Miguel A. Fernández-Blázquez

Specific Features of Subjective Cognitive Decline Predict Faster Conversion to Mild Cognitive Impairment

BACKGROUND Alzheimers disease (AD) is a silent disorder that needs the earliest possible intervention in order to reduce its high economic and social impact. It has been recently suggested that subjective cognitive decline (SCD) appears at preclinical stages many years before the onset of AD. Therefore, SCD could become an ideal target for early therapeutic intervention. OBJECTIVE The goal of this study was to evaluate the clinical significance of SCD on the conversion from a cognitively healthy stage to a mild cognitive impairment (MCI) in one-year follow-up. METHODS A total of 608 cognitively intact individuals from the Vallecas Projects cohort, a community-based prospective study to identify early markers of AD, were enrolled in this study. Participants were classified in three groups: i) No Complaints (NCg), ii) Subjects with complaints in one or more cognitive domains (SCDg), and iii) Subjects who, besides complaints, fulfilled the features of SCD Plus proposed by the International Working Group of SCD (SCD-Pg). RESULTS Individuals were followed up for a mean of 13.1 months (range 10.7-22.4). During this time, 41 volunteers developed MCI (6.7% of total sample). The conversion rate for SCD-Pg (18.9%) was significantly higher than SCDg (5.6%) and NCg (4.9%). CONCLUSION Specific features associated with SCD may help to identify individuals at high risk of fast conversion to MCI. These results highlight the importance of a close follow-up of subjects with SCD-P and include them in early intervention programs because of their increased risk for the development of MCI.

MAPT H1 Haplotype is Associated with Late-Onset Alzheimer’s Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimers disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinsons disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.

Association of perceived health and depression with older adults’ subjective memory complaints: contrasting a specific questionnaire with general complaints questions

The objectives of this paper were to evaluate the association of subjective memory complaints (SMC) with perceived state of health, mood and episodic memory (associative and everyday memory). We studied these areas using two different complaint assessment methods (three general questions and a validated scale). The study included 269 older adults (aged 65–87) with age-related memory changes, but without cognitive impairment. They were evaluated with Mini-cognitive Exam, Rivermead Behavioural Memory Test (a test of everyday memory), Paired Associates Learning Test, Memory Failures of Everyday Questionnaire, three memory complaints questions, Nottingham Health Profile and Geriatric Depression Scale. The results indicated that memory for everyday performance, mood and perceived health were independent predictors of SMC, with mood and perceived health being stronger predictors than actual memory performance. Age was not associated with subjective memory and, with regard to level of education, only the illiterate level was associated with SMC. A specific questionnaire on subjective memory was found to be preferable to an aggregate of complaints questions on self-reported memory; only health profile was found to predict the outcomes on memory complaints questions. Our conclusion is that a group of underlying factors other than everyday memory were playing a role in SMC; these SMC of subjects with age-related memory changes were mainly associated with subjective evaluations of their health.

The Vallecas Project: A Cohort to Identify Early Markers and Mechanisms of Alzheimer’s Disease

Introduction Alzheimer’s disease (AD) is a major threat for the well-being of an increasingly aged world population. The physiopathological mechanisms of late-onset AD are multiple, possibly heterogeneous, and not well understood. Different combinations of variables from several domains (i.e., clinical, neuropsychological, structural, and biochemical markers) may predict dementia conversion, according to distinct physiopathological pathways, in different groups of subjects. Methods We launched the Vallecas Project (VP), a cohort study of non-demented people aged 70–85, to characterize the social, clinical, neuropsychological, structural, and biochemical underpinnings of AD inception. Given the exploratory nature of the VP, multidimensional and machine learning techniques will be applied, in addition to the traditional multivariate statistical methods. Results A total of 1169 subjects were recruited between October 2011 and December 2013. Mean age was 74.4 years (SD 3.9), 63.5% of the subjects were women, and 17.9% of the subjects were carriers of at least one ε4 allele of the apolipoprotein E gene. Cognitive diagnoses at inclusion were as follows: normal cognition 93.0% and mild cognitive impairment (MCI) 7.0% (3.1% amnestic MCI, 0.1% non-amnestic MCI, 3.8% mixed MCI). Blood samples were obtained and stored for future determinations in 99.9% of the subjects and 3T magnetic resonance imaging study was conducted in 89.9% of the volunteers. The cohort is being followed up annually for 4 years after the baseline. Conclusion We have established a valuable homogeneous single-center cohort which, by identifying groups of variables associated with high risk of MCI or dementia conversion, should help to clarify the early physiopathological mechanisms of AD and should provide avenues for prompt diagnosis and AD prevention.

Combined Alzheimer's disease and cerebrovascular staging explains advanced dementia cognition

The absence of a consensus system for full neuropathological evaluation limits clinicopathological studies and comparability between laboratories. Combined staging for Alzheimers type and cerebral vascular pathology may allow a better classification of cases for clinical and cognitive correlation.

Clinical Relevance of Specific Cognitive Complaints in Determining Mild Cognitive Impairment from Cognitively Normal States in a Study of Healthy Elderly Controls

Introduction: Subjective memory complaints (SMC) in the elderly have been suggested as an early sign of dementia. This study aims at investigating whether specific cognitive complaints are more useful than others to discriminate Mild Cognitive Impairment (MCI) by examining the dimensional structure of the Everyday Memory Questionnaire (EMQ). Materials and Methods: A sample of community-dwelling elderly individuals was recruited (766 controls and 78 MCI). The EMQ was administered to measure self-perception of cognitive complaints. All participants also underwent a comprehensive clinical and neuropsychological battery. Combined exploratory factor analysis (EFA) and Item Response Theory (IRT) were performed to identify the underlying structure of the EMQ. Furthermore, logistic regression analyses were conducted to study whether single cognitive complaints were able to predict MCI. Results: A suitable five-factor solution was found. Each factor focused on a different cognitive domain. Interestingly, just three of them, namely Forgetfulness of Immediate Information (FII), Executive Functions (EF) and Prospective Memory (PM) proved to be effective in distinguishing between cognitively healthy individuals and MCI. Based on these results we propose a shortened EMQ version comprising 10 items (EMQ-10). Discussion: Not all cognitive complaints have the same clinical relevance. Only subjective complaints on specific cognitive domains are able to discriminate MCI. We encourage clinicians to use the EMQ-10 as a useful tool to quantify and monitor the progression of individuals who report cognitive complaints.

Subjective Cognitive Decline as a Preclinical Marker for Alzheimer's Disease: The Challenge of Stability Over Time

Subjective Cognitive Decline (SCD) refers to a self-experienced persistent decline in cognitive abilities in comparison with a prior normal status and independent of the objective performance on neuropsychological tests (Jessen et al., 2014). It has been proposed that SCDmight appear at the end of the preclinical phase of Alzheimer’s Disease (AD) even in the absence of significant objective impairment detectable on standardized neuropsychological assessment (Rabin et al., 2017). This fact explains why SCD is gaining increased prominence in neurodegenerative research as a potential marker for future Mild Cognitive Impairment (MCI) due to AD. Nevertheless, in our opinion SCD has to face up to a challenge in order to aspire to become a reliable marker of preclinical AD. This challenge is related to the temporal stability of self-reported complaints over time. This manuscript describes this challenge. SCD is considered a sign of preclinical AD that occurs even before objective cognitive impairment appears (Figure 1). A recent meta-analysis has revealed that about 25% of cognitively healthy older adults who report SCDwill developMCI due to AD in the next 4 years (Mitchell et al., 2014). In addition, these individuals have two-fold risk of progression to dementia during a 5-year follow-up period. To increase the potential usefulness of SCD the international working group called Subjective Cognitive Decline Initiative (SCD-I) agreed to a common framework and research procedures to study the role of SCD as a marker of preclinical AD (Jessen et al., 2014). Following these new standards, cognitively healthy individuals who accomplish certain conditions of SCD have been probed to have four times higher risk for developing prodromal AD in just 1-year compared to those subjects without complaints (Fernández-Blázquez et al., 2016). Despite its outstanding clinical value, recently the SCD-I also pointed out some limitations of SCD when it comes to investigating this concept (Rabin et al., 2015; Molinuevo et al., 2017). These limitations could be summarized in three different blocks:

Neuropathological heterogeneity underlying homogeneous clinicopathological correlation in advanced dementia

P2-176 ARE CORTICAL SOURCES OFAUDITORY Figure 1. Individual values of the cortical (LORETA) sources of auditory P3a and P3b peak in the Ab-negative and Ab-positive aMCI subjects. For P3a peak, the individual values for Brodmann area (BA) 8, BA 9, BA 10, ODDBALL EVENT-RELATED POTENTIALS AN EARLY DIAGNOSTIC MARKEROFALZHEIMER’S DISEASE? BA 11, BA 44, BA 45, BA 46, and BA 47 are reported. For P3b, the individual values for BA 5, BA7, BA 39, BA 40, BA 22, BA 42, BA 23, and BA 31 are reported. Claudio Babiloni, Claudio Del Percio, Nicola Marzano, Susanna Cordone, Giuseppe Noce, Christina Bagnoli, Paolo Maria Rossini, Andrea Soricelli, Flavio Nobili, David Bartres, Olivier Blin, Pierre Payoux, Regis Bordet, Bernhard W. Muller, Magda Tsolaki, Lucilla Parnetti, Ulrich Hegerl, Tilman Hensch, Juergen Dukart, Alessandro Bartolino, Gianluigi Forloni, Jill Richardson, Giovanni Battista Frisoni, Sapienza University of Rome, Rome, Italy; IRCCS San Raffaele Pisana, Rome, Italy; University of Foggia, Foggia, Italy; IRCCS SDN, Naples, Italy; IRCCS Istituto Centro SanGiovanni di Dio Fatebenefratelli, Brescia, Italy; Catholic University of Rome, Rome, Italy; University of Genoa, Genoa, Italy; Universitat de Barcelona and IDIBAPS, Barcelona, Spain; Mediterranean Institute of Cognitive Neurosciences, Marseille, France; Universit e de Toulouse, Toulouse, France; Lille 2 University, Lille, France; University of Duisburg-Essen, Essen, Germany; Aristotle University of Thessaloniki, Thessaloniki, Greece; University of Perugia, Perugia, Italy; University of Leipzig, Leipzig, Germany; Roche, Basel, Switzerland; IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy; Neurosciences Therapeutic Area, U.K., United Kingdom. Contact e-mail: claudio.babiloni@uniroma1.it

COMBINED STAGING OF ALZHEIMER'S AND CEREBROVASCULAR PATHOLOGY EXPLAINS COGNITIVE VARIABILITY IN A COHORT OF PATIENTS WITH ADVANCED DEMENTIA

a Adjusted for by ACT study data (cohort, age at death, gender, education and history of smoking) and medical record review data (hypertension, diabetes, and atrial fibrillation any time prior to death and BMI based on the height and weight found in the chart closest to age 65). b Weighted for selection to autopsy. Selection model included the following covariates (as of last ACT follow-up): ACT study cohort, age, gender, education, dementia status, history of smoking, atrial fibrillation, cerebrovascular disease, and coronary artery disease. For the selection model, information on age, gender, education, smoking, dementia, history of cerebrovascular disease and coronary artery disease were based on ACT self-reported study data, and history of atrial fibrillation was based on presence of administrative data codes indicating atrial fibrillation anytime in the 5 years prior to last ACT follow-up. Any subjects missing selection model covariates were excluded from analyses. c Bias-corrected and accelerated confidence intervals and p-values were computed using the bootstrap to account for uncertainty introduced by estimation of selection weights. Poster Presentations: P1 P427