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Background: The group of dystonia genes is expanding, and mutations of these genes have been associated with various combined dystonia syndromes. Among the latter, the cause of some dystonia parkinsonism cases remains unknown.Objective: To report patients with early-onset dystonia parkinsonism as a result of loss-of-function mutations in nuclear receptor subfamily 4 group A member 2.Methods: Phenotypic characterization and exome sequencing were carried out in 2 families.Results: The 2 patients reported here both had a history of mild intellectual disability in childhood and subsequently developed dystonia parkinsonism in early adulthood. Brain magnetic resonance imaging was normal, and DATscan suggested bilateral dopaminergic denervation. Two frameshift mutations in NR4A2 were identified: a de novo insertion (NM_006186.3; c.326dupA) in the first case and another small insertion (NM_006186.3; c.881dupA) in the second.Conclusions: NR4A2 haploinsufficiency mutations have been recently reported in neurodevelopmental phenotypes. Our findings indicate that dystonia and/or parkinsonism may appear years after initial symptoms. Mutations in NR4A2 should be considered in patients with unexplained dystonia parkinsonism. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Increased β‐secretase 1 (BACE1) protein concentration, in body fluids, is a candidate biomarker of Alzheimer's disease (AD).We reported that plasma BACE1 protein concentrations are associated with the levels of brain amyloidβ (Αβ) accumulation in cognitively healthy individuals with subjective memory complaint (SMC). Methods: In 302 individuals from the same cohort, we investigated the cross‐sectional and longitudinal association between plasma BACE1 protein concentrations and AD biomarkers of neurodegeneration (plasma t‐tau and Neurofilament light chain (NfL), fluorodeoxyglucose–positron emission tomography (FDG‐PET), brain volumes in the basal forebrain [BF], hippocampus, and entorhinal cortex). Results: We report a positive longitudinal correlation of BACE1 with both NfL and t‐tau, as well as a correlation between annual BACE1 changes and bi‐annual reduction of BF volume. We show a positive association between BACE1 and FDG‐PET signal at baseline. Conclusions: The association between plasma BACE1 protein concentrations and BF atrophy we found in cognitively healthy individuals with SMC corroborates translational studies, suggesting a role of BACE1 in neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Early biomarkers are needed to identify individuals at high risk of preclinical Alzheimer's disease (AD) (Jack et al., 2018). Electroencephalography (EEG) is a non‐invasive and cheap technique that would be an interesting screening tool for the preclinical stage of AD. Method: We included participants from the INSIGHT‐preAD cohort, which is an ongoing single‐center multimodal observational study designed to identify risk factors and markers of progression to clinical AD in 318 cognitively normal individuals aged 70–85 years with a subjective memory complaint (Dubois et al., 2018). We divided the subjects into four groups, according to their amyloid status (on 18F‐florbetapir PET) and neurodegeneration status (on 18F‐fluorodeoxyglucose PET). We analysed 314 baseline 256‐channel high‐density eyes‐closed 1‐minute resting‐state EEG recordings. We extracted 10 quantitative EEG biomarkers, including spectral measures, algorithmic complexity and functional connectivity metrics. We evaluated three different classifiers (random forest, decision tree and logistic regression) to predict amyloid and neurodegeneration status from multimodal data, combining EEG, ApoE4 genotype, demographic, neuropsychological and MRI data. We divided the dataset into a training set (n=258) and validation set (n=46). We used a 5‐fold cross‐validation on the training set to identify the optimal combination of features. Result: As recently published (Gaubert et al., 2019), the most prominent effects of neurodegeneration on EEG metrics were localized in fronto‐central regions with an increase in high‐frequency oscillations (higher beta and gamma power) and a decrease in low‐frequency oscillations (lower delta power), higher spectral entropy, higher complexity and increased functional connectivity measured by weighted Symbolic Mutual Information in theta band. In the machine learning analysis, among the different features, EEG was the most strongly predictive of neurodegeneration. Similar predictive performance was obtained when reducing the number of electrodes from 256 to 8. EEG biomarkers combined with hippocampal volumetry had a high negative predictive value (91%) and high sensitivity (82%) to predict neurodegeneration. The combination of ApoE4 genotype with demographic data was most strongly predictive of amyloid status. Conclusion: EEG could be a valuable tool to screen for or rule out neurodegeneration in elderly memory complainers. This procedure has been patented under the following PCT number: PCT/EP2019/086629. [ABSTRACT FROM AUTHOR]

Background: Early biomarkers are needed to identify individuals at high risk of preclinical Alzheimer's disease (AD) (Jack et al., 2018). Electroencephalography (EEG) is a non‐invasive and cheap technique that would be an interesting screening tool for the preclinical stage of AD. Method: We included participants from the INSIGHT‐preAD cohort, which is an ongoing single‐center multimodal observational study designed to identify risk factors and markers of progression to clinical AD in 318 cognitively normal individuals aged 70–85 years with a subjective memory complaint (Dubois et al., 2018). We divided the subjects into four groups, according to their amyloid status (on 18F‐florbetapir PET) and neurodegeneration status (on ¹⁸F‐fluorodeoxyglucose PET). We analysed 314 baseline 256‐channel high‐density eyes‐closed 1‐minute resting‐state EEG recordings. We extracted 10 quantitative EEG biomarkers, including spectral measures, algorithmic complexity and functional connectivity metrics. We evaluated three different classifiers (random forest, decision tree and logistic regression) to predict amyloid and neurodegeneration status from multimodal data, combining EEG, ApoE4 genotype, demographic, neuropsychological and MRI data. We divided the dataset into a training set (n=258) and validation set (n=46). We used a 5‐fold cross‐validation on the training set to identify the optimal combination of features. Result: As recently published (Gaubert et al., 2019), the most prominent effects of neurodegeneration on EEG metrics were localized in fronto‐central regions with an increase in high‐frequency oscillations (higher beta and gamma power) and a decrease in low‐frequency oscillations (lower delta power), higher spectral entropy, higher complexity and increased functional connectivity measured by weighted Symbolic Mutual Information in theta band. In the machine learning analysis, among the different features, EEG was the most strongly predictive of neurodegeneration. Similar predictive performance was obtained when reducing the number of electrodes from 256 to 8. EEG biomarkers combined with hippocampal volumetry had a high negative predictive value (91%) and high sensitivity (82%) to predict neurodegeneration. The combination of ApoE4 genotype with demographic data was most strongly predictive of amyloid status. Conclusion: EEG could be a valuable tool to screen for or rule out neurodegeneration in elderly memory complainers. This procedure has been patented under the following PCT number: PCT/EP2019/086629. [ABSTRACT FROM AUTHOR]

Background: The cognitive reserve (CR) moderate the effect of brain pathophysiology on cognitive deficits in Alzheimer's Disease (AD) continuum. In a previous study on individuals with subjective memory complaint (SMCs), a condition at risk for AD, from the INSIGHT‐preAD cohort, we found that CR altered the association of amyloid load with neurophysiological mechanisms generating posterior electroencephalographic (EEG) alpha rhythms in quiet wakefulness. We used educational attainment (Edu) as an indicator of CR. Method: In the present work we tested the hypothesis of the interaction of Edu and cerebral amyloid‐b load with the association between posterior alpha rhythms, as revealed by resting‐state EEG (rsEEG) activity, and functional connectivity, as revealed by functional magnetic resonance imaging (fMRI, 3‐Tesla Verio system), among cholinergic basal forebrain (BF), thalamus, and posterior cortical areas. Resting‐state EEG and fMRI data were acquired in 318 cognitively intact individuals (age between 70 and 85 years) with SMC. Participants were stratified into two groups of amyloid‐positive (SMCpos) and ‐negative (SMCneg), using the standard diagnostic markers of Alzheimer's neuropathology based on cortical‐to‐cerebellum standardized uptake value ratio in the PET imaging. Then, the education attainment level was used to stratify the SMC participants in those with a low‐to‐moderate education level (SMC Edu‐) and those with a high education level (SMC Edu+). Result: Results showed a significant positive association between temporal alpha rhythms and above‐mentioned functional connectivity in the SMC cases with low brain amyloid accumulation and education attainment (SMCneg Edu‐). In contrast, the SMCneg Edu+ seniors showed the amplest posterior alpha rhythms, but not a positive association between temporal alpha rhythms and fMRI connectivity among cholinergic BF, thalamus, and posterior cerebral cortex, possibly due to a (annulation) of high CR. Of note, the SMCpos Edu+ seniors showed this positive association, possibly due to the (neutralization) of CR and brain amyloidosis (Figure 1). Conclusion: The present results suggest that, in SMC seniors, high CR affects cortical neural synchronization mechanisms generating posterior rsEEG alpha rhythms, but not through the ascending cholinergic system to the posterior cortex. Unfortunately, these CR effects may be annulled at earlier stages of Alzheimer's amyloid pathophysiology. [ABSTRACT FROM AUTHOR]

Temporal pole epilepsy (TPE) is a poorly known and difficult to individualize subtype of temporal lobe epilepsy. Consequently, in drug‐resistant TPE, there is still a debate on the need for a large surgical removal of the temporal pole and mesial temporal structures or a limited resection of the temporal pole. We reviewed all patients who underwent presurgical evaluation for drug‐resistant epilepsy over a 17‐year period, and report here 19 patients with proven drug‐resistant temporal pole epilepsy who underwent a selective temporal pole resection with respect to mesial structures. Most (15) TPE patients exhibited seizures resembling mesiotemporal seizures, whereas the others exhibited nocturnal hyperkinetic seizures or an association of both seizure types. MRI revealed a temporal pole lesion in 58% of patients. Long‐term postoperative outcome after a conservative surgery was excellent: 63% of patients were seizure‐free (International League Against Epilepsy [ILAE] 1) at 1‐year postsurgery and 78% at 5 years. These results show that TPE has no specific electroclinical features but is a distinct type of temporal lobe epilepsy allowing a conservative surgery. Respecting the mesiotemporal structures is a valid surgical approach for drug‐resistant temporal pole epilepsy. [ABSTRACT FROM AUTHOR]

Introduction: Successful development of effective β‐site amyloid precursor protein cleaving enzyme 1 (BACE1)–targeted therapies for early stages of Alzheimer's disease requires biomarker‐guided intervention strategies. Methods: We investigated whether key biological factors such as sex, apolipoprotein E (APOE ε4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid‐β (Aβ) deposition, using positron emission tomography global standard uptake value ratios. Results: Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline Aβ–positron emission tomography global standard uptake value ratios. Discussion: Our results suggest a sexual dimorphism in BACE1‐related upstream mechanisms of brain Aβ production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods: In a large‐scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results: Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross‐sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion: For the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Introduction: Blood‐based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large‐scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods: We investigated whether plasma concentrations of the Aβ1–40/Aβ1–42 ratio, assessed using the single‐molecule array (Simoa) immunoassay, may predict brain Aβ positron emission tomography status in a large‐scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis‐driven investigation followed by a no‐a‐priori hypothesis study using machine learning. Results: The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma Aβ1–40/Aβ1–42 ratio. The accuracy is not affected by the apolipoprotein E (APOE) ε4 allele, sex, or age. Discussion: Our results encourage an independent validation cohort study to confirm the indication that the plasma Aβ1–40/Aβ1–42 ratio, assessed via Simoa, may improve future standard of care and clinical trial design. [ABSTRACT FROM AUTHOR]

Introduction: Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α‐synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α‐synuclein (α‐syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. Methods: The pathophysiological role of CSF α‐syn in asymptomatic subjects at risk of AD has not been explored. We performed a large‐scale cross‐sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT‐preAD). Results: We found a positive association between CSF α‐syn concentrations and brain β‐amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α‐syn and both CSF t‐tau and p‐tau181 concentrations. Discussion: Animal models presented evidence, indicating that α‐syn may synergistically and directly induce fibrillization of both tau and β‐amyloid. Our data indicate an association of CSF α‐syn with AD‐related pathophysiological mechanisms, during the preclinical phase of the disease. [ABSTRACT FROM AUTHOR]

Introduction: Observational multimodal neuroimaging studies indicate sex differences in Alzheimer's disease pathophysiological markers. Methods: Positron emission tomography brain amyloid load, neurodegeneration (hippocampus and basal forebrain volumes adjusted to total intracranial volume, cortical thickness, and 2‐deoxy‐2‐[fluorine‐18]fluoro‐D‐glucose–positron emission tomography metabolism), and brain resting‐state functional connectivity were analyzed in 318 cognitively intact older adults from the INSIGHT‐preAD cohort (female n = 201, male n = 117). A linear mixed‐effects model was performed to investigate sex effects and sex∗apolipoprotein E genotype interaction on each marker as well as sex∗amyloid group interaction for non‐amyloid markers. Results: Men compared with women showed higher anterior cingulate cortex amyloid load (P =.009), glucose hypometabolism in the precuneus (P =.027), posterior cingulate (P <.001) and inferior parietal (P =.043) cortices, and lower resting‐state functional connectivity in the default mode network (P =.024). No brain volumetric markers showed differences between men and women. Sex∗apolipoprotein E genotype and sex∗amyloid status interactions were not significant. Discussion: Our findings suggest that cognitively intact older men compared with women have higher resilience to pathophysiological processes of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive change in people at risk of Alzheimer's disease (AD) such as subjective memory complainers is highly variable across individuals. Methods: We used latent class growth modeling to identify distinct classes of nonlinear trajectories of cognitive change over 2 years follow‐up from 265 subjective memory complainers individuals (age 70 years and older) of the INSIGHT‐preAD cohort. We determined the effect of cortical amyloid load, hippocampus and basal forebrain volumes, and education on the cognitive trajectory classes. Results: Latent class growth modeling identified distinct nonlinear cognitive trajectories. Education was associated with higher performing trajectories, whereas global amyloid load and basal forebrain atrophy were associated with lower performing trajectories. Discussion: Distinct classes of cognitive trajectories were associated with risk and protective factors of AD. These associations support the notion that the identified cognitive trajectories reflect different risk for AD that may be useful for selecting high‐risk individuals for intervention trials. [ABSTRACT FROM AUTHOR]

Abstract: In this case study, we report the longitudinal and multimodal follow‐up of a catastrophic initial presentation of cerebral fat embolism syndrome. We show that despite the initial severity, the cognitive outcome was ultimately very good but with a highly nonlinear time‐course and prolonged loss of consciousness (more than 2 months). Repeated clinical assessments and brain‐imaging techniques (electroencephalography, event‐related potential, 18‐Fluoro‐Deoxy‐Glucose‐PET and magnetic resonance imaging) allowed us to monitor and anticipate this dynamic, providing relevant information to guide decision making in front of withdrawal of life‐sustaining therapy discussions. This case illustrates the value of multimodal functional imaging in devastating brain injuries. [ABSTRACT FROM AUTHOR]

Introduction: Although some studies have previously addressed the clinical impact of amyloid positron emission tomography (PET), none has specifically addressed its selective and hierarchical implementation in relation to cerebrospinal fluid analysis in a naturalistic setting. Methods: This multicenter study was performed at French tertiary memory clinics in patients presenting with most complex clinical situations (i.e., early‐onset, atypical clinical profiles, suspected mixed etiological conditions, unexpected rate of progression), for whom cerebrospinal fluid analysis was indicated but either not feasible or considered as noncontributory (ClinicalTrials.gov: NCT02681172). Results: Two hundred five patients were enrolled with evaluable florbetaben PET scans; 64.4% of scans were amyloid positive. PET results led to changed diagnosis and improved confidence in 66.8% and 81.5% of patients, respectively, and altered management in 80.0% of cases. Discussion: High‐level improvement of diagnostic certainty and management is provided by selective and hierarchical implementation of florbetaben PET into current standard practices for the most complex dementia cases. Highlights: Impact of amyloid positron emission tomography (PET) on diagnosis and management in a naturalistic setting.Patients with complex clinical situations in absence of conclusive cerebrospinal fluid results.Highly selected patient population and hierarchical positioning of Alzheimer's disease biomarkers.Use of amyloid PET without interfering with the clinical standard practices.Immediate benefit of amyloid PET in the most complex situations in current practice. [ABSTRACT FROM AUTHOR]

Preclinical Alzheimer's disease (AD) is a relatively recent concept describing an entity characterized by the presence of a pathophysiological biomarker signature characteristic for AD in the absence of specific clinical symptoms. There is rising interest in the scientific community to define such an early target population mainly because of failures of all recent clinical trials despite evidence of biological effects on brain amyloidosis for some compounds. A conceptual framework has recently been proposed for this preclinical phase of AD. However, few data exist on this silent stage of AD. We performed a systematic review to investigate how the concept is defined across studies. The review highlights the substantial heterogeneity concerning the three main determinants of preclinical AD: “normal cognition,” “cognitive decline,” and “AD pathophysiological signature.” We emphasize the need for a harmonized nomenclature of the preclinical AD concept and standardized population-based and case-control studies using unified operationalized criteria. [ABSTRACT FROM AUTHOR]

Introduction The corticobasal syndrome (CBS) constitutes a neurodegenerative disease spectrum with substantial phenotypical or biological heterogeneity, requiring large or multimodal studies to identify its clinico-biological signature while disentangling Alzheimer's disease (AD)-related from non-AD-related CBS. Methods We analyzed a large (N = 45) monocenter expert-clinic CBS cohort, recruited in motor and/or cognitive units to avoid recruitment biases, assessed with standardized motor and/or cognitive-language tests, brain perfusion imaging, and cerebrospinal fluid biomarkers. Results CBS mainly manifests as a motor and/or language disorder incorporating a “mixed progressive aphasia” phenotype, consistent with left-lateralized damage to frontal-parietal-temporal cortices. Biomarker expression indicates in 18% underlying AD causing predominant parietal-temporal damage and Gerstmann syndrome (sensitivity 75%; specificity 75%), whereas non-AD-CBS presented with predominant prefrontal and lexical-semantic impairment. Discussion CBS is primarily a “motor-plus-aphasia” disease unfolding into AD-related and non-AD-related variants with distinctive cognitive-anatomic patterns. CBS, and notably its “Gerstmann variant”, should be included in the new AD “lexicon” and categorized in the evolving diagnostic spectrum of “atypical AD”d. [ABSTRACT FROM AUTHOR]

Background: In 2018, the National Institute of Aging and the Alzheimer Association proposed a purely biological definition of Alzheimer's disease (AD) relying on biomarkers. While the intended use of the framework was for research purposes, it has engendered debate and challenges regarding its application in everyday clinical practice. Method: We performed a literature review and pointed out the limitations of the current purely biological definition of AD. Result: Neuropathological studies have shown that amyloid β plaques and tau tangles are often accompanied by other pathologies, so ascribing the clinical phenotype to an amyloid or tau biomarker result might be difficult. In asymptomatic people, the detection of abnormal biomarkers is fraught with problems relating to uncertainty about the prognosis, and complex judgments and ethical issues about communicating results. Even defining biomarker categories is not simple, because methods for determining positivity are not always straightforward and nominally negative biomarker values can be associated with future cognitive decline. New clinical framework proposition: To address these concerns, the IWG advocates a return to Alzheimer's disease as a clinical‐biological entity, characterised by amyloid β and tau biomarkers plus a typical clinical phenotype. We advise against measurement of amyloid β and tau biomarkers in asymptomatic people because of unreliable predictive power; nevertheless, we do provide a risk stratification scheme for such people, and abnormal amyloid β and tau biomarkers are thought to confer high risk. However, such individuals are categorised as being asymptomatic at risk of progression, not as having AD. In symptomatic people, we stress the importance of a careful clinical evaluation in view of the common occurrence of multiple pathologies, borderline biomarker measurements, and conflicting findings. Conclusion: These new recommandations of the IWG are the opportunity to debate about the definition of AD and the use of biomarkers in clinical practice and pharmacological trials. This developing topic should open a significant discussion between AD specialists (both physicians and scientists) at the 2021 AAIC. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease and related dementia (ADRD) are characterized by a progressive alteration of clinical (Cognitive and Physical functions) and subclinical (Neuroimaging, blood and CSF markers) features. Understanding the sequence and timing of these alterations is of primary importance to understand the natural history of ADRD and ultimately change its course. Pathological processes underlying ADRD evolve over years prior to dementia diagnostic on a time scale that is still hypothetical before any diagnosis is made. The objective of this work was to describe the sequence of markers changes in the Memento cohort by realigning the individual marker trajectories according to a latent disease time to overcome this issue. Method: Memento cohort is a French nationwide clinic‐based study which aims at better understanding the natural history of ADRD. Participants with mild cognitive impairment or subjective cognitive complaint were enrolled and followed‐up intensively for a maximum of 5 years. In an analytical sample of 2186 participants, we considered repeated measures of 12 ADRD markers including cognitive performances (memory, verbal fluency, executive function), neuroimaging measures (hippocampal volume, cortical thicknesses, white matter hyperintensities, glucose metabolism of region of interest of FDG‐PET), and CSF (Aβ42, p‐tau, t‐tau). We defined the latent disease time by an individual shift of the observed time, and simultaneously analyzed the ADRD marker trajectories according to this latent disease time using a multivariate mixed model adjusted on potential confounders. Result: After individual realignment of the trajectories according to the latent disease time, the temporal sequence of alterations suggested that neurodegeneration preceded cognitive decline. However, such sequence largely depended on education and ApoE4 status as illustrated in the figure. Cognitive decline appeared to be delayed among participants with high level of education, whereas changes in Aβ42 and tau proteins levels in CSF seemed to appear prior to neurodegeneration and cognitive decline mainly among ApoE ε4 carriers. Conclusion: Using longitudinal multidimensional data from a large cohort, we were able to stage participants along the pathological progression of ADRD. Our results show a large heterogeneity in temporal order markers changes which could suggest the existence of several subtypes of ADRD. [ABSTRACT FROM AUTHOR]

Background: In 2018, the National Institute of Aging and the Alzheimer Association proposed a purely biological definition of Alzheimer's disease (AD) relying on biomarkers. While the intended use of the framework was for research purposes, it has engendered debate and challenges regarding its application in everyday clinical practice. For instance, cognitively unimpaired individuals may have biomarker evidence of both amyloid and tau pathology, but may never develop clinical manifestations in their lifetime. Furthermore, a positive AD pattern may be observed in other brain diseases where AD pathology is present as co‐pathology. In this presentation, the international Working Group (IWG) presents what we consider to be the current limitations of biomarkers in the diagnosis of AD, and on the basis of this evidence we propose recommendations for how biomarkers should and should not be used for diagnosis of AD in a clinical setting. We recommend that AD diagnosis be restricted to the occurrence of positive biomarkers together with specific AD phenotypes, whereas biomarker positive cognitively unimpaired individuals should be considered only at‐risk for progression to AD. [ABSTRACT FROM AUTHOR]

Background: It has recently been proposed that the awareness of cognitive decline (ACD) may already be slightly reduced in the preclinical phase of AD, in the presence of subtle cognitive changes. This is a recent field of research, and the few studies available do not allow to appreciate the actual evolution of ACD in the pre‐dementia phases of AD. The present study describes the longitudinal trajectory of an index of ACD (ACDI) over 3 years in a cohort of cognitively‐normal elderly, its association to AD biomarkers, as well as its impact on cognitive scores' evolution. Method: 314 elderly memory complainers, as just as many study‐partners, were followed‐up for 3 years. Brain glucose metabolism and amyloid load were assessed at baseline; screening cognitive tests were performed every 6 months, and a comprehensive neuropsychological evaluation every 12 months. The ACDI was based on the subject‐informant discrepancy on a questionnaire evaluating the subject's cognitive decline. We performed a Latent Class Linear Mixed Model (LCLMM) to identify different trends of evolution of the ACDI over time, and Generalized Linear Mixed Models to analyse the impact of the baseline ACDI on the evolution of cognitive scores. Result: The LCLMM identified three classes of subjects sharing similar longitudinal trajectories of the ACDI. Most subjects (76.8%) have accurate ACD (Class 2), and have been considered as the reference group. 18.95% of subjects showed heightened ACD ("worried‐well" individuals). They were comparable to subjects with accurate ACD in terms of AD biomarkers. 4.25% of the sample showing low ACD had higher amyloid burden than the reference group, and were mostly men. The GLMM found no overall effect of baseline ACDI on the evolution of the cognitive scores. Conclusion: The study of ACD in AD, its evolution and correlates is a topic of growing interest, as it is, notably, a piece of the larger understanding of the pre‐dementia phases of AD. This can be useful for a timely diagnosis of AD, and for the selection of populations to be included in clinical trials. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to investigate the association between brain amyloid β (Aβ) accumulation and cortical microstructural changes in cognitively normal individuals with subjective memory complaints. Method: A total of 258 individuals (100 males,158 females) from the Investigation of Alzheimer's Predictors in Subjective Memory Complainers (INSIGHT‐preAD) study [Dubois et al., 2018], were included. The 18F‐florbetapir PET images were used to compute whole brain and regional standard uptake value ratios (SUVr), while T1 structural and diffusion tensor imaging (DTI) scans were analysed to calculate 3 novel cortical grey matter diffusion measures (AngleR, PerpPD and ParlPD) and the mean diffusivity (MD) [McKavanagh et al., 2019]. A linear regression model was used to study the association between the global SUVr value and whole brain cortical diffusion measures, by including the diffusion measure as the dependent variable, and age, sex, APOE genotype and global amyloid SUVr as independent predictors. Partial correlation analysis, controlling for sex, was used to investigate regional associations between SUVr and diffusion values in 6 regions of interest (bilateral anterior cingulate, posterior cingulate, frontal superior orbital, inferior parietal, precuneus, middle temporal cortex). Results were considered statistically significant after false discovery rate correction (FDR <0.05). Result: Linear regression revealed that whole brain amyloid SUVr values were positively associated with whole brain AngleR (the angle between the principal diffusion direction and the radial minicolumn direction within the cortical grey matter) (β = 0.23, p<0.001). Regional partial correlations indicated significant associations between SUVr and AngleR regional values in left anterior cingulate cortex (r=0.168;p=0.010) and bilateral precuneus (left r=0.173;p=0.005; right r=0.178;p=0.004). Conclusion: These results showed a significant relationship between Aβ accumulation and cortical architectural change in subjective memory complainers. The regional associations revealed the presence of microstructural changes in key regions commonly affected in the early stage of AD [Palmqvist et al., 2017]. Our novel cortical DTI measures could offer additional information about cortical changes, playing a potential role as index of "neurodegeneration" in the ATN framework [Jack et al., 2018] of Alzheimer's biomarkers. [ABSTRACT FROM AUTHOR]

Background: As not all the asymptomatic Alzheimer Disease (AD) subjects will progress to symptomatic stages, targeting those individuals at high risk of progression to prodromal AD is relevant, especially for disease‐modifier therapeutic trials. The aim of this study is to determine markers of progression to prodromal AD in cognitively normal individuals. Method: INSIGHT‐preAD study is a cohort of 318 cognitively normal individuals, over 70 years, with subjective memory complaints, followed‐up for 5 years. Subjects were stratified by brain amyloid status (A(+) or A(‐)) according to the uptake of 18F‐Florbetapir. Demographic, cognitive, ApoE status and imaging (MRI and FDG‐PET) were performed at baseline. Clinical and cognitive assessments were repeated every 6 months, MRI, FDG‐PET and amyloid‐PET scans every 2 years. Definition of progressors: MMSE and FCSRT scores below the threshold for inclusion in the study was indicative of a possible progression to prodromal AD. An independent and blinded committee using adjudicated prodromal AD using the IWG‐2 criteria. Statistical analysis: Comparisons between A(+) progressors and A(+) non‐progressors were performed using Wilcoxon test for continuous variables and Fisher's exact tests for qualitative variables. Result: After 5 years, 13 subjects progress to a mild cognitive impairment: 12 prodromal AD (11 typical phenotype; 1 atypical phenotype with a logopenic presentation) and 1 with a Lewy body phenotype. All the progressors were A(+), with a rate of progression of 14% among A(+) individuals. When compared to A(+) non‐progressors, the progressors had lower performance in each FCRST sub‐scores, lower total hippocampal volume (Median [Q1, Q3]: 2.43 [2.24, 2.56] versus 2.65 [2.45, 2.87]) and higher AV45 SUVr (1.23 [0.99, 1.32] versus 0.95 [0.84, 1.10], for a threshold of 0.79). Conclusion: As expected, the predicting factors from cognitively normal individuals to prodromal AD are the co‐occurrence of amyloid burden and tau pathology (represented by hippocampal volume loss and memory deficit). However, only 14% of A(+) subjects progress to prodromal AD after 5 years follow‐up. This result suggests protective and compensatory mechanisms that should be investigated to open up to innovative treatment. [ABSTRACT FROM AUTHOR]

Background: Neurofilament light (NFL) chain and total Tau (t‐Tau) proteins are established biomarkers of axonal degeneration. Increased plasma concentrations of both proteins are associated with worsening rate of cognitive performance, cerebral atrophy, and hypometabolism in prodromal and dementia phases of Alzheimer's disease (AD). Few studies explored, in cognitively healthy individuals, the potential influence of key biological factors – age, sex, Apolipoprotein E (APOE) ε4 allele – on NFL and t‐Tau plasma concentrations as well as their association with comorbidities, brain amyloid beta (Aβ) deposition, and cognitive scores. Method: The ultrasensitive SiMoA platform was used to measure plasma NFL and t‐Tau concentrations at three time points (baseline: N=316; one‐ and three‐year follow‐up: N=79) in the INSIGHT‐preAD cohort, a large observational monocentric French academic cohort (Pitié‐Salpêtrière University Hospital, Paris) of individuals with subjective memory complaints (SMC), a condition at risk for AD. Result: Age affected plasma NFL concentrations (P<0.001). Sex influenced plasma t‐Tau (P=0.003), with females showing a higher concentration increase than males, across the three time points. A significant effect of sex*age interaction was also reported (P=0.038). No effect of APOE ε4 was found on either NFL or t‐Tau. Plasma vitamin B12 deficiency was associated with increased t‐Tau concentrations. Plasma NFL significantly increased at one‐year (P=0.007) and three‐year (P<0.001) follow‐up versus baseline. Plasma t‐Tau significantly increased at three‐year follow‐up (P=0.004) versus baseline. Plasma NFL was associated with plasma t‐Tau (P=0.011) and cerebrospinal fluid NFL (P<0.001) concentrations, at baseline. Baseline plasma NFL was associated with increased Aβ deposition rate, at two‐year follow‐up, in the left posterior cingulate (P=0.019) and the bilateral inferior parietal gyri (P=0.013). Baseline plasma NFL and the rate of change of plasma t‐Tau were inversely associated with cognitive score (P=0.029 and P=0.015, respectively). Conclusion: Age and female sex affect plasma NFL and t‐Tau longitudinal trajectories, respectively, in SMC individuals. Exploring the impact of biological variables on AD biomarkers is crucial for their clinical validation in blood. Moreover, there is a potential effect of plasma NFL concentrations on brain amyloid plaques deposition. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation – a crucial early pathomechanistic alteration of Alzheimer's disease (AD) – may represent either a detrimental or a compensatory mechanism or both, based on the disease stage. YKL‐40, a glycoprotein highly expressed in human glia cells, is a candidate biomarker to in vivo track glial‐related neuroinflammation in AD. Few studies explored, in cognitively healthy individuals, the potential influence of key biological factors – age, sex, Apolipoprotein E (APOE) ε4 allele – on YKL‐40 plasma concentrations as well as its association with other AD pathophysiological mechanisms and cognitive scores. Method: We assessed the cross‐sectional and longitudinal impact of relevant biological factors – sex, age, APOE ε4 allele – on YKL‐40. Moreover, we explored the cross‐sectional and longitudinal association of YKL‐40 with: 1) global/regional brain amyloid beta (Aβ) deposition using Aβ‐positron emission tomography (PET) imaging; 2) synaptic loss, using [18F]‐fluorodeoxyglucose‐PET ([18F]‐FDG‐PET); 3) neurodegeneration using magnetic resonance imaging (MRI), i.e. hippocampal, entorhinal cortex, and basal forebrain volumes. We also sought for the potential association between YKL‐40 and the degree of cognitive performance. The study was performed in the INSIGHT‐preAD cohort (N=314, M=114, F=200, aged 70 to 85), a large observational monocentric French academic cohort (Pitié‐Salpêtrière University Hospital, Paris) of individuals with subjective memory complaints (SMC), a condition at risk for AD. We used mixed models with interaction of YKL‐40 with time. Result: Men displayed higher YKL‐40 concentrations than women at each time point investigated (b=0.171, t=2.434, P=0.015). YKL‐40 presented an age‐associated increase at each time point investigated (b=0.029, t=3.004, P=0.003). YKL‐40 was negatively associated with baseline Aβ deposition, at both global (b=‐0.025, t=‐1.992, P=0.047) and regional level. Besides, one‐year increase of YKL‐40 concentration was positively associated with memory performance, longitudinally (b=0.308, z=2.280, P=0.023). YKL‐40 showed no effect on synaptic loss or neurodegeneration. Conclusion: Plasma YKL‐40 concentrations present an age‐associated increase with men showing higher levels than women, irrespective of the time point, thus indicating a potential sexual dimorphism in neuroinflammation. Moreover, the association of higher YKL‐40 concentrations with lower overall/regional cross‐sectional Aβ deposition and higher memory scores over time indicates a non‐clinical detrimental/potential protective effect of glia activation on incipient brain amyloidosis and synaptic network homeostasis. [ABSTRACT FROM AUTHOR]

Involvement of the dopaminergic system in orthostatic tremor is controversial. The aim of this study was to detect possible dopaminergic denervation in primary orthostatic tremor (OT). Twelve consecutive patients with a firm diagnosis of primary orthostatic tremor were compared with age-matched normal controls. All the patients had a neurological examination, surface polymyography, and quantification of striatal dopamine transporters with 123I-FP-CIT SPECT imaging. There was no significant difference in 123I-FP-CIT SPECT findings between controls and patients with OT. Longstanding primary orthostatic tremor is not necessarily associated with 123I-FP-CIT SPECT abnormalities, as 8 of our patients had more than a 10-year history of OT. Primary orthostatic tremor without dopaminergic denervation remains a valid entity, although representing only a subtype of high-frequency OT. A new role may emerge for 123I-FP-CIT SPECT in distinguishing between patients whose symptoms will be restricted to OT throughout the disease course and patients at an increased risk of developing PD. © 2008 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Purpose: Ictal single-photon emission computed tomography (SPECT) may help localize the seizure-onset zone (SOZ) by detecting changes in regional cerebral blood flow induced by epileptic discharges. This imaging method also reveals hyperperfusions in areas of seizure propagation, including the hemisphere contralateral to the SOZ. We have studied the occurrence, the topography, and the clinical value of such contralateral ictal hyperperfusion areas (HPAs). Methods: We examined data from presurgical evaluations of 36 consecutive patients with pharmacoresistant partial epilepsy of various localizations. Ictal and interictal SPECT examinations were made with 99mTc-ECD, and the scans were processed for coregistration, normalization, subtraction, and merging with MRI images. Results: Contralateral HPAs were observed in 72% of the patients: 50% of mesiotemporal epilepsy cases with hippocampal sclerosis, 85.7% of the other mesiotemporal epilepsies, 85.7% of neocortical lateral temporal epilepsies, and 87.5% of extratemporal epilepsies. Contralateral HPAs were usually symmetrical to the SOZ, forming a mirror image, observed in 57.1% of the patients. They could be slightly asymmetrical in mesiotemporal epilepsies, perhaps because of the particular anatomic pathways linking temporal lobes. In neocortical epilepsies, they were located in the cortex homotopic to the SOZ. Conclusions: We show that the symmetrical nature of the mirror image usually does not disturb SPECT interpretation. It can confirm the location of the SOZ (11 patients) and even occasionally improve the precision of its definition (nine patients) by restraining several potential SOZ-related HPAs to a single one or by permitting a restricted localization of the SOZ in a large HPA. [ABSTRACT FROM AUTHOR]

Background: Early‐onset Alzheimer's disease (EOAD) differentiates from late‐onset AD by a predominant and early involvement of the parietal neocortex with hippocampal sparing, leading to non‐amnesic cognitive syndromes (deficits in working memory, visuospatial abilities, praxis, or language). The diagnosis of a neurodegenerative disease is often not the first mentioned in such young patients. We aimed to identify the inaugural symptoms and diagnosis in working age EOAD patients. Methods: We retrospectively reviewed the files of patients younger than 62 years referred to our memory clinic for cognitive dysfunction during the last year. Among 91 patients, 31 were diagnosed with AD based on clinical and biological criteria (cerebrospinal fluid biomarkers). Their mean age was 55±3.8 years. Results: Eleven EOAD patients (35%) were initially diagnosed with an occupational burnout syndrome, while logopenic aphasia or visuo‐spatial deficit were observed in the remaining 20 patients (65%). In the burnout syndrome subgroup, the delay between the first symptoms and neurological examination was 2.6±1.1 years. The initial Mini‐Mental State Examination score was 19.6±4.6/30. Neuropsychological assessment showed a severe working memory deficit, associated with mild cognitive cortical parietal syndrome. Visual inspection of brain MRI and FDG‐PET showed bilateral parietal atrophy and a severe focal hypometabolism of associative parietal cortices. No patient had family history of EAOD and the molecular genetic testing of AD mutation was negative. Conclusion: We describe, for the first time, a new clinical presentation of EOAD mimicking an occupational burnout syndrome. The severe inaugural working memory deficit due to the early cortical parietal damage leads to an inability to carry out concurrent professional tasks, a reduction of professional efficacy and a severe anxiety, in the absence of overt aphasia or episodic memory deficit at the time of initial evaluation. The patient stops working and is often referred to psychiatrists, the diagnosis being delayed until the cognitive deficit worsens, and strongly affects the autonomy at a more advanced stage of the disease. It is crucial to consider this clinical phenotype in the definition of EOAD to avoid delayed diagnosis. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) brain atrophy subtypes on structural MRI have been associated with rate of cognitive decline in AD and prodromal AD. However, previous works were based on selected amyloid‐positive and/or cognitively‐impaired patients. The clinical relevance of brain atrophy subtypes categorization in people referred to Memory Clinics for subjective cognitive complaint (SCC) or mild cognitive impairment (MCI), without any a priori assumptions regarding their amyloid status, is currently unknown. Methods: We investigated 2118 subjects from the French Memento cohort presenting either with SCC or MCI and for whom both hippocampal and cortical volumes were available at baseline. Among them, 883 also had Amyloid‐PET and/or CSF biomarkers. They were prospectively followed during 4 years for dementia status and neuropsychological performances. MRI scans at baseline were used to define groups with "limbic predominant atrophy", "hippocampal sparing atrophy", "typical/diffuse atrophy" and "no evidence of brain atrophy", based on previously described algorithms. Results: In Cox proportional‐hazards models, "typical/diffuse atrophy" and "limbic predominant atrophy" were associated with an increased risk of developing dementia over time (HR=3.67; 95%CI 2.63–5.13 and HR=1.77; 95%CI 1.05–2.98 respectively), independently of age, gender, educational level, ApoE4 genotype and CDR‐SB at baseline. Brain atrophy subtypes categorization was more informative than hippocampal and/or cortical volumes separately, when comparing Akaike information criteria of Cox models. Very similar results were found when analyses were restricted to the sample of amyloid‐positive participants (n=236) (HR=3.69; 95%CI 2.03–6.70 for "typical/diffuse atrophy" and HR=2.40; 95%CI 0.96–5.96 for "limbic predominant atrophy"). Conclusion: AD brain atrophy subtypes are associated with conversion to dementia in patients with SCC or MCI consulting in Memory Clinics, agnostic of any a priori assumptions regarding their amyloid status. Because this categorization based on structural MRI is more informative than hippocampal and/or cortical volumes, it could be widely used as a biomarker in future epidemiological and clinical studies. [ABSTRACT FROM AUTHOR]