Current Alzheimer research最新文献

Background: In most patients with frontotemporal lobe degeneration (FTLD), the degenerative process begins between the ages 45 and 65 years; onset younger than 45 years is relatively rare and considered very early onset FTLD (VEO-FTLD).

Objective: To delineate the clinical, genetic, and pathological features of VEO-FTLD.

Methods: A systematic literature review was carried out in PubMed and Embase from inception to September 2021. Patients diagnosed with definite FTLD with onset before age 45 years were included. Patients lacking detailed clinical data or both genetic and neuropathological data were excluded. Phenotypic, genotypic, and pathological data were extracted for further analyses.

Results: Data from 110 patients with VEO-FTLD, reported in a cumulative 70 publications, were included. Age of onset was 35.09 ± 7.04 (14-44) years. Sixty-seven patients were reported age at death of 42.12 ± 7.26 (24-58) years, with a disease course lasting 8.13 ± 4.69 (1-20) years. Behavioural variant frontotemporal dementia (104/110, 94.5%) was the most common clinical subtype, often manifesting as disinhibition (81.8%) and apathy (80.9%), and frequently accompanied by a cognitive deficit (90.9%) and parkinsonism (37.3%). Frequency of familial aggregation was high (familial vs. sporadic, 73/37, 66.4%); most patients carried MAPT gene mutations (72.9% in familial, 40% in sporadic), followed by C9 (18.8% in familial, 10% in sporadic), TARDBP (2.1% in familial), and VCP (2.1% in familial). The most common neuropathology subtype was tau (43.5%), followed by ubiquitin- positive (24.6%), FUS (20.3%), and TDP 43 (2.9%).

Conclusion: VEO-FTLD may have unique clinical, genetic, and neuropathological markers and should be considered in young patients with psycho-behavioral symptoms.

Background: Caring for an individual with Alzheimer's disease (AD) is an allencompassing challenge that affects daily life. Assessment of the care partner experience is needed to support the development and evaluation of successful interventions for people with AD and their care partners. We developed the 27-item Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD-27) to assess the impact of informal caregiving in the context of AD.

Objective: We assessed the psychometric validity of the ZCI-AD-27 in a population of care partners for individuals with moderate AD, and established thresholds for meaningful score change.

Methods: Secondary data were obtained from informal care partners of participants in a clinical trial (NCT01677754). Psychometric analyses were conducted to assess validity, reliability, and responsiveness of the ZCI-AD-27. Anchor-based and distribution-based methods were performed to determine clinically meaningful score change.

Results: The ZCI-AD-27 had a 12-domain factor structure, including a second-order domain termed Humanistic impact that included four key domains (Physical, Emotional, Social, and Daily life) as confirmed by confirmatory factor analysis with the adequate fit. Internal consistency (Cronbach's alpha ranging from 0.66 to 0.93 for domains), convergent validity, and discriminant validity indicated the good performance of the ZCI-AD-27. Known-groups validity analyses showed a greater impact on care partners with increasing disease severity. Responsiveness results demonstrated that the ZCI-AD- 27 is sensitive to change over time and meaningful change analyses indicated a range of meaningful score changes in this population.

Conclusion: The ZCI-AD-27 is a comprehensive, psychometrically valid measure to assess the impact of caring for individuals with moderate AD.

Background: MicroRNA (miR)-125a-3p is reported to play an important role in some central nervous system diseases, such as Alzheimer's disease (AD). However, a study has not been conducted on the mechanism of miR-125a-3p in the pathological process of AD.

Methods: First, we assessed the expression of miR-125a-3p in AD cohort. Subsequently, we altered the expressions of miR-125a-3p to assess its role in cell viability, cell apoptosis, amyloid-β (Aβ) metabolism, and synaptic activity. Finally, we identified its potential mechanism underlying AD pathology.

Results: This study unveiled the potential function of miR-125a-3p through modulating amyloid precursor protein processing. Additionally, miR-125a-3p influenced cell survival and activated synaptic expression through the modulation of Aβ metabolism in the mitogen-activated protein kinase (MAPK) pathway via fibroblast growth factor receptor 2.

Conclusion: Our study indicates that targeting miR-125a-3p may be an applicable therapy for AD in the future. However, more in vitro and in vivo studies with more samples are needed to confirm these results.

Background: Transglutaminase 2 is an ubiquitously multifunctional enzyme and the most widely studied of the transglutaminase family. Consistent with its role in promoting post-translational modifications of proteins, Transglutaminase 2 is involved in many physiological processes such as apoptosis, signal transduction, and cellular adhesion. Several findings indicate that Transglutaminase 2 plays a role in the pathological processes of various inflammation-related diseases, including neurodegenerative diseases.

Objective: We tested the potential modulatory effects on amyloid-β-induced Transglutaminase 2 expression and activities of 2-pentadecyl-2-oxazoline, a plant-derived agent, which has shown effectiveness against chronic pain and associated neuropsychiatric disorders, both in mouse and human microglial cell lines.

Methods: We used biochemistry, molecular and cell biology techniques to evaluate the potential modulatory effects on amyloid-β-induced Transglutaminase 2 expression and activities of 2- pentadecyl-2-oxazoline in mouse and human microglial cell lines.

Results: 2-pentadecyl-2-oxazoline was able to modulate amyloid-β-induced Transglutaminase 2 expression and activities in mouse and human microglial cell lines.

Conclusion: Transglutaminase 2 confirms its role as a neuroinflammation marker, the inhibition of which could be a potential preventive and therapeutic approach, while 2-pentadecyl-2-oxazoline is a potent modulator of the amyloid-β-induced Transglutaminase 2 expression and activities in mouse and human microglial cell lines.

Although microbiology and neurology are separate disciplines, they are linked to some infectious and neurological diseases. Today, microbiome is considered as one of the biomarkers of health by many researchers. This has led to the association of microbiome changes with many neurological diseases. The natural microbiota has many beneficial properties. If disrupted and altered, it can lead to irreversible complications and many neurological diseases. Therefore, according to previous studies, some preventive and therapeutic complementary therapies can prevent or restore microbiome dysbiosis and inflammation in the nervous system. With our current perception of the microbiological basis for different neurological disorders, both aspects of drug treatment and control of perturbations of the microbiome should be considered, and targeting them simultaneously will likely help to attain favorable results.

Objective: The objective of this study is to investigate the neuroprotective effects of β- sitosterol using the AlCl3 model of Alzheimer's Disease.

Methods: AlCl₃ model was used to study cognition decline and behavioral impairments in C57BL/6 mice. Animals were randomly assigned into 4 groups with the following treatments: Group 1 received normal saline for 21 days, Group 2 received AlCl₃ (10 mg/kg) for 14 days; Group 3 received AlCl3(10 mg/kg) for 14 days + β-sitosterol (25mg/kg) for 21 days; while Group 4 was administered β-sitosterol (25mg/kg) for 21 days. On day 22, we performed the behavioral studies using a Y maze, passive avoidance test, and novel object recognition test for all groups. Then the mice were sacrificed. The corticohippocampal region of the brain was isolated for acetylcholinesterase (AChE), acetylcholine (ACh), and GSH estimation. We conducted histopathological studies using Congo red staining to measure β -amyloid deposition in the cortex and hippocampal region for all animal groups.

Results: AlCl₃ successfully induced cognitive decline in mice following a 14-day induction period, as shown by significantly decreased (p < 0.001) in step-through latency, % alterations, and preference index values. These animals also exhibited a substantial decrease in ACh (p <0.001) and GSH (p < 0.001) and a rise in AChE (p < 0.001) compared to the control group. Mice administered with AlCl₃ and β-sitosterol showed significantly higher step-through latency time, % alteration time, and % preference index (p < 0.001) and higher levels of ACh, GSH, and lower levels of AChE in comparison to the AlCl₃ model. AlCl3-administered animals also showed higher β-amyloid deposition, which got significantly reduced in the β-sitosterol treated group.

Conclusion: AlCl3 was effectively employed to induce a cognitive deficit in mice, resulting in neurochemical changes and cognitive decline. β -sitosterol treatment mitigated AlCl₃-mediated cognitive impairment.

Memory is empirically described as a brain function that connects the past to the present. This reductionist approach has focused on memory function within neurons and synapses, leading to an understanding that memory loss in dementia is caused by irreversible neuronal damage. However, recent palliative case reports and the Human Connectome Project have challenged the "irreversible" paradigm by indicating that some demented patients are able to retrieve supposed 'lost' memories and cognitive functions near death. The serotonin-centric hypothesis and the lifelong oligodendrocyte differentiation capacity may explain terminal awakening symptoms in these patients. Furthermore, an increased rate of serotonin-secreting and oligodendrocyte precursor cell-triggering gut bacteria near death temporally correlates with lucid improvements in demented patients. These findings may shift the context of terminal memory retrieval from a purely neuronal to a systemic idea that bridges terminal lucidity and gut microbiota. In this review, we take the systemic approach further and point out a temporal correlation between the gut microbiome and terminal lucid episodes in Alzheimer's patients.

Background: Microglial overactivation promotes the production of various second messengers and inflammatory markers in brain tissue, resulting in neuroinflammation and neurodegeneration, which may lead to cognitive decline. The cyclic nucleotides are one of the important second messengers involved in the regulation of neurogenesis, synaptic plasticity, and cognition. The levels of these cyclic nucleotides are maintained by phosphodiesterase enzyme isoforms, particularly PDE4B, in the brain. An imbalance between PDE4B levels and cyclic nucleotides may lead to aggravating neuroinflammation.

Methods: Lipopolysaccharides (LPS) were administered intraperitoneally on alternate days for 7 days at a dose of 500 μg/kg in mice, which triggered systemic inflammation. This may lead to the activation of glial cells and may activate oxidative stress and neuroinflammatory markers in brain tissue. Furthermore, oral administration of roflumilast (0.1, 0.2, and 0.4 mg/kg) in this model ameliorated oxidative stress markers, neuroinflammation and improved neurobehavioral parameters in these animals.

Results: The detrimental effect of LPS increased oxidative stress, AChE enzyme levels, and decreased catalase levels in brain tissues, along with memory impairment in animals. Moreover, it also enhanced the activity and expression of the PDE4B enzyme, resulting in a decline in cyclic nucleotide levels. Furthermore, treatment with roflumilast improved the cognitive decline, decreased AChE enzyme level, and increased the catalase enzyme level. Roflumilast also reduced the PDE4B expression in a dose-dependent manner, which LPS up-regulated.

Conclusion: Roflumilast has shown an anti-neuroinflammatory effect and reversed the cognitive decline in LPS-induced mice model.

Objective: To explore changes in the alpha rhythm wavelength of background electroencephalography in Alzheimer's disease patients with different degrees of dementia in a resting state; examine their correlation with the degree of cognitive impairment; determine whether the alpha rhythm wavelength can distinguish mild Alzheimer's disease patients, moderately severe Alzheimer's disease patients, and healthy controls at the individual level; and identify a cut-off value to differentiate Alzheimer's disease patients from healthy controls.

Methods: Quantitative electroencephalography signals of 42 patients with mild Alzheimer's disease, 42 patients with moderately severe Alzheimer's disease, and 40 healthy controls during rest state with eyes closed were analyzed using wavelet transform. Electroencephalography signals were decomposed into different scales, and their segments were superimposed according to the same length (wavelength and amplitude) and phase alignment. Phase averaging was performed to obtain average phase waveforms of the desired scales of each lead. The alpha-band wavelengths corresponding to the ninth scale of the background rhythm of different leads were compared between groups.

Results: The average wavelength of the alpha rhythm phase of the whole-brain electroencephalography signals in Alzheimer's disease patients was prolonged and positively correlated with the severity of cognitive dysfunction (P < 0.01). The ninth-scale phase average wavelength of each lead had high diagnostic efficacy for Alzheimer's disease, and the diagnostic efficacy of lead P3 (area under the receiver operating characteristic curve = 0.873) was the highest.

Conclusion: The average wavelength of the electroencephalography alpha rhythm phase may be used as a quantitative feature for the diagnosis of Alzheimer's disease, and the slowing of the alpha rhythm may be an important neuro-electrophysiological index for disease evaluation.