Current Alzheimer Research - Volume 15, Issue 14, 2018

The incidence of both diabetes and Alzheimer's disease (AD) is increasing and is becoming a social and economic threat worldwide. Recent research studies indicate that both diseases share some pathophysiological features and that specifically, Type 2 Diabetes Mellitus (T2DM) is a risk factor of Alzheimer's disease. The aim of this study is to explore the relationship between diabetes mellitus and AD, explore the efficacy of selected drugs on patients with diabetes and AD, and compare the relative risk of diabetes for Alzheimer's disease within different clinical studies. The method of literature search in several acknowledged databases such as Web of Science, Elsevier Science Direct, PubMed and Scopus in the period from 2000 to 2015 for the following keywords: “Alzheimer's AND disease AND diabetes AND mellitus” was used. The identified studies were divided into two basic groups, based on their focus: efficacy of the selected drugs on patients suffering from AD and diabetes, and a link between diabetes and AD; as diabetes is seen as a risk factor of AD. The findings of this study confirm that there is a close and direct link between diabetes and AD, which indicates that there is a need for early diagnosis of metabolic syndrome, insulin resistance, and T2DM. In fact, the reviewed clinical trials have proved an increase in the risk of AD. However, the values of this risk are relatively low. The results also illustrate that both pharmacological (e.g., the antidiabetic drugs together with insulin dosing) and nonpharmacological (e.g., being intensively engaged in physical activities) treatments can have a positive effect. The results of this study confirm that diabetes and AD are not independent disorders since they share some common pathophysiological mechanisms. In addition, more clinical randomized control trials are needed to explore the efficacy of both pharmacological and non-pharmacological approaches to the treatment of T2DM and AD.

The pathogenic mechanisms of Alzheimer's Disease (AD) involve the deposition of abnormally misfolded proteins, amyloid β protein (Aβ) and tau protein. Aβ comprises senile plaques, and tau aggregates form Neurofibrillary Tangles (NFTs), both of which are hallmarks of AD. Autophagy is the main conserved pathway for the degeneration of aggregated proteins, Aβ, tau and dysfunctional organelles in the cell. Many animal model studies have demonstrated that autophagy normally functions as the protective factor against AD progression associated with intracytoplasmic toxic Aβ and tau aggregates. The upregulation of autophagy can also be favorable in AD treatment. An improved understanding of the signaling pathways that regulate autophagy is critical to developing AD treatments. The cellular and molecular machineries of autophagy, their function in the pathogenesis of AD, and current drug discovery strategies will be discussed in this review.

Background: The importance of the issue of the economic burden of treatment and care for people with dementia is crucial in the developed countries. The European Union and other developed countries are trying to improve the course of aging population which leads to rising costs. Their uniform registration is also one of the objectives of the developed countries' strategic plans to fight dementia. The individual steps of the plans in practical terms so far are mainly directed to the early diagnosis of diseases, records of the associated data are so far in the background. Aim: The aim of this paper is to specify a set of costs that should be constantly monitored at the national level within dementia. Methods: The main method is a literature review focused on Alzheimer's disease. The searched keywords were "Alzheimer's disease" and "costs" incurred after 2010. The studies will specify the monitored costs and determine their minimal penetration, which will then form the basis for recommendations for the monitored group of costs on a national level. Results: Results of the analysis indicate that the following main cost groups are monitored: medical direct costs (inpatient care, outpatient treatment, medication), non-medical direct costs (day care centres, community health services, respite care, accommodation costs for patients) and indirect costs (time that the carers dedicate to the patient). The issue of different naming and groups of costs calls for a common strategy in this area and defining the minimum items that should be monitored.

Background: Formaldehyde (FA) has been implicated in Alzheimer's disease (AD) pathology as an age-related factor and as a protein cross-linker known to aggregate Amyloid-Beta (Aβ) and tau protein in vitro. Higher levels of FA have also been found in patients with greater cognitive impairment and in AD patient brains. Objective: To directly evaluate the effect of chronically elevated FA levels on the primate brain with respect to AD pathological markers. Method: Young rhesus macaques (5-8 yrs, without AD related mutations) were given chronic intracerebroventricular (i.c.v.) injections of FA or vehicle over a 12-month period. Monkeys were monitored for changes in cognitive ability and evaluated post-mortem for common AD pathological markers. Results: Monkeys injected with FA were found to have significant spatial working memory impairments. Histopathological analysis revealed the presence of amyloid-β+ neuritic-like plaques, neurofibrillary tangle-like formations, increased tau protein phosphorylation, neuronal loss and reactive gliosis in three memory (and AD) related brain areas (the hippocampus, entorhinal cortex and prefrontal cortex (PFC)) of monkeys receiving i.c.v. injections of FA. ELISA assays revealed that the amounts of pT181 and Aβ42 were markedly higher in the PFC and hippocampus of FA treated monkeys. Conclusion: FA was found to induce major AD-like pathological markers and cognitive impairments in young rhesus monkeys independent of genetic predispositions. This suggests FA may play a significant role in the initiation and progression of the disease.

Introduction: Patients with dementia may be at a higher risk for death from stroke. We aimed to describe characteristics of dementia patients that died from ischemic stroke (IS) in Sweden. Methods: A retrospective longitudinal analysis of prospectively collected data of patients registered into the Swedish Dementia Registry was conducted. Data on causes of death, drugs and comorbidities were acquired from the Swedish nationwide health registers. Deaths were attributed to stroke if the death certificate contained stroke as a cause of death and the patient had a stroke registered in Riksstroke, the Swedish Stroke Register, in the year preceding death. Demographic data at the time of dementia diagnosis was compared between patients dying from IS and registered in Riksstroke, patients dying from IS without being registered in Riksstroke and those dying from other causes. Results: Out of 49823 patients diagnosed with dementia between 2007 and 2014 in primary care or specialist clinics, 14170 (28.4%) had died by the end of 2014. Of these 1180 (8.3%) had IS in their death certificate, of which 459 (38.9%) had been registered in Riksstroke. In patients who died of IS the most common type of dementia was vascular dementia while those died from other causes were most often diagnosed with Alzheimer's dementia (AD). Patients who died from IS and were registered in Riksstroke had higher MMSE score compared to other groups. Patients who died from IS took more cardiovascular medications. There were no differences in the use of antipsychotics, antidepressants, acetylcholinesterase inhibitors, memantine, anxiolytics, or hypnotics between the groups. Conclusions: There was a relatively high number of patients who died from IS as shown in their death certificate but had not been registered in Riksstroke in the year before death. This creates concerns on the accuracy of death certificate stroke diagnoses, particularly for deaths taking place outside hospitals.

Background: Mesenchymal stem cell transplantation is demonstrated to improve neurological performance in neurodegenerative diseases including Alzheimer's disease. Objective: The objective of this study is to understand the underlying mechanism of such improvement. Methods: Amyloid β (Aβ) peptide was infused into the lateral ventricle of adult Wister rats using the osmotic pump. After 15 days of continuous infusion, a mesenchymal stem cell line (B10) was transplanted in the lateral ventricle. Learning-related behavior was evaluated by 2-way shuttle avoidance test. Fifteen days after B10 transplantation, pathological and expressional changes were evaluated. Results: Compared to sham group, learning-related behavior was significantly decreased in Aβ-infused non-transplanted group, but not in B10-transplanted group. Nissl staining results demonstrated that the number of hippocampal pyramidal neurons in CA1 area in B10-transplanted group was similar to the sham group, whereas that was decreased in Aβ-infused non-transplanted group. Aβ mainly deposited in the vessels of the brains of Aβ-infused non-transplanted rats, which was decreased by B10 transplantation. Moreover, B10 transplantation increased vessel density as well as endoglin positive cells. The number of astrocyte and microglia was decreased in Aβ-infused non-transplanted group, which was returned to the level of sham animals by B10 transplantation. Real-time PCR and immunostaining results showed that B10 transplantation significantly increased IL-1β mRNA and protein expression. Conclusion: Thus, our result showed that MSC transplantation effectively decreased Aβ deposition in the cerebral vessel and increased angiogenesis, which could be a possible cause of improved neurological performance in Aβ-infused AD model rats.

Objective: The study aimed to investigate exchangeable proton signals of Aβ proteins of the brains of Alzheimer's disease (AD) model mice by using a chemical exchange-sensitive spin-lock (CESL) MR imaging technique. Method: Eight non-transgenic (Tg) mice (5 young and 3 old) and twelve Tg-APPswe/PSdE9 mice (5 young and 7 old) were used in this study. CESL Z-spectra were obtained by using two saturation powers, which were ω1 = 25 Hz with TSL = 3.0 s and ω1 = 500 Hz with TSL = 150 ms, at 71 offsets with uneven intervals between the offset frequencies at Ω = ±7.0 ppm at a 9.4-T animal MRI system. For Zspectrum analyses, regions of interest (ROIs) were drawn in the cortex, hippocampus, and thalamus of both hemispheres. Magnetization transfer ratio asymmetry (MTRasym) curves were obtained from the Zspectra. The Mann-Whitney test was used to compare the MTRasym values between the Tg and non-Tg mice for each offset frequency and for each ROI. Results: The water saturation width of the full Z-spectrum was narrow with the 25-Hz saturation power, but relatively broad with the 500-Hz saturation power. With the 25-Hz CESL saturation power, most of the MTRasym values were negative for 3.5-, 3.0-, 2.0-, and 0.9-ppm offset frequencies and the MTRasym values were significantly different between the control and Tg groups only in the left thalamus region at 3.5 ppm offset (p=0.0487). The MTRasym values were -6% to -7% for both 3.5 and 3.0 ppm, but less than -2% for both 2.0 and 0.9 ppm. With 500-Hz CESL saturation power, all the MTRasym values were positive for the 3.5-, 3.0-, 2.0-, and 0.9-ppm offset frequencies and the MTRasym values were not significantly different between the control and Tg groups at all ROIs and at all offset frequencies. However, a trend towards a significant difference was observed between the control and Tg groups in the right cortex at 3.5 ppm (p=0.0578). The MTRasym values were 6% to 9% for 3.5, 3.0, and 2.0 ppm, but less than 2% for 0.9 ppm. Conclusion: In an in-vivo AD model experiment, MTRasym values increased with the high saturation power than with the low saturation power. The MTRasym values were not significantly different, except in the left thalamus region at 3.5 ppm offset. The CESL technique should be further developed to enable its application in the brain of patients with neurodegenerative diseases.

Background: Cerebrovascular pathologies and hypertension could play a vital role in Alzheimer disease (AD) progression. However, whether cerebrovascular pathologies and hypertension accelerate the AD progression through an independent or interaction effect is unknown. Objective: To investigate the effect of the interactions of cerebrovascular pathologies and hypertension on AD progression. Method: A retrospective longitudinal study was conducted to compare AD courses in patients with different severities of cerebral White Matter Changes (WMCs) in relation to hypertension. Annual comprehensive psychometrics were performed. WMCs were rated using a rating scale for Age-related WMCs (ARWMC). Results: In total, 278 patients with sporadic AD were enrolled in this study. The mean age of the patients was 76.6 ± 7.4 years, and 166 patients had hypertension. Among AD patients with hypertension, those with deterioration in clinical dementia rating-sum of box (CDR-SB) and CDR had significantly severe baseline ARWMC scales in total (CDR-SB: 5.8 vs. 3.6, adjusted P = 0.04; CDR: 6.4 vs. 4.4, adjusted P = 0.04) and frontal area (CDR-SB: 2.4 vs. 1.2, adjusted P = 0.01; CDR: 2.4 vs. 1.7, adjusted P < 0.01) compared with those with no deterioration in psychometrics after adjustment for confounders. By contrast, among AD patients without hypertension, no significant differences in ARWMC scales were observed between patients with and without deterioration. Conclusion: The effect of cerebrovascular pathologies on AD progression between those with and without hypertension might differ. An interaction but not independent effect of hypertension and WMCs on the progression of AD is possible.

Background: There are several cortical areas related to the limbic system that form the output from the hippocampal formation whose cellular and morphological features are important for the onset and progression of AD. We hypothesized that there would be a significant difference in the size of cortical pyramidal neurons and that there would also be a hemispheric asymmetry between Alzheimer disease patients and controls. These differences would potentially be accompanied by an increase in the numbers of Fluoro-Jade B-positive degenerating cortical neurons and a corresponding decrease in the numbers of DAPI-stained cortical neuronal nuclei in subjects with AD compared to controls. Such changes could potentially be used as another marker in postmortem neuropathological diagnosis of AD. Methods: We measured absolute numbers of DAPI and Fluoro-Jade B stained cells in five cortical areas of the limbic system and four subareas of planum temporale in the post-mortem brains of subjects with Alzheimer disease. We also measured the size of pyramidal neurons in layer III in the five cortical areas of the limbic system in these subjects. All measurements were performed separately for the left and right hemisphere in order to identify asymmetries between the two hemispheres. Results: We observed a significant decrease in numbers of DAPI stained cells in layers IV-VI of the anterior cingulate gyrus on the right side, in layers I-III of the posterior cingulate gyrus on the left side, in layers IV-VI in the transition region from superior temporal gyrus into planum temporale on the right and in layers IV-VI in the transition from planum temporale to insular cortex on the left. We also observed a significant increase in the numbers of Fluoro-Jade stained cells in layers I-III of the anterior cingulate gyrus and in layers I-III on the left and layers IV-VI of the right gyrus of Heschl. Shortening of the size of layer III pyramidal neurons in subjects with Alzheimer´s disease was found in the anterior cingulate gyrus on the right, in the posterior cingulate gyrus and entorhinal cortex on the left and on the right in the parahippocampal gyrus. Conclusion: Our study demonstrates asymmetries in different cortical regions of the temporal lobe that can be used as another marker in the postmortem diagnosis of AD.