Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening.

PURPOSE: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD). METHODS: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). RESULTS: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. CONCLUSION: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.

Cumulative effects of subsequent concussions on the neural patterns of young rugby athletes: data from event-related potentials.

Our study aimed at detecting a potential cumulative effect of subsequent concussions on the neural activation patterns of young rugby athletes with or without concussion history. Event-related brain potential (ERP) data from 24 rugby players, 22-year-old on average, were retrospectively examined. All underwent a Sport Concussion Assessment Tool (SCAT2) during preseason and an on-site ERP task (P300) following a recent concussion event (<48 hours). Sixteen players suffered at least one concussion in the previous 3 years and eight were without self-reported past concussion. While no differences were reported between groups regarding symptom appraisal on the SCAT2 assessment, ERP revealed significantly decreased P3b amplitude and a trend for increased P3b latency in players who experienced prior concussions. Our data thus support the cumulative effect of concussions on neuroelectric events in young rugby players, highlighting the importance of managing player's concussion load to reduce the risk of long-term injuries.

Measures of resting state EEG rhythms for clinical trials in Alzheimer's disease: Recommendations of an expert panel.

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12 Hz) and widespread delta (< 4 Hz) and theta (4-8 Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes.

Comparison of ultrasensitive and mass spectrometry quantification of blood-based amyloid biomarkers for Alzheimer's disease diagnosis in a memory clinic cohort.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder with ß-amyloid pathology as a key underlying process. The relevance of cerebrospinal fluid (CSF) and brain imaging biomarkers is validated in clinical practice for early diagnosis. Yet, their cost and perceived invasiveness are a limitation for large-scale implementation. Based on positive amyloid profiles, blood-based biomarkers should allow to detect people at risk for AD and to monitor patients under therapeutics strategies. Thanks to the recent development of innovative proteomic tools, the sensibility and specificity of blood biomarkers have been considerably improved. However, their diagnosis and prognosis relevance for daily clinical practice is still incomplete. METHODS: The Plasmaboost study included 184 participants from the Montpellier's hospital NeuroCognition Biobank with AD (n = 73), mild cognitive impairments (MCI) (n = 32), subjective cognitive impairments (SCI) (n = 12), other neurodegenerative diseases (NDD) (n = 31), and other neurological disorders (OND) (n = 36). Dosage of ß-amyloid biomarkers was performed on plasma samples using immunoprecipitation-mass spectrometry (IPMS) developed by Shimadzu (IPMS-Shim Aß42, Aß40, APP669-711) and Simoa Human Neurology 3-PLEX A assay (Aß42, Aß40, t-tau). Links between those biomarkers and demographical and clinical data and CSF AD biomarkers were investigated. Performances of the two technologies to discriminate clinically or biologically based (using the AT(N) framework) diagnosis of AD were compared using receiver operating characteristic (ROC) analyses. RESULTS: The amyloid IPMS-Shim composite biomarker (combining APP669-711/Aß42 and Aß40/Aß42 ratios) discriminated AD from SCI (AUC: 0.91), OND (0.89), and NDD (0.81). The IPMS-Shim Aß42/40 ratio also discriminated AD from MCI (0.78). IPMS-Shim biomarkers have similar relevance to discriminate between amyloid-positive and amyloid-negative individuals (0.73 and 0.76 respectively) and A-T-N-/A+T+N+ profiles (0.83 and 0.85). Performances of the Simoa 3-PLEX Aß42/40 ratio were more modest. Pilot longitudinal analysis on the progression of plasma biomarkers indicates that IPMS-Shim can detect the decrease in plasma Aß42 that is specific to AD patients. CONCLUSIONS: Our study confirms the potential usefulness of amyloid plasma biomarkers, especially the IPMS-Shim technology, as a screening tool for early AD patients.

Validity and Performance of Blood Biomarkers for Alzheimer Disease to Predict Dementia Risk in a Large Clinic-Based Cohort.

BACKGROUND AND OBJECTIVE: Blood biomarkers for Alzheimer disease (AD) have consistently proven to be associated with CSF or PET biomarkers and effectively discriminate AD from other neurodegenerative diseases. Our aim was to test their utility in clinical practice, from a multicentric unselected prospective cohort where patients presented with a large spectrum of cognitive deficits or complaints. METHODS: The MEMENTO cohort enrolled 2,323 outpatients with subjective cognitive complaint (SCC) or mild cognitive impairment (MCI) consulting in 26 French memory clinics. Participants had neuropsychological assessments, MRI, and blood sampling at baseline. CSF sampling and amyloid PET were optional. Baseline blood Aß42/40 ratio, total tau, p181-tau, and neurofilament light chain (NfL) were measured using a Simoa HD-X analyzer. An expert committee validated incident dementia cases during a 5-year follow-up period. RESULTS: Overall, 2,277 individuals had at least 1 baseline blood biomarker available (n = 357 for CSF subsample, n = 649 for PET subsample), among whom 257 were diagnosed with clinical AD/mixed dementia during follow-up. All blood biomarkers but total tau were mildly correlated with their equivalence in the CSF (r = 0.33 to 0.46, p < 0.0001) and were associated with amyloid-PET status (p < 0.0001). Blood p181-tau was the best blood biomarker to identify amyloid-PET positivity (area under the curve = 0.74 [95% CI = 0.69; 0.79]). Higher blood and CSF p181-tau and NfL concentrations were associated with accelerated time to AD dementia onset with similar incidence rates, whereas blood Aß42/40 was less efficient than CSF Aß42/40. Blood p181-tau alone was the best blood predictor of 5-year AD/mixed dementia risk (c-index = 0.73 [95% CI = 0.69; 0.77]); its accuracy was higher in patients with clinical dementia rating (CDR) = 0 (c-index = 0.83 [95% CI = 0.69; 0.97]) than in patients with CDR = 0.5 (c-index = 0.70 [95% CI = 0.66; 0.74]). A "clinical" reference model (combining demographics and neuropsychological assessment) predicted AD/mixed dementia risk with a c-index = 0.88 [95% CI = 0.86-0.91] and performance increased to 0.90 [95% CI = 0.88; 0.92] when adding blood p181-tau + Aß42/40. A "research" reference model (clinical model + apolipoprotein E genotype and AD signature on MRI) had a c-index = 0.91 [95% CI = 0.89-0.93] increasing to 0.92 [95% CI = 0.90; 0.93] when adding blood p181-tau + Aß42/40. Chronic kidney disease and vascular comorbidities did not affect predictive performances. DISCUSSION: In a clinic-based cohort of patients with SCC or MCI, blood biomarkers may be good hallmarks of underlying pathology but add little to 5-year dementia risk prediction models including traditional predictors.

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

BACKGROUND: Memory troubles and hippocampal atrophy are considered more frequent and focal atrophy less severe in late-onset (>65 years) than in presenile behavioral variant of frontotemporal dementia (bvFTD). OBJECTIVE: To compare cerebrospinal fluid (CSF) and plasma biomarkers in late-onset and presenile bvFTD. METHODS: Multicentric retrospective study (2007-2017) on patients with clinical diagnosis of bvFTD. RESULTS: This study included 44 patients (67%) with presenile and 22 (33%) with late-onset bvFTD (comparable mean disease duration; n = 11 with causal mutations). Hippocampal atrophy was more frequent (80% versus 25.8%) and severe in late-onset bvFTD (median Scheltens score: 3 [0-4] versus 1 [0-3]), without difference after adjustment for age. Lobar atrophy and focal hypometabolism/hypoperfusion were not different between groups. The median CSF Aß1-42 and phosphorylated tau (P-tau) concentrations were in the normal range and comparable between groups. Axonal neurodegeneration biomarkers were within the normal range (CSF T-tau; plasma T-tau in late-onset bvFTD) or higher (plasma neurofilament light chain (NFL); plasma T-tau in presenile bvFTD) than the normal values, but globally not different between bvFTD groups. Plasma glial fibrillary acid protein (GFAP) was strongly increased in both bvFTD groups compared with the values in controls of the same age. CONCLUSION: The CSF and plasma biomarker profiles did not suggest a more aggressive neurodegeneration in the presenile group (comparable T-tau, NFL, and GFAP levels) or the co-existence of Alzheimer's disease in the late-onset group (comparable and within normal range CSF Aß1-42 and P-tau). The severity of the neurodegenerative process seems comparable in presenile and late-onset bvFTD.

Absence of Relationship Between Self-Reported Sleep Measures and Amyloid Load in Elderly Subjects.

Objective: To determine the relationships between self-reported sleep profile and cortical amyloid load in elderly subjects without dementia. Methods: This cross-sectional study included 143 community-dwelling participants aged ≥70 years (median: 73 years [70-85]; 87 females) with spontaneous memory complaints but dementia-free. Sociodemographic characteristics, health status, neuropsychological tests, sleep, and 18F-florbetapir (amyloid) PET data were collected. The clinical sleep interview evaluated nighttime sleep duration, but also daytime sleep duration, presence of naps, and restless leg syndrome (RLS) at time of study. Validated questionnaires assessed daytime sleepiness, insomnia, and risk of sleep apnea. The cortical standardized uptake value ratio (SUVr) was computed across six cortical regions. The relationship between sleep parameters and SUVr (cut-off ratio>1.17 and tertiles) was analyzed using logistic regression models. Results: Amyloid-PET was positive in 40.6% of participants. Almost 40% were at risk for apnea, 13.5% had RLS, 35.5% insomnia symptoms, 22.1% daytime sleepiness, and 18.8% took sleep drugs. No significant relationship was found between positive amyloid PET and nighttime sleep duration (as a continuous variable, or categorized into <6; 6-7; ≥7 h per night). Logistic regression models did not show any association between SUVr and daytime sleep duration, 24-h sleep duration, naps, RLS, daytime sleepiness, insomnia symptoms, and sleep apnea risk (before and after adjustment for APOEε4 and depressive symptoms). Conclusion: Our study did not confirm the association between amyloid-PET burden, poor sleep quantity/quality in elderly population, suggesting that the interplay between sleep, and amyloid is more complex than described.

Alzheimer's Disease: Advances in Drug Development.

As of 2018, Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. It contributes to a progressive neuron loss, deterioration of memory, and cognitive impairment. Current therapies may provide a symptomatic benefit, but do not treat the underlying process. Ongoing researches focus on understanding the causal mechanisms and finding neuropathological hallmarks of AD. Therapeutic approaches targeting senile plaques or neurofibrillary tangles have not yet resulted in a significant cognitive improvement. However, recent data according to the analysis of AD clinical trials (clinicaltrials.gov database) show promising results. This literature review aims at summarizing the recent advances and at highlighting the most promising results of the ongoing researches. It compares the merits of small-molecules, antibodies, cell, and gene-based therapies and emphasizes the need for treatment at earlier stages of the disease.

Structural, Microstructural, and Metabolic Alterations in Primary Progressive Aphasia Variants.

Neuroimaging studies have described the brain alterations in primary progressive aphasia (PPA) variants (semantic, logopenic, nonfluent/agrammatic). However, few studies combined T1, FDG-PET, and diffusion MRI techniques to study atrophy, hypometabolism, and tract alterations across the three PPA main variants. We therefore explored a large early-stage cohort of semantic, logopenic and nonfluent/agrammatic variants (N = 86) and of 23 matched healthy controls with anatomical MRI (cortical thickness), FDG PET (metabolism) and diffusion MRI (white matter tracts analyses), aiming at identifying cortical and sub-cortical brain alterations, and confronting these alterations across imaging modalities and aphasia variants. In the semantic variant, there was cortical thinning and hypometabolism in anterior temporal cortices, with left-hemisphere predominance, extending toward posterior temporal regions, and affecting tracts projecting to the anterior temporal lobes (inferior longitudinal fasciculus, uncinate fasciculus) and tracts projecting to or running nearby posterior temporal cortices: (superior longitudinal fasciculus, inferior frontal-occipital fasciculus). In the logopenic variant metabolic alterations were more extensive than atrophy affecting mainly the left temporal-parietal junction and extending toward more anterior temporal cortices. Metabolic and tract data were coherent given the alterations of the left superior and inferior longitudinal fasciculus and the left inferior frontal-occipital fasciculus. In the nonfluent/agrammatic variant cortical thinning and hypometabolism were located in the left frontal cortex but Broca's area was only affected on metabolic measures. Metabolic and tract alterations were coherent as reflected by damage to the left uncinate fasciculus connecting with Broca's area. Our findings provide a full-blown statistically robust picture of brain alterations in early-stage variants of primary progressive aphasia which has implications for diagnosis, classification and future therapeutic strategies. They demonstrate that in logopenic and semantic variants patterns of brain damage display a non-negligible overlap in temporal regions whereas they are substantially distinct in the nonfluent/agrammatic variant (frontal regions). These results also indicate that frontal networks (combinatorial syntax/phonology) and temporal networks (lexical/semantic representations) constitute distinct anatomo-functional entities with differential vulnerability to degenerative processes in aphasia variants. Finally, the identification of the specific damage patterns could open an avenue for trans-cranial stimulation approaches by indicating the appropriate target-entry into the damaged language system.

Cerebral microbleeds and CSF Alzheimer biomarkers in primary progressive aphasias.

OBJECTIVE: To reveal the prevalence and localization of cerebral microbleeds (CMBs) in the 3 main variants of primary progressive aphasia (PPA) (logopenic, semantic, and nonfluent/agrammatic), to identify the relationship with underlying Alzheimer pathology, and to explore whether CMBs contribute to language breakdown. METHODS: We used a cross-sectional design in a multicenter cohort of 82 patients with PPA and 19 similarly aged healthy controls. MRI allowed for rating CMBs (2-dimensional gradient recalled echo T2*, susceptibility weighted imaging sequences) and white matter hyperintensities. CSF Alzheimer disease biomarker analyses available in 63 of the 82 patients provided the stratification of PPA into subgroups with patients who had or did not have probable underlying Alzheimer pathology. RESULTS: The prevalence of CMBs was higher in patients with PPA (28%) than in controls (16%). They were more prevalent in logopenic PPA (50%) than in semantic PPA (18%) and nonfluent/agrammatic PPA (17%). The localization of CMBs was mainly lobar (81%) with no difference between the PPA variants. CMBs were more frequent in PPA patients with positive than with negative CSF Alzheimer disease biomarkers (67% vs 20%). Patients with and without lobar CMBs had similar volumes of white matter hyperintensities. Language and general cognitive impairment in PPA was unrelated to CMB rates. CONCLUSIONS: CMB prevalence in PPA is higher than in healthy controls. CMBs were most prevalent in the logopenic variant, were related to underlying Alzheimer pathology, and did not affect the language/cognitive impairment. Our findings also suggest that CMB detection with MRI contributes to PPA variant diagnosis, especially of logopenic PPA, and provides an estimator of the underlying neuropathology.

Diagnostic value of event-related evoked potentials N200 and P300 subcomponents in early diagnosis of Alzheimer's disease and mild cognitive impairment.

Event-related potentials (ERPs) have a large application in the evaluation of cognitive processes, particularly in Alzheimer's disease (AD). The aim of the present study was to evaluate the clinical relevance of event-related evoked potentials (N2 and P3 subcomponents) in early diagnosis of AD and mild cognitive impairment (MCI). We prospectively studied 60 subjects. They all underwent the following investigations: neurologic and neuropsychological examination; functional evaluation, i.e., ERPs; cerebral imagery (morphologic and functional). Subjects were classified into 3 groups: group 1: 30 dementia of Alzheimer type (NINCDS-ADRDA, DSM-IV criteria); group 2: 20 MCI; and group 3: 10 control subjects. ERPs were significantly different between the groups (AD, MCI, control subjects), with a marked increase of P3 latencies, particularly when compared with N2 latencies (P < 0.0001). Furthermore, sensitivity was 87% to 95% for the differentiation of AD patients from MCI and control subjects, using prolonged P3 latencies (specificity, 90% to 95%), whereas using N2 prolonged latencies, sensitivity was 70% to 75% (specificity, 70% to 90%). Moreover, in the MCI group, N2 latencies strongly discriminated MCI from control subjects, with 90% sensitivity and 70% specificity and correctly categorized 80% of MCI subjects against 73% for P3. The abnormalities of N2 and P3 components may be linked, in AD and MCI, to an alteration of automatic and controlled attention processing.

Cognitive Event-Related Potential, an Early Diagnosis Biomarker in Frail Elderly Subjects: The ERP-MAPT-PLUS Ancillary Study.

BACKGROUND: By analyzing brain synaptic function, cognitive event-related potentials (ERPs) could provide powerful and innovative tools for early Alzheimer's disease (AD) diagnosis. OBJECTIVE: We investigated the relevance of the ERP-P300 component as a potential diagnosis marker in elderly subjects at risk of developing AD. METHODS: ERP-P300 was analyzed on 85 subjects recruited from the Multidomain Alzheimer Preventive Trial (MAPT). PET-AV45 brain imaging was available from 36 subjects. RESULTS: Two ERP-P300 subgroups were identified according to their PET-AV45 status: PET-Aß positive (n = 15) and PET-Aß negative (n = 21). In the amyloid positive group, we observed a highly significant increase in P3b latency in parietal brain regions (p = 0.0052). P3b in parietal regions correctly categorized 69.4% elderly subjects from the P300-PET Aß positive group. Combined analysis of parietal P3b latencies and category fluency correctly classified 75% subjects from the P300-PET Aß positive group. CONCLUSIONS: The P300 ERP presents good predictive measure of brain amyloid load and has the potential to be used as a screening instrument for preclinical AD. The incorporation of P3b latency may be used as an adjunctive tool with neuropsychological assessment (i.e., verbal category fluency) as a specific and sensitive method for preclinical assessment of AD.

Excessive Sleepiness and Longer Nighttime in Bed Increase the Risk of Cognitive Decline in Frail Elderly Subjects: The MAPT-Sleep Study.

Objective: To identify self-reported sleep-wake disturbances that increase the risk of cognitive decline over 1-year follow-up in frail participants. Background: Risk factors for cognitive impairment need to be better identified especially at earliest stages of the pathogenesis. Sleep-wake disturbances may be critical factors to consider and were thus being assessed in this at-risk population for cognitive decline. Methods: Frail elderly participants aged ≥70 years were selected from a subsample of the Multi-domain Alzheimer Preventive Trial (MAPT) for a sleep assessment (MAPT-sleep study) at 18-month follow-up (M18). Sleep-wake disturbances were evaluated using a clinical interview (duration of daytime and nighttime sleep, time in bed, number of naps, and presence of clinically-defined sleep disorders) and numerous validated questionnaires [Epworth Sleepiness Scale for excessive daytime sleepiness (EDS), Insomnia Severity Scale and Berlin Questionnaire]. Cognitive decline was defined as a difference between the MMSE and cognitive composite scores at M24 and M36 that was ranked in the lowest decile. Multivariate logistic regression models adjusted for several potential confounding factors were performed. Results: Among the 479 frail participants, 63 developed MMSE-cognitive decline and 50 cognitive composite score decrease between M24 and M36. Subjects with EDS had an increased risk of MMSE decline (OR = 2.46; 95% CI [1.28; 4.71], p = 0.007). A longer time spent in bed during night was associated with cognitive composite score decline (OR = 1.32 [1.03; 1.71], p = 0.03). These associations persisted when controlling for potential confounders. Patients with MMSE score decline and EDS had more naps, clinically-defined REM-sleep Behavior Disorder, fatigue and insomnia symptoms, while patients with cognitive composite score decline with longer time in bed had increased 24-h total sleep time duration but with higher wake time after onset. Conclusions: The risk of cognitive decline is higher in frailty subjects with EDS and longer nighttime in bed. Early detection of sleep-wake disturbances might help identifying frail subjects at risk of cognitive decline to further propose sleep health strategies to prevent cognitive impairment. http://www.clinicaltrials.gov NCT00672685; Date of registration May, 2nd 2008.

Can event-related potential predict the progression of mild cognitive impairment?

This study was designed to evaluate the predictive value of event-related potential (ERP; N2 and P3b) in patients with mild cognitive impairment (MCI). Seventy-one patients with MCI were selected and compared with 31 healthy control subjects. They benefited from an initial assessment that included a neuropsychological evaluation and ERP. We followed them up for 1 year, and during their last visit, they benefited again from ERP and neuropsychological tests. At the end of the study, 2 subgroups of patients with MCI were differentiated according to their clinical evolution from baseline to follow-up: 41 MCI progressors (MCI-P) and 30 MCI nonprogressors (MCI-non P). The MCI-P patients had a significant decline in their executive functions compared with the MCI-non-P group at baseline and follow-up especially on trail making test B (TMT B) and verbal fluency (P < 0.0001). At baseline, MCI-P had increased P3b latencies and low P3b amplitudes compared with MCI-non P. The MCI-P showed an inversion of the P3b rostrocaudal gradient with a significant decrease in the amplitude of P3b in the parietal area compared with the MCI-non P. At follow-up, 17 MCI-P patients had converted to Alzheimer's disease (AD). There was a significant rate of decline of the amplitude of N2 and P3b in the frontal area among the groups. Furthermore, the MCI-P had a higher decrease in the rostrocaudal gradient of P3b and prolonged N2 and P3b latencies than the MCI-non P did. The sensitivity and specificity were approximately 80% and 70%, using P3b amplitude to discriminate the MCI-P from the MCI-non P. Our study underlines the interest of using N2 and P3b as neurophysiological markers for measuring MCI decline progression.

Decreased sAßPPß, Aß38, and Aß40 cerebrospinal fluid levels in frontotemporal dementia.

To improve the etiological diagnosis of neurodegenerative dementias like Alzheimer's disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181p-Tau, Aß38, Aß40, Aß42, sAßPPα, and sAßPPß. This study conducted in two centers included patients with FTD (n = 34), AD (n = 52), as well as a control group of persons without dementia (CTRL, n = 42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Aß42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAßPPß, Aß38, and Aß40 levels. Aß38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Aß38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Aß38, are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AßPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia.

Correlations between soluble α/ß forms of amyloid precursor protein and Aß38, 40, and 42 in human cerebrospinal fluid.

Cerebrospinal fluid (CSF) biomarkers are now widely used for diagnosis of Alzheimer disease (AD) in atypical clinical forms, for differential and early diagnosis, or for stratification of patients in clinical trials. Among these biomarkers, different forms of amyloid peptides (Aß) produced by the cleavage of a transmembrane precursor protein called APP (amyloid precursor protein) have a major role. Aß peptides exist in different length the most common ones having 40 (Aß40), 42 (Aß42), or 38 (Aß38) amino acids in length. APP processing by gamma-secretase releases also an amino-terminal secreted fragment called sAßPP-beta while an alternative nonamyloidogenic cleavage of APP, through an alpha-secretase, liberates another fragment called sAßPP-alpha. To decipher the molecular and pathological mechanisms leading to the production and the detection of these entities is essential for the comprehension and the prevention of AD. In this report, we present the results of the multiplex measurement of CSF Aß38, Aß40, Aß42, sAßPP-alpha, and sAßPP-beta in 60 patients mostly with dementia eventually segregated between neurochemical dementia diagnostic (NDD) positive and negative groups. The NDD classification was based on our routine Tau, P-tau(181), and Aß(42) cutoff values. We confirmed previous findings regarding the correlation between sAßPP-alpha and sAßPP-beta, as well as the potential interest of these new biomarkers. We also studied the correlation between sAßPPs and Aß peptides, as well as between Aß peptides themselves. We observed a strong correlation between Aß38 and sAßPP-beta which suggested that the production of this peptide was in direct relation with ß secretase activities. We also reported a strong correlation between Aß38 and Aß40, while Aß42 was correlated to these fragments only in nonpathological situations. These results enlighten the complex relationships between these molecular markers in both physiological and pathological situations. Our results are important for the further use of these analytes for AD diagnosis as well as for validating the cell biological hypotheses of APP processing and Aß fragment production.