Association of plasma amyloid-β oligomerization with theta/beta ratio in older adults

BackgroundOligomeric Aβ (OAβ) is a promising candidate marker for Alzheimer’s disease (AD) diagnosis. Electroencephalography (EEG) is a potential tool for early detection of AD. Still, whether EEG power ratios, particularly the theta/alpha ratio (TAR) and theta/beta ratio (TBR), reflect Aβ burden—a primary mechanism underlying cognitive impairment and AD. This study investigated the association of TAR and TBR with amyloid burden in older adults based on MDS-OAβ levels.Methods529 individuals (aged ≥60 years) were recruited. All participants underwent EEG (MINDD SCAN, Ybrain Inc., South Korea) and AlzOn™ test (PeopleBio Inc., Gyeonggi-do, Republic of Korea) for quantifying MDS-OAβ values in the plasma. EEG variables were log-transformed to normalize the data distribution. Using the MDS-OAβ cutoff value (0.78 ng/mL), all participants were classified into two groups: high MDS-OAβ and low MDS-OAβ.ResultsParticipants with high MDS-OAβ levels had significantly higher TARs and TBRs than those with low MDS-OAβ levels. The log-transformed TBRs in the central lobe (β = 0.161, p = 0.0026), frontal lobe (β = 0.145, p = 0.0044), parietal lobe (β = 0.166, p = 0.0028), occipital lobe (β = 0.158, p = 0.0058), and temporal lobe (beta = 0.162, p = 0.0042) were significantly and positively associated with increases in MDS-OAβ levels. After adjusting for the Bonferroni correction, the TBRs in all lobe regions, except the occipital lobe, were significantly associated with increased MDS-OAβ levels.ConclusionWe found a significant association of MDS-OAβ with TBR in older adults. This finding indicates that an increase in amyloid burden may be associated with an increase in the low-frequency band and a decrease in the relatively high-frequency band

Decreased Exosomal Acetylcholinesterase Activity in the Plasma of Patients With Parkinson’s Disease

Exosomes, which are small extracellular vesicles produced from various cell types, contain a variety of molecular constituents, such as proteins, lipids, and RNA. Recently, exosomal biomarkers have been investigated to probe the understanding and diagnosis of neurodegenerative disorders. Previous reports have demonstrated increased exosomal α-synuclein (α-syn) in patients with Parkinson’s disease (PD) in comparison to healthy controls (HC). Interestingly, the cholinergic loss was revealed in the central and peripheral nervous systems in histopathology and molecular neuroimaging. Thereby, we simultaneously examined acetylcholinesterase (AChE) with α-syn as exosomal markers. Exosomes were isolated from the plasma of 34 FP-CIT PET proven patients with PD and 29 HC. Exosomal α-syn and AChE activity were quantified andthe relationship with clinical parameters was analyzed. Remarkably, exosomal AChE activity was significantly decreased in PD compared to HC (P = 0.002). Moreover, exosomal AChE activity in PD revealed a strong negative correlation with disease severity, including H&Y (P = 0.007) and UPDRS part III (P = 0.047) scores. By contrast, no significant difference in exosomal α-syn concentration was observed between groups. These results support the occurrence of cholinergic dysfunction in PD, and they could be implicated with disease progression, especially motor deficits. Exosomal AChE activity with advanced exosome isolation techniques may be a reliable biomarker for the early diagnosis and prognosis of PD

Double Mutations in a Patient with Early-Onset Alzheimer’s Disease in Korea: An <i>APP</i> Val551Met and a <i>PSEN2</i> His169Asn

The etiology of early-onset Alzheimer’s disease (EOAD) is associated with alterations in the production of amyloid beta (Aβ) species caused by mutations in the APP, PSEN1, and PSEN2 genes. Mutations affect intra- or inter-molecular interactions and processes between the γ-secretase complex and amyloid precursor protein (APP), leading to the aberrant sequential cleavage of Aβ species. A 64-year-old woman presented with progressive memory decline, mild right hippocampal atrophy, and a family history of Alzheimer’s dementia (AD). Whole exome sequencing was performed to evaluate AD-related gene mutations, which were verified by Sanger sequencing. A mutation-caused structural alteration of APP was predicted using in silico prediction programs. Two AD-related mutations, in APP (rs761339914; c.G1651A; p.V551M) and PSEN2 (rs533813519; c.C505A; p.H169N), were identified. The APP Val551Met mutation in the E2 domain may influence APP homodimerization through changes in intramolecular interactions between adjacent amino acids, altering Aβ production. The second mutation was PSEN2 His169Asn mutation, which was previously reported in five EOAD patients from Korea and China, with a relatively high frequency in the East Asian population. According to a previous report, the presenilin 2 protein was predicted to result in a major helical torsion by PSEN2 His169Asn mutation. Notably, the co-existence of APP Val551Met and PSEN2 His169Asn may induce a synergistic effect by both mutations. Future functional studies are needed to clarify the pathological effects of these double mutations

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

Early-onset Alzheimer’s disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer’s disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G&gt;A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future