Amyloid-β Levels Research Articles

Feasibility evaluation of PET scan-time reduction for diagnosing amyloid-β levels in Alzheimer's disease patients using a deep-learning-based denoising algorithm

PurposeTo shorten positron emission tomography (PET) scanning time in diagnosing amyloid-β levels thus increasing the workflow in centers involving Alzheimer's Disease (AD) patients. MethodsPET datasets were collected for 25 patients injected with 18F-AV45 radiopharmaceutical. To generate necessary training data, PET images from both normal-scanning-time (20-min) as well as so-called “shortened-scanning-time” (1-min, 2-min, 5-min, and 10-min) were reconstructed for each patient. Building on our earlier work on MCDNet (Monte Carlo Denoising Net) and a new Wasserstein-GAN algorithm, we developed a new denoising model called MCDNet-2 to predict normal-scanning-time PET images from a series of shortened-scanning-time PET images. The quality of the predicted PET images was quantitatively evaluated using objective metrics including normalized-root-mean-square-error (NRMSE), structural similarity (SSIM), and peak signal-to-noise ratio (PSNR). Furthermore, two radiologists performed subjective evaluations including the qualitative evaluation and a five-point grading evaluation. The denoising performance of the proposed MCDNet-2 was finally compared with those of U-Net, MCDNet, and a traditional denoising method called Gaussian Filtering. ResultsThe proposed MCDNet-2 can yield good denoising performance in 5-min PET images. In the comparison of denoising methods, MCDNet-2 yielded the best performance in the subjective evaluation although it is comparable with MCDNet in objective comparison (NRMSE, PSNR, and SSIM). In the qualitative evaluation of amyloid-β positive or negative results, MCDNet-2 was found to achieve a classification accuracy of 100%. ConclusionsThe proposed denoising method has been found to reduce the PET scan time from the normal level of 20 min to 5 min but still maintaining acceptable image quality in correctly diagnosing amyloid-β levels. These results suggest strongly that deep learning-based methods such as ours can be an attractive solution to the clinical needs to improve PET imaging workflow.

Gardenia jasminoides J.Ellis extract GJ-4 alleviated cognitive deficits of APP/PS1 transgenic mice

BackgroundAccumulating evidence demonstrates that traditional Chinese medicines that act on multiple targets could effectively treat various multi-etiological diseases, including cerebrovascular diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and so on. Previous studies have shown that crocin richments (GJ-4), Gardenia jasminoides J.Ellis extract, provide neuroprotective effects on cognitive impairments in AD mouse models. However, the mechanism how GJ-4 improves cognition remains still unclear. PurposeThe aim of this study was to uncover the protective effects and underlying mechanism of GJ-4 on PrP-hAβPPswe/PS1ΔE9 (APP/PS1) transgenic mice. MethodsAPP/PS1 mice were given GJ-4 (10, 20, and 50 mg/kg), donepezil (5 mg/kg) and memantine (5 mg/kg) orally at eight months of age for 12 consecutive weeks. Morris water maze and novel object recognition were conducted to assess the cognitive ability of mice. The release of inflammatory cytokines was determined by RT-PCR assay, and the pathological features of neurons and microglia were assayed by immunohistochemistry and immunofluorescence assay. The expression of Aβ-related proteins and signaling pathways were determined by Western blot. ResultsThe behavioral results revealed that GJ-4 ameliorated the cognitive deficits of APP/PS1 mice measured by Morris water maze and novel object recognition tests. Mechanism studies indicated that GJ-4 significantly decreased β-amyloid (Aβ) level through reducing Aβ production and promoting Aβ degradation. It has been reported that Aβ plaques trigger the hyper-phosphorylation of tau protein in APP/PS1 mice. Consistent with previous studies, hyper-phosphorylation of tau was also occurred in APP/PS1 mice in the present study, and GJ-4 inhibited Tau phosphorylation at different sites. Overwhelming evidence indicates that neuroinflammation stimulated by Aβ and hyperphosphorylated tau is involved in the pathological progression of AD. We found that GJ-4 suppressed neuroinflammatory responses in the brain through regulating phosphatidylinositide 3-kinase/AKT (PI3K/AKT) signaling pathway activation, and subsequent expression of inflammatory proteins and release of inflammatory cytokines. ConclusionAltogether, GJ-4 ameliorated cognition of APP/PS1 transgenic mice through multiple targets, including Aβ, tau and neuroinflammation. This study provides a solid research basis for further development of GJ-4 as a potential candidate for the treatment of AD.

Differential involvement of insulin receptor substrate (IRS)-1 and IRS-2 in brain insulin signaling is associated with the effects on amyloid pathology in a mouse model of Alzheimer's disease

Insulin signaling has been implicated in the metabolism as well as aging and longevity. Type 2 diabetes mellitus and its core pathology, insulin resistance, has also been implicated in the development of Alzheimer's disease (AD) and amyloid-β deposition in humans. By contrast, genetic ablation of the insulin/IGF-1 signaling (IIS) pathway components, e.g. insulin receptor substrate (IRS)-2, has been documented to suppress amyloid-β accumulation in the brains of transgenic mice overexpressing AD mutant β-amyloid precursor protein (APP). Therefore, the brain IIS may be a key modifiable molecular target in the pathophysiology of AD. IRS-1 and IRS-2 are critical nodes in IIS as substrates for insulin receptor and IGF-1 receptor, although the functional differences between IRS-1 and IRS-2 in the adult brain are yet to be explored. To examine their relative contribution to the brain IIS activity and AD pathomechanism, we generated APP transgenic mice lacking either IRS-1 or IRS-2. IRS-1 deficiency had little effects on the brain IIS pathway associated with compensatory activation of IRS-2, whereas IRS-2 deficiency was not fully compensated by activation of IRS-1, and the downstream activation of Akt also was significantly compromised. Pathological analyses of the cortical tissues showed that the biochemical levels of soluble and insoluble amyloid-β, the amyloid-β histopathology, and tau phosphorylation were not affected by the absence of IRS-1, in contrast to the marked alteration in IRS-2 deleted mice. These results suggest the predominance of IRS-2 in the brain IIS, and support the hypothesis that reduced IIS exerts anti-amyloid effects in the brain.

Abstract P111: Effects Of Magnetic Field On Abca1-mediated Cellular Lipid Release And Adult Brain Cell Generation In Mice

Aim: This project aims to explore a novel magnetic field (MF) health care based on the cholesterol metabolism. Methods: Mouse peritoneal macrophages foam cells were incubated in CO 2 -independent culture medium containing apoA-I and were exposed in a MF (0.4 T) using the electromagnet of EPR spectrometer. C57BL/6N mice (8 week-old) were peritoneally injected F-ara-EdU (133μg/g mouse body weight) then exposed to MF under the identical condition. Mouse plasma, cerebrospinal fluid, liver and brain were harvested on the 28 th day. Lipoprotein profiles were examined enzymatic detection followed by a gel-permeable-HPLC (Skylight Biotech Inc.). Amyloid β40 and β42 levels were determined by WAKO ELISA kit. Fixed mouse brain sections (40um) were prepared by Leica CM1900 cryostat. Alexa fluor® 488 conjugates were link to F-ara-EdU by a click chemistry method and fluor positive nucleus images were captured by a confocal super resolution SpinSR10 (Olympus, Inc.). Results: ABCA1-apoA-I mediated cellular cholesterol release was not affected or reduced by the exposure in the MF of 0.4 T. The Pcsk9 expression showed significant reduction in the hepatocytes. Reduction of Abca1 expression and increase of Scarb1 were obtained non significantly. The newly generated hippocampal dentate gyrus cells in the control mice group and the MF exposed group were 1.6±1.17, and 0.47±0.62 cells per dentate gyrus section, respectively (P=0.003) despite bulk of new cells in olfactory bulbs in the both groups. Discussions: No substantial increase in cellular cholesterol export was observed by MF irradiation of mouse peritoneal macrophage cells. In addition, the lipoprotein profile showed a decrease in HDL cholesterol even after 28 days. As a result of gene expression in the liver, a decrease in ABCA1 expression and an increase in SR-BI expression inferred reduction of HDL. The number of new cells detected in the granular zone and the subgranular zone in the dentate gyrus of the hippocampus was significantly reduced in the mice subjected to the MF treatment. In the future, it is necessary to investigate in detail whether these newborn cells are neuron or glial cells.

Neuropharmacology of Cevimeline and Muscarinic Drugs-Focus on Cognition and Neurodegeneration.

At present, Alzheimer’s disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-β (Aβ) peptide in the cerebral spinal fluid of Alzheimer’s patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD.

Soluble Amyloid-β Consumption in Alzheimer's Disease.

Brain proteins function in their soluble, native conformation and cease to function when transformed into insoluble aggregates, also known as amyloids. Biophysically, the soluble-to-insoluble phase transformation represents a process of polymerization, similar to crystallization, dependent on such extrinsic factors as concentration, pH, and a nucleation surface. The resulting cross-β conformation of the insoluble amyloid is markedly stable, making it an unlikely source of toxicity. The spread of brain amyloidosis can be fully explained by mechanisms of spontaneous or catalyzed polymerization and phase transformation instead of active replication, which is an enzyme- and energy-requiring process dependent on a specific nucleic acid code for the transfer of biological information with high fidelity. Early neuronal toxicity in Alzheimer's disease may therefore be mediated to a greater extent by a reduction in the pool of soluble, normal-functioning protein than its accumulation in the polymerized state. This alternative loss-of-function hypothesis of pathogenicity can be examined by assessing the clinical and neuroimaging effects of administering non-aggregating peptide analogs to replace soluble amyloid-β levels above the threshold below which neuronal toxicity may occur. Correcting the depletion of soluble amyloid-β, however, would only exemplify 'rescue medicine.' Precision medicine will necessitate identifying the pathogenic factors catalyzing the protein aggregation in each affected individual. Only then can we stratify patients for etiology-specific treatments and launch precision medicine for Alzheimer's disease and other neurodegenerative disorders.

Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer’s disease therapeutic

In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-β pathology as well as its effects on downstream processes associated with Alzheimer’s disease pathophysiology. Here, we applied an in vivo longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used in human clinical trials to assess the efficacy of a novel brain-penetrating anti-amyloid fusion protein treatment in the McGill-R-Thy1-APP transgenic rat model. The bi-functional fusion protein consisted of a blood-brain barrier crossing single domain antibody (FC5) fused to an amyloid-β oligomer-binding peptide (ABP) via Fc fragment of mouse IgG (FC5-mFc2a-ABP). A five-week treatment with FC5-mFc2a-ABP (loading dose of 30 mg/Kg/iv followed by 15 mg/Kg/week/iv for four weeks) substantially reduced brain amyloid-β levels as measured by positron emission tomography and increased the cerebrospinal fluid amyloid-β42/40 ratio. In addition, the 5-week treatment rectified the cerebrospinal fluid neurofilament light chain concentrations, resting-state functional connectivity, and hippocampal atrophy measured using magnetic resonance imaging. Finally, FC5-mFc2a-ABP (referred to as KG207-M) treatment did not induce amyloid-related imaging abnormalities such as microhemorrhage. Together, this study demonstrates the translational values of the designed preclinical studies for the assessment of novel therapies based on the clinical biomarkers providing tangible metrics for designing early-stage clinical trials.

The Transition of Mild Cognitive Impairment Over Time: An AV45- and FDG-PET Study of Reversion and Conversion Phenomena.

Mild cognitive impairment (MCI) is a state between normal cognition and dementia. However, MCI diagnosis does not necessarily guarantee the progression to dementia. Since no previous study investigated brain positron emission tomography (PET) imaging of MCI-- to-normal reversion, we provided PET imaging of MCI- to-normal reversion using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We applied comprehensive neuropsychological criteria (NP criteria), consisting of memory, language, and attention/executive function domains, to include patients with a baseline diagnosis of MCI (n=613). According to the criteria, the year 1 status of the patients was categorized into three groups (reversion: n=105, stable MCI: n=422, conversion: n=86). Demographic, neuropsychological, genetic, CSF, and cognition biomarker variables were compared between the groups. Additionally, after adjustment for confounding variables, the deposition pattern of amyloid-β and cerebral glucose metabolism were compared between three groups via AV45- and FDG-PET modalities, respectively. MCI reversion rate was 17.1% during one year of follow-up. The reversion group had the lowest frequency of APOE ε4+ subjects, the highest CSF level of amyloid-β, and the lowest CSF levels of t-tau and p-tau. Neuropsychological assessments were also suggestive of better cognitive performance in the reversion group. Patients with reversion to normal state had higher glucose metabolism in bilateral angular and left middle/inferior temporal gyri, when compared to those with stable MCI state. Meanwhile, lower amyloid-β deposition at baseline was observed in the frontal and parietal regions of the reverted subjects. On the other hand, the conversion group showed lower cerebral glucose metabolism in bilateral angular and bilateral middle/inferior temporal gyri compared to the stable MCI group, whereas the amyloid-β accumulation was similar between the groups. This longitudinal study provides novel insight regarding the application of PET imaging in predicting MCI transition over time.

The Effects of Aβ1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2.

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer’s disease (AD), the major form of dementia, β-amyloid (Aβ) levels in the blood are increased; however, the impact of elevated Aβ levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aβ1-42, but not Aβ1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aβ1-42. Furthermore, Aβ1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aβ1-42 show that the clearance of Aβ1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aβ antibody. In conclusion, these findings suggest that the binding of Aβ1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aβ1-42 in the blood is beneficial to the fight against COVID-19 and AD.

Efficacy and Safety of Sesame Oil Cake Extract on Memory Function Improvement: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Pilot Study

The goal of treatment for mild cognitive impairment (MCI) is to reduce the existing clinical symptoms, delay the progression of cognitive impairment and prevent the progression to Alzheimer’s disease (AD). At present, there is no effective drug therapy for AD treatment. However, early intake of dietary supplements may be effective in alleviating and delaying the MCI. This study aims to evaluate the effects of sesame oil cake extract (SOCE) supplementation on cognitive function in aged 60 years or older adults with memory impairment. A total of 70 subjects received either SOCE (n = 35) or placebo (n = 35) for 12 weeks based on random 1:1 assignment to these two groups. Cognitive function was evaluated by a computerized neurocognitive function test (CNT), and changes in the concentrations of plasma amyloid β (Aβ) proteins and urine 8-OHdG (8-hydroxy-2′-deoxyguanosine) were investigated before and after the experiment. Verbal learning test index items of the CNT improved markedly in the SOCE group compared to the placebo group (p < 0.05). Furthermore, plasma amyloid-β (1–40) and amyloid-β (1–42) levels in the SOCE group decreased significantly compared to that in the placebo group (p < 0.05). There was no statistically significant difference in urine 8-OHdG between the two groups (p > 0.05). Collectively, intake of SOCE for 12 weeks appears to have a beneficial effect on the verbal memory abilities and plasma β-amyloid levels of older adults with memory impairment.

Enhancement of Insulin/PI3K/Akt Signaling Pathway and Modulation of Gut Microbiome by Probiotics Fermentation Technology, a Kefir Grain Product, in Sporadic Alzheimer's Disease Model in Mice.

Sporadic Alzheimer’s disease (AD) is the most common neurodegenerative disorder with cognitive dysfunction. Remarkably, alteration in the gut microbiome and resultant insulin resistance has been shown to be connected to metabolic syndrome, the crucial risk factor for AD, and also to be implicated in AD pathogenesis. Thus, this study, we assessed the efficiency of probiotics fermentation technology (PFT), a kefir product, in enhancing insulin signaling via modulation of gut microbiota to halt the development of AD. We also compared its effectiveness to that of pioglitazone, an insulin sensitizer that has been confirmed to substantially treat AD. AD was induced in mice by a single injection of intracerebroventricular streptozotocin (STZ; 3 mg/kg). PFT (100, 200, 400 mg/kg) and pioglitazone (30 mg/kg) were administered orally for 3 weeks. Behavioral tests were conducted to assess cognitive function, and hippocampal levels of acetylcholine (Ach) and β-amyloid (Aβ1–42) protein were assessed along with histological examination. Moreover, the expression of the insulin receptor, insulin degrading enzyme (IDE), and the phosphorylated forms of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), mammalian target of rapamycin (mTOR), and tau were detected. Furthermore, oxidative stress and inflammatory biomarkers were estimated. Treatment with PFT reversed STZ-induced neurodegeneration and cognitive impairment, enhanced hippocampal Ach levels, and reduced Aβ1–42 levels after restoration of IDE activity. PFT also improved insulin signaling, as evidenced by upregulation of insulin receptor expression and activation of PI3K/Akt signaling with subsequent suppression of GSK-3β and mTOR signaling, which result in the downregulation of hyperphosphorylated tau. Moreover, PFT significantly diminished oxidative stress and inflammation induced by STZ. These potential effects were parallel to those produced by pioglitazone. Therefore, PFT targets multiple mechanisms incorporated in the pathogenesis of AD and hence might be a beneficial therapy for AD.

Early manifestation of gait alterations in the Tg2576 mouse model of Alzheimer's disease.

There is strong clinical evidence that multifaceted gait abnormalities may be manifested at early stages of Alzheimer's disease (AD), are related to cognitive decline, and can be used as an early biomarker to identify patients at risk of progressing to full-blown dementia. Despite their importance, gait abnormalities have not been investigated in mouse models of AD, which replicate important aspects of the human disease. The Tg2576 is frequently used in AD research to test therapeutic interventions targeting cellular mechanisms contributing to the genesis of AD. This transgenic mouse strain overexpresses a mutant form of the 695 amino acid isoform of human amyloid precursor protein with K670N and M671L mutations (APPK670/671L) linked to early-onset familial AD. Tg2576 mice exhibit impaired cognitive functions and increased cortical and hippocampal soluble β-amyloid levels starting from 5months of age and increased insoluble β-amyloid levels and amyloid plaques that resemble senile plaques associated with human AD by 13months of age. To demonstrate early manifestations of gait dysfunction in this relevant preclinical model, we characterized gait and motor performance in 10-month-old Tg2576 mice and age-matched littermate controls using the semi-automated, highly sensitive, Catwalk XT system. We found that Tg2576 mice at the pre-plaque stage exhibited significantly altered duty cycle and step patterns and decreased stride length and stride time. Base-of-support, stride time variability, stride length variability, cadence, phase dispersions and gait symmetry indices were unaltered. The presence of measurable early gait abnormalities during the pre-plaque stages of AD in this relevant preclinical mouse model has direct translational relevance and supports the view that longitudinal monitoring of gait performance could be used in addition to behavioral testing to evaluate progression of the disease and to assess treatment efficacy.

Annexin A1 restores cerebrovascular integrity concomitant with reduced amyloid-β and tau pathology.

Alzheimer’s disease, characterized by brain deposits of amyloid-β plaques and neurofibrillary tangles, is also linked to neurovascular dysfunction and blood–brain barrier breakdown, affecting the passage of substances into and out of the brain. We hypothesized that treatment of neurovascular alterations could be beneficial in Alzheimer’s disease. Annexin A1 (ANXA1) is a mediator of glucocorticoid anti-inflammatory action that can suppress microglial activation and reduce blood–brain barrier leakage. We have reported recently that treatment with recombinant human ANXA1 (hrANXA1) reduced amyloid-β levels by increased degradation in neuroblastoma cells and phagocytosis by microglia. Here, we show the beneficial effects of hrANXA1 in vivo by restoring efficient blood–brain barrier function and decreasing amyloid-β and tau pathology in 5xFAD mice and Tau-P301L mice. We demonstrate that young 5xFAD mice already suffer cerebrovascular damage, while acute pre-administration of hrANXA1 rescued the vascular defects. Interestingly, the ameliorated blood–brain barrier permeability in young 5xFAD mice by hrANXA1 correlated with reduced brain amyloid-β load, due to increased clearance and degradation of amyloid-β by insulin degrading enzyme (IDE). The systemic anti-inflammatory properties of hrANXA1 were also observed in 5xFAD mice, increasing IL-10 and reducing TNF-α expression. Additionally, the prolonged treatment with hrANXA1 reduced the memory deficits and increased synaptic density in young 5xFAD mice. Similarly, in Tau-P301L mice, acute hrANXA1 administration restored vascular architecture integrity, affecting the distribution of tight junctions, and reduced tau phosphorylation. The combined data support the hypothesis that blood–brain barrier breakdown early in Alzheimer’s disease can be restored by hrANXA1 as a potential therapeutic approach.

Asymmetric Dopamine Transporter Loss Affects Cognitive and Motor Progression in Parkinson's Disease.

ABSTRACTBackgroundAsymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression.ObjectivesThe objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4‐year progression in drug‐naïve PD.MethodsFrom the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right‐handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single‐photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD‐left), and on the right side in 106 patients (PD‐right); we compared them with 196 healthy controls. Patients were followed longitudinally (2‐year and 4‐year visits), examining their clinical, cognitive, and imaging data.ResultsAt baseline, the PD‐left group showed worse performance on the Symbol Digit Modality Test, an attention and processing‐speed test, and lower cerebrospinal fluid β‐amyloid levels than the PD‐right group. These differences were maintained at follow‐up, declining over time in both groups. By contrast, the PD‐right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD‐right group showed a steeper decline, particularly during the first 2‐year follow‐up. Putaminal asymmetry assessed at baseline was maintained over time.ConclusionsThese findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Apolipoprotein E4, amyloid, and cognition in Alzheimer's and Lewy body disease

The role of apolipoprotein E4 (APOE4) in the risk of Alzheimer's disease (AD) and Lewy body disease (LBD), and their relationship with β-amyloid deposition and cognitive dysfunction, remain unclear. Using amyloid and dopamine transporter imaging, we enrolled 126 controls and 208 patients with typical AD (pure AD and Lewy body variant of AD), AD with dementia with Lewy bodies, or typical LBD (dementia with Lewy bodies with amyloid deposition and pure LBD). APOE4 was associated with an increased risk of all disease subtypes except pure LBD. APOE4 was associated with increased frontal β-amyloid burden, and typical LBD was associated with increased occipital β-amyloid levels through its interaction with APOE4. APOE4 was associated with deteriorated general cognition and memory dysfunction via its interaction with typical LBD and AD, respectively. In conclusion, the impact of APOE4 on disease risk depends on its effects on β-amyloid deposition, and APOE4 is associated with β-amyloid deposition regardless of the clinical diagnosis. However, it interacts with typical LBD to cause occipital β-amyloid deposition.

High-Sensitivity and Trace-Amount Specimen Electrochemical Sensors for Exploring the Levels of β-Amyloid in Human Blood and Tears

As the occurrence of Alzheimer's disease (AD) has increased, the detection and treatment of AD have become global social issues. Effective early detection and wide-range screening of AD allow patients to gain early control and delay brain degeneration. For these reasons, we choose electrochemical sensors to complete the detection task. Although bio-electrochemical technology for antibody and antigen sensing is not a new technology, considering the scarcity of tear samples for dementia and since the existing AD detection techniques are highly invasive and expensive for subjects, we have to use the traditional detection techniques for the early screening of Alzheimer's disease via trace-amount specimens. An AD-related protein in the eye is thought to be an important biomarker for early detection. To carry out detection using tear samples as a test specimens, a tear collection device was developed in this study that extracted 10 μL of tear fluid from a tear Schirmer strip. In this research, we distinguished healthy people in different age groups and detect Aβ in both tear and blood samples. We developed a biosensor, which could detect Aβ in tear specimen from 1 to 100 pg/mL. Also, this biosensor is inexpensive, disposable, and easy to use. In our result, the concentration of Aβ in tears was approximately 10 times more than that in blood. This study demonstrates the feasibility and prospects of future screening for AD-associated biomarkers by a dynamic comparison between blood and tears.

Focus on the Complex Interconnection between Cancer, Narcolepsy and Other Neurodegenerative Diseases: A Possible Case of Orexin-Dependent Inverse Comorbidity.

Simple SummaryThis narrative review first describes from several points of view the complex interrelationship between cancer and neurodegeneration, with special attention to the mechanisms that might underlie an inverse relationship between them. In particular, the mechanisms that might induce an imbalance between cell apoptotic and proliferative stimuli are discussed. Second, the review summarizes findings on orexins and their involvement in narcolepsy, neurodegenerative diseases, and cancer, starting from epidemiological data then addressing laboratory findings, animal models, and human clinical observational and interventional investigations. Important research efforts are warranted on these topics, as they might lead to novel therapeutic approaches to both neurodegenerative diseases and cancer.Conditions such as Alzheimer’s (AD) and Parkinson’s diseases (PD) are less prevalent in cancer survivors and, overall, cancer is less prevalent in subjects with these neurodegenerative disorders. This seems to suggest that a propensity towards one type of disease may decrease the risk of the other. In addition to epidemiologic data, there is also evidence of a complex biological interconnection, with genes, proteins, and pathways often showing opposite dysregulation in cancer and neurodegenerative diseases. In this narrative review, we focus on the possible role played by orexin signaling, which is altered in patients with narcolepsy type 1 and in those with AD and PD, and which has been linked to β-amyloid brain levels and inflammation in mouse models and to cancer in cell lines. Taken together, these lines of evidence depict a possible case of inverse comorbidity between cancer and neurodegenerative disorders, with a role played by orexins. These considerations suggest a therapeutic potential of orexin modulation in diverse pathologies such as narcolepsy, neurodegenerative disorders, and cancer.

Differential Influence of Amyloid-β on the Kinetics of Dopamine Release in the Dorsal and Ventral Striatum of Rats.

Dopaminergic dysfunction is a part of Alzheimer's disease pathology. The brain accumulation of amyloid-β of toxic form is a key link of the pathology, which, according to the literature, is also true for dopaminergic dysfunction. An increase in the amyloid-β level in the brain changes the maximum of the evoked dopamine release in the dorsal and ventralparts of the striatum of the experimental animals. Theoretically, this may be due to the change in the intensity of dopamine release from the nerve terminals or its reuptake. However, it has not been studied. To fill this gap, we examined the amyloid-β induced changes in the kinetics of the evoked dopamine release in the dorsal striatum and the nucleus accumbens core and shell. Amyloid-β solution (fragments 25-35) was injected into the ventricular system of the anesthetized male Wistar rats. Before and after injection, electrically evoked dopamine kinetics was registered with fast-scan cyclic voltammetry. The results had shown that the amount of dopamine release decreases in the dorsal striatum and increases in the nucleus accumbens shell. No changes were found in the intensity of dopamine reuptake.

Intracerebroventricularly Injected Streptozotocin Exerts Subtle Effects on the Cognitive Performance of Long-Evans Rats.

Intracerebroventricularly injected streptozotocin (STZ)-induced learning impairment has been an increasingly used rat model of Alzheimer disease. The evoked pathological changes involve many symptoms of the human disease (cognitive decline, increase in β-amyloid and phospho-tau level, amyloid plaque-like deposits). However, the model has predominantly been used with Wistar rats in the literature. The objective of the current study was to transfer it to Long-Evans rats with the ulterior aim to integrate it in a complex cognitive test battery where we use this strain because of its superior cognitive capabilities. We performed two experiments (EXP1, EXP2) with three months old male animals. At EXP1, rats were treated with 2 × 1.5 mg/kg STZ (based on the literature) or citrate buffer vehicle injected bilaterally into the lateral ventricles on days 1 and 3. At EXP2 animals were treated with 3 × 1.5 mg/kg STZ or citrate buffer vehicle injected in the same way as in EXP1 at days 1, 3, and 5. Learning and memory capabilities of the rats were then tested in the following paradigms: five choice serial reaction time test (daily training, started from week 2 or 8 post surgery in Exp1 or Exp2, respectively, and lasting until the end of the experiment); novel object recognition (NOR) test (at week 8 or 14), passive avoidance (at week 11 or 6) and Morris water-maze (at week 14 or 6). 15 or 14 weeks after the STZ treatment animals were sacrificed and brain phospho-tau/tau protein ratio and β -amyloid level were determined by western blot technique. In EXP1 we could not find any significant difference between the treated and the control groups in any of the assays. In EXP2 we found significant impairment in the NOR test and elevated β-amyloid level in the STZ treated group in addition to slower learning of the five-choice paradigm and a trend for increased phospho-tau/tau ratio. Altogether our findings suggest that the Long-Evans strain may be less sensitive to the STZ treatment than the Wistar rats and higher doses may be needed to trigger pathological changes in these animals. The results also highlight the importance of strain diversity in modelling human diseases.

Gambir catechins modulates amyloid-β concentration in cerebrospinal fluid of Alzheimer’s model rat

Neurodegeneration in Alzheimer’s disease has been reported as the consequences of amyloid-β accumulation in the brain resulted from oxidative stress. Gambir, which contains catechins as a potential antioxidant, is abundant in West Sumatra. This study aims to evaluate the effect of gambir catechins administration on amyloid-β concentration in cerebrospinal fluid [CSF] of the rats. An experimental study with a post-test only design was carried out on 12-week old female Sprague Dawley, an Alzheimer’s model rat. As many as 30 rats were divided into the control and treatment groups. Four of the six groups were treated with the catechins extract doses of 20 mg, 40 mg, 60 mg, and 100 mg per 200 g BW. Meanwhile, the other two groups were positive and negative control groups. After four weeks, the rats were sacrificed and the CSF was collected. Amyloid-β concentration measurement was using the ELISA method. The statistical analysis was using One-way ANOVA with posthoc test Tukey HSD. Treatment groups exhibited a linear decrease in amyloid-β concentration in all doses, particularly in CC3. The CC3-treated group showed the lowest amyloid-β concentration [13.325 ± 4.625 ng/ml], which is significantly lower [p < 0.05] when compared to the PC group [45.280 ± 7.590 ng/ml]. This result provides experimental evidence that gambir catechin reached its optimum neuroprotective effect on amyloid-β level in cerebrospinal fluid by 60 mg/200 g BW.