APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.

BACKGROUND: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. METHODS AND FINDINGS: We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid ß (Aß)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. CONCLUSIONS: Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

Rethinking the Cognitive Mechanisms Underlying Pantomime of Tool Use: Evidence from Alzheimer's Disease and Semantic Dementia.

OBJECTIVES: Pantomiming the use of familiar tools is a central test in the assessment of apraxia. However, surprisingly, the nature of the underlying cognitive mechanisms remains an unresolved issue. The aim of this study is to shed a new light on this issue by exploring the role of functional, mechanical, and manipulation knowledge in patients with Alzheimer's disease and semantic dementia and apraxia of tool use. METHODS: We performed multiple regression analyses with the global performance and the nature of errors (i.e., production and conception) made during a pantomime of tool use task in patients and control participants as dependent variables and tasks investigating functional, mechanical, and manipulation knowledge as predictors. RESULTS: We found that mechanical problem solving, assessing mechanical knowledge, was a good predictor of the global performance of pantomime of tool use. We also found that occurrence of conception errors was robustly predicted by the task assessing functional knowledge whereas that of production errors was not explained by only one predictor. CONCLUSIONS: Our results suggest that both functional and mechanical knowledge are important to pantomime the use of tools. To our knowledge, this is the first demonstration that mechanical knowledge plays a role in pantomime of tool use. Although impairment in pantomime of tool use tasks (i.e., apraxia) is widely explained by the disruption of manipulation knowledge, we propose that pantomime of tool use is a complex problem-solving task. (JINS, 2017, 23, 128-138).

Donepezil decreases annual rate of hippocampal atrophy in suspected prodromal Alzheimer's disease.

INTRODUCTION: The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD). METHODS: A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method. RESULTS: Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups. DISCUSSION: A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo.

Apraxia and Alzheimer's disease: review and perspectives.

Apraxia is one of the cognitive deficits that characterizes Alzheimer's disease. Despite its prevalence and relevance to diagnosing Alzheimer's disease, this topic has received little attention and is without comprehensive review. The review herein is aimed to fill this gap by first presenting an overview of the impairment caused in different clinical situations: pantomime of tool use, single tool use, real tool use, mechanical problem solving, function and manipulation knowledge tasks, and symbolic/meaningless gestures. On the basis of these results, we then propose alternative interpretations regarding the nature of the underlying mechanisms impaired by the disease. Also presented are principal methodological issues precluding firm conclusions from being drawn.

Study design and protocol of a low to high intensity computer-based cognitive training at home in supplement to standard care in patients with AD.

INTRODUCTION: Recent studies on cognitive training in patients with Alzheimer's disease (AD) showed positive long-term effects on cognition and daily living, suggesting remote computer-based programmes to increase training sessions while reducing patient's travelling. The aim of this study is to examine short-term and long-term benefits of computer-based cognitive training at home in patients with mild to moderate AD, as a complement to the training in speech and language therapists' (SLT) offices. The secondary purpose is to study training frequency required to obtain noticeable effects. METHODS AND ANALYSES: This is a national multicentre study, conducted in SLT offices. The patients follow training in one of three conditions: once a week in SLT office only (regular condition) and once a week in SLT office plus one or three times per week at home. The trainings' content in SLT office and at home is identical. For all three groups near and far transfer will be compared with evaluate training frequency's effect. Our primary outcome is executive and working memory scores in experimental tasks, and the secondary is neuropsychological tests and questionnaires' scores. Linear models' analyses are considered for all measures with a random intercept for patients and another for per practice. The fixed effects will be: three modality groups and time, repeated measures, (T0-pretraining, T1-post-training, T2-long-term follow-up) and the interaction pairs. ETHICS AND DISSEMINATION: The study got ethics approval of the national ethical committee CPP Sud Méditerranée III (No 2019-A00458-49) and of the National Commission for Information Technology and Liberties (No 919217). Informed consent is obtained from each participant. Results will be disseminated in oral communications or posters in international conferences and published in scientific journals. TRIAL REGISTRATION NUMBER: NCT04010175.

Daily life activities in patients with Alzheimer's disease or semantic dementia: Multitasking assessment.

The aim of the present study was to compare patients with mild to moderate Alzheimer's disease (AD) or semantic dementia (SD) on their cognitive processes and the severity of their daily life activity impairments. Three types of tasks were administered to patients (SD = 15; AD = 31) and 30 healthy controls (HC): 1) informant-based scales and questionnaires, 2) a neuropsychological assessment exploring executive functions, episodic and semantic memory, and 3) a new original test featuring multi-step naturalistic actions and multitasking: the Sequential Daily Life Multitasking (SDLM). We predicted that patients with AD would mainly exhibit task perplexity, associated with episodic and executive deficits on the SDLM, while the behavior of patients with SD would mostly be characterized by object perplexity, associated with semantic memory deficits. Results showed that patients with AD or SD were impaired across all neuropsychological tests, particularly episodic memory in AD and semantic memory in SD. General performance on the SDLM also appeared dramatically impaired in both patient groups, and correlated with results of questionnaires about instrumental activities and memory impairments. However, specific qualitative measurements on the SDLM did not allow us to pinpoint different patterns of errors and behavior in patients with AD versus SD. We suggest that the inability of patients in both groups to perform the SDLM may derive from a constellation of disorders or else from more subtle impairment of cognitive and conative processes that requires further exploration.

Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication.

BACKGROUND AND OBJECTIVE: To report a triplication of the amyloid-ß precursor protein (APP) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD). METHODS: Four copies of the APP gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. APP mRNA levels were assessed using reverse-transcription-digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 APP duplication carriers. RESULTS: Beginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole APP gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an APP locus triplication, which was consistent with the presence of 2 APP copies in the healthy mother and with the paternal medical history. Analysis of the APP mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in APP duplication carriers compared with controls. DISCUSSION: Increased copy number of APP is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.

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

OBJECTIVES: New diagnostic criteria for Alzheimer's disease (AD) include cerebrospinal fluid (CSF) biomarkers that allow diagnosis at the stage of mild cognitive impairment (MCI). However, the impact of CSF biomarkers in MCI populations in clinical practice has been poorly evaluated. The objective of this study is to assess the use and impact in clinical practice of AD CSF biomarkers in French memory clinics. DESIGN: We performed a nation-wide, prospective survey between March 2012 and September 2014. Data over the same period was extracted from the French National Database (Banque Nationale Alzheimer, BNA) and compared with the results of the survey. SETTING: 29 secondary and tertiary memory clinics in France. PARTICIPANTS: Clinicians prescribing lumbar puncture (LP) in order to measure AD CSF biomarkers. Clinicians completed a two-part questionnaire for each of their patients undergoing LP. PRIMARY AND SECONDARY OUTCOME MEASURES: Assessment of diagnosis, level of confidence before and after CSF biomarkers and impact on management in patients who underwent LP for CSF AD biomarkers in clinical routine. RESULTS: 977 questionnaires were completed, of which 61 were excluded because of unknown initial/final diagnosis or non-contributory CSF results. Of 916 patients reported, 153 (16.7%) had MCI as the initial diagnosis, of which 51 (33.3%) displayed an AD profile. CSF biomarkers resulted in a change in diagnosis in 44 patients (28.8%). Confidence level significantly increased after LP (8.3±1.4vs 6.73±1.18, p<0.0001), and CSF results modified management in 71/156 patients (46.4%), including 36 (23.5%) enrolled in clinical trials. Comparison of change in diagnosis with the BNA population revealed no difference (32.24%, p=0.4). CONCLUSION: This nation-wide survey, reflecting clinical practice in French memory clinics, describes the impact of CSF AD biomarkers in patients with MCI in clinical practice.

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

BACKGROUND: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. OBJECTIVE: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. METHODS: We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. RESULTS: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p < 0.0001) and associated neurologic symptoms more frequently (p < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. CONCLUSION: The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages.

Tool use disorders in neurodegenerative diseases: Roles of semantic memory and technical reasoning.

In the field of apraxia, it has been suggested that the ability to use tools and objects in daily life depends not only on semantic knowledge about tool function and context of use but also on technical reasoning about mechanical properties of tools and objects. The aim of the present work was to assess tool use abilities regarding these hypotheses in patients with neurodegenerative diseases and reduced autonomy. Performance of patients with Alzheimer's disease (AD) (n = 31), semantic dementia (SD) (n = 16) and corticobasal syndrome (CBS) (n = 7) was compared to that of healthy control participants (n = 31) in familiar tool use tasks, functional/contextual associations and mechanical problem solving (MPS). A conversion method was applied to data in order to avoid ceiling effects. Tool use disorders were found in all patient groups but the underlying reasons were different. Patients with SD had difficulties in imagining and selecting familiar tools due to the semantic loss but they performed in normal range in MPS tasks. Interestingly, they performed better with only one tool and its corresponding object, which is interpreted as a partial compensation of semantic loss by spared technical reasoning. Patients with CBS exhibited the reverse pattern, that is, MPS deficits without semantic loss. However, additional qualitative research is needed to disentangle the relative contributions of motor and technical reasoning deficits to this pattern. Both of these profiles were found in patients with AD. For all that, these patients did not commit the same errors as stroke patients with left brain-damage documented in previous works. Several hypotheses are proposed to account for the specificity of tool use disorders in neurodegenerative diseases, and recommendations are provided to caregivers.

Mechanical problem-solving strategies in Alzheimer's disease and semantic dementia.

OBJECTIVE: The goal of this study was to explore whether the tool-use disorders observed in Alzheimer's disease (AD) and semantic dementia (SD) are of the same nature as those observed in left brain-damaged (LBD) patients. Recent evidence indicates that LBD patients with apraxia of tool use encounter difficulties in solving mechanical problems, characterized by the absence of specific strategies. This pattern may show the presence of impaired mechanical knowledge, critical for both familiar and novel tool use. So, we explored the strategies followed by AD and SD patients in mechanical problem-solving tasks in order to determine whether mechanical knowledge is also impaired in these patients. METHOD: We used a mechanical problem-solving task in both choice (i.e., several tools were proposed) and no-choice (i.e., only 1 tool was proposed) conditions. We analyzed quantitative data and strategy profiles. RESULTS: AD patients but not SD patients met difficulties in solving mechanical problem-solving tasks. However, the key finding is that AD patients, despite their difficulties, showed strategy profiles that are similar to that of SD patients or controls. Moreover, AD patients exhibited a strategy profile distinct from the one previously observed in LBD patients. CONCLUSIONS: Those observations lead us to consider that difficulties met by AD patients to solve mechanical problems or even to use familiar tools may not be caused by mechanical knowledge impairment per se. In broad terms, what we call apraxia of tool use in AD is certainly not the same as apraxia of tool use observed in LBD patients. (PsycINFO Database Record

Tool use in left brain damage and Alzheimer's disease: What about function and manipulation knowledge?

Tool use disorders are usually associated with difficulties in retrieving function and manipulation knowledge. Here, we investigate tool use (Real Tool Use, RTU), function (Functional Association, FA) and manipulation knowledge (Gesture Recognition, GR) in 17 left-brain-damaged (LBD) patients and 14 AD patients (Alzheimer disease). LBD group exhibited predicted deficit on RTU but not on FA and GR while AD patients showed deficits on GR and FA with preserved tool use skills. These findings question the role played by function and manipulation knowledge in actual tool use.

Reduced Regional Cortical Thickness Rate of Change in Donepezil-Treated Subjects With Suspected Prodromal Alzheimer's Disease.

OBJECTIVE: Cortical thinning, previously identified during prodromal stages of Alzheimer's disease (AD), is a "candidate" biomarker implemented in AD clinical therapy trials. We investigated the effect of donepezil treatment on cortical thickness in mild cognitively impaired subjects with the amnestic syndrome of the hippocampal type, a prodromal at-risk group for progression to AD dementia. METHODS: Data were from a longitudinal analysis of a community-based multicenter suspected prodromal AD cohort diagnosed by the Free and Cued Selective Reminding Test (81 donepezil vs 92 placebo) enrolled in a double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day). The study started in November 2006 and concluded in August 2010. All subjects underwent 2 brain structural magnetic resonance imaging (MRI) scans, at baseline and at the end of the trial. Structural MRI images had been processed using the automated pipeline for longitudinal segmentation and surface reconstruction implemented in FreeSurfer. The primary outcome measure of this post hoc study was the annualized percentage change (APC) of cortical thickness. RESULTS: The donepezil group exhibited reduced APC cortical thinning compared to placebo in the rostral anterior cingulate (right: P = .048; left: P = .032), the orbitofrontal (right: P = .012; left: P < .048), and the right inferior frontal (P = .022) cortices and in the right insula (P = .010). These results were not statistically significant after Bonferroni correction likely due to insufficient power for cortical thickness measurements in the study group powered for the predefined hippocampus outcome. CONCLUSIONS: Our findings support the hypothesis that cortical thickness is a reliable candidate surrogate outcome in early predementia AD trials. In addition, donepezil treatment may have an impact on cortical structure/morphology in areas innervated by the medial and lateral cholinergic pathways. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00403520.

Seizures in dominantly inherited Alzheimer disease.

OBJECTIVE: To assess seizure frequency in a large French cohort of autosomal dominant early-onset Alzheimer disease (ADEOAD) and to determine possible correlations with causative mutations. METHODS: A national multicentric study was performed in patients with ADEOAD harboring a pathogenic mutation within PSEN1, PSEN2, APP, or a duplication of APP, and a minimal follow-up of 5 years. Clinical, EEG, and imaging data were systematically recorded. RESULTS: We included 132 patients from 77 families: 94 PSEN1 mutation carriers (MCs), 16 APP duplication carriers, 15 APP MCs, and 7 PSEN2 MCs. Seizure frequency was 47.7% after a mean follow-up of 8.4 years (range 5-25). After 5-year follow-up and using a Cox model analysis, the percentages of patients with seizures were respectively 19.1% (10.8%-26.7%) for PSEN1, 28.6% (0%-55.3%) for PSEN2, 31.2% (4.3%-50.6%) for APP duplications, and no patient for APP mutation. APP duplication carriers showed a significantly increased seizure risk compared to both APP MCs (hazard ratio [HR] = 5.55 [95% confidence interval 1.87-16.44]) and PSEN1 MCs (HR = 4.46 [2.11-9.44]). Among all PSEN1 mutations, those within the domains of protein hydrophilic I, transmembrane II (TM-II), TM-III, TM-IV, and TM-VII were associated with a significant increase in seizure frequency compared to other domains (HR = 4.53 [1.93-10.65], p = 0.0005). CONCLUSIONS: Seizures are a common feature of ADEOAD. In this population, risk was significantly higher in the APP duplication group than in all other groups. Within PSEN1, 5 specific domains were associated with a higher seizure risk indicating specific correlations between causative mutation and seizures.

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons.

Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

[Writing, aging and Alzheimer's disease]. / Ecriture, vieillissement, Alzheimer.

Writing is a complex and fragile cognitive function, that appeared very late in the history of mankind, and that also develops quite late in individuals. Aging does not induce changes in the lexical, semantic and syntaxic parameters of the writing description of a complex image. In the same way, spelling is not significantly altered through aging. Spelling errors are rare among seniors: they only concern infrequent words and mostly respect their pronunciation. The most frequent errors are about accents or double letters. Margins get smaller, seniors raise their pens less often and the pressure and width of writing decrease with age. Writing get progressively disorganized during Alzheimer's disease. The content of texts is primarily affected, texts becoming shorter and less coherent. Then, spelling is altered by regularization errors which are an evidence of lexical agraphia. Then, lexical agraphia gets worse and rapidly becomes mixed, combining lexical and phonological features. Finally, dementia worsens along with a massive deterioration of graphic features and spatial organization. Agraphia of Alzheimer's disease comes from a progressive and hierarchized disorganization of the various components of language and writing, due to the brain lesions in several associative areas, i.e. the parietal, temporal, occipital and frontal regions.

Sleep and Alzheimer's disease.

Sleep disorders are frequent in Alzheimer's disease (AD), with a significant impact on patients and caregivers and a major risk factor for early institutionalization. Micro-architectural sleep alterations, nocturnal sleep fragmentation, decrease in nocturnal sleep duration, diurnal napping and even inversion of the sleep-wake cycle are the main disorders observed in patients with AD. Experimental and epidemiological evidence for a close reciprocal interaction between cognitive decline and sleep alterations is growing. Management of sleep disorders in AD is pre-eminently behavioral. Association of melatonin and bright light treatment seems to be promising as well. The presence of sleep complaints, especially excessive somnolence in demented patients, should draw attention to possible associated sleep pathologies such as sleep apnea syndrome or restless legs syndrome.

Immune response to Abeta-peptides in peripheral blood from patients with Alzheimer's disease and control subjects.

To investigate the immune response to amyloid beta-peptide (Abeta: Abeta40 and Abeta42) in peripheral human blood, sera were obtained from 36 patients with Alzheimer's disease (AD) and 34 age-matched controls. ELISA assays were used to measure antibody concentrations to Abeta-peptides. T cell response was assessed using a lymphoproliferation assay. Both AD and control subjects had low and variable concentrations of antibodies against Abeta (predominantly IgG1). The mean antibody to Abeta concentrations did not differ between groups. No specific T cell response to Abeta-peptides was detected. Natural levels of antibodies to Abeta in peripheral blood are present in all human subjects and are unlikely to be useful in the identification of patients who would respond to potential AD immune therapy. Specific cellular immune responses to Abeta in human blood were not detected.

Increased cerebrospinal fluid tau levels in logopenic variant of Alzheimer's disease.

BACKGROUND: Patients with logopenic variant of primary progressive aphasia (lvPPA) display neuropathological differences from typical amnestic Alzheimer's disease (AD). OBJECTIVE: The aim of the study was to compare cerebrospinal fluid (CSF) biomarker levels between patients with lvPPA due to AD (lvPPA-AD), non-logopenic forms of AD (nlAD), and amnestic mild cognitive impairment due to AD (aMCI-AD). METHODS: CSF biomarker concentrations were assessed in 124 patients divided into three groups matched for age, level of education, center, and disease duration: lvPPA-AD (n = 30), nlAD (n = 67). and aMCI-AD (n = 27). RESULTS: p-Tau181 levels were higher in the lvPPA-AD group than in the aMCI-AD group (p < 0.05). Total tau levels were higher in the lvPPA-AD group versus those in the nlAD (p < 0.05) and aMCI-AD (p < 0.001) groups. CONCLUSIONS: These results suggest a more pronounced involvement of a taupathy in lvPPA-AD compared to aMCI-AD and a more important neuronal death in lvPPA-AD than in nlAD or aMCI-AD.

Impact of cerebro-spinal fluid biomarkers of Alzheimer's disease in clinical practice: a multicentric study.

CSF biomarkers of Alzheimer's disease are well validated in clinical research; however, their pragmatic utility in daily practice is still unappreciated. These biomarkers are used in routine practice according to Health Authority Recommendations. In 604 consecutive patients explored for cognitive disorders, questionnaires were prospectively proposed and filled. Before and after CSF biomarker results, clinicians provided a diagnosis and an estimate of their diagnostic confidence. Analysis has compared the frequency of diagnosis before and after CSF biomarker results using the net reclassification improvement (NRI) method. We have evaluated external validity comparing with data of French Bank National of AD (BNA). A total of 561 patients [Alzheimer's disease (AD), n = 253; non-AD, n = 308] were included (mean age, 68.6 years; women, 52 %). Clinically suspected diagnosis and CSF results were concordant in 65.2 % of cases. When clinical hypothesis and biological results were discordant, a reclassification occurred in favour of CSF biomarkers results in 76.9 %. The NRI was 39.5 %. In addition, the results show a statistically significant improvement in clinician confidence for their diagnosis. In comparison with BNA data, patients were younger and more frequently diagnosed with AD. Clinicians tend to heavily rely on the CSF AD biomarkers results and are more confident in their diagnoses using CSF AD biomarkers. Thus, these biomarkers appear as a key tool in clinical practice.