. Such conclusion should be cautiously evaluated.

RevDate: 2022-08-31
CmpDate: 2022-08-11

Liu Y, Ding L, Xianyu Y, et al (2022)

Research on depression in Parkinson disease: A bibliometric and visual analysis of studies published during 2012-2021.

Medicine, 101(31):e29931.

BACKGROUND: The diagnosis and treatment rate of Parkinson disease (PD) with depression has a low diagnostic rate, and there is no consensus on the choice of treatment mode. This study evaluates the global research trends of scientific outputs related to depression in PD from multiple perspectives, using a bibliometric analysis and visualization tool to scientifically analyze the knowledge from the literature.

METHODS: Literature related to depression in PD published from 2012 to 2021 was included and selected from the Web of Science Core Collection database in October 2021. CiteSpace software was used to visualize and analyze co-occurrence analyses for countries, institutions, authors, and keywords.

RESULTS: A total of 4533 articles from the Web of Science database were included. The United States made the largest contribution with the majority of publications (1215; 29.40%). Toronto University was the most productive institution. PD, depression, quality of life, dementia, nonmotor symptom, prevalence, anxiety, Alzheimer disease, symptom, and disorder would be significantly correlated with depression in PD. The current hot spots in this field focus on the following: risk factors for depression in PD, assessment scale of depression in PD, and rehabilitation of depression in PD.

CONCLUSIONS: This analysis not only reveals the current research trends and hotspots but also provides some instructive suggestions on the development of depression in PD.

RevDate: 2022-08-09

Waseem W, Anwar F, Saleem U, et al (2022)

Prospective Evaluation of an Amide-Based Zinc Scaffold as an Anti-Alzheimer Agent: In Vitro, In Vivo, and Computational Studies.

ACS omega, 7(30):26723-26737.

Alzheimer's disease is the most common progressive neurodegenerative mental disorder associated with loss of memory, decline in cognitive function, and dysfunction of language. The prominent pathogenic causes of this disease involve deposition of amyloid-β plaques, acetylcholine neurotransmitter deficiency, and accumulation of neurofibrillary tangles. There are multiple pathways that have been targeted to treat this disease. The inhibition of the intracellular cyclic AMP regulator phosphodiesterase IV causes the increase in CAMP levels that play an important role in the memory formation process. Organometallic chemistry works in a different way in treating pharmacological disorders. In the field of medicinal chemistry and pharmaceuticals, zinc-based amide carboxylates have been shown to be a preferred pharmacophore. The purpose of this research work was to investigate the potential of zinc amide carboxylates in inhibition of phosphodiesterase IV for the Alzheimer's disease management. Swiss Albino mice under controlled conditions were divided into seven groups with 10 mice each. Group I was injected with carboxymethylcellulose (CMC) at 1 mL/100 g dose, group II was injected with Streptozotocin (STZ) at 3 mg/kg dose, group III was injected with Piracetam acting as a standard drug at 200 mg/kg dosage, while groups IV-VII were injected with a zinc scaffold at the dose regimen of 10, 20, 40, and 80 mg/kg through intraperitoneal injection. All groups except group I were injected with Streptozotocin on the first day and third day of treatment at the dose of 3 mg/kg through an intracerebroventricular route to induce Alzheimer's disease. Afterward, respective treatment was continued for all groups for 23 days. In between the treatment regimen, groups were analyzed for memory and learning improvement through various behavioral tests such as open field, elevated plus maze, Morris water maze, and passive avoidance tests. At the end of the study, different biochemical markers in the brain were estimated like neurotransmitters (dopamine, serotonin and adrenaline), oxidative stress markers (superoxide dismutase, glutathione, and catalase), acetylcholinesterase (AchE), tau proteins, and amyloid-β levels. A PCR study was also performed. Results showed that the LD50 of the zinc scaffold is greater than 2000 mg/kg. Research indicated that the zinc scaffold has the potential to improve the memory impairment and learning behavior in Alzheimer's disease animal models in a dose-dependent manner. At the dose of 80 mg/kg, a maximum response was observed for the zinc scaffold. Maximum reduction in the acetylcholinesterase enzyme was observed at 80 mg/kg dose, which was further strengthened and verified by the PCR study. Oxidative stress was restored by the zinc scaffold due to the significant activation of the endogenous antioxidant enzymes. This research ended up with the conclusion that the zinc-based amide carboxylate scaffold has the potential to improve behavioral disturbances and vary the biochemical markers in the brain.

RevDate: 2022-09-17

Tarawneh R, E Penhos (2022)

The gut microbiome and Alzheimer's disease: Complex and bidirectional interactions.

Neuroscience and biobehavioral reviews, 141:104814 pii:S0149-7634(22)00303-7 [Epub ahead of print].

Structural and functional alterations to the gut microbiome, referred to as gut dysbiosis, have emerged as potential key mediators of neurodegeneration and Alzheimer disease (AD) pathogenesis through the "gut -brain" axis. Emerging data from animal and clinical studies support an important role for gut dysbiosis in mediating neuroinflammation, central and peripheral immune dysregulation, abnormal brain protein aggregation, and impaired intestinal and brain barrier permeability, leading to neuronal loss and cognitive impairment. Gut dysbiosis has also been shown to directly influence various mechanisms involved in neuronal growth and repair, synaptic plasticity, and memory and learning functions. Aging and lifestyle factors including diet, exercise, sleep, and stress influence AD risk through gut dysbiosis. Furthermore, AD is associated with characteristic gut microbial signatures which offer value as potential markers of disease severity and progression. Together, these findings suggest the presence of a complex bidirectional relationship between AD and the gut microbiome and highlight the utility of gut modulation strategies as potential preventative or therapeutic strategies in AD. We here review the current literature regarding the role of the gut-brain axis in AD pathogenesis and its potential role as a future therapeutic target in AD treatment and/or prevention.

RevDate: 2022-08-05

Singh A, Ansari VA, Mahmood T, et al (2022)

Dendrimers: A Neuroprotective Lead in Alzheimer Disease: A Review on its Synthetic approach and Applications.

Drug research [Epub ahead of print].

Alzheimer disease is a neurodegenerative disease that is signified by cognitive decline, memory loss, and erratic behavior. Dendrimers are a type of polymer that has a well-defined structure, a high degree of molecular uniformity, and a low polydispersity which have shown to be effective intracellular drug carriers for bring down the in numerous cases. The data reported by the clinical trials and chemical bonds of dendrimers loading and biological properties that may be used in the bringing out the treatment of nano formulation for Alzheimer disease. Below-range dendrimers have an unlocked figure, but higher-range dendrimers have a more globular and dense structure so handling is difficult. Dendrimers are similar in size to a variety of biological structures; for example, fifth-generation polyamidoamine (PAMAM) dendrimers are similar in size and shape to haemoglobin (5.5 nm diameter). Each generation of dendrimer is described in terms of size, shape, molecular weight, and the number of surface functional groups, with increasing growth specified in terms of 'generation number.' In contrast, Hawker and Frechet were the first to report the convergent approach. A stepwise repeating reaction strategy is used to synthesize dendrimers radically from a central core. The value of dendrimers as drug carriers is discussed in this paper. The information presented in this article can provide useful references for further studies on making dendrimers and applications.

RevDate: 2022-08-03

Kandeda AK, Nguedia D, Djeuzong E, et al (2022)

An aqueous macerate of Ziziphus jujuba reduces long-term spatial memory impairment in D-galactose treated rats: role of anti-inflammatory pathways.

Metabolic brain disease [Epub ahead of print].

Pharmacological treatments against Alzheimer disease provide only symptomatic relief and are associated with numerous side effects. Previous studies showed that a concoction of Ziziphus jujuba leaves possesses anti-amnesic effects in scopolamine-treated rats. More recently, an aqueous macerate of Z. jujuba leaves has been shown to reduce short-term memory impairment in D-galactose-treated rats. However, no study on the effect of an aqueous macerate of Z. jujuba on long-term memory impairment was performed. Therefore, this study evaluates the effect of an aqueous macerate of Z. jujuba on long-term spatial memory impairment in D-galactose-treated rats. Long-term spatial memory impairment was induced in rats by administering D-galactose (350 mg/kg/day, s.c.), once dailyfor 21 days. On the 22nd day, the integrity of this memory was assessed using the Morris water maze task. Rats that developed memory impairment were treated with tacrine (10 mg/kg, p.o.), or aspirin (20 mg/kg, p.o.), or extract (41.5, 83, and 166 mg/kg, p.o.), once daily, for 14 days. At the end of the treatment, memory impairment was once more assessed using the same paradigm. Animals were then euthanized, and some pro-inflammatory cytokine markers were analyzed in the hippocampus or blood. The extract at all doses significantly reduced the latency to attain the platforming of the water maze test. The extract (83 mg/kg) also increased the time spent in the target quadrant during the retention phase. The extract markedly reduced the concentration of pro-inflammatory cytokine markers in the hippocampus and blood. Together, these results suggest that this aqueous extract Z. jujuba reduces long-term spatial memory impairment. This effect may be mediated in part by its anti-inflammatory activity.

RevDate: 2022-08-05
CmpDate: 2022-08-05

Burke AD, D Goldfarb (2022)

Facilitating Treatment Initiation in Early-Stage Alzheimer Disease.

The Journal of clinical psychiatry, 83(4):.

Once a diagnosis of Alzheimer disease is established, a wide variety of therapy options are available to treat different stages of the disease. Patients have the opportunity to delay onset of the disease or delay its progression if diagnosed early enough through new FDA-approved disease-modifying treatments. For mild to moderate stages, new symptomatic treatments can slow the progression of the disease and improve symptoms. A multi-component approach is recommended in order to tailor treatments to each patient's needs.

RevDate: 2022-08-05
CmpDate: 2022-08-05

Burke AD, D Goldfarb (2022)

Timely Diagnosis of Alzheimer Disease.

The Journal of clinical psychiatry, 83(4):.

Diagnosing early-stage Alzheimer disease can lead to prompt initiation of treatment and slow down symptom progression. However, clinicians are not providing a diagnosis to over half of individuals who meet criteria for dementia. Tests for biomarkers, new symptomatic treatments and disease-modifying agents, and the addition of the preclinical stage to the diagnostic criteria for AD can aid in earlier disease recognition and developing treatment plans. Communicating diagnosis and information on next steps with patients and caregivers can lead to patient and caregiver involvement in decision-making and planning as well as participation in clinical trials and maximizing benefits and lifestyle interventions.

RevDate: 2022-09-16
CmpDate: 2022-09-16

Cupido AJ, Reeskamp LF, Hingorani AD, et al (2022)

Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease: A Factorial Mendelian Randomization Study.

JAMA cardiology, 7(9):955-964.

Importance: Cholesteryl ester transfer protein inhibition (CETP) has been shown to increase levels of high-density lipoprotein cholesterol (HDL-C) and reduce levels of low-density lipoprotein cholesterol (LDL-C). Current LDL-C target attainment is low, and novel phase 3 trials are underway to investigate whether CETP inhibitors result in reduction of cardiovascular disease risk in high-risk patients who may be treated with PCSK9-inhibiting agents.

Objective: To explore the associations of combined reduction of CETP and PCSK9 concentrations with risk of coronary artery disease (CAD) and other clinical and safety outcomes.

Two-sample 2 × 2 factorial Mendelian randomization study in a general population sample that includes data for UK Biobank participants of European ancestry.

Exposures: Separate genetic scores were constructed for CETP and PCSK9 plasma protein concentrations, which were combined to determine the associations of combined genetically reduced CETP and PCSK9 concentrations with disease.

Main Outcomes and Measures: Blood lipid and lipoprotein concentrations, blood pressure, CAD, age-related macular degeneration, type 2 diabetes, any stroke and ischemic stroke, Alzheimer disease, vascular dementia, heart failure, atrial fibrillation, chronic kidney disease, asthma, and multiple sclerosis.

Results: Data for 425 354 UKB participants were included; the median (IQR) age was 59 years (51-64), and 229 399 (53.9%) were female. The associations of lower CETP and lower PCSK9 concentrations with CAD are similar when scaled per 10-mg/dL reduction in LDL-C concentrations (CETP: odds ratio [OR], 0.74; 95% CI, 0.67 to 0.81; PCSK9: OR, 0.75; 95% CI, 0.71 to 0.79). Combined exposure to lower CETP and PCSK9 concentrations was associated with an additive magnitude with lipids and all outcomes, and we did not observe any nonadditive interactions, most notably for LDL-C (CETP: effect size, -1.11 mg/dL; 95% CI, -1.40 to -0.82; PCSK9: effect size, -2.13 mg/dL; 95% CI, -2.43 to -1.84; combined: effect size, -3.47 mg/dL; 95% CI, -3.76 to -3.18; P = .34 for interaction) and CAD (CETP: OR, 0.96; 95% CI, 0.94 to 1.00; PCSK9: OR, 0.94; 95% CI, 0.91 to 0.97; combined: OR, 0.90; 95% CI, 0.87 to 0.93; P = .83 for interaction). In addition, when corrected for multiple testing, lower CETP concentrations were associated with increased age-related macular degeneration (OR, 1.11; 95% CI, 1.04 to 1.19).

Conclusions and Relevance: Our results suggest that joint inhibition of CETP and PCSK9 has additive effects on lipid traits and disease risk, including a lower risk of CAD. Further research may explore whether a combination of CETP- and PCSK9-related therapeutics can benefit high-risk patients who are unable to reach treatment targets with existing options.

RevDate: 2022-08-02

Suh JY, Lee HJ, Sim DY, et al (2022)

Hypolipogenic effects of Icariside E4 via phosphorylation of AMPK and inhibition of MID1IP1 in HepG2 cells.

Phytotherapy research : PTR [Epub ahead of print].

Though icariside E4 (IE4) is known to have anti-noceptive, anti-oxidant, anti-Alzheimer and anti-inflammatory effects, there was no evidence on the effect of IE4 on lipid metabolism so far. Hence, the hypolipogenic mechanism of IE4 was investigated in HepG2 hepatocellular carcinoma cells (HCCs) in association with MID1 Interacting Protein 1(MID1IP1) and AMPK signaling. Here, IE4 did not show any toxicity in HepG2 cells, but reduced lipid accumulation in HepG2 cells by Oil Red O staining. MID1IP1 depletion decreased the expression of SREBP-1c and fatty acid synthase (FASN) and induced phosphorylation of ACC in HepG2 cells. Indeed, IE4 activated phosphorylation of AMPK and ACC and inhibited the expression of MID1IP1 in HepG2 cells. Furthermore, IE4 suppressed the expression of SREBP-1c, liver X receptor-α (LXR), and FASN for de novo lipogenesis in HepG2 cells. Interestingly, AMPK inhibitor compound C reversed the ability of IE4 to reduce MID1IP1, SREBP-1c, and FASN and activate phosphorylation of AMPK/ACC in HepG2 cells, indicating the important role of AMPK/ACC signaling in IE4-induced hypolipogenic effect. Taken together, these findings suggest that IE4 has hypolipogenic potential in HepG2 cells via activation of AMPK and inhibition of MID1IP1 as a potent candidate for treatment of fatty liver disease.

RevDate: 2022-07-29

Trejo-Castro AI, Carrion-Alvarez D, Martinez-Torteya A, et al (2022)

A Bibliometric Review on Gut Microbiome and Alzheimer's Disease Between 2012 and 2021.

Frontiers in aging neuroscience, 14:804177.

Research on the microbiome has drawn an increasing amount of attention over the past decade. Even more so for its association with disease. Neurodegenerative diseases, such as Alzheimer's disease (AD) have been a subject of study for a long time with slow success in improving diagnostic accuracy or identifying a possibility for treatment. In this work, we analyze past and current research on microbiome and its positive impact on AD treatment and diagnosis. We present a bibliometric analysis from 2012 to 2021 with data retrieved on September 2, 2021, from the Scopus database. The query includes "Gut AND (Microbiota OR Microbiome) AND Alzheimer*" within the article title, abstract, and keywords for all kinds of documents in the database. Compared with 2016, the number of publications (NPs) on the subject doubled by 2017. Moreover, we observe an exponential growth through 2020, and with the data presented, it is almost certain that it will continue this trend and grow even further in the upcoming years. We identify key journals interested in the subject and discuss the articles with most citations, analyzing trends and topics for future research, such as the ability to diagnose the disease and complement the cognitive test with other clinical biomarkers. According to the test, mild cognitive impairment (MCI) is normally considered an initial stage for AD. This test, combined with the role of the gut microbiome in early stages of the disease, may improve the diagnostic accuracy. Based on our findings, there is emerging evidence that microbiota, perhaps more specifically gut microbiota, plays a key role in the pathogenesis of diseases, such as AD.

RevDate: 2022-08-13
CmpDate: 2022-07-29

Yıldırım ÖÇ, Arslan ME, Öner S, et al (2022)

Boron Nitride Nanoparticles Loaded with a Boron-Based Hybrid as a Promising Drug Carrier System for Alzheimer's Disease Treatment.

International journal of molecular sciences, 23(15):.

The search for an innovative and effective drug delivery system that can carry and release targeted drugs with enhanced activity to treat Alzheimer's disease has received much attention in the last decade. In this study, we first designed a boron-based drug delivery system for effective treatment of AD by integrating the folic acid (FA) functional group into hexagonal boron nitride (hBN) nanoparticles (NPs) through an esterification reaction. The hBN-FA drug carrier system was assembled with a new drug candidate and a novel boron-based hybrid containing an antioxidant as BLA, to constitute a self-assembled AD nano transport system. We performed molecular characterization analyses by using UV-vis spectroscopy, Fourier transform infrared spectrophotometer (FTIR), scanning electron microscope (SEM), Energy-dispersive X-ray spectroscopy (EDS) and Zeta potential investigations. Second, we tested the anti-Alzheimer properties of the carrier system on a differentiated neuroblastoma (SHSY5-Y) cell line, which was exposed to beta-amyloid (1-42) peptides to stimulate an experimental in vitro AD model. Next, we performed cytotoxicity analyses of synthesized molecules on the human dermal fibroblast cell line (HDFa) and the experimental AD model. Cytotoxicity analyses showed that even higher concentrations of the carrier system did not enhance the toxicological outcome in HDFa cells. Drug loading analyses reported that uncoated hBN nano conjugate could not load the BLA, whereas the memantine loading capacity of hBN was 84.3%. On the other hand, memantine and the BLA loading capacity of the hBN-FA construct was found to be 95% and 97.5%, respectively. Finally, we investigated the neuroprotective properties of the nano carrier systems in the experimental AD model. According to the results, 25 µg/mL concentrations of hBN-FA+memantine (94% cell viability) and hBN-FA+BLA (99% cell viability) showed ameliorative properties against beta-amyloid (1-42) peptide toxicity (50% cell viability). These results were generated through the use of flow cytometry, acetylcholinesterase (AChE) and antioxidant assays. In conclusion, the developed drug carrier system for AD treatment showed promising potential for further investigations and enlightened neuroprotective capabilities of boron molecules to treat AD and other neurodegenerative diseases. On the other hand, enzyme activity, systematic toxicity analyses, and animal studies should be performed to understand neuroprotective properties of the designed carrier system comprehensively.

RevDate: 2022-07-31
CmpDate: 2022-07-29

Khasawneh RR, Abu-El-Rub E, Alzu'bi A, et al (2022)

Corpus callosum anatomical changes in Alzheimer patients and the effect of acetylcholinesterase inhibitors on corpus callosum morphometry.

PloS one, 17(7):e0269082.

The Corpus Callosum (CC) is an important structure that includes the majority of fibers connecting the two brain hemispheres. Several neurodegenerative diseases may alter CC size and morphology leading to its atrophy and malfunction which may play a role in the pathological manifestations found in these diseases. The purpose of the current study is to determine any possible changes in CC size in patients suffering from Alzheimer's disease. The Study also investigated the effect of acetylcholinesterase inhibitors (AChEIs) on the size of CC and its association with improvement in the Alzheimer disease severity scores. Midsagittal size of CC were recorded prospectively from 439 routine T1-weighted MRI brain images in normal individuals. The internal skull surface was measured to calculate CC/ internal skull surface ratio. Two groups of patients were studied: 300 (150 male / 150 female) were healthy subjects and 130 (55 males / 75 females) had Alzheimer disease. Out of the 130 Alzheimer disease pateints, 70 patients were treated with Donepezil or Rivastigmine or both. The size of the CC was measured based on T1-weighted MRI images after the treatment to investigate any possible improvement in CC size. The mean surface area of CC in controls was 6.53±1.105 cm2. There was no significant difference between males and females (P < 0.627), and CC/ internal skull surface ratio was 4.41±0.77%. Patients with mild or severe Alzheimer disease showed a significant reduction in CC size compared to healthy controls. Treating mild Alzheimer patients with either Donepezil or Rivastigmine exerts a comparable therapeutic effect in improving the CC size. There was more improvement in the size of CC in patients with severe Alzheimer disease by using combined therapy of Donepezil and Rivastigmine than using single a medication. we measured the mean size of the various portions of the corpus callosum in normal individuals and Alzheimer patients before and after taking Donepezil and Rivastigmine. Alzheimer patients have pronounced reduction in CC which is corrected after taking Donepezil and Rivastigmine leading to remarkable improvement in Alzheimer disease severity scores.

RevDate: 2022-08-10
CmpDate: 2022-07-28

Kouhnavardi S, Ecevitoglu A, Dragačević V, et al (2022)

A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions.

Biomolecules, 12(7):.

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson's and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders.


RJR Experience and Expertise


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


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


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


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


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


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


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


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

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E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

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

Research Gate page for R J Robbins

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

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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