Current Alzheimer Research - Volume 19, Issue 9, 2022

Alzheimer’s disease (AD) is an age-related neurodegenerative disease seriously influencing the quality of life and is a global health problem. Many factors affect the onset and development of AD, but specific mechanisms underlying the disease are unclear. Most studies investigating AD have focused on neurons and the gray matter in the central nervous system (CNS) but have not led to effective treatments. Recently, an increasing number of studies have focused on white matter (WM). Magnetic resonance imaging and pathology studies have shown different degrees of WM abnormality during the progression of AD. Myelin sheaths, the main component of WM in the CNS, wrap and insulate axons to ensure conduction of the rapid action potential and axonal integrity. WM damage is characterized by progressive degeneration of axons, oligodendrocytes (OLs), and myelin in one or more areas of the CNS. The contributions of OLs to AD progression have, until recently, been largely overlooked. OLs are integral to myelin production, and the proliferation and differentiation of OLs, an early characteristic of AD, provide a promising target for preclinical diagnosis and treatment. However, despite some progress, the key mechanisms underlying the contributions of OLs to AD remain unclear. Given the heavy burden of medical treatment, a better understanding of the pathophysiological mechanisms underlying AD is vital. This review comprehensively summarizes the results on WM abnormalities in AD and explores the relationship between OL progenitor cells and the pathogenesis of AD. Finally, the underlying molecular mechanisms and potential future research directions are discussed.

The COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), a respiratory pathogen with neuroinvasive potential. Neurological COVID-19 manifestations include loss of smell and taste, headache, dizziness, stroke, and potentially fatal encephalitis. Several studies found elevated proinflammatory cytokines, such as TNF-α, IFN-γ, IL-6 IL-8, IL- 10 IL-16, IL-17A, and IL-18 in severely and critically ill COVID-19 patients may persist even after apparent recovery from infection. Biomarker studies on CSF and plasma and serum from COVID-19 patients have also shown a high level of IL-6, intrathecal IgG, neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and tau protein. Emerging evidence on the matter has established the concept of COVID-19-associated neuroinflammation, in the context of COVID-19-associated cytokine storm. While the short-term implications of this condition are extensively documented, its longterm implications are yet to be understood. The association of the aforementioned cytokines with the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, may increase COVID-19 patients' risk of developing neurodegenerative diseases. Analysis of proinflammatory cytokines and CSF biomarkers in patients with COVID-19 can contribute to the early detection of the disease's exacerbation, monitoring the neurological implications of the disease and devising risk scales, and identifying treatment targets.

Background: Recent findings suggest that both dietary protein intake and hand grip strength (HGS) were associated with cognitive function, however, few studies have been devoted specifically to the mediation effect of HGS on the association of the dietary protein with cognitive function. Objective: To confirm the hypothesis that HGS mediated the association of dietary protein intake with cognitive function in the elderly, which was modified by triglyceride level and methylenetetrahydrofolate reductase (MTHFR) gene status. Methods: This cross-sectional study included 3,268 participants. Dietary protein intake, HGS, and cognitive function were collected by food frequency questionnaires (FFQ), grip measurements and mini mental state examination (MMSE), respectively. In this mediation analysis, dietary protein intake was entered as an independent variable, HGS was entered as a mediator, and cognitive function was entered as a dependent variable. Results: HGS significantly mediated the associations of dietary protein (β = 0.0013, 95% CI: 0.0007, 0.0022), animal protein (β = 0.0024, 95% CI: 0.0012, 0.0037), and plant protein intake (β = 0.0011, 95% CI: 0.0001, 0.0023) with cognitive function in total participants, with the mediated proportion of 16.19%, 12.45% and 20.57%, respectively. Furthermore, significant mediation effects of HGS on the associations of dietary protein, animal protein, and plant protein intake with MMSE score were found in the elderly without hypertriglyceridemia or in MTHFR C677T CC/CT carriers. Conclusion: This study suggested that HGS mediated the association of dietary protein intake with cognitive function, and this mediation effect was modified by triglyceride level and MTHFR C677T gene status.

Aims: Exploring the neurobiological mechanisms of early AD damage. Background: The early diagnosis of Alzheimer's disease (AD) has a very important impact on the prognosis of AD. However, the early symptoms of AD are not obvious and difficult to diagnose. Existing studies have rarely explored the mechanism of early AD. AMPARs are early important learning memory-related receptors. However, it is not clear how the expression levels of AMPARs change in early AD. Objective: We explored learning memory abilities and AMPAR expression changes in APP/PS1 mice at 4 months, 8 months, and 12 months. Methods: We used the classic Morris water maze to explore the learning and memory impairment of APP/PS1 mice and used western blotting to explore the changes in AMPARs in APP/PS1 mice. Results: We found that memory impairment occurred in APP/PS1 mice as early as 4 months of age, and the impairment of learning and memory gradually became serious with age. The changes in GluA1 and p-GluA1 were most pronounced in the early stages of AD in APP/PS1 mice. Conclusion: Our study found that memory impairment in APP/PS1 mice could be detected as early as 4 months of age, and this early injury may be related to GluA1.

Background: Trace elements were suggested to have a main role in modulating cognitive function. However, there are several controversial findings regarding the association between serum trace element concentration and cognitive function in patients with cognitive disorders. Methods: Thus, this study aimed to evaluate the changes in serum trace element concentrations in elderly with cognitive dysfunction versus the participants with normal cognitive function. This crosssectional study included 191 older adults over 60 years from Birjand County, Iran. Participants were assessed for cognitive performance and serum trace elements concentration, including aluminum (AL), cobalt (Co), cadmium (Cd), Chrome (Cr), copper (Cu), Iron (Fe), magnesium (Mg), manganese (Mn), selenium (Se) and zinc (Zn). Our findings showed no significant difference in the serum concentration of AL, Co, Cr, Zn, Fe, Mg, Mn, and Se of elderly with cognitive dysfunction versus the subjects with normal cognitive function. Results: However, the concentration of Cu significantly increased in the serum of the elderly with cognitive dysfunction versus participants with normal function. In conclusion, our study indicated an increase in the serum concentration of Cu in the elderly with cognitive dysfunction in the sample of the Birjand Longitudinal Aging Study. Conclusion: However, due to the main limitations of our study, including low sample size and crosssection design, these findings should be interpreted with caution.

Background: Currently available medication for Alzheimer’s disease (AD) slows cognitive decline only temporarily but has failed to bring about long term positive effects. For this slowly progressive neurodegenerative disease, so far, no disease modifying therapy exists. Objective: The study aims to find out if non-pharmacologic non-invasive neuromodulatory repetitive transcranial magnetic stimulation (rTMS) may offer a new alternative or an add on therapeutic strategy against loss of cognitive functions. Methods: In this exploratory intervention study, safety and symptom development before and after frontopolar cortex stimulation (FPC) using intermittent theta burst stimulation (iTBS) at 10 subsequent working days was monitored as add-on treatment in 28 consecutive patients with AD. Out of these, 10 randomly selected patients received sham stimulation as a control. Serum concentrations of neurotransmitter precursor amino acids, immune activation and inflammation markers, brain-derived neurotrophic factor (BDNF), and nitrite were measured. Results: Treatment was well tolerated, and no serious adverse effects were observed. Improvement of cognition was detected by an increase in Mini Mental State Examination score (MMSE; p<0.01, paired rank test) and also by an increase in a modified repeat address phrase test, part of the 6-item cognitive impairment test (p<0.01). A trend to increase the clock drawing test (CDT; p = 0.08) was also found in the verum treated group. Furtheron, in 10 of the AD patients with additional symptoms of depression treated with iTBS, a significant decrease in the HAMD-7 scale (p<0.01) and a trend to lower serum phenylalanine concentrations (p = 0.08) was seen. No changes in the parameters tested were found in the sham treated patients. Conclusion: Our preliminary results may indicate that iTBS is effective in the treatment of AD. Also a slight influence of iTBS on the metabolism of phenylalanine was found after 10 iTBS sessions. An impact of iTBS to influence the enzyme phenylalanine hydroxylase (PAH), as found in the previous series of treatment resistant depression, could not be seen in our first observational trial in 10 AD patients with comorbidity of depression. Longer treatment periods for several weeks in a higher number of AD patients with depression could cause more intense and disease modifying effects visible in different neurotransmitter concentrations important in the pathogenesis of AD.