Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer\u27s disease and PET amyloid-positive patient identification

BACKGROUND: Cerebrospinal fluid biomarker profiles characterized by decreased amyloid-beta peptide levels and increased total and phosphorylated tau levels at threonine 181 (pT181) are currently used to discriminate between Alzheimer\u27s disease and other neurodegenerative diseases. However, these changes are not entirely specific to Alzheimer\u27s disease, and it is noteworthy that other phosphorylated isoforms of tau, possibly more specific for the disease process, have been described in the brain parenchyma of patients. The precise detection of these isoforms in biological fluids remains however a challenge. METHODS: In the present study, we used the latest quantitative mass spectrometry approach, which achieves a sensitive detection in cerebrospinal fluid biomarker of two phosphorylated tau isoforms, pT181 and pT217, and first analyzed a cohort of probable Alzheimer\u27s disease patients and patients with other neurological disorders, including tauopathies, and a set of cognitively normal controls. We then checked the validity of our results on a second cohort comprising cognitively normal individuals and patients with mild cognitive impairments and AD stratified in terms of their amyloid status based on PiB-PET imaging methods. RESULTS: In the first cohort, pT217 but not pT181 differentiated between Alzheimer\u27s disease patients and those with other neurodegenerative diseases and control subjects much more specificity and sensitivity than pT181. T217 phosphorylation was increased by 6.0-fold in patients with Alzheimer\u27s disease whereas T181 phosphorylation was only increased by 1.3-fold, when compared with control subjects. These results were confirmed in the case of a second cohort, in which the pT217 cerebrospinal fluid levels marked out amyloid-positive patients with a sensitivity and a specificity of more than 90% (AUC 0.961; CI 0.874 to 0.995). The pT217 concentrations were also highly correlated with the PiB-PET values (correlation coefficient 0.72; P \u3c 0.001). CONCLUSIONS: Increased cerebrospinal fluid pT217 levels, more than those of pT181, are highly specific biomarkers for detecting both the preclinical and advanced forms of Alzheimer\u27s disease. This finding should greatly improve the diagnosis of Alzheimer\u27s disease, along with the correlations found to exist between pT217 levels and PiB-PET data. It also suggests that pT217 is a promising potential target for therapeutic applications and that a link exists between amyloid and tau pathology

Socioeconomic inequalities in dementia risk among a French population-based cohort: quantifying the role of cardiovascular health and vascular events

This study aimed to investigate the role of cardiovascular health (CVH) and vascular events as potential contributors to socioeconomic inequalities in dementia using causal mediation analyses. We used data from the Three-City Cohort, a French population-based study with 12 years of follow-up, with active search of dementia cases and validated diagnosis. Individual socioeconomic status was assessed using education, occupation and income. A CVH score as defined by the American Heart Association and incident vascular events were considered separately as mediators. We performed multi-level Cox proportional and Aalen additive hazard regression models to estimate the total effects of socioeconomic status on dementia risk. To estimate natural direct and indirect effects through CVH and vascular events, we applied two distinct weighting methods to quantify the role of CVH and vascular events: Inverse Odds Ratio Weighting (IORW) and Marginal Structural Models (MSM) respectively. Among 5581 participants, the risk of dementia was higher among participants with primary education (HR 1.60, 95%CI 1.44-1.78), blue-collar workers (HR 1.62, 95%CI 1.43-1.84) and with lower income (HR 1.23, 95%CI 1.09-1.29). Using additive models, 571 (95% CI 288-782) and 634 (95% CI 246-1020) additional cases of dementia per 100 000 person and year were estimated for primary education and blue-collar occupation, respectively. Using IORW, the CVH score mediate the relationship between education or income, and dementia (proportion mediated 17% and 26%, respectively). Yet, considering vascular events as mediator, MSM generated indirect effects that were smaller and more imprecise. Socioeconomic inequalities in dementia risk were observed but marginally explained by CVH or vascular events mediators

HIV Neuroinfection and Alzheimer’s Disease: Similarities and Potential Links?

Environmental factors such as chemicals, stress and pathogens are now widely believed to play important roles in the onset of some brain diseases, as they are associated with neuronal impairment and acute or chronic inflammation. Alzheimer’s disease (AD) is characterized by progressive synaptic dysfunction and neurodegeneration that ultimately lead to dementia. Neuroinflammation also plays a prominent role in AD and possible links to viruses have been proposed. In particular, the human immunodeficiency virus (HIV) can pass the blood-brain barrier and cause neuronal dysfunction leading to cognitive dysfunctions called HIV-associated neurocognitive disorders (HAND). Similarities between HAND and HIV exist as numerous factors involved in AD such as members of the amyloid and Tau pathways, as well as stress-related pathways or blood brain barrier (BBB) regulators, seem to be modulated by HIV brain infection, leading to the accumulation of amyloid plaques or neurofibrillary tangles (NFT) in some patients. Here, we summarize findings regarding how HIV and some of its proteins such as Tat and gp120 modulate signaling and cellular pathways also impaired in AD, suggesting similarities and convergences of these two pathologies

A Complex Relationship Between Suicide, Dementia, and Amyloid: A Narrative Review

Background: Suicide rates are high among older adults and many conditions have been related to suicide in this population: chronic illnesses, physical disabilities, cancer, social isolation, mental disorders and neurocognitive disorders.Objectives: Among neurocognitive disorders, analysis of the relationships between dementia and suicidal behaviors led to conflicting results and some questions are still without answer. Particularly, it is not known whether (i) Alzheimer's disease (AD) increases the risk of suicidal ideation and suicide attempts (SA) or the frequency of death by suicide; (ii) the presence of suicidal ideation or SA in people older than 65 years of age is an early dementia sign; and (iii) amyloid load in frontal areas facilitates SA by modifying the decision-making pathway.Methods: Therefore, in this narrative review, we searched the PubMed database using the medical subject heading (MeSH) terms (“Suicide” AND “Depression”) OR (“Amyloid” OR “Dementia”) to identify recent (from 2000 to 2017) original studies on the links between suicidal behavior, dementia and brain amyloid load. We also explored the clinical and pathophysiological role of depression in these relationships.Results and Discussion: The findings from these studies suggest that late stage dementia could protect against suicidal ideation and SA. Conversely, the risk of complete suicide is increased during the early phase of cognitive decline.Conclusions: Serious cognitive impairment and decline of executive functions could protect against negative thoughts related to cognitive disability awareness and against suicide planning.Several factors, including brain amyloid load, could be involved in the increased suicide rate early after the diagnosis of dementia

A Complex Relationship Between Suicide, Dementia, and Amyloid: A Narrative Review

International audienceBackground: Suicide rates are high among older adults and many conditions have been related to suicide in this population: chronic illnesses, physical disabilities, cancer, social isolation, mental disorders and neurocognitive disorders. Objectives: Among neurocognitive disorders, analysis of the relationships between dementia and suicidal behaviors led to conflicting results and some questions are still without answer. Particularly, it is not known whether (i) Alzheimer's disease (AD) increases the risk of suicidal ideation and suicide attempts (SA) or the frequency of death by suicide; (ii) the presence of suicidal ideation or SA in people older than 65 years of age is an early dementia sign; and (iii) amyloid load in frontal areas facilitates SA by modifying the decision-making pathway. Methods: Therefore, in this narrative review, we searched the PubMed database using the medical subject heading (MeSH) terms ("Suicide" AND "Depression") OR ("Amyloid" OR "Dementia") to identify recent (from 2000 to 2017) original studies on the links between suicidal behavior, dementia and brain amyloid load. We also explored the clinical and pathophysiological role of depression in these relationships. Results and Discussion: The findings from these studies suggest that late stage dementia could protect against suicidal ideation and SA. Conversely, the risk of complete suicide is increased during the early phase of cognitive decline. Conclusions: Serious cognitive impairment and decline of executive functions could protect against negative thoughts related to cognitive disability awareness and against suicide planning.Several factors, including brain amyloid load, could be involved in the increased suicide rate early after the diagnosis of dementia

Contribution des différentes taches graphiques à l'évaluation du tremblement essentiel

National audienc

Orthostatic Hypotension and Risk of Incident Dementia: Results From a 12-Year Follow-Up of the Three-City Study Cohort

International audienceSeveral studies indicate a potential link between orthostatic hypotension (OH) and incident dementia but without substantial evidence to date. Our objective is to study the association between OH and dementia in a cohort of elderly individuals. To do so, baseline lying and standing blood pressure measurements were taken from 7425 subjects in the Three-City study. These subjects were then followed-up for 12 years. Cox proportional hazard models, adjusted for potential confounders, were used to estimate the risk of incident dementia according to OH status. Sensitivity analysis was performed using the so-called illness-death model, a specific statistical method which takes into account competitive risk with death. OH frequency was found to be around 13%, and 760 cases of dementia were diagnosed during follow-up. We observed significant associations between the presence of OH at baseline and the occurrence of dementia during the follow-up, with an increased risk of at least 25% observed regardless of the OH threshold and the statistical method used. In conclusion, there is an association between OH and dementia. Considering that OH is a common condition and is easy to measure, OH measurements could help to identify subjects with higher risk of dementia. Moreover, reducing OH could be a step to prevent conversion to dementia

Contribution Of Different Drawing Tasks In The Assessment Of Essential Tremor

International audienc

Corrigendum to "Increased perfusion in supplementary motor area during a REM sleep behaviour episode" [Sleep Med 12(5) (2011) 531-2]

SCOPUS: er.jinfo:eu-repo/semantics/publishe