Cholinergic Antagonists and Behavioral Disturbances in Neurodegenerative Diseases.

Cholinergic antagonists interfere with synaptic transmission in the central nervous system and are involved in pathological processes in patients with neurocognitive disorders (NCD), such as behavioral and psychological symptoms of dementia (BPSD). In this commentary, we will briefly review the current knowledge on the impact of cholinergic burden on BPSD in persons with NCD, including the main pathophysiological mechanisms. Given the lack of clear consensus regarding symptomatic management of BPSD, special attention must be paid to this preventable, iatrogenic condition in patients with NCD, and de-prescription of cholinergic antagonists should be considered in patients with BPSD.

Incremental Value of CSF Biomarkers in Clinically Diagnosed AD and Non-AD Dementia.

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-Tau181, Aß42, Aß40 concentrations, and Aß42/Aß40 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-Tau181, Aß42 concentrations and Aß42/Aß40 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 Aß42/Aß40 ratio was more useful than the Aß40 concentration in discriminating AD from non-AD populations in daily practice. These results indicate that the Aß42/Aß40 ratio should be assessed in all cases, independently of Aß42 concentrations.

Post-translational modification-derived products are associated with frailty status in elderly subjects.

Background Identifying frail elderly subjects is of paramount importance in order to conduct a tailored care. The characterization of frailty status is currently based on the collection of clinical data and on the use of various tools such as Fried's criteria, which constitutes a difficult and time-consuming process. Up to now, no biological markers have been described as reliable tools for frailty characterization. We tested the hypothesis that a link between frailty and protein molecular aging existed. This study aimed therefore at determining whether post-translational modification derived products (PTMDPs), recognized as biomarkers of protein aging, were associated with frailty status in elderly subjects. Methods Frailty status was determined according to Fried's criteria in 250 elderly patients (>65 years old) hospitalized in a short-term care unit. Serum concentrations of protein-bound PTMDPs, including carboxymethyllysine (CML), pentosidine, methylglyoxal-hydroimidazolone-1 and homocitrulline (HCit), were determined by liquid chromatography coupled with tandem mass spectrometry, and tissue content of advanced glycation end-products was assessed by skin autofluorescence (SAF) measurement. Associations between PTMDPs and frailty status were analyzed using logistic regression models. Results Frail patients had significantly (p<0.01) higher CML, HCit, and SAF values compared to non-frail and pre-frail subjects. By multivariate analysis, only HCit concentrations and SAF values remained associated with frailty status (p=0.016 and p=0.002, respectively), independently of age, comorbidities, renal function, C-reactive protein and albumin concentrations. Conclusions HCit and SAF are significantly associated with frailty status in elderly subjects. This study suggests that PTMDPs constitute promising biomarkers for identifying frail patients and guiding personalized patient care.

Threshold for a Reduction in Anticholinergic Burden to Decrease Behavioral and Psychological Symptoms of Dementia.

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 = 84.1 ± 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 (F×S) score of the Neuropsychiatric Inventory-Nursing 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 = 84.1 ± 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 F×S 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.

Factors related to use of potentially inappropriate psychotropic drugs in 2,343 residents of 19 nursing homes.

To identify factors that influence use of potentially inappropriate psychotropic drugs among elderly residents living in nursing homes (NH). Cross-sectional, multicentre study among 65+ years NH residents, based on queries performed on the PATHOS database and on prescription information from residents' medical data. Medications were coded using the Anatomical Therapeutical Chemical classification. Psychotropic agents were classed using Delay and Deniker's classification, and the Beers Criteria (Beers list 2015 update) were used to identify potentially inappropriate psychotropic drugs (PIPs). Logistic regression was performed to identify factors related to use of potentially inappropriate psychotropic drugs, and factors related to PIPs. The average number of drugs per subject (n=2,343) was 7.8±3.5. In total, 1,709 (71.6%) subjects were taking psychotropic drugs (1.8±0.9 psychotropic drugs per user). Psychotropic agents represented 17.4% of the 18,143 drugs used by the whole study population. The frequency of PIPs was 44.1%. By multivariable analysis, the use of psychotropic drug was significantly associated with behavioural disorders (OR 3.21, 95%CI [2.46-4.18]); depression (OR 8.79, 95%CI [6.64-11.6]); anxiety (OR 3.43, 95%CI [2.45-4.8]); psychosis (OR 2.05, 95%CI [1.28-3.30]), use of >4 drugs (OR 4.85, 95%CI [3.60-6.53]); and dehydration (OR 0.49, 95%CI [0.32-0.75]). PIPs was significantly associated to behavioural disorders (odds ratio (OR) 1.56, 95% confidence interval (CI) [1.89-1.29]); depression (OR 2.90, 95%CI [3.60-2.3]); anxiety (OR 1.68, 95%CI [2.32-1.22]); dementia (OR 2.43, 95%CI [2.96-1.99]); use of >4 drugs (OR 3.41, 95%CI [4.90-2.37]); dehydration (OR 0.53, 95%CI [0.76-0.37]), arthritis/arthrosis of the hip (OR 1.48, 95%CI [2.04-1.07]) and arthritis/arthrosis of the shoulder (OR 2.06, 95%CI [3.43-1.23]). Regular review of prescriptions and emphasis on non-drug therapy of behavioural disorders in elderly subjects can help to reduce the rate of prescription of psychotropic drugs and PIPs in NH residents.

Inherited and Acquired Decrease in Complement Receptor 1 (CR1) Density on Red Blood Cells Associated with High Levels of Soluble CR1 in Alzheimer's Disease.

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.

Reduction of the Anticholinergic Burden Makes It Possible to Decrease Behavioral and Psychological Symptoms of Dementia.

OBJECTIVE: The aim of this study was to evaluate the impact of a reduction of the anticholinergic burden (AB) on the frequency and severity of behavioral and psychological symptoms of dementia (BPSD) and their repercussions on the care team (occupational disruptiveness). METHODS: In this prospective, single-center study in an acute care unit for Alzheimer disease (AD) and related disorders, 125 elderly subjects (mean age: 84.4 years) with dementia presented with BPSD. The reduction of the AB was evaluated by the Anticholinergic Cognitive Burden Scale. BPSD were evaluated with the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). The effect of the reduction of the AB on the BPSD was studied using logistic regression adjusting for the variables of the comprehensive geriatric assessment. RESULTS: Seventy-one subjects (56.8%) presenting with probable AD, 32 (25.6%) mixed dementia (AD and vascular), 17 (13.6%) vascular dementia, and 5 (4.0%) Lewy body dementia were included. Reducing the AB by at least 20% enabled a significant decrease in the frequency × severity scores of the NPI-NH (adjusted odds ratio: 3.5; 95% confidence interval: 1.6-7.9) and of the occupational disruptiveness score (adjusted odds ratio: 9.9; 95% confidence interval: 3.6-27.3). CONCLUSION: AB reduction in elderly subjects with dementia makes is possible to reduce BPSD and caregiver burden. Recourse to treatments involving an AB must be avoided as much as possible in these patients, and preferential use of nonpharmacologic treatment management plans is encouraged.