The complement receptor 1 (CR1) gene was shown to be involved in Alzheimer’s disease (AD). We previously showed that AD is associated with low density of the long CR1 isoform, CR1*2 (S). Here, we correlated phenotype data (CR1 density per erythrocyte (CR1/E), blood soluble CR1 (sCR1)) with genetic data (density/length polymorphisms) in AD patients and healthy controls. CR1/E was enumerated using flow cytometry, while sCR1 was quantified by ELISA. CR1 polymorphisms were assessed using restriction fragment length polymorphism (RFLP), pyrosequencing, and high-resolution melting PCR. In AD patients carrying the H allele (HindIII polymorphism) or the Q allele (Q981H polymorphism), CR1/E was significantly lower when compared with controls carrying the same alleles (p < 0.01), contrary to sCR1, which was significantly higher (p < 0.001). Using multivariate analysis, a reduction of 6.68 units in density was associated with an increase of 1% in methylation of CR1 (estimate −6.68; 95% confidence intervals (CIs) −12.37, −0.99; p = 0.02). Our data show that, in addition to inherited genetic factors, low density of CR1/E is also acquired. The involvement of CR1 in the pathogenesis of AD might be linked to insufficient clearance of amyloid deposits. These findings may open perspectives for new therapeutic strategies in AD.
Background: Cerebrospinal fluid (CSF) biomarkers are used to diagnose Alzheimer disease (AD), especially in atypical clinical presentations. No consensus currently exists regarding cut-off values. This study aimed, firstly, to define optimal cut-off values for CSF biomarkers, and secondly, to investigate the most relevant diagnostic strategy for AD based on CSF biomarker combinations. Methods: A total of 380 patients were prospectively included: 140 with AD, 240 with various neurological diagnoses (non-AD). CSF biomarkers were measured using ELISA. Univariate and multivariate analyses were performed using random forest and logistic regression approaches. Results: Univariate receiver operating curve curves analysis of T-Tau, P-Tau 181 , Aβ 42 , Aβ 40 concentrations, and Aβ 42 /Aβ 40 ratio levels showed AD cut-off values of ≥355, ≥57, ≤706, ≥10,854, and ≤0.059 ng/L, respectively. Multivariate analysis using random forest and logistic regression found that the algorithm based on P-Tau 181 , Aβ 42 concentrations and Aβ 42 /Aβ 40 ratio yielded the best discrimination between AD and non-AD populations. The cross-validation technique of the final model showed a mean accuracy of 0.85 and a mean AUC of 0.89. Conclusion: This study confirms that the Aβ 42 /Aβ 40 ratio was more useful than the Aβ 40 concentration in discriminating AD from non-AD populations in daily practice. These results indicate that the Aβ 42 /Aβ 40 ratio should be assessed in all cases, independently of Aβ 42 concentrations.
Background: A high anticholinergic burden (AB) is associated with the occurrence of behavioral and psychological symptoms (BPSDs), which are frequent in dementia. Objectives: Our aim was to determine the threshold for a reduction in AB that would lead to a clinically significant improvement in BPSDs (in terms of frequency, severity, and disruptiveness). Design: A single-center prospective study. Settings: Dedicated geriatric care unit specializing in the management of patients with dementia. Participants: The study involved older patients with dementia, hospitalized for management of BPSDs. Methods: One hundred forty-seven patients were included (mean age ¼ 84.1 AE 5.2 years). The AB was assessed using 3 scales, namely, the Anticholinergic Drug Scale (ADS), the Anticholinergic Cognitive Burden scale (ACB), and the Anticholinergic Risk Scale (ARS). A clinically significant improvement in BPSDs was defined as a reduction of 4 points in the frequency  severity (FÂS) score of the Neuropsychiatric InventoryeNursing Home (NPI-NH) questionnaire. The threshold for a reduction in AB that corresponded to a clinically significant improvement in BPSDs was determined by multiple linear regression.Results: One hundred forty-seven patients were included (mean age ¼ 84.1 AE 5.2 years). Using the ADS, a reduction of 2 points in AB in patients with moderate-intensity BPSDs was associated with a clinically significant improvement in the FÂS score of the NPI-NH [6.34, 95% confidence interval (CI) 4.54-8.14], and a reduction of 3 points was associated with a clinically significant improvement in the occupational disruptiveness score (4.26, 95% CI 3.11-5.41). Conclusions/Implications: In older patients with dementia presenting BPSDs, the risk-benefit ratio of anticholinergic drugs is debatable and, where possible, drugs with a lower AB would be preferable. Because BPSDs are a frequent cause of hospitalization, a standardized approach to analysis and reduction of AB is warranted in this population. Depending on the scale used to assess anticholinergic burden (AB), a small reduction in AB is associated with a decrease in frequency, severity, and disruptiveness of moderate-intensity BPSDs. Drugs with a high AB should be avoided where possible in older patients with dementia, and drugs with a lower AB would be preferable. Heterogeneity between the assessment scales for AB precludes generalization of the impact of a reduction in AB on BPSDs.
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