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On July 6, 2023, the U.S. Food and Drug Administration (FDA) approved lecanemab (Leqembi) for the treatment of Alzheimer's dementia (AD) patients. In 2 clinical trials, lecanemab reduced amyloid in the brain and slowed cognitive decline. Here, I review in detail the clinical trial by van Dyck et al. (2023) entitled "Lecanemab in early Alzheimer's disease", published in The New England Journal of Medicine on January 5, 2023. In this 18-month trial, lecanemab did not slow cognitive decline in women. This is especially significant because women have a twofold increased risk of AD compared to men, that is, there are 2 times more women than men living with AD. Lecanemab did not slow cognitive decline in APOE4 carriers; rather, it enhanced the decline in study participants with 2 APOE4 genes. This is bad news for AD patients, 60-75% of whom carry at least 1 APOE4 gene. These negative results regarding lecanemab's therapeutic value make me wonder if the approval of lecanemab was the worst decision of the FDA up till now, after the approval of aducanumab on June 7, 2021. [ABSTRACT FROM AUTHOR]

Background. The pathophysiology of Alzheimer's disease (AD) is not fully understood and that new biomarkers for the condition should be presented. Objectives. Our study aimed to determine the blood levels of some biochemical molecules and peptide proteins in AD, which is accepted as the most common cause of dementia in the world, and to elucidate the relationship between them. Materials and methods. The study consisted of 2 groups: 40 newly diagnosed AD patients and 40 healthy individuals. Plasma levels between the 2 groups and the correlation between them were statistically analyzed. Results. The median brain-derived neurotrophic factor (BDNF) level in the AD group was found to be higher and statistically significant compared to the control group (p = 0.033). Conclusions. According to our literature review, this is the first article in which these molecules have been studied together in AD patients. In this study, we revealed the importance of these parameters and especially the instrumental role of BDNF in the form and function of the brain in AD patients. Interestingly, in the patient group, all parameters in our study showed a positive and significant positive relationship with one another (p < 0.001). [ABSTRACT FROM AUTHOR]

Background. At least 55 million individuals suffer from dementia globally, of which Alzheimer’s disease (AD) accounts for 60-70% of cases. Alzheimer’s disease is the only major cause of death that is still growing. However, the molecular mechanisms are largely unknown in the progress of AD. Objectives. The goal of the study was to assess whether lncRNA brain-derived neurotrophic factor antisense (BDNF-AS) could affect processes underlying the regulation of neuronal cell apoptosis in rat and cellular models of AD by directing the expression of miR-125b-5p. Materials and methods. The amyloid-β (Aβ)1-42-induced rat and cellular models of AD were established. Changes in learning and memory in rats were detected with the use of the Morris water maze. Cell viability and apoptosis were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) test and flow cytometry. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to detect the expression of lncRNA BDNF-AS and miR-125b-5p, and western blotting was utilized to examine proteins. The correlations between lncRNA BDNF-AS and miR-125b-5p were demonstrated using dual-luciferase reporter gene assays. Results. Our results showed that BDNF-AS was upregulated and miR-125b-5p was downregulated in the rat and cellular AD models. The addition of si-BDNF-AS and miR-125b-5p mimics shortened the escape latency and swimming distance in the rat model. Furthermore, the knockdown of BDNF-AS or the administration of miR-125b-5p mimic significantly suppressed cell apoptosis, cell inflammatory, and inflammatory pathway-related proteins, while these cellular activities were promoted in rat and cellular models of AD. Additionally, miR-125b-5p was found to be a BDNF-AS target gene that was linked negatively with BDNF-AS in AD. Conclusions. Through regulation of miR-125b-5p, lncRNA BDNF-AS suppressed cell death, inflammation and inflammatory pathway-related proteins in AD models, which provides a potential biomarker and therapeutic target in the clinical treatment of AD. [ABSTRACT FROM AUTHOR]

Background. Alzheimer's disease (AD) is the most common type of dementia. At present, some drug and non-drug therapies can be used to slow disease progression or prevent cognitive deterioration. More treatment options still need to be explored. Objectives. A meta-analysis was performed to compile the relevant evidence for the use of glucagon-like peptide-1 (GLP-1) receptor agonists in preventing AD. Materials and methods. We systematically searched English and Chinese databases, including Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, and Weipu website (VIP), based on the PICOS (Participants, Interventions, Comparisons, Outcomes, Study design) principles. The reviewers evaluated the search results and conducted the analysis; 5 articles with a total sample size of 184 patients were included. Changes in cognitive function, body mass index (BMI), blood glucose level, and insulin content were analyzed. Results. A low risk of bias and no publication bias were found in these studies. The following results were obtained: 1) cognitive function: mean difference (MD) = 2.16, 95% confidence interval (95% CI): 1.45-2.88; 2) BMI change: MD = -1.16, 95% CI: -1.71--0.61; and 3) blood glucose change: standard MD (SMD) = -0.64, 95% CI: -1.21--0.88. No statistically significant difference was found in insulin content. Conclusions. In this review, we showed that GLP-1 receptor agonists can effectively change cognitive function, BMI and blood glucose levels in patients with AD. This provides relevant clues for the prevention of AD. However, more studies are needed to refine these conclusions. [ABSTRACT FROM AUTHOR]

Background. Psychosis is a very common feature of Alzheimer's disease (AD) that can emerge as the neuro-degenerative disease progresses. The 5-hydroxytryptamine (5-HT2A) receptors are located postsynaptically to serotonergic neurons in the frontal cortex and mediate both excitatory and inhibitory neurotransmissions. However, the effectiveness and tolerance of negative modulators of 5-HT2A receptors in Alzheimer's disease psychosis (ADP) are uncertain. Objectives. To detect the negative modulators of the 5-HT2A receptor as a cure for ADP. Materials and methods. The primary outcome indicator was the total Neuropsychiatric Inventory (NPI) score. Other prognostic indicators included Mini-Mental State Examination (MMSE), the Katz Index of Independence in Activities of Daily Living (KATZ), the discontinuation rate, and adverse events. Results. Compared to placebo, 5-HT2A inverse agonists significantly reduced the NPI total score, the KATZ and the MMSE score. The pooled odds ratio (OR) was 1.64 (95% confidence interval (95% CI): 1.01-2.65) and the heterogeneity variance was estimated at Tau² = 0.52 with an I² value of 90%, a χ² value of 111.31, p = 0.04, and z-value of 2.01. The risk difference (RD) between the 5-HT2A receptor negative modulators and placebo groups was 0.12 (95% CI: 0.00-0.24) and the heterogeneity was estimated at Tau² = 0.03, χ² value of 127.23, degrees of freedom (df) value of 9, I2 value of 93%, z-value of 1.92, and p-value of 0.01 (<0.05). Conclusions. Our results suggest that negative modulators of 5-HT2A receptors are beneficial and welltolerated in the treatment of ADP. [ABSTRACT FROM AUTHOR]

Background. New glucagon-like peptide-1 (GLP-1) analogues developed in recent years have a long halflife and offer further prospects for clinical application. At present, the neuroprotection of GLP-1 analogues in Alzheimer's disease (AD) has just begun to be explored. Objectives. To investigate how glucagon-like peptide-1 (liraglutide) plays a protective role in AD by regulating tau activation and BACE1 expression. Material and methods. Human neuroblastoma cell line SH-SY5Y cells were cultured in vitro and pretreated with different concentrations of liraglutide, and then treated with different concentrations of okadaic acid (OA) in order to observe the apoptosis of the SH-SY5Y cells. After liraglutide treatment, the apoptosis of neurons in AD rats was detected using flow cytometry, and tau activation and ß-site APP cleaving enzyme 1 (BACE1) expression were detected using western blot. Results. Different concentrations of OA were able to induce apoptosis of SH-SY5Y cells in a dose-dependent manner. Different concentrations of liraglutide were used to pretreat SH-SY5Y cells, which were able to protect the SH-SY5Y cells from apoptosis induced by OA. Okadaic acid significantly increased tau activation and BACE1 expression in the SH-SY5Y cells, which was blocked with liraglutide pretreatment. The results of a water maze experiment showed that liraglutide had significant protective effects on memory and cognitive ability in AD rats induced with OA, inhibited apoptosis of neural cells in AD rats, and inhibited tau activation and BACE1 expression of neural cells in AD rats induced with OA. Conclusions. Liraglutide has a protective effect on AD in vivo and in vitro, which may be mediated by preventing neuronal apoptosis and inhibiting the activation of tau and the expression of BACE1. [ABSTRACT FROM AUTHOR]

Background. Parkinson's disease (PD) is a progressive neurodegenerative disorder with a characteristic clinical picture. Apart from classical movement disorders, a significant role is also played by non-motor symptoms, in particular cognitive impairments, which have a significant impact on the quality of life of the patients. Tau protein and amyloid beta are well-known non-specific biomarkers in Alzheimer's disease (AD). Objectives. The study assessed the practical value of determining tau protein and amyloid beta (Aβ42) in the blood serum of patients with PD and their relationship with cognitive impairments, radiographic image and the used dose of L-DOPA. Material and methods. The neuropsychological assessment was carried for 64 patients with PD. The levels of amyloid beta 1-42 (Aβ42) and tau proteins in serum were also measured. Results. The Aβ42 level in the serum was statistically higher in patients with longer duration of the disease (p < 0.05) and those who were taking a higher dose of L-DOPA (p < 0.05). The average level of tau protein in the serum was slightly lower in the study groups than in the control group and showed no statistical significance. No correlation was found between the levels of tau protein and Aβ42 and the results of neuropsychological tests. Tau protein correlated with hippocampal atrophy (p < 0.05). Conclusions. Serum levels of Aβ42 and tau protein in PD may be a useful marker for the assessment of cognitive impairments. The role of L-DOPA in the process of dementia in PD remains unclear. [ABSTRACT FROM AUTHOR]

Background. Paraoxonase 1 (PON1) is an enzyme with the capability to protect against lipid oxidation and atherosclerotic lesions formation. Impaired antioxidative capacity and enhanced lipid peroxidation (reflected by malondialdehyde rise) accompany dementias. Objectives. The aim of this study was to discern the possible differences in the activity and phenotype distribution of PON1, and lipid peroxidation level in dementias of neurodegenerative and vascular pathology, to assess whether they reflect structural changes in the brain, and to evaluate their potential as dementia markers. Material and methods. Paraoxonase 1 arylesterase activity and polymorphisms (dual-substrate method), and malondialdehyde/thiobarbituric acid reactive substances (MDA/TBARS) levels were determined spectrophotometrically in 257 serum samples derived from 136 dementive patients (with Alzheimer's disease (AD; n = 63), vascular dementia (VaD; n = 40) and mixed-type dementia (MD; n = 33), as well as from 121 non-dementive individuals. The results were analyzed with reference to dementia type and severity (assessed with Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales), structural brain changes (estimated with magnetic resonance imaging (MRI) -- Global Cortical Atrophy (GCA), Medial Temporal lobe Atrophy (MTA) and Fazekas scales)) and brain ischemia (Hachinski Ischemic Scale (HIS) index), and evaluated using receiver operating characteristic (ROC) analysis. Results. Malondialdehyde/thiobarbituric acid reactive substances were increased in dementia (more in VaD than AD). In patients with vascular involvement, MDA/TBARS elevation reflected a degree of global cortical atrophy. Paraoxonase 1 activity was decreased in patients with dementia, especially in patients with severe cognitive deficits. In VaD, a drop in PON1 reflected a degree of MTA and brain ischemia. MDA/TBARS displayed 75% accuracy as a general dementia marker, but, similarly to PON1, were a poor differential marker. Conclusions. Both indices were more associated with vascular involvement and the severity of brain atrophy or ischemia rather than with degree of cognitive decline. [ABSTRACT FROM AUTHOR]

Background. The extracellular actin scavenging system (EASS) is composed of plasma Gc-globulin and gelsolin, and is responsible for the elimination of toxic actin from the bloodstream. Objectives. In this study, we assessed the actin-free Gc-globulin concentrations in blood plasma and cerebrospinal fluid (CSF) obtained from subjects with neurodegenerative and inflammatory diseases of the central nervous system (CNS) as well as in a control group. Material and methods. Using an enzyme-linked immunosorbent assay (ELISA), we measured the actinfree Gc-globulin concentrations in blood plasma and CSF obtained from subjects diagnosed with Alzheimer's disease (AD) (n = 20), amyotrophic lateral sclerosis (ALS) (n = 12), multiple sclerosis (MS) (n = 42), tick-borne encephalitis (TBE) (n = 12), and from a control group (n = 20). Results. The concentrations of free Gc-globulin in plasma collected from patients diagnosed with AD (509.6 ±87.6 mg/L) and ALS (455.5 ±99.8 mg/L) did not differ significantly between each other, but were significantly higher compared to the reference group (311.7 ±87.5 mg/L) (p < 0.001 and p < 0.006, respectively) as well as to MS (310.8 ±66.6 mg/L) (p < 0.001 and p < 0.001, respectively) and TBE (256.7 ±76 mg/L) (p < 0.001 and p < 0.003, respectively). In CSF collected from patients diagnosed with AD and ALS, the concentrations of free Gc-globulin were 2.6 ±1.1 mg/L and 2.7 ±1.9 mg/L, respectively. They did not differ significantly between each other and were significantly higher compared to the reference group (1.5 ±0.9 mg/L) (p < 0.005 and p < 0.041, respectively). Interestingly, in patients with AD, significantly higher values of Gc-globulin were detected compared to MS patients (1.7 ±0.9 mg/L) (p < 0.013). Conclusions. Higher concentrations of free Gc-globulin in blood plasma and CSF collected from patients suffering from neurodegenerative diseases may indicate a potential role of this protein in their pathogenesis, and represent a potential tool for the diagnosis of CNS diseases. [ABSTRACT FROM AUTHOR]

The aim of this review is to present data from the available literature concerning CXCL9, CXCL10 and CXCL11, as well as their receptor 3 (CXCR3) in selected diseases of the central nervous system (CNS), such as tickborne encephalitis (TBE), neuroborreliosis (NB), Alzheimer's disease (AD), and multiple sclerosis (MS). CXCL9, CXCL10, and CXCL11 lack glutamic acid-leucine-arginine (ELR), and are unique, because they are more closely related to each other than to any other chemokine. The aforementioned chemokines are especially involved in Th1-type response and in various diseases, as their expression correlates with the tissue infiltration of T cells. Their production is strongly induced by interferon gamma (IFN-Υ), the most typical Th1 cytokine. They act by binding to the CXC3 receptor. Knowledge about the action mechanism of CXCR3 and its ligands may be useful in the treatment of CNS diseases. However, data in the literature concerning the evaluation of CXCL9, CXCL10, CXCL11, and their receptor with the use of the enzyme-linked immunosorbent assay (ELISA) method is limited. [ABSTRACT FROM AUTHOR]

Background. Cognitive assessment is central to the diagnosis of cognitive impairment and dementia, and it should be performed in all patients in the early stages of the disease. Recently, the 3rd version of Addenbrooke's Cognitive Examination (ACE-III) has been developed in order to improve the previous versions. Objectives. The aim of this study was to determine the psychometric properties of the Portuguese version of ACE-III, namely: reliability and discriminative validity (sensitivity and specificity) in the identification of mild cognitive impairment (MCI) and dementia, in comparison to other neuropsychological screening tests, as well as to establish its concurrent and divergent validity. Material and methods. The study encompassed a sample of 90 participants distributed into 3 groups: Control (n = 30), MCI (n = 30) and Dementia (n = 30). In addition to ACE-III, Clinical Dementia Rating (CDR) and Montreal Cognitive Assessment (MoCA) were also used. Results. The reliability of ACE-III was very good (α = 0.914). ACE-III significantly differentiated the 3 groups. The receiver operating characteristic (ROC) curves significantly favored ACE-III in comparison to another screening test - MoCA. ACE-III presented higher levels of sensitivity and specificity. Its total score correlated positively with the results on MoCA (ρ = 0.912; p < 0.001) and negatively with a depression scale (ρ = -0.505; p < 0.001). Conclusions. The Portuguese version of ACE-III has very good reliability and high diagnostic capacity in the context of MCI and dementia. ACE-III also holds concurrent and divergent validity. [ABSTRACT FROM AUTHOR]

Background. Although Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and characterized by memory impairment, only symptomatic treatments are available. Objectives. Because recombinant human erythropoietin (rhEPO) has various neuroprotective effects and improves cognitive function in animal models of neurodegenerative disorders, we investigated the therapeutic effects of rhEPO in an intracerebroventricular (ICV)-streptozotocin (STZ) animal model of sporadic-AD. Material and methods. A total of 24 Sprague-Dawley adult rats were divided into 4 groups of naive control (n = 6), sham-operated (n = 6), ICV-STZ + saline (n = 6) and ICV-STZ + rhEPO (n = 6). Twelve rats with Alzheimer's disease, induced by STZ injection (3 mg/kg) into both lateral ventricles using a stereotaxic frame (bilaterally ICV-STZ), were divided into 2 groups 5 days after the STZ injection: one treated with rhEPO 5000 (IU/kg/day, i.p.) and the other with 0.9% NaCl (1 mL/kg/day, i.p.) for 2 weeks. The sham-operated rats received bilaterally ICV-0.9% NaCl. No surgical operation or treatment was given to the naive-control animals. On day 20, a passive avoidance learning (PAL) test was used followed by sacrification and removal of the brain tissue in all animals. Brain TNF-α and ChAT levels were determined, and neurons in the hippocampal CA1 and CA3 regions were counted by Cresyl violet staining. Results. ICV-STZ was found to significantly shorten the latency time on the PAL, increase brain TNF-α level, and decrease brain ChAT activity and the number of neurons in the hippocampal CA1 and CA3 regions. On the other hand, rhEPO significantly attenuated all these detrimental effects induced by STZ. Conclusions. RhEPO treatment significantly prevented the ICV-STZ-induced memory deficit by attenuating the hippocampal neuronal loss, neuroinflammation and cholinergic deficit in rats. This result suggests that rhEPO may be beneficial for treating AD. [ABSTRACT FROM AUTHOR]