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Background The overall prevalence of headaches decreases with age; however headaches remain frequent in aged individuals who are also affected by other disorders such as cognitive decline. Despite the high frequency of both conditions in these persons, the association between headaches and cognitive decline is underexplored, underdiagnosed and poorly understood. Objective In the present article, we aim to provide a comprehensive review of existing data concerning the link between headache and cognitive decline. Methods We undertook a systematic literature review to report articles that focus on headaches (including all types of headaches) and neurocognitive disorders of degenerative causes. Results Only 9 studies have explored the association between headaches and neurocognitive decline. Methods were highly variable from population-based study to short series of patients using either database or questionnaire during consultation. Studies focusing on Familial Alzheimer's Disease revealed a very high prevalence of headaches in mutation carrier patients compared to non-carrier patients. Conclusion The association between headaches and cognitive decline is underexplored. Future studies are needed to address the pathophysiological mechanisms to improve the treatment of these underestimated headaches.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia have a strong clinical, genetic, and pathological connection but association of ALS with Alzheimer’s disease (AD) is seldom reported. We report a series of 5 cases of AD associated with ALS. Our patients presented with cognitive deterioration with episodic memory impairment meeting criteria for AD. ALS occurred subsequently in all cases and its phenotype was not homogenous. Amyloid process was confirmed in four cases with cerebrospinal fluid biomarkers. One case underwent postmortem exam, demonstrating hallmarks lesions of both diseases. This series highlights that ALS-AD phenotype could be a specific underexplored entity.

Background: The TNI-93 is a quick memory test designed for all patients regardless of their education level. A significant proportion of patients with Alzheimer’s disease (AD) are illiterate or poorly educated, and only a few memory tests are adapted for these patients. Objective: In this study we aimed at assessing the diagnostic value of the TNI-93 for diagnosis of patients with biologically confirmed amyloid status. Methods: We included all patients who had an analysis of AD cerebrospinal fluid biomarkers, a neuropsychological assessment including a TNI-93 and an anatomical brain imaging at Avicenne Hospital between January 2009 and November 2019. We compared the TNI-93 scores in patients with amyloid abnormalities (A+) and patients without amyloid abnormalities (A-) according to the AT(N) diagnostic criteria. Results: 108 patients were included (mean age: 66.9±8.5 years old, mean education level: 8.9±5.2 years). Patients from the A + group (N= 80) were significantly more impaired than patients from the A- group (N= 28) on immediate recall (A+: 5.9±2.8; A-: 7.4±2.6; p = 0.001), free recall (A+: 3.5±2.7; A-: 5.9±2.8; p ≤ 0.001), total recall (A+: 5.7±3.5; A-:7.8±2.8; p ≤ 0.001), and on number of intrusions during the recall phase (A+: 1±1.8; A-: 0.1±0.3; p = 0.002). ROC curves revealed that the best scores to discriminate A + from A- patients were immediate recall (Area under curve (AUC): 0.70), number of encoding trials (AUC: 0.73), free recall (AUC: 0.74), and total recall (AUC: 0.74). Conclusion: The TNI-93’s immediate, free, and total recalls are valuable tools for the 39 diagnosis of AD.

Post-lumbar puncture headache is the main adverse event from lumbar puncture and occurs in 3.5% to 33% of patients, causing functional and socio-professional disability. We searched the post-lumbar puncture headache literature and, based on this review and personal expertise, identified and addressed 19 frequently asked questions regarding post-lumbar puncture headache risk factors and prevention. Among the nonmodifiable factors, older age is associated with a lower incidence of post-lumbar puncture headache, while female sex, lower body mass index, and history of headache might be associated with increased risk. The use of atraumatic, noncutting needles is the most effective intervention for post-lumbar puncture headache prevention. These needles are not more difficult to use than cutting needles. Other commonly recommended measures (eg, fluid supplementation, caffeine) appear unhelpful, and some (eg, bed rest) may worsen post-lumbar puncture headache.

International audience; Cognitive decline (CD) is a common condition amongst elderly, affecting memory, language or thinking. Patients experiencing CD have a higher incidence rate of post-operative neurocognitive disorders 1. Moreover, for a fraction of these patients

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.

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 11 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 [18 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, [18 F]FDG-PET/computed tomography (CT) was available as part of routine care. No subject had a clinical history of ICH. Regional standardized [18 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, [18 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.

Many patients who have suffered from acute COVID infections have long-lasting symptoms affecting several organs including the brain. This long COVID status can include “brain fog” and cognitive deficits that can disturb activities of daily living and can delay complete recovery. Here, we report two cases of neurological long COVID with abnormal FDG PET findings marked by hypometabolic regions of the cingulate cortex.

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.

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 Lariboisiere 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.

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.

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.

Background Dementia with Lewy body (DLB) is a common neurodegenerative disease that warrants specific care, which remains largely underdiagnosed. Our objective was to assess the knowledge of DLB by health professionals in comparison with that of Alzheimer's disease (AD), to better understand the reasons of its under-diagnosis. Methods We conducted a descriptive and analytical study processing the results of an online questionnaire submitted to French healthcare professionals between December 1, 2020 and March 1, 2021. Results A total of 490 healthcare professionals responded to the questionnaire. We observed a poorer knowledge of DLB compared to AD both subjective as highlighted on the self-assessment questionnaires and objective since the diagnostic criteria and therapeutic specificities were less known for DLB compared to AD. Conclusions DLB appears as a disease that is still too poorly known by health professionals. To improve training is therefore a decisive objective in order to optimize the therapeutic care and support of patients with DLB and their relatives.

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) [1] , [2] , [3] . 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 one month of monitored abstinence from alcohol. Standardized uptake values (SUV) 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. A principal component analysis (PCA) on the subjects’ ROIs SUV ratios was conducted. 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 (ACC) (−2.24 [± 1.19]). Hypometabolism (Z-score Table 1 ). 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). The PCA identified two principal components. The first principal component explains 59.49% of the variance and it is formed by the clustering of six specific ROIs: sensorimotor cortex, parietal superior cortex, parietal inferior cortex, precuneus, occipital lateral cortex and primary visual cortex. The second explains 14.52% of the variance and it is formed by three ROIs: the PFM, ACC and temporal mesial cortex. Conclusions Predominant prefrontal and cingulate cortex hypometabolism was the most frequent brain 18FDG-PET pattern in our sample of patients with ARCI and WE. We believe that brain 18FDG-PET could be a potential imaging biomarker of ARCI, and predictive values for both differential diagnosis and prognosis should be prospectively tested.

Purpose of review Ketogenic diets (KD) are validated treatments of pharmacoresistant epilepsy. Their interest in neurodegenerative diseases such as Alzheimer's disease (AD) has been suggested, because ketone bodies may reduce neuroinflammation, improve neurotransmitters transport pathway, synaptic maintenance, and reduce brain β-amyloid deposition. In this updated review, we aimed at critically examining the evidence of the past 2 years regarding KD or ketogenic supplements (KS) on cognitive and biological/neuropathological outcomes. We conducted our search in preclinical studies (animal models of AD) or in humans with or without cognitive impairment. Recent findings Overall, 12 studies were included: four in animal models of AD and eight in humans. In preclinical studies, we found additional evidence for a decrease in cerebral inflammation as well as in specific features of AD: β-amyloid, aggregates of tau protein under KD/KS. Several AD mouse models experienced clinical improvements. Human studies reported significant cognitive benefits, improved brain metabolism and biomarkers change under KD/KS, despite rather short-term interventions. Adherence to KD or KS was acceptable with frequent, but minor gastrointestinal adverse effects. Summary The present review gathered additional evidence for both pathophysiological and clinical benefits of KS/KD in AD. Further studies are warranted with a biomarker-based selection of AD participants and long-term follow-up.

Sleep dysregulation is a feature of dementia but it remains unclear whether sleep duration prior to old age is associated with dementia incidence. Using data from 7959 participants of the Whitehall II study, we examined the association between sleep duration and incidence of dementia (521 diagnosed cases) using a 25-year follow-up. Here we report higher dementia risk associated with a sleep duration of six hours or less at age 50 and 60, compared with a normal (7 h) sleep duration, although this was imprecisely estimated for sleep duration at age 70 (hazard ratios (HR) 1.22 (95% confidence interval 1.01–1.48), 1.37 (1.10–1.72), and 1.24 (0.98–1.57), respectively). Persistent short sleep duration at age 50, 60, and 70 compared to persistent normal sleep duration was also associated with a 30% increased dementia risk independently of sociodemographic, behavioural, cardiometabolic, and mental health factors. These findings suggest that short sleep duration in midlife is associated with an increased risk of late-onset dementia., Sleep dysregulation has been linked to dementia, but it is unknown whether sleep duration earlier in life is associated with dementia risk. Here, the authors show higher dementia risk associated with short sleep duration (six hours or less) in a longitudinal study of middle and older age adults.

Background: Surgery and anesthesia can result in temporary or permanent deterioration of the cognitive functions, for which causes remain unclear. In this pilot study, we analyzed the determinants of cognitive decline following a non-emergency elective prosthesis implantation surgery for hip or knee.Methods: Prospective single-center study investigating psychomotor response time and changes in MoCA scores between the day before (D-1) and 2 days after (D+2) following surgery in Lariboisière Hospital (Paris, France). 60 patients (71.9±7.1-year-old, 72% women) were included. Collected data consisted in sociodemographic data, treatment, comorbidities and type of anesthesia (local, general or both). Furthermore, we evaluated pain and well-being before as well as after the surgery using point scales. Findings: Post-operative (D+2) MoCA scores were significantly lower than pre-operative ones (D-1) with a difference of 2.25+3.0pts (p=0.004), we found no significant difference between locoregional and general anesthesia. Pre-operative benzodiazepine or anticholinergic treatment were also associated to a drop in MoCA scores (p=0.023). Finally, the use of ketamine during anesthesia (p=0.034) and the well-being (p=0.023) evaluated before intervention, were both linked to a reduced cognitive impact.Discussion: In this pilot study, we observed a post-operative short-term cognitive decline following a lower limb surgery. We also identified pre and perioperative independent factors linked to cognitive decline following surgery. In a next stage, a larger cohort should be used to confirm the impact of these factors on cognitive decline.

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 18 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 P Results: Fourteen patients fulfilling the Boston criteria for probable CAA (≥2 exclusively lobar microbleeds) were identified. Significant hypometabolism ( P range, 0.047 to 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.

Background There is limited evidence on the characteristics and outcome of patients with dementia hospitalised for novel coronavirus infection (COVID-19). Method We conducted a prospective study in 2 gerontologic COVID units in Paris, France, from March 14, 2020, to May 7, 2020. Patients with dementia hospitalised for confirmed COVID-19 infection were systematically enrolled. A binary logistic regression analysis was performed to identify factors associated with mortality at 21 days. Results We included 125 patients. Median age was 86 (IQI 82–90); 59.4% were female. Most common causes of dementia were Alzheimer’s disease, mixed dementia and vascular dementia. 67.2% had ≥ 2 comorbidities; 40.2% lived in a long-term care facility. The most common symptoms at COVID-19 onset were confusion and delirium (82.4%), asthenia (76.8%) and fever (72.8%) before polypnea (51.2%) and desaturation (50.4%). Falls were frequent at the initial phase of the disease (35.2%). The fatality rate at 21 days was 22.4%. Chronic kidney disease and CRP at admission were independent factors of death. Persisting confusion, mood and behavioural disorders were observed in survivors (19.2%). Conclusion COVID-19 in demented individuals is associated with severe outcome in SARS-CoV-2 infection and is characterised by specific clinical features and complications, with confusion and delirium at the forefront. COVID-19 testing should be considered in front of any significant change from baseline.

International audience; The behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome resulting from various causes of neuronal demises associated with frontotemporal lobar degeneration. Symptoms include behavioral and personality changes, social cognitive impairment, and executive function deficits. There is a significant clinical overlap between this syndrome and various primary psychiatric disorders (PPD). Structural and functional neuroimaging are considered helpful to support the diagnosis of bvFTD, but their sensitivity and specificity remain imperfect. There is growing evidence concerning the potential of neurofilaments as biomarkers reflecting axonal and neuronal lesions. Ultrasensitive analytic platforms have recently enabled neurofilament light chains' (NfL) detection not only from cerebrospinal fluid but also from peripheral blood samples in FTD patients. In this short review, we present recent advances and perspectives for the use of NfL assessments as biomarkers of neuroaxonal damage to differentiate bvFTD from primary psychiatric disorders.

Bipolar disorder is associated with an increased risk of dementia with aging. Little is known regarding this association, limiting appropriate diagnosis and management. We aimed to describe the characteristics of bipolar patients with late cognitive impairment for whom the hypothesis of an underlying neurodegenerative disease had been raised. We performed a retrospective multicenter study, recruiting bipolar patients over 50 years old from five French tertiary memory centers who had undergone cerebrospinal fluid (CSF) biomarker assessment for Alzheimer’s disease (AD). Clinical, neuropsychological, and paraclinical characteristics were analyzed and 78 patients were included. The mean age at the onset of cognitive impairment was 62.4 years (±9.2). The mean MMSE score was 22.8 (±4.5), the mean FAB was 11.7 (±3.9), and the mean FCRST was 15.8 (±7.4)/36.8 (±9.7) (free/total recall). A total of 48.6% of the patients displayed cognitive fluctuations, and 38.2% showed cognitive improvement during follow-ups, and 56.3% of the patients showed Parkinsonism, of which 12.7% had never received antipsychotics. Among patients who underwent DAT-scans, 35.3% displayed dopaminergic denervation, 10.3% of patients had CSF AD biological signature (“A+ T+” profile), while 56.4% had other abnormal CSF profiles. Thus, clinical presentation was dominated by executive dysfunction, episodic memory impairment, fluctuating cognition, and a high frequency of Parkinsonism. Specifically, high frequency of delusional episodes suggests limited tolerance of psychotropic drugs. Most patients had abnormal CSF biomarker profiles, but only a minority displayed AD’s specific biomarker signature. Therefore, while our results unveil shared common neurocognitive features in bipolar patients with cognitive impairment of suspected neurodegenerative origin they suggest a participation of various underlying pathologies rather than a common degenerative mechanism in the pathophysiology of this condition.

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 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.

Background: Synaptic proteins are increasingly studied as biomarkers for synaptic dysfunction and loss, which are early and central events in Alzheimer’s disease (AD) and strongly correlate with the degree of cognitive decline. In this study, we specifically investigated the synaptic binding partners neurexins (NRXN) and neuroligins (Nlgn), to assess their biomarker’s potential. Methods: We developed a parallel reaction monitoring mass spectrometric method for the simultaneous quantification of NRXNs and Nlgns in cerebrospinal fluid (CSF) of neurodegenerative diseases, focusing on AD. Specifically, NRXN-1α, NRXN-1β, NRXN-2α, NRXN-3α and Nlgn1, Nlgn2, Nlgn3 and Nlgn4 proteins were targeted. Findings: The proteins were investigated in a clinical cohort including CSF from controls (n=22), mild cognitive impairment (MCI) due to AD (n=44), MCI due to other conditions (n=46), AD (n=77) and a group of non-AD dementia (n=28). No difference in levels of NRXNs and Nlgns was found between AD (both at dementia and MCI stages) or controls or the non-AD dementia group for any of the targeted proteins. NRXN and Nlgn proteins correlated strongly with each other, but only a weak correlation with the AD core biomarkers and the synaptic biomarkers neurogranin and growth-associated protein 43, was found, possibly reflecting different pathogenic processing at the synapse. Interpretation: We conclude that NRXN and Nlgn proteins do not represent suitable biomarkers for synaptic pathology in AD. The panel developed here could aid in future investigations of the potential involvement of Nlgns and NRXNs in synaptic dysfunction in other disorders of the central nervous system. Funding: HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG- 720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen for Gamla Tjanarinnor, Hjarnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB- 201809- 2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). The funders had no role in data collection, analysis, or decision to publish. EC received support from Gamla tjanarinnor, Stohnes stiftelse, Demensfonden and Emil och Maria Palms stiftelse. AV is supported by Fondation Ophtalmologique Adolphe de Rothschild, Fondation Chatrier and AAIHP association. Declaration of Interest: HZ has served at scientific advisory boards for Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. KB has served as a consultant or at advisory board for Axon, Biogen, CogRx, Lilly, MegQu, Novartis and Roche Diagnostics. OH has acquired research support (for the institution) from Roche, Pfizer, GE Healthcare, Biogen, Eli Lilly and AVID Radiopharmaceuticals. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen and Roche. All other authors have nothing to declare. Ethical Approval: The use of these patient samples was approved by the Ethics Committee at the University of Gothenburg (EPN 140811).

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.

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 behavioural/mood variant, the cognitive variant and the mixed behavioural/cognitive variant. Cerebral MRI revealed signs of diffuse atrophy with abnormal axonal findings using the diffusion tensor imaging methods. Cerebral PET tau revealed increased standardised 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.

BackgroundNeurogranin (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.MethodsIn 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).ResultsThe 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 P = 0.00001, respectively) and in patients with MCI-AD (5.69 ng/L,P P 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).ConclusionsAssessments 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.

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.

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., In a case-control study using cerebrospinal fluid biomarkers, Hana Saddiki and colleagues investigate how age is related to the association between Apolipoprotein E genotype and Alzheimer's disease, among individuals with and without Alzheimer's disease in Europe and the US., Author summary Why was this study done? The ε4 allele of apolipoprotein E (APOE) gene (APOE4) and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The recent development of diagnostic criteria based on biomarkers that reflect brain β-amyloid and tau lesions (β-amyloid deposition, pathologic tau, neurodegeneration [A/T/N] classification]) increases homogeneity in diagnosed cases. The strength of association of AD with risk factors can be better determined using biomarker-based AD compared with AD diagnosis based only on clinical criteria because the latter are known to lack specificity as a result of difficulties in ruling out other causes of dementia. What did the researchers do and find? We compared the overall and age-specific association between APOE4 and AD using a case–control study that included 1,593 AD cases from memory clinics with positive cerebrospinal fluid biomarkers and 11,723 dementia-free controls drawn from two longitudinal cohort studies. The use of a large number of cases and controls allows assessment of whether the association between APOE4 and AD is dependent on age. Compared with controls, patients with AD were more likely to carry one APOE4 (odds ratio [OR] = 4.6) or two APOE4 (OR = 25.3). This association was significantly modified by age, with the strongest association seen between 65 and 70 years of age and weaker associations at the two tails of the age distribution. What do these findings mean? Incorporating biomarkers for diagnosis of AD identified an association with APOE4 that is apparently greater than has been previously reported using clinical diagnosis of the disease. The impact of APOE4 on the risk of AD was strongest between the 65 and 70 years of age, earlier than the mean age at diagnosis in this study, which was 72.8 years.

Background CSF Alzheimer's disease (AD) biomarkers allow classifying individuals based on their levels of amyloid and neurodegeneration pathologies. Objective To investigate the distribution of AD biomarker profiles from patients suffering from cognitive disorders. Methods We analyzed 3001 patients with cognitive disorders and referred by 18 French memory clinics located in and around Paris. Patients were classified as normal, amyloidosis (A+/N-), amyloidosis and neurodegeneration (A+/N+) or suspected non-AD pathophysiology (SNAP), according to their CSF levels of biomarkers. Analysis were performed for the overall population and stratified by gender, age quintiles, and Mini-Mental State Examination (MMSE) score quintiles. Results were compared to previous findings in cohorts of healthy elderly adults. Results 37% of the sample were classified as A+/N+, 22% were classified A+/N-, and 15% as SNAP. The A+/N+ profile was associated with female gender, advanced age, and lower MMSE score, while the A+/N-profile was observed more frequently in men and the distribution was stable across age and MMSE. The SNAP profile showed no association with gender or age, was less frequent in patients with lower MMSE, and had a lower repartition than the one previously reported in asymptomatic populations. Conclusions While A+/N+ patients had the clinical characteristics typically observed in AD, A+/N-patients had a different epidemiological pattern (higher frequency in men, no association with advanced age or lower MMSE). The SNAP profile was less frequent than previously reported in the general elderly population, suggesting that this profile is not a frequent cause of memory impairment in this population.

Background: Few patients with a normal cerebrospinal fluid (CSF) biomarker profile fulfill the clinical criteria for Alzheimer disease (AD). Objective: The aim of this study was to test the hypothesis of misdiagnoses for these patients. Method: Patients from the e-PLM centers fulfilling the core clinical criteria for probable AD dementia or mild cognitive impairment due to AD (AD-MCI), with normal CSF Aβ1-42, T-tau and P-tau biomarkers and clinical follow-up, were included. Clinical and imaging data were reviewed by an independent board, from baseline (visit with clinical evaluation and CSF analysis) to the end of the follow-up, for a final diagnosis. Results: In the e-PLM cohort of 1098 AD patients with CSF analysis, 37 (3.3%) patients (20 with AD dementia core clinical criteria and 17 with AD-MCI core clinical criteria) had normal CSF biomarker profile and a clinical follow-up. All patients presented with episodic memory impairment and 27 (73%) had medial temporal lobe atrophy on MRI-scan. After a median follow-up of 36 months (range 7-74), the final diagnosis was AD MCI or dementia for 9 (24%) patients, and unlikely due to AD for 28 (76%) patients. A misdiagnosis was corrected in 18 (49%) patients (mood disorders, non-AD degenerative dementia, vascular cognitive impairment, alcohol cognitive disorders, temporal epilepsy and hippocampal sclerosis), and 10 (27%) patients had cognitive disorders of undetermined etiology. Conclusion: AD diagnosis (MCI or dementia) with normal CSF biomarkers is a rare condition. A clinical follow- up is particularly recommended to consider an alternative diagnosis.

Alzheimer's disease (AD) is characterized by accumulations of amyloid-β (Aβ42) and hyperphosphorylated tau proteins, associated with neuroinflammation, synaptic loss, and neuronal death. Several studies indicate that c-Jun N-terminal kinase (JNK) is implicated in the pathological features of AD. We have investigated in 5XFAD mice, the therapeutic effects of Brimapitide, a JNK-specific inhibitory peptide previously tested with higher concentrations in another AD model (TgCRND8). Three-month-old 5XFAD and wild-type littermate mice were treated by intravenous injections of low doses (10 mg/kg) of Brimapitide every 3 weeks, for 3 or 6 months (n = 6-9 per group). Cognitive deficits and brain lesions were assessed using Y-maze, fear-conditioning test, and histological and biochemical methods. Chronic treatment of Brimapitide for 3 months resulted in a reduction of Aβ plaque burden in the cortex of 5XFAD treated mice. After 6 months of treatment, cognitive deficits were reduced but also a significant reduction of cell death markers and the pro-inflammatory IL-1β cytokine in treated mice were detected. The Aβ plaque burden was not anymore modified by the 6 months of treatment. In addition to modulating cognition and amyloid plaque accumulation, depending on the treatment duration, Brimapitide seems experimentally to reduce neuronal stress in 5XFAD mice.

BackgroundDifferential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) is not straightforward, especially in the early stages of disease. We compared AD biomarkers (phospho-Tau181, total-Tau, Aβ42 and Aβ40) in cerebrospinal fluid (CSF) of patients with DLB and AD, focusing especially on the prodromal stage.MethodsA total of 1221 CSF were collected in different memory centres (ePLM network) in France and analysed retrospectively. Samples were obtained from patients with prodromal DLB (pro-DLB; n=57), DLB dementia (DLB-d; n=154), prodromal AD (pro-AD; n=132) and AD dementia (n=783), and control subjects (CS; n=95). These centres use the same diagnostic procedure and criteria to evaluate the patients.ResultsIn patients with pro-DLB, CSF Aβ42 levels appeared much less disrupted than in patients at the demented stage (DLB-d) (Ppro-DLB; PDLB-d). On average, Aβ40 levels in patients with DLB (pro-DLB and DLB-d) were much below those in patients with pro-AD (P181 levels were unaltered in patients with DLB (pro-DLB and DLB-d).ConclusionsReduced levels of CSF Aβ42 were found in patients with DLB but rather at a later stage, reaching those of patients with AD, in whom Aβ42 levels were decreased even at the prodromal stage. At the prodromal stage of DLB, the majority of patients presented a normal CSF profile. CSF t-Tau and phospho-Tau181 were the best biomarkers to discriminate between AD and DLB, whatever the stage of disease.

The role of biomarkers in clinical research was recently highlighted in the new criteria for the diagnosis of Alzheimer's disease. Cerebro-spinal fluid (CSF) biomarkers (total Tau protein, threonine 181 phosphorylated Tau protein and amyloid Aβ1-42 peptide) are associated with cerebral neuropathological lesions observed in Alzheimer's disease (neuronal death, neurofibrillary tangle with abnormal Tau deposits and amyloid plaque). Aβ1-40 amyloid peptide dosage helps to interpret Aβ1-42 results. As suggested in the latest international criteria and the French HAS (Haute Autorite de sante) recommendations, using theses CSF biomarkers should not be systematic but sometimes could be performed to improve confidence about the diagnostic of Alzheimer's disease in young subjects or in complex clinical situations. Future biomarkers actually in development will additionally help in diagnostic process (differential diagnosis) and in prognostic evaluation of neurodegenerative diseases.

International audience; Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders in older adults, affecting millions of individuals worldwide and leading to irreversible cognitive decline. The main neuropathological features of AD are brain amyloid deposition and neurofibrillary tangles. The biomarkers of AD are highly accurate in detecting these pathophysiological and neuropathological changes, up to several decades before the onset of cognitive impairment. They specifically reflect the presence of abnormal proteins in the brain, and can be measured reliably in the cerebrospinal fluid of affected individuals and in plasma for research purposes. Their implementation in clinical practice, together with neuropsychological assessment and neuroimaging, strongly increases diagnostic precision. Thus, amyloid and tau biomarkers can help rule out differential diagnoses such as vascular cognitive impairment or frontotemporal lobar degeneration. They also enable earlier diagnosis and are used in research to characterize the preclinical stage of AD. The new definition of AD has highlighted the usefulness of these biomarkers, shifting the focus from symptoms to biological and brain changes in living patients. Recent longitudinal studies demonstrated the ability of these biomarkers to predict future cognitive decline, regardless of the stage of the disease. Ongoing drug trials against AD systematically require diagnostic confirmation with biomarkers. Apart from clinical research, they have been increasingly used for several years in clinical practice, in secondary and tertiary-referral memory clinics. Nevertheless, their use has been raising ethical issues, in particular in the oldest old or in patients with multimorbidity. Their interpretation in patients older than 90 years is limited by the lack of evidence. The implications of a misdiagnosis of AD should be taken into account. Besides, there may be discrepancies between the biological diagnosis and the clinical course of the disease. In the absence of clear guidelines for their utilization, we hereby discuss their potential interests and limitations in older individuals.

In presence of lobar microbleeds, the exact clinical features related to the level of Aβ42, Aβ40 and to the Aβ40/Aβ42 ratio in the cerebrospinal fluid (CSF) are poorly known. We analyzed in 28 consecutive patients with such lesions, whose clinical or additional magnetic resonance imaging features are related to these biomarkers. The results showed that the presence of absence of hypertension, the extent or the antero-posterior distribution of white matter hyperintensities, the presence or absence of vascular lesions in the deepest parts of the brain, and the presence of dementia are related to variations of Aβ42, Aβ40 or of the Aβ40/Aβ42 ratio in the cerebrospinal fluid.

International audience; 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

ObjectiveTo 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.MethodsThis 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.ResultsAll 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 APOE ε4.ConclusionAll 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 evidenceThis retrospective study provides Class II evidence that CSF synaptic biomarkers discriminate patients with AD from those without AD.

International audience; Context: Cerebrospinal fluid (CSF) biomarkers are valuable tools for the diagnosis of neurological diseases. We aimed to investigate within a retrospective multicentric study the final diagnosis associated with very high CSF Tau levels and to identify patterns of biomarkers that would differentiate them in clinical practice, to help clinical biologists into physicians' counseling.Patients and methods: Within the national multicentric network ePLM, we included 1743 patients from January 1, 2008, to December 31, 2013, with CSF biomarkers assayed by the same Innotest assays (protein Tau, phospho-Tau [pTau], and Aβ 1-42). We identified 205 patients with protein Tau concentration higher than 1200 pg/mL and final diagnosis.Results: Among those patients, 105 (51.2%) were suffering from Alzheimer's disease, 37 (18%) from sporadic Creuztfeldt-Jakob disease, and 63 (30.7%) from other neurological diseases including paraneoplastic/ central nervous system tumor, frontotemporal dementia, other diagnoses, amyloid angiopathy, Lewy body dementia, and infections of the central nervous system. Phospho-Tau, Aβ1-42 and Aβ1-42/pTau values differed significantly between the three groups of patients (p < .001). An Aβ1-42/pTau ratio between 4.7 and 9.7 was suggestive of other neurological diseases (threshold in AD: 8.3). CSF 14-3-3 was useful to discriminate Alzheimer's disease from Creuztfeldt-Jakob disease in case of Aβ1-42 concentrations 60 pg/mL.Conclusion: This work emphasizes the interest of a well-thought-out interpretation of CSF biomarkers in neurological diseases, particularly in the case of high Tau protein concentrations in the CSF.

ObjectiveWe 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.SettingsWe 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.ParticipantsPatients, 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 measureDescriptive statistics of the population of interest was the primary measure.ResultsIn 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.ConclusionsAD 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.