Current Alzheimer Research - Volume 15, Issue 10, 2018

Background: Neuroinflammation plays an important role in the pathogenesis of various neurodegenerative diseases including Alzheimer’s disease (AD). Suppressor of cytokine signaling 3 (SOCS3) is an anti-inflammatory molecule that suppresses cytokine signaling and inflammatory gene expression in different cells including microglia. Objective: The pathways through which SOCS3 could be upregulated are poorly described. Cinnamic acid is a metabolite of cinnamon, a natural compound that is being widely used all over the world as a spice or flavoring agent. Here, we examined if cinnamic acid could upregulate SOCS3 in microglia. Method: Microglia and astroglia isolated from mouse brain as well as BV-2 microglial cells were treated with cinnamic acid followed by monitoring the level of SOCS3 and different proinflammatory molecules by RT-PCR and real-time PCR. To nail down the mechanism, we also performed ChIP analysis to monitore the recruitment of cAMP response element binding (CREB) to the socs3 gene promoter and carried out siRNA knockdown of CREB. Results: Cinnamic acid upregulated the expression of SOCS3 mRNA and protein in mouse BV-2 microglial cells in dose- and time-dependent manner. Accordingly, cinnamic acid also increased the level of SOCS3 and suppressed the expression of inducible nitric oxide synthase and proinflammatory cytokines (TNFα, IL-1β and IL-6) in LPSstimulated BV-2 microglial cells. Similar to BV-2 microglial cells, cinnamic acid also increased the expression of SOCS3 in primary mouse microglia and astrocytes. We have seen that cAMP response element is present in the promoter of socs3 gene, that cinnamic acid induces the activation of CREB, that siRNA knockdown of CREB abrogates cinnamic acid-mediated upregulation of SOCS3, and that cinnamic acid treatment leads to the recruitment of CREB to the socs3 gene. Conclusions: These studies suggest that cinnamic acid upregulates the expression of SOCS3 in glial cells via CREB pathway, which may be of importance in neuroinflammatory and neurodegenerative disorders.

Background: A varying response to cholinesterase inhibitor (ChEI) treatment has been reported among patients with Alzheimer’s disease (AD). Whether the individual-specific response directly affects time to nursing home placement (NHP) was not investigated. Objective: We examined the relationship between the 6-month response to ChEI and institutionalization. Methods: In a prospective, observational, multicenter study, 881 outpatients with a clinical AD diagnosis and a Mini-Mental State Examination score of 10-26 at the start of ChEI therapy (baseline) were included. The participants were evaluated using cognitive, global, and activities of daily living (ADL) scales at baseline and semiannually over 3 years. The date of NHP was recorded. Results: During the study, 213 patients (24%) were admitted to nursing homes. The mean ± standard deviation time from baseline (AD diagnosis) to NHP was 20.8 ± 9.3 months. After 6 months of ChEI treatment, the improved/unchanged individuals had longer time to NHP than those who worsened. The prolonged time to NHP was 3 months for cognitive response (P=0.022), 4 months for global response (P=0.004), 6 months for basic ADL response (P<0.001), and 8 months for response in all three scales (P<0.001). No differences were detected between the improved and unchanged groups in any scales. Conclusion: Patients who exhibit a positive short-term response to ChEI can expect to stay in their own home for 3-8 months longer. These findings underline the importance of a comprehensive clinical examination including various assessment scales to evaluate treatment response and provide a more accurate prognosis.

Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by a multi-factorial etiology that is not completely understood. Donepezil is a first-line acetylcholinesterase inhibitor used for the treatment of AD that has been found, in addition to its potent acetylcholinesterase inhibitory effect, to act through other non-cholinergic mechanisms such as affecting mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator (PGC1α). Mitochondrial biogenesis and PGC-1α, at least in part, are associated with hepatic fatty acid oxidation and ketogenesis. Whether donepezil regulates ketogenesis in AD treatment remains unclear. Ketogenesis is important in the progression of AD and is a critical consideration during the therapeutic strategy selection for AD. Thus, our goals were to determine the differences in ketone bodies in patients with AD who were taking donepezil treatment and those who were not, to elucidate the potential effect of AD and donepezil therapy on ketone body metabolic parameters, and to discover the effect of donepezil therapy on ketogenesis in patients with AD. Methods: Cross-sectional analysis was performed on plasma collected from 145 individuals, namely, elderly adults as healthy controls (n=30), newly diagnosed patients with AD (n=30), patients with AD who responded to donepezil therapy (n=48) and patients with AD who did not respond to donepezil therapy (n=37). Gas chromatography-mass spectrometry was performed to quantify the lipids in the plasma. The level of β-hydroxybutyrate, a metabolite, was determined by liquid chromatographytandem mass spectrometry, and to gain further insight into the effect of donepezil on ketogenesis, the effects of donepezil were investigated in a mouse model. Results: The level of β-hydroxybutyrate decreased in AD patients, and donepezil elevated the plasma level of β-hydroxybutyrate. Donepezil increased the plasma and liver levels of β-hydroxybutyrate in mice as well as the hepatic expression of PGC-1α and the mitochondrial expression of HMG-CoA synthetase 2 (HMGCS2) in response to fasting, causing a subsequent increase in ketogenesis. Conclusions: Our study revealed that impaired ketogenesis is a metabolic feature of AD. Donepezil had effects on ketogenesis in mice and reversed the decrease in the level of β-hydroxybutyrate found in patients with AD.

Background: Alzheimer's disease (AD) pathology consists of intraneuronal neurofibrillary tangles, made of hyperphosphorylated tau and extracellular accumulation of beta amyloid (Aβ) in Aβ plaques. There is an extensive debate as to which pathology initiates and is responsible for cellular loss in AD. Methods: Using confocal and light microscopy, post mortem brains from control and AD cases, an antibody to SOD2 as a marker for mitochondria and an antibody to all forms of tau, we analyzed mitochondrial density in tau positive neurons along with nuclear degradation by calculating the raw integrative density. Results: Our findings showed an extensive staining of aggregated tau in cell bodies, dystrophic neurites and neurofilaments in AD with minimal staining in control tissue, along with a marked decrease in mitochondria in tau positive (tau+) neurons. The control or tau negative (tau-) neurons in AD contained an even distribution of mitochondria, which was greatly diminished in tau+ neurons by 40%. There were no significant differences between control and tau- neurons in AD. Tau+ neurons showed marked nuclear degradation which appeared to progress with the extent of tau aggregation. The aggregated tau infiltrated and appeared to break the nuclear envelope with progressively more DNA exiting the nucleus and associating with the aggregated intracellular tau. Conclusion: We report that the mitochondrial decrease is likely due to a decrease in the protein synthesis rather than a redistribution of mitochondria because of the decreased axonal transport. We suggest that the decrease in mitochondria and nuclear degradation are key mechanisms for the neuronal loss seen in AD.

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis and a common occurrence of comorbid diseases such as depression. It is accepted that the presence of the 4 allele of the gene that encodes apolipoprotein E (APOE) is the strongest genetic risk factor for the development of sporadic AD. Melatonin, cortisol, homocysteine, and prolactin are presumed to be risk factors or biomarkers for stress- and age-related disorders. Objective: The interplay between the APOE genotype and plasma biomarkers was examined in patients with AD presenting with or without depression to contribute to understanding the interdependence of various molecular mechanisms in the pathophysiology of AD. Method: The APOE genotype and morning plasma melatonin, cortisol, homocysteine, and prolactin concentrations were measured in 85 patients with AD and 44 elderly controls. Results: A significant association between AD and the allele (ε4) or genotype (ε3/ε4 or ε4/ε4) frequencies of APOE was confirmed. Plasma homocysteine and cortisol levels were significantly increased in patients with AD compared to those in controls, independent of the presence of comorbid depressive symptoms or the severity of dementia. Significantly lower plasma melatonin concentration was found in patients with AD but not in controls, who were noncarriers of the APOE 4 allele, regardless of the presence of depression or the severity of dementia in AD. Conclusion: Our findings indicate the existence of a little-known specific APOE-mediated mechanism that increases the plasma melatonin level in a subgroup of patients with AD who are carriers of the APOE ε4 allele.

Background: Alzheimer’s disease (AD) is a form of dementia characterized by failure of memory that becomes more severe with the progression of the disease. The Free and Cued Selective Reminding Test (FCSRT) is a clinical test used to evaluate such a deficit. However, since the cognitive performances could depend also on the psychophysiological state of the individual, it is important to monitor that state through the peripheral autonomic activity during the execution of the test. Thermal infrared imaging has been used for this kind of assessment in order to preserve the free and unbiased interaction between doctor and patient, thanks to the contactless features of the technique. Objective: To investigate whether the variation of facial temperature parameters during the FCSRT is indicative of different autonomic states in the early AD with respect to healthy controls (HC). Results: At a group level, a greater sympathetic activity for the HC with respect to AD during the execution of the test was found, indicative of a suppression of anxiety associated with the performances of the FCSRT in AD patients. Conclusion: These results indicate that AD and HC may present different autonomic activity associated with the execution of a cognitive task, thus suggesting a different modulation of high-cognition and emotion network.

The progressive supranuclear palsy is a progressive neurodegenerative disease characterized by Parkinsonism, oculomotor abnormalities, early postural instability and cognitive impairment. Neurodegeneration in PSP is associated with tau protein, but the mechanisms by which tau abnormalities lead to cell dysfunction and death are not well understood. Neuro-behavioural problems related to the fear and loss of autonomy can determinate many bioethical implications. Careful planning involving patients’ families, academic and industry researchers were necessary to ensure improvement in quality of life.

Introduction: Alzheimer’s disease (AD) is the most common cause of dementia, characterized by a progressive decline in cognition and function. Current treatment options for AD include the cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine, as well as the N-methyl-Daspartate receptor antagonist memantine. Treatment guidelines recommend the use of ChEIs as the standard of care first-line therapy. Several randomized clinical studies have demonstrated the benefits of ChEIs on cognition, global function, behavior and activities of daily living. However, patients may fail to achieve sustained clinical benefits from ChEIs due to lack/loss of efficacy and/or safety, tolerability issues, and poor adherence to the treatment. The purpose of this review is to explore the strategies for continued successful treatment in patients with AD. Methods: Literature search was performed for articles published in PubMed and MEDLINE, using prespecified search terms. Articles were critically evaluated for inclusion based on their titles, abstracts, and full text of the publication. Results and Conclusion: The findings of this review indicate that dose up-titration and switching between ChEIs may help to improve response to ChEI treatment and also address issues such as lack/loss of efficacy or safety/tolerability in patients with AD. However, well-designed studies are needed to provide robust evidence.

In the nineties, numerous studies began to highlight the problem of the increasing number of people with Alzheimer's disease in developed countries, especially in the context of demographic progress. At the same time, the 21st century is typical of the development of advanced technologies that penetrate all areas of human life. Digital devices, sensors, and intelligent applications are tools that can help seniors and allow better communication and control of their caregivers. The aim of the paper is to provide an up-to-date summary of the use of technological solutions for improving health and safety for people with Alzheimer’s disease. Firstly, the problems and needs of senior citizens with Alzheimer’s disease (AD) and their caregivers are specified. Secondly, a scoping review is performed regarding the technological solutions suggested to assist this specific group of patients. Works obtained from the following libraries are used in this scoping review: Web of Science, PubMed, Springer, ACM and IEEE Xplore. Four independent reviewers screened the identified records and selected relevant articles which were published in the period from 2007 to 2018. A total of 6,705 publications were selected. In all, 128 full papers were screened. Results obtained from the relevant studies were furthermore divided into the following categories according to the type and use of technologies: devices, processing, and activity recognition. The leading technological solution in the category of devices are wearables and ambient noninvasive sensors. The introduction and utilization of these technologies, however, bring about challenges in acceptability, durability, ease of use, communication, and power requirements. Furthermore, it needs to be pointed out that these technological solutions should be based on open standards.