Publications by authors named "Claire Paquet"

103 Publications

CHRONIC TRAUMATIC ENCEPHALOPATHY.

Neurochirurgie 2021 Feb 20. Epub 2021 Feb 20.

Université de Paris et Inserm U 1144, Centre de Neurologie Cognitive, APHP, Hôpital Lariboisière FW, 75010 Paris, France.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repeated traumatic brain injury (TBI). This disorder is mainly observed in subjects at risk for brain traumatisms including boxers, American football and European football (soccer) players as well as war veterans. Neuropathological findings are marked by abnormally phosphorylated tau accumulations at the depth of cerebral sulci as well as TDP43, Aβ and α-synuclein positive staining. It has been described 3 clinical variants: the behavioral/mood variant, the cognitive variant and the mixed behavioral/cognitive variant. Cerebral MRI revealed signs of diffuse atrophy with abnormal axonal findings using the diffusion tensor imaging methods. Cerebral PET tau revealed increased standardized uptake value ratio (SUVR) levels in various brain regions of CTE patients compared to controls. The place of CTE among other neurodegenerative diseases is still debated. The focus of CTE management must be on prevention. The best way to prevent CTE in athletes is to put in place strict and appropriate measures by physicians. An individual with concussion should not be allowed to play again immediately (and sometimes never) in cases of abnormal neurological symptoms or imaging abnormalities.
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http://dx.doi.org/10.1016/j.neuchi.2021.02.003DOI Listing
February 2021

Brain Glucose Metabolism in Cerebral Amyloid Angiopathy: An FDG-PET Study.

Stroke 2021 Feb 22:STROKEAHA120032905. Epub 2021 Feb 22.

Department of Neurology, Sainte-Anne Hospital, INSERM U1266, Université de Paris, France (J.-C.B.).

Background And Purpose: The in vivo diagnosis of cerebral amyloid angiopathy (CAA) is currently based on the Boston criteria, which largely rely on hemorrhagic features on brain magnetic resonance imaging. Adding to these criteria F-fluoro-deoxy-D-glucose (FDG) positron emission tomography, a widely available imaging modality, might improve their accuracy. Here we tested the hypothesis that FDG uptake is reduced in posterior cortical areas, particularly the primary occipital cortex, which pathologically bear the brunt of vascular Aβ deposition.

Methods: From a large memory clinic database, we retrospectively included all patients in whom both brain magnetic resonance imaging and FDG positron emission tomography had been obtained as part of routine clinical care and who fulfilled the Boston criteria for probable CAA. None had a history of symptomatic intracerebral hemorrhage. FDG data processing involved (1) spatial normalization to the Montreal Neurology Institute/International Consortium for Brain Mapping 152 space and (2) generation of standardized FDG uptake (relative standardized uptake value; relative to the pons). The relative standardized uptake value data obtained in 13 regions of interest sampling key cortical areas and the cerebellum were compared between the CAA and age-matched control groups using 2 separate healthy subject databases and image-processing pipelines. The presence of significant hypometabolism (2-tailed <0.05) was assessed for the bilaterally averaged regions-of-interest relative standardized uptake values.

Results: Fourteen patients fulfilling the Boston criteria for probable CAA (≥2 exclusively lobar microbleeds) were identified. Significant hypometabolism ( range, 0.047 to <0.0001) consistently affected the posterior cortical areas, including the superior and inferior parietal, primary visual, lateral occipital, lateral temporal, precuneus, and posterior cingulate regions of interest. The anterior cortical areas were marginally or not significantly hypometabolic, and the cerebellum was spared.

Conclusions: Supporting our hypothesis, significant glucose hypometabolism predominantly affected posterior cortical regions, including the visual cortex. These findings from a small sample may have diagnostic implications but require replication in larger prospective studies. In addition, whether they generalize to CAA-related symptomatic intracerebral hemorrhage warrants specific studies.
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http://dx.doi.org/10.1161/STROKEAHA.120.032905DOI Listing
February 2021

Cerebrospinal Fluid Biomarkers in Patients With Alcohol Use Disorder and Persistent Cognitive Impairment.

Alcohol Clin Exp Res 2021 Jan 24. Epub 2021 Jan 24.

Département de Psychiatrie et de Médecine Addictologique, Hôpital Fernand Widal, APHP, Paris, France.

Background: The prevalence of cognitive impairment is high among alcohol-dependent patients. Although the clinical presentation of alcohol-related cognitive disorder (ARCD) may resemble that of Alzheimer's disease (AD), the prognosis and treatment of the 2 diseases are different. Cerebrospinal fluid (CSF) biomarkers (tau, phosphorylated tau, and amyloid β) have high diagnostic accuracy in AD and are currently being used to discriminate between psychiatric disorders and AD, but are not used to diagnose ARCD. The aim of this study was to characterize CSF biomarkers in a homogeneous, cognitively impaired alcohol-dependent population.

Methods: This single-center study was conducted in an addiction medicine department of a Parisian Hospital. We selected patients with documented persistent cognitive impairment whose MoCA (Montreal Cognitive Assessment) score was below 24/30 after at least 1 month of documented inpatient abstinence from alcohol. We measured the CSF biomarkers (tau, phosphorylated tau, and amyloid β 1-42 and 1-40) in 73 highly impaired alcohol-dependent patients (Alcohol Use Disorders Identification Test score over 11 for women and 12 for men) with.

Results: Patients' average age was 60 ± 9.1 years and 45 (61.6%) had a normal CSF profile, 8 (11.0%) had a typical CSF AD profile, and 20 (27.4%) had an intermediate CSF profile.

Conclusions: This study revealed a high prevalence of AD in alcohol-dependent patients with persistent cognitive deficits and several anomalies in their CSF profiles. Thus, it is important to consider AD in the differential diagnosis of persistent cognitive deficits in patients with alcohol dependence and to use CSF biomarkers in addition to imaging and neuropsychological testing to evaluate alcohol-related cognitive impairment.
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http://dx.doi.org/10.1111/acer.14554DOI Listing
January 2021

[ F]FDG PET may differentiate cerebral amyloid angiopathy from Alzheimer's disease.

Eur J Neurol 2021 Jan 18. Epub 2021 Jan 18.

Department of Neurology, Sainte-Anne Hospital, Université de Paris, Paris, France.

Background: Cerebral amyloid angiopathy (CAA) is a frequent cause of both intracerebral hemorrhage (ICH) and cognitive impairment in the elderly. Diagnosis relies on the Boston criteria, which use magnetic resonance imaging markers including ≥2 exclusively lobar cerebral microbleeds (lCMBs). Although amyloid positron emission tomography (PET) may provide molecular diagnosis, its specificity relative to Alzheimer's disease (AD) is limited due to the prevalence of positive amyloid PET in cognitively normal elderly. Using early-phase C-Pittsburgh compound B as surrogate for tissue perfusion, a significantly lower occipital/posterior cingulate (O/PC) tracer uptake ratio in probable CAA relative to AD was recently reported, consistent with histopathological lesion distribution. We tested whether this finding could be reproduced using [ F]fluorodeoxyglucose (FDG)-PET, a widely available modality that correlates well with early-phase amyloid PET in both healthy subjects and AD.

Methods: From a large memory clinic database, we retrospectively included 14 patients with probable CAA (Boston criteria) and 21 patients with no lCMB fulfilling AD criteria including cerebrospinal fluid biomarkers. In all, [ F]FDG-PET/computed tomography (CT) was available as part of routine care. No subject had a clinical history of ICH. Regional standardized [ F]FDG uptake values normalized to the pons (standard uptake value ratio [SUVr]) were obtained, and the O/PC ratio was calculated.

Results: The SUVr O/PC ratio was significantly lower in CAA versus AD (1.02 ± 0.14 vs. 1.19 ± 0.18, respectively; p = 0.024).

Conclusions: Despite the small sample, our findings are consistent with the previous early-phase amyloid PET study. Thus, [ F]FDG-PET may help differentiate CAA from AD, particularly in cases of amyloid PET positivity. Larger prospective studies, including in CAA-related ICH, are however warranted.
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http://dx.doi.org/10.1111/ene.14743DOI Listing
January 2021

Positive effects of lumbar puncture simulation training for medical students in clinical practice.

BMC Med Educ 2021 Jan 6;21(1):18. Epub 2021 Jan 6.

Université de Paris, Medical School, Paris, France.

Background: Lumbar puncture (LP) is an invasive medical procedure that can be done by any doctor. Several simulation-based trainings have been built however the evaluations of the theoretical knowledge and the impact of the simulation-based training have never been performed in real life. The objective was to evaluate the impact of a LP training on the theoretical knowledge improvement and the performance of a LP in clinical practice.

Methods: Before and after medical students' training, theoretical knowledge and confidence level were assessed. Over a 6 months period, the impact of simulation training was evaluated by the success rate of students' first LP carried out in hospitalized patients and compared to the results of a no-training control.

Results: Students' theoretical knowledge and confidence level showed significant improvement after simulation training on 115 students (p < 0.0001). The evaluation in real life based on 41 students showed that the success rate of the first LP in patients was higher in the LP simulation group compared to the control group (67% vs 14%, p = 0.0025). The technical assistance was also less frequently needed in the LP simulation group (19% vs 57%, respectively, p = 0.017). The rate of students who participated in this educational study was low.

Discussion: Simulation-based teaching was an effective way to improve students' theoretical and practical knowledge. Whether this approach translates to other procedural skills in real clinical settings merits further study. The low participation rate in the study is due to the fact that students are not used to be included in educational studies and to the complexity of evaluation in routine clinical practice.
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http://dx.doi.org/10.1186/s12909-020-02452-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789333PMC
January 2021

High-sensitivity quantification of acetylcholine and choline in human cerebrospinal fluid with a validated LC-MS/MS method.

Talanta 2021 Mar 11;224:121881. Epub 2020 Nov 11.

Université Paris-Saclay, UVSQ, INSERM, Infection et inflammation, Département de Biotechnologie de la Santé, Montigny le Bretonneux, France; Hôpital Foch, Département des maladies des voies respiratoires, Suresnes, France. Electronic address:

Acetylcholine is the neurotransmitter of the parasympathetic nervous system, synthesized from choline and involved in several neurodegenerative diseases. Exploration of cholinergic neurotransmission in the human central nervous system is limited by the lack of a sensitive and specific method for the determination of acetylcholine and choline expression. We developed an hydrophilic interaction liquid chromatography - mass spectrometry method for the quantification of both molecules in human cerebrospinal fluid samples. An extensive selectivity study towards endogenous interfering compounds, in particular γ-butyrobetain, was performed and the method was validated according to the European Medicine Agency and Food and Drug Administration guidelines for the validation of bioanalytical methods. The performance of the method was excellent with a lower limit of quantification at 5 ng/L (34.2 pmol/L) for acetylcholine and 5 μg/L for choline, a precision in the range 1.3-11.9% and an accuracy between 85.2 and 113.1%. This suitability of the method for the quantification of acetylcholine and choline in clinical samples was demonstrated with the analysis of patient cerebrospinal fluid samples. Altogether, this validated method allows the simultaneous quantitative analysis of acetylcholine and choline in human cerebrospinal fluid with high sensitivity and selectivity. It will allow to better characterize the cholinergic neurotransmission in human pathologies and to study the effects of drugs acting on this system.
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http://dx.doi.org/10.1016/j.talanta.2020.121881DOI Listing
March 2021

Full-length and C-terminal neurogranin in Alzheimer's disease cerebrospinal fluid analyzed by novel ultrasensitive immunoassays.

Alzheimers Res Ther 2020 12 22;12(1):168. Epub 2020 Dec 22.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital/Mölndal, SE-431 80, Mölndal, Sweden.

Background: Neurogranin (Ng) is a neuron-specific and postsynaptic protein that is abundantly expressed in the brain, particularly in the dendritic spine of the hippocampus and cerebral cortex. The enzymatic cleavage of Ng produces fragments that are released into cerebrospinal (CSF), which have been shown to be elevated in Alzheimer's disease (AD) patients and predict cognitive decline. Thus, quantification of distinctive cleavage products of Ng could elucidate different features of the disease.

Methods: In this study, we developed novel ultrasensitive single molecule array (Simoa) assays for measurement of full-length neurogranin (FL-Ng) and C-terminal neurogranin (CT-Ng) fragments in CSF. The Ng Simoa assays were evaluated in CSF samples from AD patients (N = 23), mild cognitive impairment due to AD (MCI-AD) (N = 18), and from neurological controls (N = 26).

Results: The intra-assay repeatability and inter-assay precision of the novel methods had coefficients of variation below 7% and 14%, respectively. CSF FL-Ng and CSF CT-Ng median concentrations were increased in AD patients (6.02 ng/L, P < 0.00001 and 452 ng/L, P = 0.00001, respectively) and in patients with MCI-AD (5.69 ng/L, P < 0.00001 and 566 ng/L, P < 0.00001) compared to neurological controls (0.644 ng/L and 145 ng/L). The median CSF ratio of CT-Ng/FL-Ng were decreased in AD patients (ratio = 101, P = 0.008) and in patients with MCI-AD (ratio = 115, P = 0.016) compared to neurological controls (ratio = 180). CSF of FL-Ng, CT-Ng, and ratio of CT-Ng/FL-Ng could each significantly differentiate AD patients from controls (FL-Ng, AUC = 0.907; CT-Ng, AUC = 0.913; CT-Ng/FL-Ng, AUC = 0.775) and patients with MCI-AD from controls (FL-Ng, AUC = 0.937; CT-Ng, AUC = 0.963; CT-Ng/FL-Ng, AUC = 0.785).

Conclusions: Assessments of the FL-Ng and CT-Ng levels in CSF with the novel sensitive immunoassays provide a high separation of AD from controls, even in early phase of the disease. The novel Ng assays are robust and highly sensitive and may be valuable tools to study synaptic alteration in AD, as well as to monitor the effect on synaptic integrity of novel drug candidates in clinical trials.
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http://dx.doi.org/10.1186/s13195-020-00748-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756958PMC
December 2020

Clinical relevance of brain atrophy subtypes categorization in memory clinics.

Alzheimers Dement 2020 Dec 15. Epub 2020 Dec 15.

Univ. Bordeaux, Inserm U1219, Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Pôle de Sante Publique, CHU de Bordeaux, Bordeaux, France.

Introduction: The clinical relevance of brain atrophy subtypes categorization in non-demented persons without a priori knowledge regarding their amyloid status or clinical presentation is unknown.

Methods: A total of 2083 outpatients with either subjective cognitive complaint or mild cognitive impairment at study entry were followed during 4 years (MEMENTO cohort). Atrophy subtypes were defined using baseline magnetic resonance imaging (MRI) and previously described algorithms.

Results: Typical/diffuse atrophy was associated with faster cognitive decline and the highest risk of developing dementia and Alzheimer's disease (AD) over time, both in the whole analytic sample and in amyloid-positive participants. Hippocampal-sparing and limbic-predominant atrophy were also associated with incident dementia, with faster cognitive decline in the limbic predominant atrophy group. Lewy body dementia was more frequent in the hippocampal-sparing and minimal/no atrophy groups.

Discussion: Atrophy subtypes categorization predicted different subsequent patterns of cognitive decline and rates of conversion to distinct etiologies of dementia in persons attending memory clinics.
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http://dx.doi.org/10.1002/alz.12231DOI Listing
December 2020

Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for Alzheimer's disease diagnosis.

Alzheimers Dement 2020 Nov 30. Epub 2020 Nov 30.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Introduction: Phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) is an established Alzheimer's disease (AD) biomarker. Novel immunoassays targeting N-terminal and mid-region p-tau181 and p-tau217 fragments are available, but head-to-head comparison in clinical settings is lacking.

Methods: N-terminal-directed p-tau217 (N-p-tau217), N-terminal-directed p-tau181 (N-p-tau181), and standard mid-region p-tau181 (Mid-p-tau181) biomarkers in CSF were evaluated in three cohorts (n = 503) to assess diagnostic performance, concordance, and associations with amyloid beta (Aβ).

Results: CSF N-p-tau217 and N-p-tau181 had better concordance (88.2%) than either with Mid-p-tau181 (79.7%-82.7%). N-p-tau217 and N-p-tau181 were significantly increased in early mild cognitive impairment (MCI)-AD (A+T-N-) without changes in Mid-p-tau181 until AD-dementia. N-p-tau217 and N-p-tau181 identified Aβ pathophysiology (area under the curve [AUC] = 94.8%-97.1%) and distinguished MCI-AD from non-AD MCI (AUC = 82.6%-90.5%) signficantly better than Mid-p-tau181 (AUC = 91.2% and 70.6%, respectively). P-tau biomarkers equally differentiated AD from non-AD dementia (AUC = 99.1%-99.8%).

Discussion: N-p-tau217 and N-p-tau181 could improve diagnostic accuracy in prodromal-AD and clinical trial recruitment as both identify Aβ pathophysiology and differentiate early MCI-AD better than Mid-p-tau181.
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http://dx.doi.org/10.1002/alz.12236DOI Listing
November 2020

Copper and zinc isotopic excursions in the human brain affected by Alzheimer's disease.

Alzheimers Dement (Amst) 2020 19;12(1):e12112. Epub 2020 Oct 19.

Centre de Neurologie Cognitive Hopital Lariboisière Fernand-Widal GHU Nord APHP Université de Paris, and Inserm Paris France.

Introduction: Alzheimer's disease (AD) is neuropathologically marked by amyloid beta (Aβ) plaques and neurofibrillary tangles. Little is known about isotopic compositions of human AD brains. Here we study this in comparison with control subjects for copper and zinc.

Methods: We use mass-spectrometry methods, developed to study extraterrestrial materials, to compare the copper and zinc isotopic composition of 10 AD and 10 control brains.

Results: Copper and zinc natural isotopic compositions of AD brains are statistically different compared to controls, and correlate with Braak stages.

Discussion: The distribution of natural copper and zinc isotopes in AD is not affected by the diet, but is a consequence of Aβ plaques and tau fibril accumulation. This is well predicted by the changes of the chemical bonding environment caused by the development of Aβ lesions and accumulation of tau proteins. Future work will involve testing whether these changes affect brain functions and are propagated to body fluids.
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http://dx.doi.org/10.1002/dad2.12112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571480PMC
October 2020

STAT3 inhibition protects against neuroinflammation and BACE1 upregulation induced by systemic inflammation.

Immunol Lett 2020 Dec 21;228:129-134. Epub 2020 Oct 21.

INSERM U1144 Optimisation Thérapeutique en Neuropsychopharmacologie, Université de Paris, Paris, France; Centre de Neurologie Cognitive/CMRR Paris Nord Ile de France, APHP Nord Université de Paris, Lariboisière Hospital, Paris, France. Electronic address:

Abnormal activation of the transcriptional factor STAT3 (signal transducer and activator of transcription 3) was recently associated with Alzheimer Disease (AD). STAT3 phosphorylation is critical for cytokine secretion linked to neuroinflammation. Moreover, STAT3 may act as a transcriptional regulator of BACE1 (β-APP cleaving enzyme-1), the key enzyme in amyloid β (Aβ) production. We have previously shown that neuroinflammation and increased brain BACE1 levels triggered by LPS-induced systemic inflammation in wild-type mice are associated with an enhanced STAT3 activation. Using this LPS model, the goal of this study was to investigate if a STAT3 inhibitor administration could be protective against neuroinflammation and abnormal BACE1 regulation. Our results show that intraperitoneal injection of Stattic, a molecule that selectively inhibits the activation of STAT3, decreases LPS-induced microglial activation in the hippocampus. In addition, STAT3 inhibition reduced brain levels of cytokines IL-6, IL-1β and TNF-α triggered by LPS systemic administration. A significant reduction of BACE1 levels was observed in the hippocampus of mice treated with LPS and Stattic compared to those exposed to LPS alone. Taking together, our results show that Stattic can protect hippocampus against two pathological hallmarks of AD, and pave the way for further explorations of the therapeutic potential of STAT3 inhibition in AD.
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http://dx.doi.org/10.1016/j.imlet.2020.10.004DOI Listing
December 2020

COVID-19 in Older Adults: A Series of 76 Patients Aged 85 Years and Older with COVID-19.

J Am Geriatr Soc 2020 12 28;68(12):2735-2743. Epub 2020 Oct 28.

Université de Paris, INSERM U1144 Optimisation Thérapeutique en Neuropsychopharmacologie, Paris, France.

Background: Clinical presentation and risk factors of death in COVID-19 in oldest adults have not been well characterized.

Objectives: To describe clinical features and outcome of COVID-19 in patients older than 85 years and study risk factors for mortality.

Design: Prospective cohort.

Participants And Setting: Patients aged 85 years and older, admitted in noncritical care units at the University Hospital Lariboisière Fernand-Widal (Paris, France) for confirmed severe acute respiratory syndrome coronavirus 2 infection were included and followed up for 21 days.

Measurements: Clinical and laboratory findings were collected. Cox survival analysis was performed to explore factors associated with death.

Results: From March 14 to April 11, 2020, 76 patients (median age = 90 (86-92) years; women = 55.3%) were admitted for confirmed COVID-19. Of the patients, 64.5% presented with three or more comorbidities. Most common symptoms were asthenia (76.3%), fever (75.0%) and confusion and delirium (71.1%). An initial fall was reported in 25.0% of cases, and digestive symptoms were reported in 22.4% of cases. COVID-19 was severe in 51.3% of cases, moderate in 32.9%, and mild in 15.8%. Complications included acute respiratory syndrome (28.9%), cardiac decompensation (14.5%), and hypotensive shock (9.0%). Fatality at 21 days was 28.9%, after a median course of disease of 13 (8-17) days. Males were overrepresented in nonsurvivors (68.2%). In survivors, median length of stay was 12 (9-19.5) days. Independent predictive factors of death were C-reactive protein level at admission and lymphocyte count at nadir.

Conclusion: Specific clinical features, multiorgan injury, and high case fatality rate are observed in older adults with COVID-19. However, rapid diagnosis, appropriate care, and monitoring seem to improve prognosis.
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http://dx.doi.org/10.1111/jgs.16894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675559PMC
December 2020

Cerebrospinal fluid A beta 1-40 peptides increase in Alzheimer's disease and are highly correlated with phospho-tau in control individuals.

Alzheimers Res Ther 2020 10 2;12(1):123. Epub 2020 Oct 2.

Univ Montpellier, INSERM, CHU Montpellier (CMRR), Montpellier, France.

Background: Amyloid pathology, which is one of the characteristics of Alzheimer's disease (AD), results from altered metabolism of the beta-amyloid (Aβ) peptide in terms of synthesis, clearance, or aggregation. A decrease in cerebrospinal fluid (CSF) level Aβ1-42 is evident in AD, and the CSF ratio Aβ42/Aβ40 has recently been identified as one of the most reliable diagnostic biomarkers of amyloid pathology. Variations in inter-individual levels of Aβ1-40 in the CSF have been observed in the past, but their origins remain unclear. In addition, the variation of Aβ40 in the context of AD studied in several studies has yielded conflicting results.

Methods: Here, we analyzed the levels of Aβ1-40 using multicenter data obtained on 2466 samples from six different cohorts in which CSF was collected under standardized protocols, centrifugation, and storage conditions. Tau and p-tau (181) concentrations were measured using commercially available in vitro diagnostic immunoassays. Concentrations of CSF Aβ1-42 and Aβ1-40 were measured by ELISA, xMAP technology, chemiluminescence immunoassay (CLIA), and mass spectrometry. Statistical analyses were calculated for parametric and non-parametric comparisons, linear regression, correlation, and odds ratios. The statistical tests were adjusted for the effects of covariates (age, in particular).

Results: Regardless of the analysis method used and the cohorts, a slight but significant age-independent increase in the levels of Aβ40 in CSF was observed in AD. We also found a strong positive correlation between the levels of Aβ1-40 and p-tau (181) in CSF, particularly in control patients.

Conclusions: These results indicate that an increase in the baseline level of amyloid peptides, which are associated with an increase in p-tau (181), may be a biological characteristic and possibly a risk factor for AD. Further studies will be needed to establish a causal link between increased baseline levels of Aβ40 and the development of the disease.
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http://dx.doi.org/10.1186/s13195-020-00696-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532565PMC
October 2020

[Transcranial cerebral stimulation in Alzheimer's disease].

Rev Prat 2020 02;70(2):173-174

Centre de neurologie cognitive, hôpital Lariboisière-Fernand- Widal, AP-HP, université de Paris, Inserm U 1144, Paris, France.

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February 2020

[Therapeutic perspectives in Alzheimer's disease].

Authors:
Claire Paquet

Rev Prat 2020 Feb;70(2):170-172

Centre de neurologie cognitive, groupe hospitalier Lariboisière-Fernand- Widal, université de Paris, Inserm U1144, Paris, France.

Therapeutic perspectives in Alzheimer's disease. Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders, affecting millions of people worldwide and leads to irreversible cognitive decline. The main neuropathological features of AD are the production of abnormal conformational protein (Amyloid Peptide, abnormally phosphorylated tau protein) leading to brain deposits, neuronal and synaptic loss and neurotransmitter deficiency including acetylcholine. The lesions occur 10 to 15 years before the first symptoms. The presence of specific markers in the cerebrospinal fluid is reflecting AD abnormalities (allow determining the presence of these abnormalities in living patients). Currently, only symptomatic treatments (acetylcholinesterase inhibitors and anti-glutamatergics) have been shown to be effective and have been marketed since the late 1990s. Since the early 2000s, therapeutic research has focused on the development of treatments that could modify the evolution of the disease either by increasing the elimination of abnormal proteins, or by decreasing their production and/or their diffusion into the brain. The two current targets are Aβ peptide and the abnormally phosphorylated Tau protein. Regarding the Aβ peptide, the therapeutic trials aimed at increasing its elimination were negative (ineffective) at the stage of major cognitive impairment but give hope for efficacy at the early stage of the disease. Therapeutic trials to reduce its production have been shown to be ineffective or deleterious to patients. Concerning the tau protein, the molecules under development aim at reducing its dissemination in the brain. Altogether, all potential disease modifying treatments are under development.
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February 2020

Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker-based case-control study.

PLoS Med 2020 08 20;17(8):e1003289. Epub 2020 Aug 20.

Université de Paris, Inserm U1153, Epidemiology of Ageing and Neurodegenerative diseases, Paris, France.

Background: The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD.

Methods And Findings: This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD.

Conclusions: In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.
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http://dx.doi.org/10.1371/journal.pmed.1003289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446786PMC
August 2020

CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer's disease.

Alzheimers Res Ther 2020 07 20;12(1):88. Epub 2020 Jul 20.

Inserm U 1144, University de Paris, Paris, France.

Background: The presynaptic protein neuregulin1 (NRG1) is cleaved by beta-site APP cleaving enzyme 1 (BACE1) in a similar way as amyloid precursor protein (APP) NRG1 can activate post-synaptic receptor tyrosine-protein kinase erbB4 (ErbB4) and was linked to schizophrenia. The NRG1/ErbB4 complex is neuroprotective, can trigger synaptogenesis and plasticity, increases the expression of NMDA and GABA receptors, and can induce neuroinflammation. This complex can reduce memory formation. In Alzheimer's disease (AD) brains, NRG1 accumulates in neuritic plaques. It is difficult to determine if NRG1 has beneficial and/or detrimental effects in AD. BACE1 levels are increased in AD brains and cerebrospinal fluid (CSF) and may lead to enhanced NRG1 secretion, but no study has assessed CSF NRG1 levels in AD and mild cognitive impairment (MCI) patients.

Methods: This retrospective study included 162 patients suffering from AD dementia (54), MCI with progression to AD dementia (MCI-AD) (27), non-AD MCI (30), non-AD dementias (30), and neurological controls (27). All patients had neurological examinations, brain MRI, and neuropsychological evaluations. After written informed consent and using enzyme-linked immunosorbent assays (ELISAs), CSF samples were evaluated for Aβ1-42, Aβ1-40, total tau (T-tau), phosphorylated tau on threonine 181 (P-tau), BACE1, growth-associated protein 43 (GAP 43), neurogranin (Ng), and NRG1.

Results: Levels of NRG1 were significantly increased in the CSF of AD (+ 36%) and MCI-AD (+ 28%) patients compared to neurological controls and also non-AD MCI and non-AD dementias. In addition, in AD and MCI-AD patients, NRG1 levels positively correlated with Aβ1-42 but not with T-tau, P-tau, and BACE1 levels and negatively correlated with MMSE scores. A longitudinal follow-up study of AD patients revealed a trend (p = 0.08) between CSF NRG1 levels and cognitive decline. In the overall population, NRG1 correlated with MMSE and the synaptic biomarkers GAP 43 and neurogranin.

Conclusions: Our results showed that CSF NRG1 levels are increased in AD and MCI-AD as compared to controls and other dementias. CSF NRG1 levels are associated with cognitive evolution, and a major outcome of our findings is that synaptic NRG1 could be involved in the pathophysiology of AD. Modulating brain NRG1 activity may represent a new therapeutic target in AD.
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http://dx.doi.org/10.1186/s13195-020-00655-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372801PMC
July 2020

Dissection of synaptic pathways through the CSF biomarkers for predicting Alzheimer disease.

Neurology 2020 08 25;95(8):e953-e961. Epub 2020 Jun 25.

From the Université de Paris INSERM U1144 (M.T., E.C., J.D., J.H., C.P.), France; Clinical Neurochemistry Laboratory (A.S., K.H., A.B., H.Z., K.B.), Sahlgrenska University Hospital; Institute of Neuroscience and Physiology (A.S., K.H., A.B., H.Z., K.B.), Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; and Center of Cognitive Neurology (E.C., J.D., J.H., C.P.), Lariboisière Fernand-Widal Hospital, APHP, Paris, France.

Objective: To assess the ability of a combination of synaptic CSF biomarkers to separate Alzheimer disease (AD) and non-AD disorders and to help in the differential diagnosis between neurocognitive diseases.

Methods: This was a retrospective cross-sectional monocentric study. All participants explored with CSF assessments for neurocognitive decline were invited to participate. After complete clinical and imaging evaluations, 243 patients were included. CSF synaptic (GAP-43, neurogranin, SNAP-25 total, SNAP-25aa40, synaptotagmin-1) and AD biomarkers were blindly quantified with ELISA or mass spectrometry. Statistical analysis compared CSF levels between the various groups of AD dementias (n = 81), mild cognitive impairment (MCI)-AD (n = 30), other MCI (n = 49), other dementias (OD) (n = 49), and neurologic controls (n = 35) and their discriminatory powers.

Results: All synaptic biomarkers were significantly increased in patients with MCI-AD and AD-dementia compared to the other groups. All synaptic biomarkers could efficiently discriminate AD dementias from OD (AUC ≥0.80). All but synaptotagmin were also able to discriminate patients with MCI-AD from controls (area under the curve [AUC] ≥0.85) and those with AD dementias from controls (AUC ≥0.80). Overall, CSF SNAP-25aa40 had the highest discriminative power (AUC 0.93 between patients with AD dementias and controls or OD, AUC 0.90 between those with MCI-AD and controls). Higher levels were associated with 2 alleles of ε4.

Conclusion: All synaptic biomarkers tested had a good discriminatory power to distinguish patients with AD abnormal CSF from those with non-AD disorders. SNAP25aa40 demonstrated the highest power to discriminate AD CSF-positive patients from patients without AD and neurologic controls in this cohort.

Classification Of Evidence: This retrospective study provides Class II evidence that CSF synaptic biomarkers discriminate patients with AD from those without AD.
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http://dx.doi.org/10.1212/WNL.0000000000010131DOI Listing
August 2020

Are ketogenic diets promising for Alzheimer's disease? A translational review.

Alzheimers Res Ther 2020 04 14;12(1):42. Epub 2020 Apr 14.

INSERM U1144 Optimisation Thérapeutique en Neuropsychopharmacologie, Université de Paris, Paris, France.

Background: Brain amyloid deposition and neurofibrillary tangles in Alzheimer's disease (AD) are associated with complex neuroinflammatory reactions such as microglial activation and cytokine production. Glucose metabolism is closely related to neuroinflammation. Ketogenic diets (KDs) include a high amount of fat, low carbohydrate and medium-chain triglyceride (MCT) intake. KDs lead to the production of ketone bodies to fuel the brain, in the absence of glucose. These nutritional interventions are validated treatments of pharmacoresistant epilepsy, consequently leading to a better intellectual development in epileptic children. In neurodegenerative diseases and cognitive decline, potential benefits of KD were previously pointed out, but the published evidence remains scarce. The main objective of this review was to critically examine the evidence regarding KD or MCT intake effects both in AD and ageing animal models and in humans.

Main Body: We conducted a review based on a systematic search of interventional trials published from January 2000 to March 2019 found on MEDLINE and Cochrane databases. Overall, 11 animal and 11 human studies were included in the present review. In preclinical studies, this review revealed an improvement of cognition and motor function in AD mouse model and ageing animals. However, the KD and ketone supplementation were also associated with significant weight loss. In human studies, most of the published articles showed a significant improvement of cognitive outcomes (global cognition, memory and executive functions) with ketone supplementation or KD, regardless of the severity of cognitive impairments previously detected. Both interventions seemed acceptable and efficient to achieve ketosis.

Conclusion: The KD or MCT intake might be promising ways to alter cognitive symptoms in AD, especially at the prodromal stage of the disease. The need for efficient disease-modifying strategies suggests to pursue further KD interventional studies to assess the efficacy, the adherence to this diet and the potential adverse effects of these nutritional approaches.
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http://dx.doi.org/10.1186/s13195-020-00615-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158135PMC
April 2020

Cerebrospinal Fluid and Plasma Biomarkers do not Differ in the Presenile and Late-Onset Behavioral Variants of Frontotemporal Dementia.

J Alzheimers Dis 2020 ;74(3):903-911

Memory Research and Resources Alzheimer Center, Department of Neurology, University Hospital Center, Gui de Chauliac Hospital, Montpellier, France.

Background: Memory troubles and hippocampal atrophy are considered more frequent and focal atrophy less severe in late-onset (>65 years) than in presenile behavioral variant of frontotemporal dementia (bvFTD).

Objective: To compare cerebrospinal fluid (CSF) and plasma biomarkers in late-onset and presenile bvFTD.

Methods: Multicentric retrospective study (2007-2017) on patients with clinical diagnosis of bvFTD.

Results: This study included 44 patients (67%) with presenile and 22 (33%) with late-onset bvFTD (comparable mean disease duration; n = 11 with causal mutations). Hippocampal atrophy was more frequent (80% versus 25.8%) and severe in late-onset bvFTD (median Scheltens score: 3 [0-4] versus 1 [0-3]), without difference after adjustment for age. Lobar atrophy and focal hypometabolism/hypoperfusion were not different between groups. The median CSF Aβ1-42 and phosphorylated tau (P-tau) concentrations were in the normal range and comparable between groups. Axonal neurodegeneration biomarkers were within the normal range (CSF T-tau; plasma T-tau in late-onset bvFTD) or higher (plasma neurofilament light chain (NFL); plasma T-tau in presenile bvFTD) than the normal values, but globally not different between bvFTD groups. Plasma glial fibrillary acid protein (GFAP) was strongly increased in both bvFTD groups compared with the values in controls of the same age.

Conclusion: The CSF and plasma biomarker profiles did not suggest a more aggressive neurodegeneration in the presenile group (comparable T-tau, NFL, and GFAP levels) or the co-existence of Alzheimer's disease in the late-onset group (comparable and within normal range CSF Aβ1-42 and P-tau). The severity of the neurodegenerative process seems comparable in presenile and late-onset bvFTD.
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http://dx.doi.org/10.3233/JAD-190378DOI Listing
January 2020

Cerebrospinal fluid lipocalin 2 as a novel biomarker for the differential diagnosis of vascular dementia.

Nat Commun 2020 01 30;11(1):619. Epub 2020 Jan 30.

Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.

The clinical diagnosis of vascular dementia (VaD) is based on imaging criteria, and specific biochemical markers are not available. Here, we investigated the potential of cerebrospinal fluid (CSF) lipocalin 2 (LCN2), a secreted glycoprotein that has been suggested as mediating neuronal damage in vascular brain injuries. The study included four independent cohorts with a total n = 472 samples. LCN2 was significantly elevated in VaD compared to controls, Alzheimer's disease (AD), other neurodegenerative dementias, and cognitively unimpaired patients with cerebrovascular disease. LCN2 discriminated VaD from AD without coexisting VaD with high accuracy. The main findings were consistent over all cohorts. Neuropathology disclosed a high percentage of macrophages linked to subacute infarcts, reactive astrocytes, and damaged blood vessels in multi-infarct dementia when compared to AD. We conclude that CSF LCN2 is a promising candidate biochemical marker in the differential diagnosis of VaD and neurodegenerative dementias.
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http://dx.doi.org/10.1038/s41467-020-14373-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992814PMC
January 2020

Dose-dependent neuroprotective effect of the JNK inhibitor Brimapitide in 5xFAD transgenic mice.

Brain Res 2020 01 4;1727:146587. Epub 2019 Dec 4.

Université de Paris, INSERM UMR-S 1144, F-75006 Paris, France; Centre de Neurologie Cognitive, AP-HP, Hôpital Fernand-Widal, F-75475 Paris, France. Electronic address:

Alzheimer's disease (AD) is a neurodegenerative disease mainly affecting old people. According to the "amyloid cascade hypothesis", the accumulation of Aβ oligomers could lead to kinase activation and Tau phosphorylation. Activated kinases include c-Jun N-terminal kinase (JNK) and previous studies highlighted the beneficial effects of the JNK-specific inhibitor Brimapitide (10 mg/kg) in 5xFAD transgenic mice. Our aim was to evaluate the effects of decreasing doses of Brimapitide on cognition and neurodegeneration in early treated 5xFAD mice. Three month-old 5xFAD were intravenously treated for 6 months with either Brimapitide (3 mg/kg or 0.3 mg/kg) or Nacl. Cognition and amyloid burden, neuronal and synaptic impairments were evaluated. Low doses of Brimapitide (0.3 mg/kg) reduced neuronal degeneration and improved cognition in treated mice compared to non-treated mice. Amyloid burden and synaptic degeneration only decreased with the 3 mg/kg dose. This JNK inhibitor can afford neuroprotection but with a differential effect on amyloid deposition in 5xFAD mice. Brimapitide might partially prevent ongoing neurodegeneration in 5xFAD mice.
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http://dx.doi.org/10.1016/j.brainres.2019.146587DOI Listing
January 2020

Brain 18FDG-PET pattern in patients with alcohol-related cognitive impairment.

Eur J Nucl Med Mol Imaging 2020 02 19;47(2):281-291. Epub 2019 Aug 19.

Département de Psychiatrie et de Médecine Addictologique, Groupe Hospitalier Saint-Louis Lariboisière Fernand-Widal, Hôpital Fernand Widal, Paris, France.

Purpose: Brain positron emission tomography using 18F-fluorodeoxyglucose (18FDG-PET) provides a metabolic assessment of brain function that is useful for differential diagnosis among several neurodegenerative diseases manifested by cognitive impairment (CI). The purpose of the study is to describe the pattern of 18FDG-PET abnormalities in patients with CI related to alcohol use disorder.

Methods: Patients admitted to the addiction medicine department of a university hospital in Paris between January 2017 and October 2018 with a confirmed diagnosis of alcohol-related cognitive impairment (ARCI) or Wernicke encephalopathy (WE) were included. Brain 18FDG-PET uptake was measured after at least 1 month of monitored abstinence from alcohol. Standardized uptake values were obtained for 13 regions of interest (ROI) and normalized to the pons. Individual patients' ROI Z-scores were calculated from healthy sex- and age-matched controls provided by Cortex ID software.

Results: Twenty-five patients were included in the analysis (20 males and 5 females; mean age 57.6 years (45-76 years old)). The group consisted of 19 ARCI and 6 WE cases. The mean hypometabolism was most severe in the prefrontal medial cortex (PFM) (- 2.80 (± 1.30)), the prefrontal lateral cortex (- 2.20 (± 1.35)), and the anterior cingulate cortex (- 2.24 (± 1.19)). Hypometabolism (Z-score < - 2) was most frequent in the PFM (72.0% of the sample, N = 18). Other regions were also affected (with 5.32/13 hypometabolic ROIs on average (SD = 4.16, range 0-13)). The Z-scores in the 13 ROIs did not differ significantly between the ARCI and WE patients (p ≥ 0.05).

Conclusions: Predominant prefrontal and cingulate cortex hypometabolism was the most frequent brain 18FDG-PET pattern in our sample of patients with ARCI and WE.
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http://dx.doi.org/10.1007/s00259-019-04487-1DOI Listing
February 2020

Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer's Disease Before 51 Years.

J Alzheimers Dis 2019 ;71(1):227-243

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France.

Background: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants.

Objective: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD.

Methods: We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved.

Results: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p < 0.0001) and associated neurologic symptoms more frequently (p < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges.

Conclusion: The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages.
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http://dx.doi.org/10.3233/JAD-190193DOI Listing
October 2020

How many patients are eligible for disease-modifying treatment in Alzheimer's disease? A French national observational study over 5 years.

BMJ Open 2019 06 24;9(6):e029663. Epub 2019 Jun 24.

Neurology, CHU de la Pitiè Salpêtrière-AP-HP, Paris, France.

Objective: We aimed to study the epidemiology of the prodromal and mild stages of Alzheimer's disease (AD) patients who are eligible for clinical trials with disease-modifying therapies.

Settings: We analysed two large complementary databases to study the incidence and characteristics of this population on a nationwide scope in France from 2014 to 2018. The National Alzheimer Database contains data from 357 memory centres and 90 private neurologists. Data from 2014 to 2018 have been analysed.

Participants: Patients, 50-85 years old, diagnosed with AD who had an Mini-Mental State Exam (MMSE) score of ≥20 were included. We excluded patients with mixed and non-AD neurocognitive disorders.

Primary Outcome Measure: Descriptive statistics of the population of interest was the primary measure.

Results: In the National Alzheimer Database, 550 198 patients were assessed. Among them, 72 174 (13.1%) were diagnosed with AD and had an MMSE ≥20. Using corrections for specificity of clinical diagnosis of AD, we estimated that about 50 000 (9.1%) had a prodromal or mild AD. In the combined electronic clinical records database of 11 French expert memory centres, a diagnosis of prodromal or mild AD, certified by the use of cerebrospinal fluid AD biomarkers, could be established in 195 (1.3%) out of 14 596 patients.

Conclusions: AD was not frequently diagnosed at a prodromal or mild dementia stage in France in 2014 to 2018. Diagnosis rarely relied on a pathophysiological marker even in expert memory centres. National databases will be valuable to monitor early stage AD diagnosis efficacy in memory centres when a disease-modifying treatment becomes available.
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http://dx.doi.org/10.1136/bmjopen-2019-029663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597622PMC
June 2019

What is the clinical impact of cerebrospinal fluid biomarkers on final diagnosis and management in patients with mild cognitive impairment in clinical practice? Results from a nation-wide prospective survey in France.

BMJ Open 2019 05 30;9(5):e026380. Epub 2019 May 30.

Université de Paris, UMRS-1144, Inserm, F-75010 Paris, France.

Objectives: New diagnostic criteria for Alzheimer's disease (AD) include cerebrospinal fluid (CSF) biomarkers that allow diagnosis at the stage of mild cognitive impairment (MCI). However, the impact of CSF biomarkers in MCI populations in clinical practice has been poorly evaluated. The objective of this study is to assess the use and impact in clinical practice of AD CSF biomarkers in French memory clinics.

Design: We performed a nation-wide, prospective survey between March 2012 and September 2014. Data over the same period was extracted from the French National Database (Banque Nationale Alzheimer, BNA) and compared with the results of the survey.

Setting: 29 secondary and tertiary memory clinics in France.

Participants: Clinicians prescribing lumbar puncture (LP) in order to measure AD CSF biomarkers. Clinicians completed a two-part questionnaire for each of their patients undergoing LP.

Primary And Secondary Outcome Measures: Assessment of diagnosis, level of confidence before and after CSF biomarkers and impact on management in patients who underwent LP for CSF AD biomarkers in clinical routine.

Results: 977 questionnaires were completed, of which 61 were excluded because of unknown initial/final diagnosis or non-contributory CSF results. Of 916 patients reported, 153 (16.7%) had MCI as the initial diagnosis, of which 51 (33.3%) displayed an AD profile. CSF biomarkers resulted in a change in diagnosis in 44 patients (28.8%). Confidence level significantly increased after LP (8.3±1.4vs 6.73±1.18, p<0.0001), and CSF results modified management in 71/156 patients (46.4%), including 36 (23.5%) enrolled in clinical trials. Comparison of change in diagnosis with the BNA population revealed no difference (32.24%, p=0.4).

Conclusion: This nation-wide survey, reflecting clinical practice in French memory clinics, describes the impact of CSF AD biomarkers in patients with MCI in clinical practice.
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http://dx.doi.org/10.1136/bmjopen-2018-026380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549619PMC
May 2019

Biomarker profiles of Alzheimer's disease and dynamic of the association between cerebrospinal fluid levels of β-amyloid peptide and tau.

PLoS One 2019 14;14(5):e0217026. Epub 2019 May 14.

Cognitive Neurology Center, Saint Louis-Lariboisiere-Fernand Widal Hospital, AP-HP, Université de Paris, Paris, France.

Objective: To investigate the relationship between cerebrospinal fluid (CSF) β-amyloid peptide (Aβ42) and CSF Tau in a large population of patients referred to memory clinics for investigation of cognitive dysfunction.

Methods: We analyzed Alzheimer's disease (AD) biomarkers in CSF taken from 3565 patients referred to 18 French memory clinics. Patients were classified into four profiles according to levels of CSF biomarkers (A: amyloidosis, N: neurodegeneration). The association between CSF Tau and CSF Aβ42 were analyzed using general linear regression models, in the overall population and stratified by biomarkers profiles. We compared linear and quadratic models using Akaike information criterion. We also assessed change in biomarker profiles in a subset of patients who had 2 assessments of biomarkers.

Results: CSF Tau was negatively associated with CSF Aβ42 in the overall population, following a non-linear quadratic model. However, the nature of this association was different in the 4 profiles: positive association in A-N- profile, negative association in A-N+ and A+N+ profiles, lack of association in A+N- patients. When considering patients with longitudinal data on profiles, 36% of those initially classified as A-N+ evolved to an A+N+ profile.

Conclusions: The nature of the association between CSF Aβ42 and CFS Tau depends on the A/N profiles of patients. These results suggest an increase in CSF Aβ42 early in the disease before its decline while tau pathology progresses, this pattern is particularly observed in non-APOE4 subjects. This phenomenon may explain why some patients with neurodegeneration only markers convert to an AD profile (A+N+) over time.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217026PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516653PMC
February 2020

CSF level of β-amyloid peptide predicts mortality in Alzheimer's disease.

Alzheimers Res Ther 2019 03 28;11(1):29. Epub 2019 Mar 28.

Cognitive Neurology Center, Saint Louis - Lariboisiere - Fernand Widal Hospital, AP-HP, Université Paris Diderot, Sorbonne Paris Cité, 200 rue du Faubourg Saint Denis, 75010, Paris, France.

Objective: Alzheimer's disease (AD) is the sixth leading cause of death, with an average survival estimated between 5 and 10 years after diagnosis. Despite recent advances in diagnostic criteria of AD, few studies have used biomarker-based diagnostics to determine the prognostic factors of AD. We investigate predictors of death and institutionalization in a population of AD patients with high probability of AD physiopathology process assessed by positivity of three CSF biomarkers.

Methods: Three hundred twenty-one AD patients with abnormal values for CSF beta-amyloid peptide (Aβ42), tau, and phosphorylated tau levels were recruited from a memory clinic-based registry between 2008 and 2017 (Lariboisiere hospital, Paris, France) and followed during a median period of 3.9 years. We used multivariable Cox models to estimate the hazard ratio (HR) of death and institutionalization for baseline clinical data, genotype of the apolipoprotein E (APOE), and levels of CSF biomarkers.

Results: A total of 71 (22%) patients were institutionalized and 57 (18%) died during the follow-up. Greater age, male sex, lower MMSE score, and lower CSF Aβ42 level were associated with an increased risk of mortality. One standard deviation lower CSF Aβ42 (135 pg/mL) was associated with a 89% increased risk of death (95% CI = 1.25-2.86; p = 0.002). This association was not modified by age, sex, education, APOE ε4, and disease severity. There was no evidence of an association of tau CSF biomarkers with mortality. None of the CSF biomarkers were associated with institutionalization.

Conclusions: Lower CSF Aβ42 is a strong prognostic marker of mortality in AD patients, independently of age or severity of the disease. Whether drugs targeting beta-amyloid peptide could have an effect on mortality of AD patients should be investigated in future clinical trials.
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http://dx.doi.org/10.1186/s13195-019-0481-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440001PMC
March 2019

[Biomarkers of Alzheimer's disease in older and oldest old patients].

Geriatr Psychol Neuropsychiatr Vieil 2019 03;17(1):65-72

Centre de neurologie cognitive Paris-Nord, Hôpital Lariboisière-Fernand Widal, AP-HP, Paris, France, Inserm U942 BioCanVas, Hôpital Lariboisière, Paris, France.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in older patients, leading to progressive cognitive impairment. Brain amyloid and tau deposits are the main pathological features of the disease and may appear several decades before the onset of clinical symptoms. The biomarkers of AD, measured in the plasma or in the cerebrospinal fluid, reflect the brain accumulation of beta-amyloid and tau. Therefore, they enable early and more accurate etiological diagnosis when combined with brain neuroimaging and neuropsychological assessment. The new definition of AD brings biomarkers forward, shifting the focus from symptoms to brain changes in living patients. The growing body of evidence from longitudinal studies has established their ability to improve the accuracy of AD diagnosis but also to predict the progression of cognitive impairment. The biomarkers of AD are also important for recruiting participants who are at increased risk of developing AD dementia in drug trials. Beyond their role in clinical research, these tools have been increasingly used for several years in clinical practice in secondary and tertiary-referral memory clinics. However, interpreting the results of AD biomarkers may be delicate in the oldest old patients with comorbidity. A tailored, patient-centered decision is mandatory in these situations. Complicated ethical issues may also arise in using these biomarkers in asymptomatic subjects. In the absence of clear guidelines for their utilization, we hereby discuss their potential interests and limitations in older adults.
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http://dx.doi.org/10.1684/pnv.2019.0779DOI Listing
March 2019

Bright light therapy improved sleep disturbances in a patient with dementia with Lewy bodies.

Psychogeriatrics 2020 Jan 19;20(1):124-125. Epub 2019 Mar 19.

Paris Diderot University - Paris VII, Paris, France.

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http://dx.doi.org/10.1111/psyg.12448DOI Listing
January 2020