Performance on the RI-48 Cued Recall Test Best Predicts Conversion to Dementia at the 5- and 10-Year Follow-Ups

TheRI-48 cued recall test was devised to discriminate between healthy elderly and patients with mild cognitive impairment who are at risk of developing Alzheimer's disease (AD). However, no long-term follow-up studies have been conducted using this test

Pengaruh Brand Trust dan Brand Equity terhadap Loyalitas Konsumen pada Produk Kosmetik Wardah (Survey Konsumen pada PT. Paragon Technology And Innovation Cabang Pekanbaru)

The purpose of this study was to determine the influence of brand trust ( X1 ) and brand equity ( X2 ) customer loyalty ( Y ) in cosmetic products Wardah ( consumer survey on PT . Paragon technology and innovation branches pekanbaru ) . The method in this research is quantitatively using SPSS 21 program , where samples were used that consumers using cosmetic products Wardah by respondents as many as 100 people sampling technique is accidental sampling using the formula slovin . The results showed that the test results simultaneously obtained from the F count was 34.888 while the value of F table 3.090 . This means that F count> F table and significant value 0,000 < alpha of 0.05 . This means that brand trust and brand equity simultaneously significant effect on consumer loyalty to cosmetic products Wardah

Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains

TAR DNA-binding protein 43 (TDP-43) inclusions are pathological hallmarks of patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Loss of TDP-43 in zebrafish engenders a severe muscle and vascular phenotype with a concomitant elevation of filamin C (FLNC) levels, an observation confirmed in the frontal cortex of FTLD-TDP patients. Here, we aimed to further assess the contribution of FLNC to frontotemporal dementia (FTD) etiology. We conducted a mutational screening of FLNC in a cohort of 529 unrelated Belgian FTD and FTD-ALS patients, and a control cohort of 920 unrelated and age-matched individuals. Additionally we performed an in-depth characterization of FLNC expression levels in FTD patients and a murine FTD model. In total 68 missense variants were identified of which 19 (MAF C) loss-of-function mutation. Increased FLNC levels were, to a lesser extent, also identified in a FLNC p.V831I variant carrier and in FTD patients with the p.R159H mutation in valosin-containing protein (VCP). The GRN-associated increase of FLNC was confirmed in the frontal cortex of aged Grn knockout mice starting at 16-18 months of age. Combined quantitative proteomic and bioinformatic analyses of the frontal cortex of FTD patients possessing elevated FLNC levels, identified multiple altered protein factors involved in accelerated aging, neurodegeneration and synaptogenesis. Our findings further support the involvement of aberrant FLNC expression levels in FTD pathogenesis. Identification of increased FLNC levels in aged Grn mice and impaired pathways related to aging and neurodegeneration, implies a potential role for FLNC in mediating or accelerating the aging process

Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frame-shift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K(v)4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K(v)4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate

TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS

Cognitive and biological markers of mild cognitive impairment and early Alzheimer's disease

De nombreuses études ont montré que des troubles cognitifs légers chez les personnes âgées (« mild cognitive impairment » dans la littérature anglo-saxonne), même d’apparence mineure, ont un potentiel élevé d’évolution vers une démence, en particulier de type Alzheimer. Notre recherche a eu pour but de déceler des déficits cognitifs ou des modifications biologiques chez des patients âgés présentant des troubles cognitifs légers afin de prédire une évolution péjorative vers la démence d’Alzheimer. On sait que les troubles de mémoire pour les faits récents sont fortement liés à la présence de la maladie d’Alzheimer au stade débutant. La manière d’évaluer la mémoire épisodique (mémoire des événements vécus) est importante pour une détection optimale du déficit d’apprentissage d’une nouvelle information, lié à l’atteinte précoce des structures hippocampiques, caractéristique de la maladie d’Alzheimer. Nous avons montré qu’un test de mémoire épisodique basé sur le contrôle des phases d’apprentissage et de rappel est tout aussi sensible mais plus spécifique dans la détection de la maladie d’Alzheimer débutante que les tests classiquement utilisés dans ce contexte. Des études récentes ainsi que des prédictions venant de modèles théoriques suggèrent que la mémoire pour les évènements passés pourrait aussi être déficitaire dans la maladie d’Alzheimer débutante. Nous avons étudié cet aspect chez les malades Alzheimer et chez certains sujets présentant des troubles cognitifs légers. Nous avons montré qu’ils étaient tout aussi déficitaires dans le rappel des évènements passés que dans celui des évènements récents, alors que le rappel de l’information personnelle de type sémantique était comparativement moins atteint. Ceci va à l’encontre de ce que nous avons constaté chez un sujet atteint d’une aphasie progressive dégénérative de forme fluente (connue aussi sous le nom de démence sémantique). Finalement, nous avons répliqué sue une population indépendante des données récentes de la littérature concernant la valeur diagnostique de la protéine TAU et de l’amyloïde Β42 dosés dans le liquide céphalo-rachidien pour distinguer les patients atteints de la maladie d’Alzheimer dés le stade de troubles cognitifs légers. Nous avons montré que le taux de protéine TAU dans le liquide céphalorachidien est corrélé avec le degré d’atteinte de la mémoire épisodique. De plus, le taux d’amyloïde Β42 est un meilleur prédicteur de l’évolution vers la maladie d’Alzheimer endéans les 20 mois pour les sujets présentant des trubles cognitifs légersThe term "mild cognitive impairment" (MCI) has been proposed to describe those elderly individuals with slight cognitive and, particularly, memory impairments. Past research has increasingly recognised that even minimal cognitive deficits in elderly people might be early indicators of the risk of developing dementia, particularly of the Alzheimer type. Our research aimed to disclose those specific cognitive and/or biological markers present in patients clinically labelled as MCI that might be highly predictive of the underlying Alzheimer's disease(AD) pathology. Previous research showed that poor memory for recent events strongly predicts the future occurence of dementia of the Alzheimer type. We found that the way episodic memory (i.e. memory for specific events) is assessed matters for an optimal detection of "hippocampal" type memory impairment, specific to early AD. We showed that a memory test based on controlled encoding and retrieval conditions is as sensitive but more specific that usual tests based on free delayed recall in differentiating incipient AD patients at the stage of MCI from healthy controls. Recent evidence, as well as new models of memory functioning, suggested that memory for past events could also be impaired in very early AD, maybe as early as the stage of MCI. We addressed this issue in early AD and MCI patients and showed that both groups of patients were specifically impaired on the recall of past episodes, just as they are for the recall of recent ones, and less so for remembering personal semantic information. An opposite pattern was found in another type of neurodegenerative disorders, fluent progressive aphasia (semantic dementia), whose neuropathology has a different topographical distribution compared to AD. Finally, we replicated recent findings suggesting that the level of protein TAU in the cerebrospinal fluid (CSF) of MCI patients is elevated whereas the level of Amyloid beta42 is low, just as it is the case in patients with established AD. In addition, we showed that the level of TAU protein in CSF correlated with episodic memory performance, whereas a low level of Amyloid beta42 was able to predict those patients with MCI who progressed to dementia within 20 months, which is earlier than those with higher levels.Thèse de doctorat en sciences médicales (neurologie) (MED 3)--UCL, 200