Oligomeric amyloid-ß is a major toxic species associated with Alzheimer’s disease pathogenesis. Methods used to measure oligomeric amyloid-β in the blood have increased in number in recent years. The Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ) is a specific method to measure oligomerization tendencies in the blood. The objective of this study was to determine the association between amyloid-ß oligomerization in the plasma and structural changes of the brain. We studied 162 subjects composed of 92 community-based normal healthy subjects, 17 with subjective cognitive decline, 14 with mild cognitive impairment and 39 with Alzheimer’s disease dementia. All subjects underwent MDS-OAβ and three-dimensional T1 magnetic resonance imaging. To determine the structural changes of the brain that are statistically correlated with MDS-OAβ level, we used voxel-based morphometry with corrections for age and total intracranial volume covariates. We found brain volume reduction in the bilateral temporal, amygdala, parahippocampal and lower parietal lobe and left cingulate and precuneus regions (family-wise error, p < 0.05). Reduction was also found in white matter in proximity to the left temporal and bilateral lower parietal lobes and posterior corpus callosum (family-wise error, p < 0.05). Brain volume increment was not observed in any regions within grey or white matter. Findings suggest that substantial correlation exists between amyloid ß oligomerization in the blood and brain volume reduction in the form of Alzheimer’s disease despite of uncertainty in the casual relationship.

Ryoo N, et al. J Korean Med Sci. 2020 Oct;35(42):e383. https://doi.org/10.3346/jkms.2020.35.e383

Background: Recently, several studies suggested potential involvements of α-synuclein in Alzheimer’s disease (AD) pathophysiology. Higher concentrations of α-synuclein were reported in cerebrospinal fluid (CSF) of AD patients with a positive correlation towards CSF tau, indicating its possible role in AD. We analyzed the CSF biomarkers to verify whether α-synuclein could be an additional supported biomarker in AD diagnosis.Methods: In this cross-sectional study, CSF samples of 71 early-onset AD, 34 late-onset AD, 11 mild cognitive impairment, 17 subjective cognitive decline, 45 Parkinson’s disease, and 32 healthy control (HC) were collected. CSF amyloid-β1-42 (A), total tau (N), and phosphorylated tau181 (T) were measured by commercial ELISA kits, and in-house ELISA kit was developed to quantify α-synuclein. The cognitive assessments and amyloid-PET imaging were also performed.Results: CSF α-synuclein manifested a tendency to increase in AD and to decreased in Parkinson’s disease compared to HC. The equilibrium states of total tau and α-synuclein concentrations were changed significantly in AD, and the ratio of total tau/α-synuclein (N/αS) was dramatically increased in AD than HC. Remarkably, N/αS revealed a strong positive correlation with tau phosphorylation rate. Also, the combination of N/αS with amyloid-β1-42/phosphorylated tau181 ratio had the best diagnosis performance (AUC = 0.956, sensitivity = 96%, specificity = 87%). In concordance analysis, N/αS showed the higher diagnostic agreement with amyloid-β1-42 and amyloid-PET. Analysis of biomarker profiling with N/αS had distinctive characteristics and clustering of each group. Especially, among the group of suspected non-Alzheimer’s disease pathophysiology, all A−T+N+ patients with N/αS+ were reintegrated into AD.Conclusions: The high correlation of α-synuclein with tau and the elevated N/αS in AD supported the involvement of α-synuclein in AD pathophysiology. Importantly, N/αS improved the diagnostic performance, confirming the needs of incorporating α-synuclein as a biomarker for neurodegenerative disorders. The incorporation of a biomarker group [N/αS] could contribute to provide better understanding and diagnosis of neurodegenerative disorders.

Background: Fibrinogen is considered a marker of vascular pathology, indicating a weakened blood-brain barrier, and has a causative role in neuroinflammation and neurodegeneration. Little is known about the relationship between fibrinogen levels and cognitive function in patients with mild cognitive impairment (MCI). We aimed to investigate differences in cognitive profiles according to plasma fibrinogen levels in patients with MCI and the influence of plasma fibrinogen levels on cognitive decline. Methods: This retrospective cohort study included 643 patients with MCI: 323 patients in the high fibrinogen (high fib) group and 320 patients in the low fibrinogen (low fib) group. A multiple linear regression model was performed to compare cognitive test performance between groups. The Cox proportional hazard model was used to analyze the hazard ratio of fibrinogen level for disease progression. Results: The high fib group demonstrated poorer performance in attention, executive function, and confrontation naming than the low fib group. After adjustment for APOE genotype, the high fib group was associated with poor attention and executive function. After adjustment for vascular risk factors including body mass index, hypertension, diabetes mellitus, dyslipidemia, and smoking history, the high fib group showed declined attention and confrontation naming ability. High fibrinogen levels did not predict disease progression to CDR 1. Conclusion: High plasma fibrinogen levels were associated with poor performance in attention in patients with MCI, regardless of APOE genotype or vascular risk factors.

In patients with amyloid-positive mild cognitive impairment (MCI), neurodegenerative biomarkers such as medial temporal lobe atrophy (MTA) are useful to predict disease progression to dementia. Although posterior atrophy (PA) is a well-known neurodegenerative biomarker of Alzheimer’s disease, little is known about PA as a predictor in patients with amyloid-positive MCI. We included 258 patients with amyloid-positive MCI with at least one follow-up visit, and who had low cerebrospinal fluid (CSF) β-amyloid1–42 concentration. Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative study. We assessed PA and MTA on magnetic resonance imaging (MRI) using visual rating scales and retrospectively determined progression to dementia during the follow-up period of up to 3 years (median 24 months). The Cox proportional hazards model was used to analyze hazard ratios (HRs) of PA and MTA for disease progression. Additionally, subjects were divided into four groups according to brain atrophy pattern (no atrophy, MTA only, PA only, both MTA and PA), and HRs for disease progression were compared with the no atrophy reference group. Analyses were conducted with and without adjustment for CSF phosphorylated tau181p (p-tau) and baseline demographics. A total of 123 patients (47.7%) showed MTA and 174 patients (67.4%) showed PA. Of the total cohort, 139 cases (53.9%) progressed to dementia. PA and MTA were associated with an increased risk for progression to dementia (HR 2.244, 95% confidence interval (CI) 1.497–3.364, and HR 1.682, 95% CI 1.203–2.352, respectively). In the analysis according to atrophy pattern, HR (95% CI) for progression was 2.998 (1.443–6.227) in the MTA only group, 3.126 (1.666–5.864) in the PA only group, and 3.814 (2.045–7.110) in both MTA and PA group. These results remained significant after adjustment. In patients with amyloid-positive MCI, PA could predict progression to dementia independently of MTA.

Although driving by adults with cognitive impairment is an important public health concern, little is known about the indicators of driving cessation in patients with mild cognitive impairment (MCI). We aimed to investigate the prevalence of driving cessation in patients with MCI and the predictive value of cognitive performances for driving cessation. Patients with MCI were recruited in the Seoul National University Bundang Hospital; they met following inclusion criteria. Age range of 51–80 years, Clinical Dementia Rating scale score of 0.5, and ever car drivers including former and current drivers. All participants underwent comprehensive standardized cognitive assessments and information on driving status was obtained via an interview using a systematic questionnaire. The median age of the 135 participants was 72 years, and 54 participants (40%) were women; 93 patients (68.9%) were current drivers and 42 (31.1%) were former drivers. In univariate analysis, former drivers showed poorer performances in digit span backward and categorical fluency tests than current drivers. In multivariate logistic regression analysis, a poor digit span backward test score was significantly related with driving cessation (odds ratio: 0.493, 95% confidence interval: 0.258–0.939). In patients with MCI, poor performance in the digit span backward test, which represents impaired working memory capacity, was associated with a higher probability of driving cessation.