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Background: Patients with the semantic variant of Primary Progressive Aphasia (svPPA) offer a unique opportunity to study the relationship between lexical retrieval and semantics, as they a...

Background: Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases. The Study of Glial fibrillary acidic protein (GFAP), an astrocytic damage marker, may be helpful to better understand the different neurodegenerative diseases. We investigated the diagnostic performance of plasma GFAP (pGFAP), plasma neurofilament (pNfL) and their combination in frontotemporal dementia (FTD) and Alzheimer’s disease (AD). We studied their clinical utility in predicting disease progression. Methods: We measured pGFAP and pNfL concentrations in 72 FTD, 56 AD and 83 cognitively normal participants (CN) using Single Molecule Array technology. Of 211 participants, 199 had CSF and 122 had MRI. We compared cross-sectional biomarker levels between groups, studied their diagnostic performance and assessed correlation with CSF biomarkers, cognitive performance and cortical thickness. The prognostic performance was investigated analyzing cognitive decline between group comparisons by tertile. Results: Unlike pNfL, which was increased similarly in both clinical groups, pGFAP was increased in FTD but lower than in AD (all pConclusions: pGFAP and pNfL differed in FTD and AD, their combination could be useful to distinguish the two diseases. pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD.

ObjectiveTo investigate the clinical utility of 3 CSF biomarkers along the clinical spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).MethodsWe analyzed 3 CSF biomarkers: the soluble β-fragment of amyloid precursor protein (sAPPβ), YKL-40, and neurofilament light (NfL) in FTD (n = 86), ALS (n = 38), and a group of age-matched cognitively normal controls (n = 49). Participants with FTD with a CSF profile of Alzheimer disease were excluded. We compared cross-sectional biomarker levels between groups, studied their correlation with cognitive and functional scales (global cognitive z score, frontotemporal lobar degeneration Clinical Dementia Rating, revised ALS Functional Rating Scale, and ALS progression rate), survival, and cortical thickness.ResultsWe found increased levels of YKL-40 and decreased levels of sAPPβ in both FTD and ALS groups compared to controls. The lowest sAPPβ levels and sAPPβ/YKL-40 ratio were found in the FTD group. In FTD, sAPPβ and the sAPPβ/YKL-40 ratio correlated with the disease severity. In the whole ALS-FTD spectrum, NfL levels and the NfL:sAPPβ ratio correlated with global cognitive performance (r = −0.41, p < 0.001 and r = −0.44, p < 0.001, respectively). In the ALS group, YKL-40 correlated with disease progression rate (r = 0.51, p = 0.001) and was independently associated with shorter survival. In both FTD and ALS groups, the sAPPβ/YKL-40 ratio showed a positive correlation with cortical thickness in frontotemporal regions.ConclusionssAPPβ, YKL-40, and NfL could represent valuable tools for the staging and prognosis of patients within the ALS-FTD clinical spectrum.Classification of evidenceThis study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to assess frontotemporal neurodegeneration and the progression rate in the ALS-FTD continuum.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case–control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case–control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.

Lifelong bilingualism may contribute to cognitive reserve (CR) in neurodegenerative diseases as shown by a delay of the age at symptom onset in bilinguals with Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). However, some studies have failed to show this bilingual advantage, suggesting that it might depend on the type and degree of bilingualism. In the present study, we tested the hypothesis that active bilingualism, defined as the continuous use of the two languages as opposed to second language exposition only, may protect against cognitive decline. Moreover, we investigated whether bilingualism as a CR factor may be explained by an advantage within the executive control (EC) system. To do so, we collected clinical measures (age at onset of cognitive symptoms, age at the first medical visit for cognitive impairments, and age at diagnosis) in patients with MCI and patients with AD with different degrees of language experience and usage of Catalan and Spanish. Additionally, all participants were tested on four EC tasks and one long-term memory recognition task. First, results from multiple regression analyses showed that active bilingualism was a significant predictor of delay in the age at onset for all the clinical measures in MCI, but not AD patients. Second, the effect of active bilingualism was independent of occupation, educational level and job attainment across the individuals’ lifespan. Finally, although we did not find an effect of active bilingualism across all EC tasks, we did find an effect for conflict resolution. These results are discussed in the context of CR hypotheses, suggesting that compensatory mechanisms may play a role in protecting against cognitive decline. This work was supported by the Fundació La Marató de TV3 (373/C/2014), the European Union’s Seventh Framework Program for Research (No. 613465), the Agencia Estatal de Investigación (AEI, National Research Agency) and Fondo Europeo de Desarrollo Regional (FEDER, European Regional Development Fund) under the projects PSI2017-87784-R and RED2018-102615-T. The Ramón y Cajal research program of the Spanish Ministry of Science, Innovation, and Universities supported MC (RYC-2013-14013) and MH (RYC-2016-19477).

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure. ispartof: JOURNAL OF ALZHEIMERS DISEASE vol:74 issue:1 pages:213-225 ispartof: location:Netherlands status: published

ObjectiveTo characterize the cortical macrostructure and microstructure of behavioral and cognitive changes along the amyotrophic lateral sclerosis (ALS)–frontotemporal dementia (FTD) continuum.MethodsWe prospectively recruited 88 participants with a 3T MRI structural and diffusion-weighted imaging sequences: 31 with ALS, 20 with the behavioral variant of FTD (bvFTD), and 37 cognitively normal controls. Participants with ALS underwent a comprehensive cognitive and behavioral assessment and were dichotomized into ALS without cognitive or behavioral impairment (ALSno-cbi; n = 12) and ALS with cognitive or behavioral impairment (ALScbi; n = 19). We computed cortical thickness and cortical mean diffusivity using a surface-based approach and explored the cortical correlates of cognitive impairment with the Edinburgh Cognitive and Behavioral ALS Screen.ResultsThe ALSno-cbi and ALScbi groups showed different patterns of reduced cortical thickness and increased cortical mean diffusivity. In the ALSno-cbi group, cortical thinning was restricted mainly to the dorsal motor cortex. In contrast, in the ALScbi group, cortical thinning was observed primarily on frontoinsular and temporal regions bilaterally. There were progressive cortical mean diffusivity changes along the ALSno-cbi, ALScbi, and bvFTD clinical continuum. Participants with ALS with either cognitive or behavioral impairment showed increased cortical mean diffusivity in the prefrontal cortex in the absence of cortical thickness.ConclusionsCortical mean diffusivity might be a useful biomarker for the study of extramotor cortical neurodegeneration in the ALS-FTD clinical spectrum.Classification of evidenceThis study provides Class III evidence that the cortical microstructure correlates with cognitive impairment in the ALS-FTD continuum.

BACKGROUND Dementia with Lewy bodies (DLB) is a heterogeneous disease in which clinical presentation, symptoms, and evolution widely varies between patients. OBJECTIVE To investigate the existence of clinical subtypes in DLB based on the initial clinical presentation. METHODS 81 patients with a clinical diagnosis of probable DLB were consecutively included. All patients underwent a neurological evaluation including a structured questionnaire about neuropsychiatric symptoms and sleep, an assessment of motor impairment (Unified Parkinson Disease Rating Scale subscale III), and a formal neuropsychological evaluation. Onset of core symptoms (hallucinations, parkinsonism, and fluctuations) and dementia were systematically reviewed from medical records. We applied a K-means clustering method based on the initial clinical presentation. RESULTS Cluster analysis yielded three different groups. Patients in cluster I (cognitive-predominant, n = 46) presented more frequently with cognitive symptoms (95.7%, n = 44, p < 0.001), and showed a longer duration from onset to DLB diagnosis (p < 0.001) than the other clusters. Patients in cluster II (neuropsychiatric-predominant, n = 22) were older at disease onset (78.1±5 versus 73.6±6.1 and 73.6±4.2 in clusters I and III, respectively, both p < 0.01), presented more frequently with psychotic symptoms (77.3%, n = 17), and had a shorter duration until the onset of hallucinations (p < 0.001). Patients in cluster III (parkinsonism-predominant, n = 13) showed a shorter time from onset to presence of parkinsonism (p < 0.001) and dementia (0.008). CONCLUSIONS Three clinical subtypes of DLB can be defined when considering the differential initial presentations. The proposed subtypes have distinct clinical profiles and progression patterns.

Introduction The aim of the present study is to describe the pattern of suicide deaths in the region of Osona (Barcelona) during the period 2013–2015, and to analyse the use of the Psychological Autopsy (PA) method. Material and methods It is a retrospective design using the suicide deaths register (n = 31). The PA sample (n = 14) was composed of adult relatives and close friends, recruited from the Consorci Hospitalari de Vic. The PA method was performed using the Semi-Structured Interview for Psychological Autopsy (SSIPA), adapted and validated to the Spanish language (Garcia-Caballero et al., 2010). Results The main profile was of a male, married, with no psychiatric history, and used methods like hanging or being running over by a train. In the sub-sample on which the PA was carried out, it was observed that the main precipitating or motivating factors were those related to social, family, and health problems. The prevalence of diagnosed psychopathologies was not a majority profile, but vulnerable personality traits were found. As most of the cases showed previous preparations and verbalisations regarding their intention, it can be concluded that the decision was not impulsive but deliberate. Conclusions The PA method is an efficient tool to describe and obtain data about suicide that may be relevant and useful in the design and implementation of prevention programmes. Moreover, it may help to perceive the individual characteristics of each region promoting a better adjustment and individualisation of these programmes.

Resumen Introduccion El objetivo del presente estudio es describir el perfil de las muertes por suicidio en la comarca de Osona (Barcelona) durante el periodo 2013-2015 y analizar la aplicacion de la tecnica autopsia psicologica (AP). Material y metodos El diseno es retrospectivo a partir del registro de suicidios (n = 31). La muestra de la AP (n = 14) estuvo formada por familiares y personas adultas proximas al fallecido, reclutadas a traves del registro del Consorci Hospitalari de Vic. Se utilizo el metodo de la AP mediante la Semi-Structured Interview for Psychological Autopsy (SSIPA), una entrevista semiestructurada adaptada y validada al espanol (Garcia-Caballero et al., 2010). Resultados El perfil mayoritario de las muertes por suicidio corresponde a varones, casados, sin antecedentes psiquiatricos que utilizaron metodos como el ahorcamiento o el arrollamiento por tren. En la submuestra en que se realizo la AP se observa que los factores precipitantes o motivadores estan relacionados con problemas a nivel social, familiar y de salud. La prevalencia de psicopatologias diagnosticadas no fue mayoritaria, pero se detectaron rasgos de personalidad vulnerables. En muchos casos hubo preparativos y verbalizaciones previas respecto a sus intenciones, por lo que se deduce que la decision fue tomada de forma premeditada y no impulsiva. Conclusiones La AP representa una herramienta eficaz para la obtencion de datos relativos al suicidio que pueden ser relevantes y utiles en el diseno y la implementacion de programas de prevencion, ayudando a detectar la idiosincrasia particular de cada region y permitiendo una mayor adaptacion e individualizacion de dichos programas.

Background Episodic memory impairment is the core feature of typical Alzheimer's disease. Objective To evaluate the performance of two commonly used verbal memory tests to detect mild cognitive impairment due to Alzheimer's disease (MCI-AD) and to predict progression to Alzheimer's disease dementia (AD-d). Methods Prospective study of MCI patients in a tertiary memory disorder unit. Patients underwent an extensive neuropsychological battery including two tests of declarative verbal memory: The Free and Cued Selective Reminding Test (FCSRT) and the word list learning task from the Consortium to Establish a Registry for Alzheimer's disease (CERAD-WL). Cerebrospinal fluid (CSF) was obtained from all patients and MCI-AD was defined by means of the t-Tau/Aβ1-42 ratio. Logistic regression analyses tested whether the combination of FCSRT and CERAD-WL measures significantly improved the prediction of MCI-AD. Progression to AD-d was analyzed in a Cox regression model. Results A total of 202 MCI patients with a mean follow-up of 34.2±24.2 months were included and 98 (48.5%) met the criteria for MCI-AD. The combination of FCSRT and CERAD-WL measures improved MCI-AD classification accuracy based on CSF biomarkers. Both tests yielded similar global predictive values (59.9-65.3% and 59.4-62.8% for FCSRT and CERAD-WL, respectively). MCI-AD patients with deficits in both FCSRT and CERAD-WL had a faster progression to AD-d than patients with deficits in only one test. Conclusions The combination of FCSRT and CERAD-WL improves the classification of MCI-AD and defines different prognostic profiles. These findings have important implications for clinical practice and the design of clinical trials.

Introduction Dementia affects cognitive functions and has a direct impact on the ability to perform activities of daily living. Studies have focused on the impact of cognition-focused interventions on cognitive functions, but less on the daily functionality of people with dementia. The aim of this study was to review systematically evidence of the effectiveness of cognition-focused interventions on the ability of people with dementia to perform activities of daily living. Method A search of randomised controlled trials was performed in 10 databases to find all available evidence on the subject. Two reviewers independently selected articles based on predetermined inclusion criteria. The articles had to describe randomised controlled trials involving cognition-focused interventions in people with some form of dementia, aged 65 years or over, and specify their score on the Mini-Mental State Examination or the Clinical Dementia Rating. Eleven articles met the inclusion criteria for the review. Results Cognitive rehabilitation through functional tasks led to maintenance or improvement in everyday tasks in some cases. In cognitive stimulation studies the subjects maintained their performance in activities of daily living with respect to the control condition, but this was not the case in reminiscence stimulation groups. Subjects who underwent cognitive training of cognitive functions did not show significant improvements in activities of daily living. Conclusion The evidence on the effectiveness of cognition-focused interventions suggests that multi-component programmes that include cognitive rehabilitation or cognitive stimulation could maintain or improve functionality in people with dementia.

Introduction We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). Methods Neuroimaging features of CAA, apolipoprotein ( APOE ), and cerebrospinal fluid amyloid β (Aβ) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD ( n = 42), and healthy controls ( n = 68). Results CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE e4 genotype was borderline significantly associated with CAA in sporadic EOAD ( P = .06) but not with DS or ADAD. There were no differences in Aβ040 levels between groups or between subjects with and without CAA. Discussion CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aβ40 levels are not a useful biomarker for CAA in AD.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures of amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.

Introduction: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.Methods: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.Results: Eight metabolites were associated with amyloid b and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.Discussion: PFAMs have been found increased and associated with amyloid b burden in CSF and clinical measures. Crown Copyright (C) 2019 Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

The role of innate immunity in dementia with Lewy bodies (DLB) has been little studied. We investigated the levels in cerebrospinal fluid (CSF) of glial proteins YKL-40, soluble TREM2 (sTREM2) and progranulin in DLB and their relationship with Alzheimer’s disease (AD) biomarkers. We included patients with DLB (n = 37), prodromal DLB (prodDLB, n = 23), AD dementia (n = 50), prodromal AD (prodAD, n = 53), and cognitively normal subjects (CN, n = 44). We measured levels of YKL-40, sTREM2, progranulin, Aβ1–42, total tau (t-tau) and phosphorylated tau (p-tau) in CSF. We stratified the group DLB according to the ratio t-tau/Aβ1–42 (≥0.52, indicative of AD pathology) and the A/T classification. YKL-40, sTREM2 and progranulin levels did not differ between DLB groups and CN. YKL-40 levels were higher in AD and prodAD compared to CN and to DLB and prodDLB. Patients with DLB with a CSF profile suggestive of AD copathology had higher levels of YKL-40, but not sTREM2 or PGRN, than those without. T+ DLB patients had also higher YKL-40 levels than T−. Of these glial markers, only YKL-40 correlated with t-tau and p-tau in DLB and in prodDLB. In contrast, in prodAD, sTREM2 and PGRN also correlated with t-tau and p-tau. In conclusion, sTREM2 and PGRN are not increased in the CSF of DLB patients. YKL-40 is only increased in DLB patients with an AD biomarker profile, suggesting that the increase is driven by AD-related neurodegeneration. These data suggest a differential glial activation between DLB and AD.

Background: Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown. Objective: To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects. Methods: We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimer's disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals. Results: CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOE epsilon 4 allele did not. Amyloid-beta(42), t-tau, p-tau, and YKL-40 levels correlated weakly with PGRN in CSF. We found a weak correlation (r = 0.362) between plasma and CSF PGRN levels in cognitively normal individuals. Conclusions: Our findings do not support a diagnostic value of CSF PGRN in neurodegenerative diseases. Our data confirm that levels of PGRN in plasma do not reflect accurately levels in CSF in cognitively normal controls. These data should be considered in clinical trials aiming to increase PGRN.

The H1 haplotype of the 17q21.31 inversion polymorphism has been consistently associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson's disease in Caucasians. Recently, large polymorphic segmental duplications resulting into complex rearrangements at this locus with a high diversity range in human populations have been revealed. We sought to explore whether the two multi-allelic copy number variants that are present in the H1 clade (with segmental duplications of 300 and 218 kilobases in length) could be responsible for the known H1-related risk of developing these neurodegenerative disorders. A total of 857 Spanish subjects including 330 patients with Parkinson's disease, 96 with progressive supranuclear palsy, 55 with corticobasal degeneration, 51 dementia with Lewy bodies, and 325 neurologically healthy controls, were genotyped for the H1/H2 haplotype. Subsequently, the two copy number variants that are characteristic of the H1 haplotype were evaluated through a high-resolution approach based on droplet digital polymerase chain reaction, in all H1 homozygous subjects. The H1 allele was significantly overrepresented in all diagnostic groups compared with controls (Parkinson's disease, P = 0.0001; progressive supranuclear palsy, P = 1.22 × 10(-6) ; corticobasal degeneration, P = 0.0002; and dementia with Lewy bodies, P = 0.032). However, no dosage differences were found for any of the two copy number variants analyzed. The H1 haplotype is associated with the risk of several neurodegenerative disorders, including dementia with Lewy bodies. However, common structural diversity within the 17q21.31-H1 clade does not explain this genetic association.

We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia. ispartof: FRONTIERS IN AGING NEUROSCIENCE vol:10 ispartof: location:Switzerland status: published

Cerebrospinal fluid YKL-40 has been described as a marker of glial inflammation. We aimed to study the relationship between YKL-40 and brain structure and its interactions with core Alzheimer's disease (AD) biomarkers. We measured cortical thickness (CTh) and cerebrospinal fluid biomarkers (amyloid-beta 1-42 [A beta 42], total tau, p-tau, and YKL-40) of 80 cognitively normal controls and 27 patients with amnestic mild cognitive impairment. Subjects were classified as A beta 42+ (550 pg/mL). CTh difference maps were derived from the interaction and correlation analyses in the whole sample and within clinical groups. There was a strong correlation between YKL-40 and markers of neurodegeneration (total tau and p-tau). In the whole sample, we found a negative correlation between YKL-40 and CTh in AD vulnerable areas in A beta 42+ subjects but not in A beta 42 participants. Our results suggest that YKL-40 could track the inflammatory processes associated to tau-related neurodegeneration in the presence of the AD pathophysiological process. (C) 2015 Elsevier Inc. All rights reserved.

Introduction: Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimer's disease (AD). Methods: We included healthy control subjects (N = 254), mild cognitive impairment (N = 41), and AD dementia (N = 31) patients. Participants underwent a lumbar puncture and a 3 T magnetic resonance imaging. Healthy control subjects were classified following National Institute on Aging-Alzheimer's Association stages (stage 0, N = 220; stage 1, N = 25; and stage 2/3, N = 9). We assessed the cortical MD, cortical FW, and cortical thickness (CTh) changes along the AD continuum. Results: Microstructural and macrostructural changes show a biphasic trajectory. Stage 1 subjects showed increased CTh and decreased MD and FW with respect the stage 0 subjects. Stage 2/3 subjects showed decreased CTh and increased cortical MD and FW, changes that were more widespread in symptomatic stages. Discussion: These results support a biphasic model of changes in AD, which could affect the selection of patients for clinical trials and the use of magnetic resonance imaging as a surrogate marker of disease modification. (C) 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

In the context of bilingual research, little is known about the effects of neurodegenerative disorders (NDs) on the processing of two languages in a bilingual. In a recent cross-sectional study, we showed that Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD) had similar effects on lexico-semantic processes in the two languages of highly proficient bilinguals (Costa et al., Neuropsychologia, 2012, 50, 740–53). In the present longitudinal study, we extend this finding by looking at the pattern of language deterioration over time in the same population of Catalan-Spanish bilingual patients. All the participants completed three language-processing tasks (picture naming, word translation and word comprehension), both in their dominant (L1) and non-dominant (L2) language. At one year, the final group was made up of 50 patients: 15 with MCI and 35 with AD. For AD but not MCI, the language deterioration over time was the same in both languages, as previously reported in the cross-sectional study. The results are discussed in the frame of the hypothesis of shared lexico-semantic processing in highly proficient bilinguals and the influence of executive control deficits in language production. This work was supported by grants from the Spanish Government (PSI2008-01191, PSI2011-23033, PSI2014-52210-P, Consolider Ingenio 2010CSD2007-00048), Catalan Government (2014SGR1210), La Marató-TVE Foundation (20141030-31) and European Research Council under the European Community's Seventh Framework (FP7/2007–2013 Cooperation grant agreement 613465-AThEME). MC was supported by a Ramón y Cajal postdoctoral fellowship from the Spanish Government. MH was supported by the postdoctoral fellowship ‘Formación Posdoctoral’ within the Spanish Government program ‘Programa Estatal de Promoción del Talento y su Empleabilidad del Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016’.

Background Biomarkers in the cerebrospinal fluid (CSF) can track specific pathophysiological pathways underlying Alzheimer's disease (AD). The connection between these biomarkers remains unclear. Objective To study six CSF biomarkers in a clinical cohort of patients with different neurodegenerative conditions. Methods We measured markers of amyloid-β protein precursor (AβPP) processing (Aβ42, sAβPPβ, β-secretase activity), neuronal damage (total tau, p-tau), and inflammation (YKL-40) in CSF from 194 participants with the following diagnoses: subjective cognitive impairment or non-amnestic mild cognitive impairment (na-SCI, n = 44), amnestic mild cognitive impairment (aMCI, n = 45), dementia of the Alzheimer type (DAT, n = 59), frontotemporal dementia (FTD, n = 22), and 24 cognitively normal controls. We compared biomarkers between clinical groups and CSF-profile groups, and we analyzed the correlation between biomarkers. Results CSF levels of sAβPPβ were decreased in FTD patients compared to the other groups. YKL-40 was elevated in DAT and FTD, and also in aMCI patients. CSF Aβ42 correlated positively with β-secretase activity (RS = 0.262) and sAβPPβ (RS = 0.341). CSF YKL-40 correlated positively with total tau (RS = 0.467) and p-tau (RS = 0.429). CSF p-tau and sAβPPβ contributed significantly to distinguish DAT from FTD. Conclusions CSF biomarkers of AβPP processing correlate with each other and are decreased in FTD. The inflammatory marker YKL-40 is increased in different neurodegenerative diseases, even in early stages, and it correlates with biomarkers of neurodegeneration. This suggests that inflammation is a common feature in AD and FTD. A combination of CSF biomarkers tracking distinct pathophysiological processes may be useful to classify subjects with neurodegenerative conditions.

Background: Subjective cognitive decline (SCD) is gaining importance as a focus of investigation, but adequate tools are needed for its quantification. Objective: To develop and validate a questionnaire to quantify SCD, termed the Subjective Cognitive Decline Questionnaire (SCD-Q). Methods: 124 controls (CTR), 144 individuals with SCD, 83 mild cognitive impairment subjects, 46 Alzheimer's disease patients, and 397 informants were included. The SCD-Q contains: part I, named MyCog, which is answered by the subject; and part II, TheirCog, which includes the same questions and is answered by the informant or caregiver. The 24 SCD-Q items assess the perceived subjective decline in memory, language, and executive functions in the last two years. Results: The MyCog scores of controls differed significantly from those of the other groups (p < 0.05) and there were significant differences in TheirCog scores between all groups. The optimal TheirCog cut-off score for discriminating between individuals with and without cognitive impairment was 7/24 (sensitivity 85%, specificity 80%). MyCog scores correlated significantly with anxiety and depression (r = 0.29, r = 0.43, p < 0.005), but no correlations were found with neuropsychological tests. TheirCog scores correlated significantly with most of the neuropsychological tests (p < 0.05). Informants' depression and anxiety influenced TheirCog scores in controls and SCD groups. Conclusion: Self-perceived cognitive decline, measured by the SCD-Q part I (MyCog), discriminated SCD from CTR. Part II (TheirCog) was strongly related to subjects' objective cognitive performance, and discriminated between subjects with or without cognitive impairment. The SCD-Q is a useful tool to measure self-perceived cognitive decline incorporating the decliner and the informant perspective.

Objective To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer disease (AD). Methods In this cross-sectional study, normal controls (n = 145) from the Alzheimer's Disease Neuroimaging Initiative underwent structural 3T magnetic resonance imaging (MRI) and lumbar puncture. CSF β-amyloid1–42 (Aβ) and phospho-tau181p (p-tau) levels were measured by Luminex assays. Samples were dichotomized using published cutoffs (Aβ+/Aβ− and p-tau+/ptau−). CTh was measured by Freesurfer. CTh difference maps were derived from interaction and correlation analyses. Clusters from the interaction analysis were isolated to analyze the directionality of the interaction by analysis of covariance. Results We found a significant biomarker interaction between CSF Aβ and CSF p-tau levels affecting brain structure. Cortical atrophy only occurs in subjects with both Aβ+ and p-tau+. The stratified correlation analyses showed that the relationship between p-tau and CTh is modified by Aβ status and the relationship between Aβ and CTh is modified by p-tau status. p-Tau–dependent thinning was found in different cortical regions in Aβ+ subjects but not in Aβ− subjects. Cortical thickening was related to decreasing CSF Aβ values in the absence of abnormal p-tau, but no correlations were found in p-tau+ subjects. Interpretation Our data suggest that interactions between biomarkers in AD result in a 2-phase phenomenon of pathological cortical thickening associated with low CSF Aβ, followed by atrophy once CSF p-tau becomes abnormal. These interactions should be considered in clinical trials in preclinical AD, both when selecting patients and when using MRI as a surrogate marker of efficacy. Ann Neurol 2014;76:223–230

Background/Aims: Elevated total plasma homocysteine (tHcy) is a risk factor for cardiovascular and cerebrovascular disease, and it has also been proposed as an independent risk factor for dementia and Alzheimer’s disease (AD). Its relationship with cognitive impairment, however, remains unclear. We aimed to determine the relationship of tHcy levels with clinical diagnoses and cognitive performance in a sample of outpatients with cognitive impairment. Methods: Plasma tHcy, folate, vitamin B12 and creatinine levels were assessed in individuals evaluated at the Memory Disorder Unit. Diagnoses included subjective memory complaints (SMC, n = 27), mild cognitive impairment (MCI, n = 142), AD (n = 139) and vascular dementia (VD, n = 17). All patients underwent extensive neuropsychological testing to evaluate attention, memory, language, and visuoconstructional and executive functions, as well as depression and impairments of daily living activities. Results: tHcy levels did not differ between patients with SMC, MCI, AD or VD. Increased tHcy was associated with worse performance in geometric figure copy and clock drawing tests. Conclusions: tHcy levels did not discriminate between diagnostic groups of patients with cognitive impairments. Elevated tHcy levels in these patients appear to have a detrimental effect on visuoconstructional performance.

Alzheimer's disease (AD) is the most common cause of dementia in the adult population. Tools capable of detecting predementia and established diagnoses of dementia are very important for assessing these patients. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief neuropsychological battery that has been successful at detecting cognitive impairment in degenerative and nondegenerative neurological diseases. The objective of this study was to test reliability and sensibility and obtain normative data of a Spanish adaptation of the RBANS. In this study, 50 participants with AD and 336 healthy participants stratified according to the Spanish Census, with different levels of education, were tested with the RBANS (Form A). Descriptive analyses were performed on a pilot sample from the general population, and comparative analyses were performed on data from the two samples. We obtained an overall reliability coefficient (Cronbach's alpha) of .92. RBANS showed strong specificity and moderately low sensitivity. Participants in the AD group performed significantly worse on most subtests than control participants. Implications with regard to the specificity and sensitivity of the Spanish version of the RBANS are discussed.

clinical characteristics of probable CAA based on Boston’s criteria and also investigated predictive factors associated with certain features of CAA. Methods: We retrospectively reviewed patients diagnosed as probable CAA based on the Boston’s criteria who underwent MRI, including gradient echo (GRE) andfluid attenuated inversion recovery (FLAIR) images and clinical assessment fromAugust 2006 toMay 2013.AllGRE images of each subject were reviewed by 1 rater to describe the location and numbers of intracranial hemorrhages. The white matter hyperintensity was rated based on rating scales proposed by Clinical Research Center for Dementia of South Korea (CREDOS). Statistical analyses were performed using SPSS version 21.0 and SAS 6.0.Results: A total of 92 patients were included in this study. Themean age of onsetwas 68.669.9years (M:F1⁄461:31). Sixty-three patients (68%) had hypertension. The initial diagnoses included cognitive impairment (48 patients, 52%), lobar ICH (14 patients, 15.2%), and lacunar infarction (10 patients, 10.9%). Thirty-nine patients had deep microbleeds. Fifty-three patients (57%) showed posterior dominant distribution (parietal and occipital lobe) of hemorrhages. Themedian number of microbleeds was 15 [interquartile range (IQR): 7-41.33]. Patients with posterior dominant location were older (p 1⁄40.028) and complained of cognitive decline more often (p 1⁄40.034). This group had more microbleeds (p1⁄40.006) and showed more severewhitematter hyperintensities (p1⁄40.008). They also tended to have lower recall score of MMSE than the other group. Patients with deep microbleeds showed more severe white matter hyperintensities (p 1⁄40.002). Twenty-four patients performed follow-up MR imaging. The mean interval time was 28.6624.2 months. Large number of microbleeds at baseline was associated with increasing rate of newmicrobleeds at follow-up scan.Conclusions:We found the impact of location of intracranial hemorrhages on cognitive impairment andwhitematter hyperintensities in patientswithCAA.Thedistribution and the number of microbleeds at baseline were factors associated with disease progression. These data indicate that early evaluation of the location and number of microbleeds can be helpful to assess clinical characteristics and prognosis in patients with probable CAA.

To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer disease (AD).In this cross-sectional study, normal controls (n = 145) from the Alzheimer's Disease Neuroimaging Initiative underwent structural 3T magnetic resonance imaging (MRI) and lumbar puncture. CSF β-amyloid1-42 (Aβ) and phospho-tau₁₈₁p (p-tau) levels were measured by Luminex assays. Samples were dichotomized using published cutoffs (Aβ(+) /Aβ(-) and p-tau(+) /ptau(-)). CTh was measured by Freesurfer. CTh difference maps were derived from interaction and correlation analyses. Clusters from the interaction analysis were isolated to analyze the directionality of the interaction by analysis of covariance.We found a significant biomarker interaction between CSF Aβ and CSF p-tau levels affecting brain structure. Cortical atrophy only occurs in subjects with both Aβ(+) and p-tau(+). The stratified correlation analyses showed that the relationship between p-tau and CTh is modified by Aβ status and the relationship between Aβ and CTh is modified by p-tau status. p-Tau-dependent thinning was found in different cortical regions in Aβ(+) subjects but not in Aβ(-) subjects. Cortical thickening was related to decreasing CSF Aβ values in the absence of abnormal p-tau, but no correlations were found in p-tau(+) subjects.Our data suggest that interactions between biomarkers in AD result in a 2-phase phenomenon of pathological cortical thickening associated with low CSF Aβ, followed by atrophy once CSF p-tau becomes abnormal. These interactions should be considered in clinical trials in preclinical AD, both when selecting patients and when using MRI as a surrogate marker of efficacy.

Diagnosis of rapidly progressive dementia (RPD) poses a complex medical challenge that requires an exhaustive evaluation. Although prion diseases, in particular Creutzfeldt-Jakob disease (CJD), are often suspected, many other nonprion diseases may present as RPD. Our aim was to review the causes of RPD in our center to better understand the underlying conditions. We reviewed clinical, neuroimaging, and cerebrospinal fluid data from patients with RPD admitted to our hospital from 1994 to 2009. Forty-nine patients (mean age at onset 72.4 y) with RPD were admitted to our center during the study period. The mean interval between the onset of symptoms and admission was 4.6 months. The final clinical diagnoses were as follows: nonprion neurodegenerative diseases (36.8%), CJD (30.6%), vascular dementia (8.2%), toxic-metabolic conditions (8.2%), and other disorders (16.2%). Among cases with informed death (n = 19), the average survival time was 8.6 +/- 9.5 months. Survival was shorter among patients with prion disease (n = 10) than in those with other diagnoses (n = 9, P = 0.004). In conclusion, nonprion neurodegenerative diseases are the most common cause of RPD in our center. Our results suggest that although CJD is often suspected as a cause of RPD, its frequency depends on the referral differences across specialized centers

Elevated total plasma homocysteine (tHcy) is a risk factor for cardiovascular and cerebrovascular disease, and it has also been proposed as an independent risk factor for dementia and Alzheimer's disease (AD). Its relationship with cognitive impairment, however, remains unclear. We aimed to determine the relationship of tHcy levels with clinical diagnoses and cognitive performance in a sample of outpatients with cognitive impairment.Plasma tHcy, folate, vitamin B12 and creatinine levels were assessed in individuals evaluated at the Memory Disorder Unit. Diagnoses included subjective memory complaints (SMC, n = 27), mild cognitive impairment (MCI, n = 142), AD (n = 139) and vascular dementia (VD, n = 17). All patients underwent extensive neuropsychological testing to evaluate attention, memory, language, and visuoconstructional and executive functions, as well as depression and impairments of daily living activities.tHcy levels did not differ between patients with SMC, MCI, AD or VD. Increased tHcy was associated with worse performance in geometric figure copy and clock drawing tests.tHcy levels did not discriminate between diagnostic groups of patients with cognitive impairments. Elevated tHcy levels in these patients appear to have a detrimental effect on visuoconstructional performance.