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.

No impact of a prescription booklet on medication consumption in nursing home residents from 2011 to 2014: a controlled before-after study.

BACKGROUND: Older persons are particularly exposed to adverse events from medication. Among the various strategies to reduce polypharmacy, educational approaches have shown promising results. We aimed to evaluate the impact on medication consumption, of a booklet designed to aid physicians with prescriptions for elderly nursing home residents. METHODS: Among 519 nursing homes using an electronic pill dispenser, we recorded the daily number of times that a drug was administered for each resident, over a period of 4 years. The intervention group comprised 113 nursing homes belonging to a for-profit geriatric care provider that implemented a booklet delivered to prescribers and pharmacists and specifically designed to aid with prescriptions for elderly nursing home residents. The remaining 406 nursing homes where no such booklet was introduced comprised the control group. Data were derived from electronic pill dispensers. The effect of the intervention on medication consumption was assessed with multilevel regression models, adjusted for nursing home status. The main outcomes were the average daily number of times that a medication was administered and the number of drugs with different presentation identifier codes per resident per month. RESULTS: 96,216 residents from 519 nursing homes were included between 1 January 2011 and 31 December 2014. The intervention group and the control group both decreased their average daily use of medication (- 0.05 and - 0.06). The booklet did not have a statistically significant effect (exponentiated difference-in-differences coefficient 1.00, 95% confidence interval 0.99-1.02, P = .45). CONCLUSION: We observed an overall decrease in medication consumption in both the control and intervention groups. Our analysis did not provide any evidence that this reduction was related to the use of the booklet. Other factors, such as national policy or increased physician awareness, may have contributed to our findings.

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.

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.

Factors associated with quality of life in patients with Alzheimer's disease.

BACKGROUND: Evaluation of health-related quality of life (HRQoL) in patients with Alzheimer's disease (AD) is necessary to ensure optimal management. Several scales for assessing HRQoL of patients with AD exist, in particular the Quality of Life in Alzheimer's Disease (QoL-AD), which includes an evaluation by the caregiver of the patient's HRQoL. The aim of this study was to identify factors associated with patient, caregiver and overall HRQoL as assessed by the QoL-AD. METHODS: Cross-sectional multicenter study in subjects aged 65 years and older, with mild to moderate AD. HRQoL scores from the QoL-AD were recorded (3 scores, corresponding to patient, caregiver and overall), as well as sociodemographic variables for the patient and the caregiver, and data from the geriatric cognitive assessment (cognitive, psycho-behavioral, functional evaluations). Caregiver burden was evaluated using the Zarit caregiver burden scale. Factors associated with each QoL-AD score were identified by multivariate linear regression using t-tests and ß estimations. Study was registered in Clinical Trial.gov (NCT02814773). RESULTS: In total, 123 patients with AD were included. For the patient QoL-AD evaluation, depression was significantly associated with lower HRQoL (ß = - 2.56 ± 1.28, p = 0.04), while polypharmacy (ß = - 1.80 ± 0.99, p = 0.07) and anxiety (ß = - 1.70 ± 1.01, p = 0.09) tended to be associated with lower HRQoL scores. In terms of caregiver evaluations, depression (ß = - 3.46 ± 1.09, p = 0.002), polypharmacy (ß = - 1.91 ± 0.92, p = 0.04) and the presence of caregiver burden (ß = - 3.50 ± 0.91, p = 0.0002) were associated with lower HRQoL. For the overall evaluation, depression (ß = - 3.26 ± 1.02, p = 0.002) and polypharmacy (ß = - 1.85 ± 0.81, p = 0.03) were significantly related to lower HRQoL. CONCLUSIONS: Depression and polypharmacy were two factors influencing HRQoL in patients with AD, both by patient self-report and on the caregiver report. Thus, despite the discrepancies between HRQoL as assessed by patients with AD and HRQoL as assessed by their caregiver, the caregiver's assessment may be used to guide patient management when the patient can no longer complete QoL evaluations. Moreover, the association between caregiver burden and the caregiver's QoL-AD score underlines the need to take caregivers into consideration in the overall management of the AD patient.

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.

[The suitability of sending nursing home residents over 75 to emergency departments]. / Pertinence des passages aux urgences des résidents d'Ehpad de 75 ans et plus.

The care provided to elderly people aged over 75 must be specific and multidisciplinary. An emergency department, which is seeing increasing numbers of patients passing through its doors, notably with the provision of an ambulatory care service, would not appear to be a suitable place for this fragile population, often with multiple pathologies. A study is looking at the suitability of the emergency department for nursing home residents, who have regular access to medical care, unlike elderly people living at home.

Risk Factors for Adverse Drug Reactions in Older Subjects Hospitalized in a Dedicated Dementia Unit.

OBJECTIVE: To identify risk factors for the occurrence of adverse drug reactions (ADRs) based on geriatric evaluation. DESIGN: Longitudinal prospective study from May 2010 to November 2011. SETTING: Dedicated acute geriatric care unit specializing in the management of patients with dementia syndrome (Alzheimer disease or related syndromes) at the University Hospital of Reims, France. PARTICIPANTS: Older patients with dementia syndrome (Alzheimer disease or related syndromes). MEASUREMENTS: Sociodemographic variables and comprehensive geriatric assessment were recorded. Occurrence of ADRs was noted. Risk factors for ADR were identified by multivariate logistic regression. RESULTS: During the study period, 293 patients were included; average age was 82 ± 8 years; the majority were women (61.4%). Average Mini-Mental State Examination score was 13 ± 8; average activities of daily living (ADL) score was 3.6 ± 2.1. Independent risk factors for occurrence of at least one ADR were polypharmacy (≥5 drugs/day) (OR: 4.0, 95% CI: 1.1-14.1) and dependence on at least 1 ADL (OR: 2.6, 95% CI: 1.1-6.5). CONCLUSIONS: Risk factors for ADRs were polypharmacy and dependence on at least one ADL. Our findings underline the importance of taking into consideration the characteristics of the patients when prescribing drugs in this specific population. Prescriptions should be re-evaluated at each follow-up.

The prescription of antiplatelet medication in a very elderly population: An observational study in 15 141 ambulatory subjects.

OBJECTIVE: Despite the frequent use of antiplatelet medication (AM) in the elderly patients, very few studies have investigated its prescription. We describe AM prescription through retrospective study in ambulatory elderly patients. METHOD: All subjects aged over 80 years with a medical prescription delivered in March 2015 and affiliated to the Mutualité Sociale Agricole de Bourgogne. Subjects with prescriptions for AM were compared with those without. RESULTS: A total of 15 141 ambulatory elderly patients (83-89 years, 61.3% of women) were included and 4412 (29.14%) had a prescription for AM. The latter were more frequently men than those without AM (43% vs 36.93%, P < .0001) and more frequently had chronic comorbidities (77.24% vs 64.65%, P < .0001). Compared with ambulatory subjects without AM, those with AM more frequently had coronary heart disease (35.15% vs 14.49%), severe hypertension (30% vs 25.65%), diabetes (27.42% vs 20.64%), peripheral arterial diseases (16.28% vs 5.96%) and disabling stroke (9% vs 5.56% (all P < .0001). In addition, they had more prescriptions of beta-blockers (45.24% vs 36.90%), angiotensin conversion enzyme inhibitor (31.35% vs 25.44%), calcium channel blockers (33.34% vs 27.90%), nitrate derivatives (10.6% vs 6.03%) or hypolipidemic agents (HA; 49.81% vs 29.72%) (all P < .0001) than those without AM. CONCLUSION: In this study, which is very interested for its size and the advanced age of the subjects, long-course AM was prescribed in one third of ambulatory elderly patients. Coronary heart disease, severe hypertension and diabetes were more frequent in AM subjects. However, the low percentage of declared strokes was surprising. We provide additional data to doctors following subjects with AM.

Impact of functional alterations on quality of life in patients with Alzheimer's disease.

AIM: To identify factors associated with health-related quality of life (HRQoL) as assessed by the Dementia Quality of Life (DQoL) in patients with Alzheimer's disease (AD), focusing particularly on functional alterations. METHODS: Cross-sectional multicenter study in subjects aged 65 years or older with mild to moderate AD. HRQoL was measured using the DQoL (five domains: self-esteem, positive affect/humor, negative affect, feeling of belonging, and sense of esthetics). Functional alterations were assessed based on activities of daily living (ADLs) and instrumental activities of daily living (IADLs). We also recorded socio-demographic characteristics of the patient and their carer, and comprehensive geriatric assessment including MMSE and psycho-behavioral data (Neuropsychiatric Inventory, Cornell depression score). Factors associated with each domain of the DQol were identified by multivariate linear regression. RESULTS: In total, 123 subjects were included (mean age 82 ± 6 years, 64% women). Two of the five domains of the DQoL were significantly associated with factors based on functional evaluation. The ability to transfer within the home and the ability to use the telephone were associated with an increase in HRQoL in the 'self-esteem' domain (p = 0.02 and 0.05, respectively). Ability to get dressed without assistance was associated with lower HRQoL in the 'negative affect' domain (p = 0.0007). CONCLUSION: Alterations in functional capacity have a significant effect on HRQoL in several domains of the DQoL.

Comparison of QoL-AD and DQoL in elderly with Alzheimer's disease.

OBJECTIVE: The Dementia Quality of Life (DQoL) and the Quality of Life in Alzheimer's Disease (QoL-AD) are the two most widely used dementia-specific QoL instruments in the world. We aimed to compare the psychometric properties of these two instruments and identify which is most adapted to use in geriatric consultations. METHODS: To evaluate the psychometric properties of the French language validation of DQoL and QoL-AD, 123 patients aged 65 years and over suffering from AD (Mini Mental State Examination score ≥10) were recruited in seven French hospitals and one Switzerland hospital. The DQoL comprises 29 items, ranked on a five-point Likert scale and measuring five QoL domains: self-esteem, positive affect, negative affect, feeling of belonging and sense of aesthetics. The QoL-AD contains 13 items giving an overall score ranging from 13 to 52 and evaluating the domains of interpersonal relationships, financial difficulties, physical condition, memory, mood and overall health. RESULTS: Both questionnaires showed adequate reproducibility at 2 weeks interval (intra-class correlation coefficient >0.80), good internal consistency (Cronbach's alpha coefficient >0.70) and good convergent validity with the general health dimension of the Duke Health Profile. The time required to complete the QoL-AD was significantly shorter (p < 0.0001). DQoL had better discriminant capacity (with at least one dimension significant for each subgroup of severity of cognitive decline, dependency, presence of depression or behavioural disorders). CONCLUSIONS: For quick evaluation of QoL during consultations in geriatric care, the QoL-AD is preferable, whereas for the purposes of research and more in-depth evaluation, the DQoL is more suitable.

[Characteristics of nursing home residents in the Marne department]. / Caractéristiques des résidents en Ehpad dans le département de la Marne.

A study was carried out in the Marne department with the aim of describing the comorbidities and the treatments of a representative sample of the population living in nursing homes. It reveals the most frequent pathologies and the most commonly prescribed classes of therapies thereby aiding the assessment of the care costs of elderly people and the anticipation of their needs.

Factors associated with caregivers' underestimation of quality of life in patients with Alzheimer's disease.

OBJECTIVE: The aim of this study was to identify the factors associated with differences between how Alzheimer's disease (AD) patients and their caregivers rate the patient's health-related quality of life (QoL). METHODS: Cross-sectional, multicentre study. Patients were 65 years or more, suffering from mild to moderate AD, native French speakers, with a main caregiver. Interrater agreement of the QoL-AD was assessed using the intraclass coefficient. A generalised linear model was used to identify factors related to the difference in health-related QoL scores between patients and their caregivers. RESULTS: The 122 patients of the study were 82 ± 6 years old and mainly women (69%). Independent factors related to the difference between patients and caregivers were: Mini Mental State Exam score (ß = 0.32; 95% CI = 0.05-0.59); instrumental activities of daily living score (ß = -0.61; 95% CI = -1.14 to -0.07); total Neuropsychiatric Inventory score (ß = 0.10; 95% CI = 0.05-0.59), and Zarit's burden score (ß = 0.09; 95% CI = 0.01-0.17). CONCLUSION: Practitioners must take into account the trend towards underestimation when health-related QoL is rated by caregivers or proxies.

Association of Low Handgrip Strength with Chemotherapy Toxicity in Digestive Cancer Patients: A Comprehensive Observational Cohort Study (FIGHTDIGOTOX).

In the FIGHTDIGO study, digestive cancer patients with dynapenia experienced more chemotherapy-induced neurotoxicities. FIGHTDIGOTOX aimed to evaluate the relationship between pre-therapeutic handgrip strength (HGS) and chemotherapy-induced dose-limiting toxicity (DLT) or all-grade toxicity in digestive cancer patients. HGS measurement was performed with a Jamar dynamometer. Dynapenia was defined according to EWGSOP2 criteria (<27 kg (men); <16 kg (women)). DLT was defined as any toxicity leading to dose reduction, treatment delay, or permanent discontinuation. We also performed an exploratory analysis in patients below the included population's median HGS. A total of 244 patients were included. According to EWGSOP2 criteria, 23 patients had pre-therapeutic dynapenia (9.4%). With our exploratory median-based threshold (34 kg for men; 22 kg for women), 107 patients were dynapenic (43.8%). For each threshold, dynapenia was not an independent predictive factor of overall DLT and neurotoxicity. Dynapenic patients according to EWGSOP2 definition experienced more hand-foot syndrome (p = 0.007). Low HGS according to our exploratory threshold was associated with more all-grade asthenia (p = 0.014), anemia (p = 0.006), and asthenia with DLT (p = 0.029). Pre-therapeutic dynapenia was not a predictive factor for overall DLT and neurotoxicity in digestive cancer patients but could be a predictive factor of chemotherapy-induced anemia and asthenia. There is a need to better define the threshold of dynapenia in cancer patients.

Association Between the Tissue and Circulating Advanced Glycation End-Products and the Micro- and Macrovascular Complications in Type 1 Diabetes: The DIABAGE Study.

INTRODUCTION: Type 1 diabetes is associated with an increased risk of vascular complications. We aimed to investigate the association between serum and tissue advanced glycation end-products (AGEs) and micro- and macrovascular complications in type 1 diabetes (T1D). METHODS: We conducted a cross-sectional study on 196 adults with T1D (mean age 44.53 ± 16, mean duration of diabetes 22 ± 12 years, mean HbA1c 8 ± 1.2%). AGEs were measured in blood serum (i.e., carboxymethyllysine (CML), methylglyoxal-hydroimidazolone-1 (MGH1), and pentosidine) and by measurement of skin autofluorescence (SAF). Associations between AGEs levels and vascular complications were analyzed using binary logistic regression. Correlations between AGEs and pulse wave velocity (PWV) were also assessed by linear regressions. Significant differences were set for p values less than 0.05. RESULTS: We found positive associations between different AGEs and vascular complications. SAF was associated with both microangiopathy (retinopathy: OR = 1.92, p = 0.011; neuropathy: OR = 2.02, p = 0.04; any microangiopathy: OR = 2.83, p < 0.0001) and macroangiopathy (coronaropathy: OR = 3.11, p = 0.009; any macroangiopathy: OR = 2.78, p = 0.003). For circulating AGEs, pentosidine was significantly associated with coronaropathy (OR = 1.61, p = 0.01) and any macroangiopathy (OR = 1.52, p = 0.005) while MGH1 was associated with nephropathy (OR 1.72, p = 0.03). Furthermore, a significant linear correlation was found between PWV and SAF (r = 0.43, p < 0.001), pentosidine (r = 0.28, p < 0.001), and MGH1 (r = 0.16, p = 0.031), but not for CML (r = 0.03, p = 0.598). CONCLUSIONS: Skin autofluorescence appears to be a useful marker for investigating both micro- and macrovascular complications in T1D. In this study, pentosidine was associated with macroangiopathy and MGH1 with nephropathy among the circulating AGEs. Furthermore, the correlations between PWV and AGEs may suggest their value in early prediction of vascular complications in T1D.

One-year COVID-19 outcomes on the oncology care patient pathway: Results of a French descriptive, cross-sectional comprehensive study (ONCOCARE-COV).

BACKGROUND: The COVID-19 pandemic led to a widely documented disruption in cancer care pathway. Since a resurgence of the pandemic was expected after the first lockdown in France, the global impact on the cancer care pathway over the year 2020 was investigated. AIMS: This study aimed to describe the changes in the oncology care pathway for cancer screening, diagnosis, assessment, diagnosis annoucement procedure and treatment over a one-year period. MATERIALS & METHODS: The ONCOCARE-COV study was a comprehensive, retrospective, descriptive, and cross-sectional study comparing the years 2019 and 2020. All key indicators along the cancer care pathway assessing the oncological activity over four periods were described. This study was set in a high-volume, public, single tertiary care center divided in two complementary sites (Reims University Hospital and Godinot Cancer Institute, Reims, France) which was located in a high COVID-19 incidence area during both peaks of the outbreak. RESULTS: A total of 26,566 patient's files were active during the year 2020. Breast screening (-19.5%), announcement dedicated consultations (-9.2%), Intravenous and Hyperthermic Intraoperative Intraperitoneal Chemotherapy (HIPECs) (-25%), and oncogeriatric evaluations (-14.8%) were heavily disrupted in regard to 2020 activity. We identified a clear second outbreak wave impact on medical announcement procedures (October, -14.4%), radiotherapy sessions (October, -16%), number of new health record discussed in multidisciplinary tumor board meeting (November, -14.6%) and HIPECs (November, -100%). Moreover, 2020 cancer care activity stagnated compared to 2019. DISCUSSION: The oncological care pathway was heavily disrupted during the first and second peaks of the COVID-19 outbreak. Between lockdowns, we observed a remarkable but non-compensatory recovery as well as a lesser impact from the pandemic resurgence. However, in absence of an increase in activity, a backlog persisted. CONCLUSION: Public health efforts are needed to deal with the consequences of the COVID-19 pandemic on the oncology care pathway.

Association between anticholinergic burden and hospital readmission in older patients: a prospective analysis.

OBJECTIVE: Despite known adverse effects of anticholinergic (AC) medication, little work has been devoted to the impact of high anticholinergic burden on the rate of hospital readmission. The purpose of this study was to analyze prospectively the link between high AC burden and the rate of all-cause thirty-day hospital readmission in older people. STUDY DESIGN: This was a prospective non-interventional study conducted from January to August 2019 in one acute-care geriatric ward. All hospital stays of patients aged at least 75 years who were discharged to their home were included in the analysis. AC burden was determined from discharge prescriptions using the Anticholinergic Drug Scale (ADS) and the Anticholinergic Risk Scale (ARS), and defined as high if ≥3. RESULTS: The analysis concerned 350 hospital stays. Median patient age was 88 years (interquartile interval 84-91). In a multivariate analysis, the risk of hospital readmission within 30 days was not increased for patients with high AC burden (ADS≥3): odds ratio 1.16 [95% confidence interval 0.56-2.37], compared to a patient whose anticholinergic burden was not high. CONCLUSION: Unlike retrospective studies on this issue, the findings of our prospective analysis do not support a higher risk of hospital admission within 30 days for older people with high AC burden as assessed from their discharge prescriptions.

Acquired decrease of the C3b/C4b receptor (CR1, CD35) and increased C4d deposits on erythrocytes from ICU COVID-19 patients.

In order to study the mechanisms of COVID-19 damage following the complement activation phase occurring during the innate immune response to SARS-CoV-2, CR1 (the regulating complement activation factor, CD35, the C3b/C4b receptor), C4d deposits on Erythrocytes (E), and the products of complement activation C3b/C3bi, were assessed in 52 COVID-19 patients undergoing O2 therapy or assisted ventilation in ICU units in Rheims France. An acquired decrease of CR1 density on E from COVID-19 patients was observed (Mean = 418, SD = 162, N = 52) versus healthy individuals (Mean = 592, SD = 287, N = 400), Student's t-test p < 10-6, particularly among fatal cases, and in parallel with several parameters of clinical severity. Large deposits of C4d on E in patients were well above values observed in normal individuals, mostly without concomitant C3 deposits, in more than 80% of the patients. This finding is reminiscent of the increased C4d deposits on E previously observed to correlate with sub endothelial pericapillary deposits in organ transplant rejection, and with clinical SLE flares. Conversely, significant C3 deposits on E were only observed among » of the patients. The decrease of CR1/E density, deposits of C4 fragments on E and previously reported detection of virus spikes or C3 on E among COVID-19 patients, suggest that the handling and clearance of immune complex or complement fragment coated cell debris may play an important role in the pathophysiology of SARS-CoV-2. Measurement of C4d deposits on E might represent a surrogate marker for assessing inflammation and complement activation occurring in organ capillaries and CR1/E decrease might represent a cumulative index of complement activation in COVID-19 patients. Taken together, these original findings highlight the participation of complement regulatory proteins and indicate that E are important in immune pathophysiology of COVID-19 patients. Besides a potential role for monitoring the course of disease, these observations suggest that novel therapies such as the use of CR1, or CR1-like molecules, in order to down regulate complement activation and inflammation, should be considered.

Measuring Erythrocyte Complement Receptor 1 Using Flow Cytometry.

CR1 (CD35, Complement Receptor type 1 for C3b/C4b) is a high molecular weight membrane glycoprotein of about 200 kDa that controls complement activation, transports immune complexes, and participates in humoral and cellular immune responses. CR1 is present on the surface of many cell types, including erythrocytes, and exhibits polymorphisms in length, structure (Knops, or KN, blood group), and density. The average density of CR1 per erythrocyte (CR1/E) is 500 molecules per erythrocyte. This density varies from one individual to another (100-1,200 CR1/E) and from one erythrocyte to another in the same individual. We present here a robust flow cytometry method to measure the density of CR1/E, including in subjects expressing a low density, with the help of an amplifying immunostaining system. This method has enabled us to show the lowering of CR1 erythrocyte expression in diseases such as Alzheimer's disease (AD), systemic lupus erythematosus (SLE), AIDS, or malaria.

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.